Clinical trial NCT04029116
Conditions: Recurrent Vulvovaginal Candidiasis
Keywords: Recurrent yeast infection Recurrent yeast vaginitis Chronic yeast vaginitis Ibrexafungerp SCY-078 RVVC
Sponsor: Scynexis, Inc.
Start date: 2019-10-21; Completion date: 2021-11-29
Enrollment: 440 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of oral ibrexafungerp (formerly "SCY-078") compared to placebo in female subjects 12 years and older with recurrent VVC (RVVC).

Detailed description:
This study is a Phase 3, multicenter, randomized, double-blind study to evaluate the efficacy and safety of oral ibrexafungerp (formerly "SCY-078") compared to placebo in female subjects 12 years and older with RVVC. The primary objective of the study is to evaluate the efficacy of oral ibrexafungerp in preventing recurrences of VVC in subjects with RVVC based on Clinical Success. Approximately 320 subjects are planned to be enrolled into the study. All subjects will receive treatment with oral fluconazole for their acute episode present at screening. Subjects who respond to fluconazole for their acute episode will be enrolled in the prevention of recurrence phase of the study and randomized to ibrexafungerp or placebo.

Subjects who fail treatment with fluconazole for their acute episode will be included in a nested open label Sub-Study, in which they will be offered one-day oral ibrexafungerp for their unresolved acute episode.

Arms: arm 1: Oral Fluconazole 150 mg every 72 hours for 3 doses followed by Oral Ibrexafungerp 300 mg BID (one day) every 4 weeks for a total of 6 dosing days arm 2: Oral Fluconazole 150 mg every 72 hours for 3 doses followed by Oral Placebo BID (one day) every 4 weeks for a total of 6 dosing days
Interventions: intervention 1: Fluconazole Tablet intervention 2: IBREXAFUNGERP intervention 3: Placebo oral tablet
Intervention descriptions: intervention 1: 150 mg every 72 hours for 3 doses intervention 2: 300 mg BID (one day) every 4 weeks for a total of 6 dosing days intervention 3: BID (one day) every 4 weeks for a total of 6 dosing days

Protocol documents:
Prot_000.pdf: 
 
 
SCYNEXIS, Inc. 
Clinical Trial Protocol 
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Efficacy and Safety of Oral Ibrexafungerp (SCY-078) 
Compared to Placebo in Subjects with Recurrent Vulvovaginal Candidiasis 
SCYNEXIS Protocol Number SCY-078-304 
SCYNEXIS, Inc. 
1 Evertrust Plaza, 13th Floor 
Jersey City, NJ 07302 
 
Original Protocol Issue Date: 03 June 2019 (Version 1.0) 
 
US IND Number 107,521 
EudraCT Number: 2019-002600-40 
STATEMENT OF CONFIDENTIALITY 
The information in this document contains trade secrets and commercial information 
that are privileged or confidential and may not be disclosed unless such disclosure is 
required by federal or state law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or 
confidential and may not be further disclosed by them. These restrictions on disclosure 
will apply equally to all future information supplied to you which is indicated as 
privileged or confidential. 


SCYNEXIS, Inc. 
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1.0 
Contact Information 
 
Contract Research 
Organization 
PPD 
 
 
Study Medical Monitor 
Nkechi Azie, MD 
 
 
Clinical Project Manager 
Philip Deane 
 
 
Sponsor 
SCYNEXIS, Inc. 
1 Evertrust Plaza, 13th Floor 
Jersey City, NJ 07302  
Phone: +1.201.884.5485 
Fax: +1.201.884.5490 
Email: info@scynexis.com 
 
 
 


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2.0 
Protocol Approvals 
 
PROTOCOL ID: SCY-078-304 
 
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Oral Ibrexafungerp (SCY-078) Compared to Placebo 
in Subjects with Recurrent Vulvovaginal Candidiasis  
SCYNEXIS, Inc. Approval: 
 
 
 
 
 
David Angulo  
Chief Medical Officer 
1 Evertrust Plaza, 13th Floor 
Jersey City, NJ 07302 
Phone: 1 201 884 5471 
E-mail: davidangulo@scynexis.com 
 
Date 
 


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Investigator Agreement Statement` 
PROTOCOL ID: SCY-078-304 
 
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Oral Ibrexafungerp (SCY-078) Compared to Placebo 
in Subjects with Recurrent Vulvovaginal Candidiasis  
 
I understand that all documentation provided to me by SCYNEXIS, Inc. or its designated 
representative(s) concerning this study that has not been published previously will be 
kept in the strictest confidence. This documentation includes the study protocol, 
Investigator’s Brochure, case report forms, and other scientific data. This study will not 
commence without the prior written approval of a properly constituted Institutional 
Review Board or Ethics Committee. No changes will be made to the study protocol 
without the prior written approval of SCYNEXIS, Inc. and the Institutional Review 
Board/Ethics Committee, except where necessary to eliminate an immediate hazard to the 
subject. All patients will provide a written informed consent prior to participation. 
I have read the protocol, including all appendices, and I agree that it contains all 
necessary details for me and my staff to conduct this study as described. I have read, 
understood and agree to abide by all the conditions and instructions contained in this 
protocol, and in compliance with International Conference on Harmonization (ICH) 
guidelines, Good Clinical Practices (GCP), Safety Reporting obligations and any 
applicable local requirements. 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
 
Principal Investigator’s Name (Printed) 
 
 
 
 


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TABLE OF CONTENTS 
1.0 
Contact Information ................................................................................................ 2 
2.0 
Protocol Approvals ................................................................................................. 3 
Table of Contents ................................................................................................................ 5 
3.0 
Revision History ................................................................................................... 10 
4.0 
Abbreviations ........................................................................................................ 11 
5.0 
Protocol Synopsis.................................................................................................. 13 
6.0 
Schematic of Study Design ................................................................................... 23 
7.0 
Background Information and Scientific Rationale ............................................... 24 
7.1 
Background Information ............................................................................... 24 
7.2 
Rationale for the Study ................................................................................. 28 
7.2.1 
Rationale for Study Indication and Population ......................................... 28 
7.2.2 
Rationale for Selected Dosing Regimen ................................................... 29 
7.2.3 
Rationale for Study Endpoints and Efficacy Outcomes ........................... 29 
7.2.4 
Rationale for the Study Design ................................................................. 30 
8.0 
Study Objectives ................................................................................................... 30 
8.1 
Primary Objective ......................................................................................... 30 
8.2 
Key Secondary Objective ............................................................................. 30 
8.3 
Other Secondary Objectives ......................................................................... 30 
9.0 
Study Endpoints .................................................................................................... 30 
9.1 
Primary Endpoint .......................................................................................... 30 
9.2 
Key Secondary Endpoint .............................................................................. 31 
9.3 
Other Secondary Endpoints .......................................................................... 31 
10.0 
Study Design ......................................................................................................... 31 
10.1 
Overall Description of the Study .................................................................. 31 
10.1.1 
Study Visits ............................................................................................... 33 
10.1.2 
Study Assessments .................................................................................... 37 
10.2 
Blinding, Randomization and Stratification ................................................. 38 
10.3 
Study Duration .............................................................................................. 39 
10.4 
Number of Centers ........................................................................................ 39 
11.0 
Study Population ................................................................................................... 39 
11.1 
Inclusion Criteria .......................................................................................... 39 


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11.2 
Exclusion Criteria ......................................................................................... 41 
11.3 
Discontinuation Criteria ................................................................................ 42 
11.4 
Replacement of Discontinued Subjects ........................................................ 42 
12.0 
Study Treatments .................................................................................................. 43 
12.1 
Study Treatment Groups ............................................................................... 43 
12.1.1 
Acute Phase ............................................................................................... 43 
12.1.2 
Prevention of Recurrence Phase ............................................................... 43 
12.2 
Dietary Requirements ................................................................................... 44 
12.3 
Study Drugs .................................................................................................. 44 
12.3.1 
Ibrexafungerp (SCY-078) Description ..................................................... 44 
12.3.2 
Formulation, Packaging and Labelling ..................................................... 45 
12.3.3 
Storage and Stability ................................................................................. 46 
12.4 
Drug Accountability...................................................................................... 46 
12.5 
Subject Compliance with Study Drug Dosing .............................................. 47 
13.0 
Non-Study Treatments .......................................................................................... 47 
13.1 
Prior and Concomitant Medications ............................................................. 47 
13.2 
Prohibited Medications ................................................................................. 47 
13.3 
Medications to be Administered with Caution and Monitored as Appropriate
 
48 
13.4 
Study Restrictions ......................................................................................... 48 
14.0 
Study Procedures .................................................................................................. 48 
14.1 
Informed Consent.......................................................................................... 49 
14.2 
Assignment of Subject Number .................................................................... 49 
14.3 
Inclusion and Exclusion Criteria ................................................................... 49 
14.4 
Medical History and Demographics ............................................................. 49 
14.5 
Abbreviated Physical Examination ............................................................... 49 
14.6 
Urine Pregnancy Test .................................................................................... 50 
14.7 
Vulvovaginal Samples .................................................................................. 50 
14.8 
Vulvovaginal Examination and Rating of Signs by the Investigator Using the 
VSS Scale...................................................................................................................... 51 
14.9 
Rating of Vulvovaginal Symptoms by the Subject Using the VSS Scale .... 51 
14.10 
Dispensing and Dosing of Open-Label Fluconazole .................................... 51 
14.11 
Dispensing, Completion, Review and Collection of Subject Diaries ........... 52 


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14.12 
Sample Collection for Safety Laboratory Tests ............................................ 52 
14.13 
Collection of Open-Label Fluconazole Supplies and Evaluation of Treatment 
Compliance ................................................................................................................... 53 
14.14 
Assessment of Clinical Outcome following Fluconazole Treatment ........... 53 
14.15 
Randomization .............................................................................................. 54 
14.16 
Dispensing and Dosing of Blinded Study Drug ............................................ 54 
14.17 
Assessment of Quality of Life ...................................................................... 54 
14.18 
Assessment of Potential Recurrence and Use of Rescue Antifungal 
Medication .................................................................................................................... 54 
14.18.1 Categories of Recurrences ........................................................................ 55 
14.18.2 Procedures for Potential Recurrences ....................................................... 55 
14.18.3 Rescue Antifungal Therapy ...................................................................... 56 
14.19 
Collection of Blinded Study Drug Supplies and Evaluation of Treatment 
Compliance ................................................................................................................... 57 
14.20 
Vital Signs ..................................................................................................... 57 
14.21 
Prior and Concomitant Medication Review .................................................. 57 
14.22 
Adverse Event Monitoring ............................................................................ 57 
15.0 
Study Schedule...................................................................................................... 58 
16.0 
Safety Assessments and Monitoring ..................................................................... 62 
16.1 
Definition of an Adverse Event .................................................................... 62 
16.2 
Definition of a Serious Adverse Event ......................................................... 62 
16.3 
Events of Clinical Interest ............................................................................. 63 
16.4 
Overdose ....................................................................................................... 63 
16.5 
Pregnancy ...................................................................................................... 63 
16.6 
Unexpected Adverse Event ........................................................................... 64 
16.7 
Study Monitoring .......................................................................................... 64 
16.8 
Grading of Adverse Events ........................................................................... 64 
16.9 
Causality Assessment.................................................................................... 65 
16.10 
Adverse Event Collection Timeframe .......................................................... 65 
16.11 
Serious Adverse Event Reporting Requirements .......................................... 65 
16.12 
Adverse Event and Serious Adverse Event Follow-up ................................. 65 
16.13 
Serious Adverse Event Reporting – Procedures for Investigators ................ 66 
16.14 
Procedures for Emergency Unblinding ......................................................... 66 


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17.0 
Data Collection, Study Monitoring and Record Management.............................. 66 
17.1 
Data Collection and Reporting...................................................................... 66 
17.2 
Investigator Study Files ................................................................................ 67 
17.3 
Retention of Records..................................................................................... 67 
18.0 
Analytical Plan ...................................................................................................... 68 
18.1 
Sample Size Determination........................................................................... 68 
18.2 
Analysis Populations ..................................................................................... 68 
18.3 
Subject Disposition, Discontinuation, and Baseline Data ............................ 69 
18.4 
Handling of Missing Data, Dose Adjustments, and Early Withdrawals....... 69 
18.5 
Prior and Concomitant Medications ............................................................. 69 
18.6 
Efficacy ......................................................................................................... 70 
18.6.1 
Efficacy Assessments................................................................................ 70 
18.6.2 
Efficacy Analyses ..................................................................................... 70 
18.7 
Safety ............................................................................................................ 71 
18.7.1 
Safety Assessments ................................................................................... 71 
18.7.2 
Analyses .................................................................................................... 71 
18.8 
Interim Analyses ........................................................................................... 71 
19.0 
Ethics and Protection of Human Patients.............................................................. 72 
19.1 
Ethical Conduct of the Study ........................................................................ 72 
19.2 
Institutional Review Board/Ethics Committee Review ................................ 72 
19.3 
Informed Consent.......................................................................................... 72 
19.4 
Future Use of Samples .................................................................................. 72 
19.5 
Subject Privacy and Subject Confidentiality ................................................ 73 
19.6 
Study Termination ........................................................................................ 73 
19.7 
Financial Disclosure...................................................................................... 73 
20.0 
References ............................................................................................................. 74 
21.0 
Appendices ............................................................................................................ 75 
21.1 
Appendix A:  Prohibited Medications and Medications to be Administered 
with Caution .................................................................................................................. 75 
21.1.1 
Prohibited Medications ............................................................................. 75 
21.1.2 
Medications to be administered with Caution and Monitored as 
Appropriate ............................................................................................................... 76 
21.2 
Appendix B:  Vulvovaginal Signs and Symptoms Scale .............................. 77 


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21.3 
Appendix C: Protocol for Study SCY-078-304S .......................................... 78 
21.3.1 
Protocol Synopsis...................................................................................... 78 
21.3.2 
Schematic of Study Design ....................................................................... 83 
21.3.3 
Background Information and Scientific Rationale ................................... 84 
21.3.4 
Study Objectives ....................................................................................... 85 
21.3.5 
Study Endpoints ........................................................................................ 85 
21.3.6 
Study Design ............................................................................................. 86 
21.3.7 
Study Population ....................................................................................... 88 
21.3.8 
Study Treatments ...................................................................................... 89 
21.3.9 
Non-Study Treatments .............................................................................. 90 
21.3.10 Study Procedures ...................................................................................... 91 
21.3.11 Study Schedule.......................................................................................... 96 
21.3.12 Safety Assessments and Monitoring ......................................................... 99 
21.3.13 Data Collection, Study Monitoring and Record Management.................. 99 
21.3.14 Analytical Plan .......................................................................................... 99 
21.3.15 Ethics and Protection of Human Patients................................................ 102 
21.3.16 References ............................................................................................... 103 
 
LIST OF FIGURES 
Figure 1 
Schematic of Study Design ........................................................................... 23 
Figure 2 
Chemical Structure of Ibrexafungerp (SCY-078) Citrate ............................. 45 
LIST OF TABLES 
Table 1: 
Double-Blind Oral Ibrexafungerp Dosing Regimen ..................................... 44 
Table 2: 
Schedule of Visits and Procedures (Study SCY-078-304) ........................... 58 
 
 
 
 


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Revision History 
 
Not applicable 
 
 


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4.0 
Abbreviations 
 
ABBREVIATION 
DEFINITION 
AE 
adverse event 
ALT/SGOT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST/SGPT 
aspartate aminotransferase 
BID 
twice a day 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
Cmax 
maximum concentration 
CMH test 
Cochran-Mantel-Haenszel test 
CPK 
creatine phosphokinase 
CRO 
contract research organization 
CYP 
cytochrome P450 
EC 
ethics committee 
ECI 
event of clinical interest 
eCRF 
electronic case report from 
EDC 
electronic data capture 
EOFU 
end of follow-up 
FDA 
Food and Drug Administration 
FU 
follow-up 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
hCG 
human chorionic gonadotropin 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ID 
identification 


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ABBREVIATION 
DEFINITION 
IRB 
institutional review board 
ITT population 
intent-to-treat population 
IWRS 
Interactive web response 
IV 
intravenous 
KOH 
potassium hydroxide 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat population 
OATP1B3 
organic anion-transporting polypeptide 1B3  
P-gp 
P-glycoprotein 
PI 
principal investigator 
PP population 
per-protocol population 
QD 
once a day 
QOL 
quality of life 
RBC 
red blood cell 
RVVC 
recurrent vulvovaginal candidiasis 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
TOC 
test of cure 
ULN 
upper limit of normal 
VSS Scale 
Vulvovaginal Signs and Symptoms Scale 
VVC 
vulvovaginal candidiasis 
WBC 
white blood cell 
 
 


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5.0 
Protocol Synopsis 
 
Title: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Oral Ibrexafungerp (SCY-078) Compared to Placebo in 
Subjects with Recurrent Vulvovaginal Candidiasis 
STUDY OBJECTIVES: 
Primary Objective:  
• 
To evaluate the efficacy of oral ibrexafungerp versus placebo in preventing recurrences of 
vulvovaginal candidiasis (VVC) in subjects with recurrent VVC (RVVC) based on Clinical 
Success. 
Key Secondary Objective:  
• To evaluate the efficacy of oral ibrexafungerp versus placebo in preventing recurrences of 
VVC in subjects with RVVC based on Mycologically Proven Recurrences at Test of Cure 
(TOC). 
Other Secondary Objectives:  
• 
To evaluate the efficacy of oral ibrexafungerp versus placebo in preventing recurrences 
(Mycologically Proven, Presumed or Suspected) of VVC in subjects with RVVC. 
• 
To evaluate the efficacy of oral ibrexafungerp versus placebo in preventing recurrences of 
VVC in subjects with RVVC based on the number of Recurrences (Mycologically Proven, 
Presumed or Suspected) of VVC. 
• 
To evaluate the efficacy of oral ibrexafungerp versus placebo in subjects with RVVC 
based on Quality of Life (QOL) outcomes. 
• 
To evaluate the safety and tolerability of oral ibrexafungerp in subjects with RVVC. 
STUDY ENDPOINTS: 
Primary Endpoint:  
• 
Efficacy as measured by the percentage of subjects with documented Clinical Success  
(defined as subjects having a TOC evaluation and no Mycologically Proven, Presumed or 
Suspected Recurrences of VVC) up to TOC (Week 24). 
Key Secondary Endpoint:  
• 
Efficacy as measured by the percentage of subjects with no Mycologically Proven 
Recurrence (defined as an episode of VVC with a total composite score ≥ 3 on the 
Vulvovaginal Signs and Symptoms [VSS] Scale and a culture positive for Candida spp. 
that required antifungal treatment) at TOC (Week 24). 
Other Secondary Endpoints:  
Efficacy as measured by: 
• 
The percentage of subjects with no Mycologically Proven Recurrence at Week 4, Week 8, 
Week 12, and Week 36 (end of follow-up [EOFU]). 


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• 
The time to the first Recurrence (Mycologically Proven, Presumed or Suspected) of VVC 
through EOFU. 
• 
The percentage of subjects with Mycological Eradication (negative fungal culture) at 
Week 12, Week 24 (TOC) and Week 36 (EOFU). 
• 
The percentage of subjects with no Mycologically Proven, Presumed or Suspected 
Recurrences at Week 4, Week 8, Week 12 and Week 36 (EOFU). 
• 
The percentage of subjects with no Mycologically Proven or Presumed Recurrences at 
Week 4, Week 8, Week 12, TOC (Week 24) and Week 36 (EOFU). 
• 
The proportion of subjects in three ordered categories related to the number of Recurrences 
(Mycologically Proven, Presumed or Suspected) of VVC from Baseline (Day 1) to TOC 
(Week 24) and Week 36 (EOFU). The three categories of recurrence are defined as (i) 0 to 
1 episodes, (ii) 2 to 3 episodes, and (iii) ≥ 4 episodes. 
• 
The absolute number of Mycologically Proven, Presumed or Suspected Recurrences from 
Baseline (Day 1) to TOC (Week 24) and Week 36 (EOFU). 
• 
Absolute improvement in QOL outcomes at Week 12, Week 24 (TOC) and Week 36 
(EOFU) as measured by EQ-5D, SF-36 and FSDS. 
Safety and tolerability as measured by: 
• 
Adverse events (AEs), vital signs, treatment discontinuation and safety laboratory tests at 
TOC (Week 24). 
STUDY PHASE: 3 
STUDY DESIGN: This study is a Phase 3, multicenter, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of oral ibrexafungerp (formerly “SCY-
078”) compared to placebo in female subjects 12 years and older with RVVC. The primary 
objective of the study is to evaluate the efficacy of oral ibrexafungerp versus placebo in 
preventing recurrences of VVC in subjects with RVVC based on Clinical Success.  
The study will consist of a Screening visit, an Acute Phase with open-label fluconazole and a 
Prevention of Recurrence Phase with randomized ibrexafungerp or placebo. Screening and the 
beginning of the Acute Phase (Day -14) may occur on the same day. Approximately 320 
subjects are planned to be enrolled into the open-label Acute Phase of the study in order to 
randomize approximately 240 subjects into the double-blind Prevention of Recurrence Phase, 
which will consist of 6 monthly, single-day treatments with the randomized study drug.  
A Nested Sub-Study will be made available to subjects who fail treatment with fluconazole 
during the Acute Phase and are not eligible for randomization into the Prevention of 
Recurrence Phase (see Section 21.3 [Appendix C] for Sub-Study details). 
Study Visits 
Study visits will consist of scheduled on-site visits, phone contacts, and lab visits (Acute Phase 
only), as well as unscheduled visits. Whenever possible, on-site visits and phone contacts will 
be scheduled to occur on the date of dosing (or as close to the date of dosing as possible) to 
facilitate reminding subjects to take their study doses. This is applicable for the Baseline 
(Day 1), Week 4, Week 8, Week 12, Week 16 (phone contact), and Week 20 (phone contact) 
visits.  
Phone contacts will be conducted to check for AEs, treatment compliance, potential recurrence, 
and concomitant medication use, including other antifungal agents. Unscheduled visits will be 
conducted anytime that there are symptoms indicating a potential recurrence or an AE. 


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• 
Screening (Days -16 to -14):  To be eligible for inclusion, subjects must have a history of 
at least three episodes of VVC in the past 12 months (including the current episode), a total 
composite score ≥ 4 on the VSS Scale, a positive potassium hydroxide (KOH) test, and a 
normal vaginal pH (≤ 4.5). Screening and the beginning of the Acute Phase (Day -14) may 
occur on the same day. 
• 
Acute Phase (Days -14 to -1): Eligible subjects will receive active treatment with open-
label oral fluconazole 150 mg administered once a day (QD) on Days -14, -11 and -8, for a 
total of 3 doses. Subjects will be dispensed subject diaries where they will rate their 
vulvovaginal symptoms.  
• 
Prevention of Recurrence Phase: The occurrence of a recurrence is the key efficacy 
parameter in this study. Subjects who have a culture-confirmed Candida spp. infection 
from the sample collected at Screening, achieve significant resolution of their vulvovaginal 
signs and symptoms on fluconazole (defined as a total composite score ≤ 2 on the VSS 
Scale) at Baseline (Day 1) and continue to meet all other eligibility criteria will be 
randomized into the Prevention of Recurrence Phase. A Nested Sub-Study will be made 
available to subjects who fail treatment with fluconazole during the Acute Phase and are 
not eligible for randomization into the Prevention of Recurrence Phase. Subjects who are 
not eligible for this study or the Nested Sub-Study will be discontinued. Subjects will be 
assessed for potential recurrences throughout the Study Treatment Period and the Follow-
up Period. 
o Study Treatment Period (Baseline [Day 1] through Week 24 [TOC]): Subjects will 
be randomized at a 1:1 ratio to receive one of two study treatments (oral ibrexafungerp 
or placebo administered as a single-day treatment repeated every 4 weeks [28 days 
(±3)] for a total of 6 single-day treatments) in a double-blind manner. Each single-day 
treatment will consist of two doses of ibrexafungerp 300 mg each or placebo given 12 
(±4) hours apart (total single-day ibrexafungerp dose = 600 mg).  Subjects will take the 
study drug on Day 1 (Baseline), Week 4, Week 8, Week 12, Week 16 and Week 20, 
regardless of recurrence or administration of antifungal medication. Subjects will 
receive their first dose of study drug at the site and self-administer the remaining doses 
at home. During the Study Treatment Period, both clinical and mycological evaluations 
will be completed at protocol-specified time points and anytime that there is suspicion 
of a potential recurrence. Vaginal examinations will be performed by the investigator 
to rate the signs of infection on the VSS Scale and subjects will rate their vulvovaginal 
symptoms on subject diaries on a weekly basis and at the time of each scheduled or 
unscheduled visit to the site. Mycological examinations will include KOH, fungal 
culture, species identification and susceptibility testing. 
o Follow-up Period (Week 25 through Week 36 [EOFU]): Subjects will enter the 
Follow-up Period regardless of recurrence or rescue antifungal medication use. Both 
clinical and mycological evaluations will be completed at protocol-specified time 
points during the Follow-up Period, and anytime that a recurrence is presumed. 
Subjects will complete all follow-up (FU) visits regardless of recurrence or rescue 
antifungal medication use and rate their vulvovaginal symptoms in their subject diaries 
on a weekly basis until the EOFU (Week 36 visit). Subjects will continue to be 
evaluated for potential recurrence, antifungal medication use and safety throughout this 
period. 
Recurrences during the Prevention of Recurrence Phase 
The occurrence of a recurrence is the key efficacy parameter in this study. Randomized 
subjects will be assessed for potential recurrence at all visits during the Prevention of 


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Recurrence Phase following Day 1 (Baseline) (i.e., from Day 2 through Week 36 [EOFU]), 
including phone contacts, scheduled visits and unscheduled visits, as well as in between visits. 
If during a phone contact or at any other time there is suspicion of a potential recurrence (any 
kind of recurrence, i.e., Mycologically Proven, Presumed or Suspected), subjects will be 
instructed to visit the study center for a proper evaluation of their recurrence before initiating 
any VVC treatment. 
Potential recurrences will be assessed based on clinical and mycological outcomes and need for 
other antifungal treatment. If a subject has symptoms suggestive of Candida infection (itching, 
burning, irritation) that in the opinion of the investigator may require antifungal therapy, the 
following procedures must be completed: 
• 
Rate and document symptoms in the electronic case report form (eCRF), 
• 
Perform vaginal examination to rate signs and document in the eCRF,  
• 
Measure vaginal pH at the site and document results in the eCRF, 
• 
Collect vaginal sample for KOH testing and investigation of potential bacterial vaginosis 
and Trichomonas vaginalis infection at the site or by the local laboratory, and  
• 
Collect vaginal samples for fungal culture by the central laboratory.  
All of the procedures above should be completed prior to administration of rescue antifungal 
medication. Subjects participating in the study should be strongly discouraged from self-
administering any treatment for a potential recurrence.  Ideally, if the severity of the 
symptoms allows based on the investigator’s judgment, the initiation of antifungal therapy 
should be delayed until results from the vaginal culture are available to confirm that the 
episode is due to Candida spp. and not to other cause of vaginitis. 
In this study, Recurrences of VVC will be broken into three categories: 
• 
Mycologically Proven Recurrence: An episode of VVC with a total composite score ≥ 3 
on the VSS Scale and a culture positive for Candida spp. that required antifungal 
treatment. 
• 
Presumed Recurrence: An episode of VVC with a total composite score ≥ 3 on the VSS 
Scale that required antifungal treatment and for which there is a positive KOH microscopy 
but no positive fungal culture.  
• 
Suspected Recurrence: An episode of VVC that required treatment with an antifungal 
agent (including self-administration with over-the-counter antifungals) regardless of VSS 
composite score but for which there is no mycological evidence of disease, such as a 
positive KOH microscopy or fungal culture.  
Subjects with a Mycologically Proven Recurrence should receive antifungal therapy.  
If a subject experiences one or more recurrences during the Study Treatment Period Phase (i.e., 
either a Mycologically Proven Recurrence or a Presumed Recurrence or a Suspected 
Recurrence) she will continue her scheduled study drug administration and will complete all 
scheduled visits until reaching EOFU. 
All antifungal therapy administered during the study should be documented in the electronic 
data capture (EDC) system, with the reason for use clearly indicated (e.g., Mycologically 
Proven Recurrence, Presumed Recurrence, Suspected Recurrence). 
 


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Efficacy (Clinical, Mycological and Patient-Reported Outcomes [QOL]) and Safety 
Assessments 
Efficacy assessments will be based on clinical evaluations, mycological testing and quality of 
life (QOL) questionnaires. The primary efficacy endpoint of the study is the percentage of 
subjects with documented Clinical Success (defined as subjects having a TOC evaluation and 
no Mycologically Proven, Presumed or Suspected Recurrences of VVC) up to TOC (Week 24).  
The key secondary efficacy endpoint is the percentage of subjects with no Mycologically 
Proven Recurrence (defined as an episode of VVC with a total composite score ≥ 3 on the VSS 
Scale and a culture positive for Candida spp. that required antifungal treatment) at TOC (Week 
24). Efficacy will also be assessed by other secondary efficacy and patient-reported outcomes 
(see STUDY ENDPOINTS above). 
Safety procedures will include collection of AEs, treatment discontinuations, abbreviated 
physical examination, vital signs, safety laboratory tests and prior and concomitant 
medications. 
Clinical Evaluation  
The signs (edema, erythema and excoriation or fissures) and symptoms (itching, burning and 
irritation) of infection will be assessed by the investigator and the subject, respectively, on the 
VSS Scale. The VSS Scale is a standardized, pre-defined scale where each sign and symptom 
will be given a numerical rating based on severity (absent = 0; mild = 1; moderate = 2; severe 
= 3) to calculate a total composite VSS score. The symptoms of infection will be rated by the 
subject on a weekly basis and at the time of each scheduled or unscheduled visit to the site 
throughout the Prevention of Recurrence Phase. Vaginal examinations will be conducted by the 
investigator to rate the subject’s signs of infection at protocol-specified visits and anytime that 
there is suspicion of a potential recurrence.  
Mycological Testing 
Mycological tests will include direct wet mount microscopic examination to visualize clue 
cells indicative of bacterial vaginosis or trichomonas, direct microscopic examination with 
10% KOH to identify yeast, and fungal cultures. The direct wet mount and KOH examination 
will be performed locally at Screening for the determination of subject eligibility and then 
anytime that a recurrence is suspected. If the investigator suspects Herpes virus, Neisseria 
gonorrhoeae or Chlamydia trachomatis infection, a vaginal sample will be collected and sent 
to a designated central laboratory. Fungal cultures will be performed centrally at Screening and 
at protocol-specified time points for species identification and susceptibility testing. Fungal 
cultures will also be done anytime that a recurrence is suspected during the Prevention of 
Recurrence Phase and for antifungal susceptibility testing for subjects with positive cultures.  
Quality of Life 
QOL will be assessed by EQ-5D, SF-36 and FSDS at protocol-specified time points to assess 
improvement in QOL outcomes.  
TARGET POPULATION: The study population will include female subjects 12 years and 
older with RVVC. 
INCLUSION CRITERIA:  
Subjects must fulfill all of the following KEY criteria at Screening and/or Baseline (Day 1) to 
be eligible for study admission: 
1. Subject is a post menarchal female subject 12 years and older at Screening and is in good 
general health based on medical history, physical examination, vital sign measurements 
and safety laboratory tests performed at the Screening visit and prior to administration of 
the initial dose of study drug.  


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2. Subject has a diagnosis of symptomatic VVC that meets the following criteria at 
Screening:  
a) A total composite score of ≥ 4 on the VSS Scale.  
b) Positive microscopic examination with 10% KOH in a vaginal sample collected at 
Screening revealing yeast forms (hyphae/pseudohyphae) or budding yeasts 
c) Normal vaginal pH (≤ 4.5). 
d) A minimum of three episodes of VVC in the past 12 months, including the current 
episode, that required administration of antifungal medication. Besides the current 
episode, at least one of the previous episodes in the past 12 months is required to have 
been a physician-diagnosed episode of VVC, with at least one positive test confirming 
vaginal yeast infection (e.g., KOH, culture or fungal polymerase chain reaction).  
3. Subject meets the following criteria at Baseline (Day 1): 
a) Significant resolution of signs and symptoms of Candida infection (total composite 
score ≤ 2 on the VSS Scale). 
b) Culture positive for Candida spp. in a vaginal sample collected at Screening. 
c) Normal vaginal pH (≤ 4.5). 
4. Subject is able to take oral tablets and capsules. 
EXCLUSION CRITERIA: 
A subject will be excluded from participation in the study if she meets any of the following 
KEY exclusion criteria:  
1. Subject has any vaginal condition other than RVVC that may interfere with the diagnosis 
or evaluation of response to therapy, such as suspected or confirmed concurrent causes of 
vulvovaginitis and/or cervicitis including bacterial vaginosis, Trichomonas, Herpes virus, 
Neisseria gonorrhoeae, Chlamydia, symptomatic human papillomavirus infection or other 
mixed infections. 
2. Subject received systemic and/or topical vaginal antifungal treatment, including 
prescription or over-the-counter products, within 28 days prior to the Day -14 visit.  
3. Subject is receiving or anticipates to require treatment with the prohibited medications 
(including prescription and over-the-counter medications, supplements, and herbal 
products) during the following timeframes: 
a) Systemic and topical vaginal antifungal treatment other than study drug and rescue 
medication (if needed), as specified in the protocol, anytime during the study. 
b) Select CYP3A4/5 inducers during the 14 days prior to enrollment and during study 
treatment 
c) Select strong CYP3A4/5 inhibitors during 48 hours prior to enrollment and during 
study treatment.  
d) Select P-gp substrates during the 48 hours prior to enrollment or during study 
treatment with ibrexafungerp. 
e) Topical vaginal corticosteroids from 7 days prior to the Screening visit to the Week 24 
(TOC) visit. 
4. Subject has active menstruation at the Screening visit. Note: The Screening visit may be 
rescheduled if required. 
5. Subject has a history of or an active cervical/vaginal cancer. 
STUDY DRUGS:  
The study drug administered during the study will consist of oral ibrexafungerp (150-mg 
tablets) and ibrexafungerp matching placebo tablets for the double-blind Prevention of 


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Recurrence Phase, and oral fluconazole (150-mg tablets or capsules) for the open-label Acute 
Phase. Study drug will be provided by the Sponsor. 
Ibrexafungerp citrate drug product for oral administration will be supplied as a tablet 
containing 150 mg of ibrexafungerp active ingredient on a free-base basis. In addition to the 
active ingredient, the tablet formulation also contains silicified microcrystalline cellulose, 
crospovidone, mannitol, colloidal silicon dioxide, magnesium stearate (non-bovine) and 
butylated hydroxyanisole. 
Fluconazole drug product will be sourced commercially and will be provided as a tablet or 
capsule containing 150 mg of active ingredient.  
The placebo product matching ibrexafungerp will be supplied as a tablet matching the size and 
appearance of the active tablet. The tablet formulation contains silicified microcrystalline 
cellulose, crospovidone, mannitol, colloidal silicon dioxide, magnesium stearate (non-bovine) 
and butylated hydroxyanisole.  
STUDY TREATMENT GROUPS:  
Acute Phase 
Subjects who meet all study eligibility criteria at Screening will enter the Acute Phase of the 
study and will receive oral fluconazole, as follows: 
• 
Oral fluconazole 150 mg QD on Days -14, -11 and -8 
The first dose of fluconazole will be administered on Day -14 at the study site, after all other 
visit procedures have been done. Subjects will self-administer the remaining doses at home. 
Prevention of Recurrence Phase 
Subjects who have a culture-confirmed VVC from the sample collected at Screening, achieve a 
significant resolution of the signs and symptoms of infection (total composite score ≤ 2 on the 
VSS Scale) at Baseline (Day 1) and continue to meet all study eligibility criteria will be 
randomized at a 1:1 ratio to one of the following two treatment groups:  
• 
Oral ibrexafungerp administered as a single-day treatment repeated every 4 weeks (28 days 
[±3]) for a total of 6 single-day treatments (Baseline [Day 1], Week 4, Week 8, Week 12, 
Week 16 and Week 20). Each single-day treatment will consist of two doses of 300 mg 
each given 12 (±4) hours apart (total single-day dose = 600 mg).  
• 
Matching oral placebo administered as a single-day treatment repeated every 4 weeks (28 
days [±3]) for a total of 6 single-day treatments (Baseline [Day 1], Week 4, Week 8, Week 
12, Week 16 and Week 20). Each single-day treatment will consist of two doses of placebo 
given 12 (±4) hours apart. 
Subjects will receive their first dose of double-blind study drug at the site and will self-
administer the remaining doses at home. Subjects must take the two doses of study drug 12 
hours apart (±4 hours), preferably with or immediately after a meal.  
STUDY BLINDING, RANDOMIZATION AND STRATIFICATION:  This is a 
randomized, double-blind study. All site and sponsor personnel will be blinded to treatment 
assignment. 
Approximately 320 subjects are planned to be enrolled into the open-label Acute Phase of the 
study in order to randomize approximately 240 subjects at a 1:1 ratio to one of the two study 
treatment groups. All randomization of subjects will be managed electronically through an 
interactive web response system (IWRS). 


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Subjects will be stratified at randomization based on the presence or absence of uncontrolled 
diabetes mellitus, defined as A1C levels ≥ 8.00% at Baseline (Uncontrolled diabetes mellitus: 
YES or NO), and by geographical region (USA or Ex-USA).  
STUDY EVALUATIONS 
Clinical Evaluation: The signs (edema, erythema and excoriation or fissures) and symptoms 
(itching, burning and irritation) of infection will be assessed by the investigator and the subject, 
respectively, on the VSS Scale. The VSS Scale is a standardized, predefined scale where each 
sign and symptom will be given a numerical rating based on severity (absent = 0; mild = 1; 
moderate = 2; severe = 3) to calculate a total composite score.  
Mycological Testing: Mycological tests will include direct wet mount microscopic 
examination to visualize clue cells indicative of bacterial vaginosis or trichomonas, direct 
microscopic examination with 10% KOH to identify yeast, and fungal cultures.  
QOL: QOL will be assessed by EQ-5D, SF-36 and FSDS at protocol-specified time points to 
assess improvement in QOL outcomes. 
Safety Evaluations: Safety will be evaluated throughout the study, including the following 
parameters: AEs, physical examination, vital signs, safety laboratory tests and study treatment 
discontinuations. 
STATISTICAL ANALYSES: 
Sample Size Determination 
The primary endpoint of the study is the percentage of subjects with documented Clinical 
Success up to TOC (Week 24). Assuming response rates of 65% and 43% for ibrexafungerp 
and placebo, respectively; 90% power; and an alpha level of 0.05, approximately 240 subjects 
randomized at a 1:1 ratio are needed to declare a difference between ibrexafungerp and placebo 
at Week 24 based on Fisher’s Exact test.  
In order to be randomized, a subject should have achieved the proposed significant resolution 
of signs and symptoms (total composite score ≤2 on the VSS Scale) after receiving fluconazole 
therapy for an acute episode and have a positive culture for Candida spp. from the sample 
collected at Screening. It is estimated that approximately 320 subjects will need to enter the 
Acute Phase to provide 240 subjects randomized to the Prevention of Recurrence Phase.  
Enrollment into the Acute Phase will be discontinued when approximately 240 subjects have 
been randomized.  
Analysis Populations 
The study populations to be used in the analyses are defined as follows: 
• 
Intent-to-Treat (ITT) Population: All randomized subjects. 
• 
Modified Intent-to-Treat (mITT) Population: All randomized subjects who have a 
confirmed mycological culture for yeast at Screening and a negative culture for yeast 
at Baseline (Day 1). 
• 
Per-Protocol (PP) Population: All ITT subjects who did not have major protocol 
deviations likely to affect study efficacy and who have available data at the TOC visit.  
Note that subjects who discontinue due to a study-drug-related AE will be classified as 
failures for the analyses of efficacy under the PP population. 
• 
Safety Population: All randomized subjects who received at least one dose of study 
drug (ibrexafungerp or placebo) and who have at least one post-Baseline (Day 1) 
evaluation. 


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Efficacy Analysis 
Efficacy assessments will be based on clinical evaluations, mycological testing and QOL.  
The primary efficacy endpoint of the study is the percentage of subjects with documented 
Clinical Success (defined as subjects having a TOC evaluation and no Mycologically Proven, 
Presumed or Suspected Recurrences of VVC) up to TOC (Week 24).  The key secondary 
efficacy endpoint is the percentage of subjects with no Mycologically Proven Recurrence 
(defined as an episode of VVC with a total composite score ≥ 3 on the VSS Scale and a culture 
positive for Candida spp. that required antifungal treatment) at TOC (Week 24). Other 
secondary efficacy endpoints will also be assessed (see STUDY ENDPOINTS above).  
The following efficacy outcomes will be evaluated in the study: 
• 
Clinical Success: Subjects having a TOC evaluation and no Mycologically Proven, 
Presumed or Suspected Recurrences of VVC. 
• 
Recurrence of VVC: In this study, Recurrence of VVC will be broken into three 
categories:  
o Mycologically Proven Recurrence: An episode of VVC with a total composite 
score ≥ 3 on the VSS Scale and a culture positive for Candida spp. that required 
antifungal treatment.  
o Presumed Recurrence: An episode of VVC with a total composite score ≥ 3 on 
the VSS Scale that required antifungal treatment and for which there is a positive 
KOH microscopy but no positive fungal culture. 
o Suspected Recurrence: An episode of VVC that required treatment with an 
antifungal agent (including self-administration with over-the-counter antifungals) 
regardless of VSS composite score but for which there is no mycological evidence 
of disease, such as a positive KOH microscopy or fungal culture.  
• 
Mycological Eradication: Negative fungal culture (no growth of Candida species). 
The primary endpoint, the percentage of subjects with documented Clinical Success up to TOC 
(Week 24), will be analyzed using a Cochran-Mantel-Haenszel (CMH) test adjusted for site; p-
values and 95% confidence intervals will be presented. Subjects whose results are missing at 
TOC (Week 24) will be imputed as failures in the analysis. In the event that model 
convergence is an issue with a stratified analysis, alternative methods for accounting for site, or 
an unstratified analysis will be considered. A sensitivity analysis will be performed on the ITT 
population where subjects with missing values will be removed from the analysis.  
For other continuous efficacy endpoints, a two-way analysis of variance (ANOVA) model will 
be used including effects for treatment and site; p-values and 95% confidence intervals will be 
presented. For other categorical endpoints, the CMH test adjusted for site will be performed, 
and p-values and 95% confidence intervals will be presented. 
For the ordered categorical endpoint, a proportional odds model will be fitted accounting for 
the effects of treatment and site.  The proportional odds model will fit an ordered regression 
model for the ordinal dependent variable as described by McCullagh (1980).  If the assumption 
of proportional odds is violated alternative analyses will be considered which require a weaker 
assumption. 
Safety Analysis 
Safety will be evaluated throughout the study, including the following parameters: AEs, study 
treatment discontinuations, vital signs, safety laboratory tests and prior and concomitant 


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medications. 
No formal statistical analysis is planned for the safety data. Safety analyses will be conducted 
using the safety population. AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) Version 19.1 or higher. The incidence and severity of treatment-
emergent AEs and serious AEs (SAEs) and their relationship to treatment will be summarized 
by system organ class and preferred term. The percentage of subjects who discontinued study 
treatment and the reasons for discontinuation will be summarized by treatment group. 
Laboratory evaluations and vital signs will be summarized as observed values and as changes 
from Baseline (Day 1) by treatment group. In addition, shifts (with respect to the reference 
range) from Baseline (Day 1) will be presented for laboratory tests by treatment group. 
 
 
 


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6.0 
Schematic of Study Design 
 
Figure 1 
Schematic of Study Design 
 
 
Abbreviations: D = Day; EOFU = end of follow-up; S&S = signs 
and symptoms; TOC = Test of Cure; W = Week 
Screening 
(Days -16 to -14) 
Acute Phase 
Fluconazole Treatment 
(Days -14 to -1)  
Study Treatment Period 
(Day 1 through Week 24 [TOC]) 
Double-blind treatment 
Randomized 1:1 
If significant resolution of S&S at 
Baseline (Day 1) 
Ibrexafungerp once 
every 4 weeks for a 
total of 6 doses 
(D1 through W20) 
Placebo once 
every 4 weeks for 
a total of 6 doses 
(D1 through W20) 
Follow-up Period 
(Week 25 through Week 36) 
Prevention 
of 
Recurrence 
Phase  
(Day 1 
through 
EOFU or 
presumed 
recurrence) 
If no significant resolution of S&S 
at Baseline (Day 1), a nested sub-
study will be available 


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7.0 
Background Information and Scientific Rationale 
7.1 
Background Information 
Vulvovaginal Candidiasis 
Vulvovaginal candidiasis (VVC) is a common fungal infection caused by Candida spp. and is a 
significant morbidity condition in women from all social classes. 
Information on the incidence of VVC is incomplete, since the disease is not a reportable entity 
and data collection is hampered by inaccuracies of diagnosis and the use of non-representative 
study populations.1 VVC affects 70%–75% of women at least once during their lives, most 
frequently young women of childbearing age. Approximately 40%–50% of women will 
experience a recurrence2 and 5% to 8% of adult women have a recurrent vulvovaginal 
candidiasis (RVVC).3  
Current treatments for VVC include topical antifungals and the use of oral prescription 
antifungals, such as single doses of fluconazole.  There are no currently approved products to 
prevent recurrence of VVC in patients with RVVC. The entity of RVVC has been defined as at 
least three symptomatic episodes in the previous 12 months, although some investigators define 
it as four attacks in a year. This is an entirely arbitrary differentiation, not based on any data or 
study and it is likely that women identified by both definitions are identical.4   
C. albicans is responsible for the majority of infections in women with RVVC and the majority 
remain susceptible to azoles implying that the host, along with the pathogen, contributes to the 
pathophysiology of RVVC. 
RVVC is likely a multifactorial disease including genetic predisposition to enhanced vaginal 
colonization where, in the presence of secondary triggering mechanisms, the carrier state is 
transformed into a proinflammatory state by a host’s hyperactive local immune response. Long-
term antifungal suppressive therapy may help control the host’s mucosal reaction by keeping the 
vaginal fungal load at markedly reduced levels.4 Several long-term maintenance regimens using 
either topical azoles or oral azoles (e.g., ketoconazole, itraconazole, and fluconazole) have been 
studied showing benefit in preventing recurrences of VVC. Although there have been few 
comparative studies, the best results were obtained with long-term maintenance therapy using 
once weekly fluconazole 150 mg for 6 months.5,6 The most important limitation of the 
suppressive therapy with fluconazole is exactly that: suppression of growth rather than 
eradication of the yeast. Even though yeast organisms are dramatically reduced in number, below 
the level of detection by conventional culture technique, they persist in low numbers in the 
vaginal lumen, triggering the VVC episode upon discontinuation of fluconazole. A fungicidal 
drug and regimen may be able to address this significant limitation of current therapies for 
RVVC and may be associated with a more sustained benefit after discontinuation of therapy.   
This study aims to demonstrate the efficacy and define the safety of a 6-month dosing regimen of 
oral ibrexafungerp to prevent recurrences in subjects with RVVC. 
The glucan synthesis inhibitor ibrexafungerp  
Ibrexafungerp (SCY-078) is a member of a new class of antifungal agents and is an orally active, 
semi-synthetic, triterpene derivative of the natural product enfumafungin. Ibrexafungerp is a 


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structurally distinct class of glucan synthesis inhibitor that inhibits the synthesis of the fungal cell 
wall polymer β-(1,3)-D-glucan. Time-kill studies have demonstrated that ibrexafungerp has in 
vitro fungicidal activity against Candida spp. isolates similar to that observed with the 
echinocandins.  
Ibrexafungerp is being developed as the first oral and intravenous (IV) glucan synthesis inhibitor 
for the treatment and prevention of fungal infections caused by Candida and Aspergillus species 
with the potential to provide the therapeutic advantages of both an IV and oral formulation.  
Antifungal activity 
The spectrum and potency of activity of ibrexafungerp has been evaluated by numerous 
independent laboratories against an extensive panel of clinically relevant yeast and mold isolates 
using the Clinical and Laboratory Standards Institute (M27-A3 guidelines)7 and European 
Committee on Antimicrobial Susceptibility Testing methods. Overall, the epidemiological 
studies have demonstrated that ibrexafungerp has potent, broad-spectrum activity against the 
majority of the clinical isolates tested. These studies have laid the foundation in support of the 
use of ibrexafungerp for the treatment of invasive fungal infections.  
Activity against Candida spp. 
Ibrexafungerp has been evaluated against > 2000 Candida isolates, including all clinically 
relevant species, more than 300 C. glabrata isolates and 100 C. auris isolates. These in vitro 
studies have demonstrated the broad spectrum of anti-Candida activity of ibrexafungerp. 
Additionally, ibrexafungerp demonstrated in vitro activity against pre-formed biofilms, which is 
a relevant feature when addressing catheter-related Candida infections and, potentially, RVVC. 
Studies conducted with azole- and echinocandin-resistant strains have shown that ibrexafungerp 
retains activity (i.e., no significant change in minimum inhibitory concentration when compared 
to wild type) against > 90% of azole-resistant strains and > 70% of Candida strains with FKS 
mutations commonly associated with echinocandin resistance. Interestingly, although 
ibrexafungerp and the echinocandins share a similar mechanism of action (β-[1,3]-D-glucan 
synthesis inhibition), their clearly different molecular structure provides them with some 
differentiating characteristics in terms of microbiological activity.  
Ibrexafungerp was evaluated in vitro against clinical isolates of echinocandin-resistant strains of 
Candida spp., the majority of which contained mutations in the FKS gene. Overall, it was active 
against the majority of the echinocandin-resistant strains tested. Significantly, ibrexafungerp was 
active against approximately 70% of the isolates containing the most commonly reported FKS 
mutation associated with echinocandin resistance in C. glabrata (S663P in FKS2 and S645P in 
FKS1). Selection of ibrexafungerp resistance in vitro occurs at a low frequency. A deletion at 
position F659 in FKS2 of C. glabrata was the predominant mutation observed in these studies; 
notably, ibrexafungerp did not select for mutations at positions S663 or S645. These results 
suggest that ibrexafungerp inhibits glucan synthase in a manner different from that of 
echinocandins.  
The in vitro studies also included several multidrug-resistant isolates. Consistent with the data 
described above, ibrexafungerp was active against > 70% of these isolates. Ibrexafungerp has 
also demonstrated a potent activity against life-threatening and multi-drug-resistant C. auris 
strains at concentrations indicative of potential clinically relevant effects.  


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Activity against Aspergillus spp. 
The in vitro activity of ibrexafungerp has been evaluated against > 450 clinical Aspergillus 
isolates, including most clinically relevant species and azole-resistant strains. The results 
demonstrated potent activity of ibrexafungerp against all of the strains tested.  
Murine models of invasive fungal infections  
The antifungal efficacy of ibrexafungerp has been evaluated in several murine models of 
disseminated candidiasis and aspergillosis. In a disseminated C. albicans model, ibrexafungerp 
was more active than fluconazole at all doses. Murine models of ibrexafungerp in disseminated 
candidiasis caused by C. glabrata and C. tropicalis indicated activity across multiple Candida 
species. The ibrexafungerp area under the concentration-time curve in plasma necessary to 
achieve target efficacy in these models was estimated to be 15.4 ± 2.2 μM•hr. 
Nonclinical experience  
Toxicology studies in rats and dogs have been conducted with ibrexafungerp following oral 
administration for 6 and 9 months, respectively. The results from the non-clinical safety program 
are supportive of the doses and treatment duration intended in this study.  
The in vitro studies indicated that ibrexafungerp metabolism was predominantly oxidative, with 
cytochrome P450 (CYP) 3A being the primary enzyme involved in its oxidative metabolism. 
Strong inhibitors of CYP3A would be expected to increase plasma levels of ibrexafungerp; 
therefore, the concurrent administration of ibrexafungerp with such inhibitors is prohibited.  
Clinical experience  
To date, over 500 subjects and patients have received either oral or IV formulations of 
ibrexafungerp in Phase 1 and Phase 2 studies. Ibrexafungerp was generally well tolerated 
following single oral doses of up to 1600 mg and multiple oral doses of up to 800 mg/day for 28 
consecutive days in Phase 1 studies. Reported adverse events (AEs) after oral administration 
have been generally transient and primarily mild to moderate in intensity. The most frequently 
reported AEs have been mild gastrointestinal events (nausea, vomiting, diarrhea and abdominal 
pain).  
A Phase 2 study of oral ibrexafungerp as step-down therapy from IV echinocandin in patients 
with invasive candidiasis has been completed. Following three to ten days of IV echinocandin 
therapy, 21 patients received either ibrexafungerp or fluconazole. Ibrexafungerp was well 
tolerated, with an AE profile typical of this population, with the most common treatment-related 
AEs being gastrointestinal in nature (i.e., nausea and diarrhea). The results from this study also 
indicated that the higher dose of ibrexafungerp tested (750 mg once a day [QD]) is predicted to 
achieve the target exposure at steady state in the majority of patients.  
A Phase 2 proof-of-concept study of oral ibrexafungerp in patients with acute VVC has also been 
completed. In this multicenter, randomized, active-controlled, evaluator-blinded study of oral 
ibrexafungerp compared to oral fluconazole in adult female patients with acute VVC, 96 patients 
with an acute, moderate to severe, symptomatic episode of vulvovaginal candidiasis were 
randomized at a 1:1:1 ratio to receive either oral ibrexafungerp 750 mg with a 1250 mg loading 
dose for three days, oral ibrexafungerp 750 mg with a 1250 mg loading dose for five days or a 
single dose of oral fluconazole. Ibrexafungerp was well tolerated, with the most common AEs 


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being mild gastrointestinal events. The high clinical cure rates observed in this study are 
supportive of the clinically relevant antifungal activity of ibrexafungerp in this form of Candida 
infection.  
In addition, a Phase 2 study to compare the safety and efficacy of oral ibrexafungerp vs. oral 
fluconazole in subjects with acute VVC (DOVE) has been completed. The primary objective of 
the study was dose selection for our Phase 3 pivotal program in VVC. This Phase 2b study was a 
randomized, multicenter, double-blind, active-controlled, dose-finding study designed to 
evaluate the safety, efficacy, tolerability and pharmacokinetics of five dosing regimens of oral 
ibrexafungerp in patients with moderate-to-severe (defined as a signs and symptoms score of 7 or 
greater) acute VVC, with oral fluconazole as a reference arm. The study enrolled a total of 186 
patients and 153 patients were included in the culture-confirmed, modified intent-to-treat 
population.  The study was not intended, nor powered, to achieve statistically significant 
differences in any of the evaluated endpoints. The total doses tested ranged from 600 mg to 1800 
mg and the dosing durations explored were 1 or 3 days. The maximum duration of treatment of 3 
days was based on a previous Phase 2a study, in which we showed that 3 days of treatment 
performed similarly to 5 days, so in the DOVE study we explored 3 days and a shorter treatment 
duration. 
The primary efficacy endpoint was clinical cure, defined as complete resolution of all signs and 
symptoms at the Day 10 (Test of Cure [TOC]) visit without the need of additional antifungal 
therapy. Secondary endpoints included mycological eradication and composite endpoints 
including both clinical cure and mycological eradication. In this Phase 2 study, response was also 
evaluated as the percentage of subjects achieving a noticeable improvement in their signs and 
symptoms by achieving a composite signs and symptoms score of 0 or 1, the absolute change in 
signs and symptoms from Baseline and the need for rescue antifungal therapy. 
All doses tested achieved meaningful clinical cure and mycological eradication rates but the dose 
that provides the best combination of attributes for this indication is the ibrexafungerp 600 mg 
dose administered as 300 mg twice a day (BID) for 1 day.  
At Day 10, the TOC visit, the ibrexafungerp 600 mg dose showed clinical and mycological 
response rates in line with the reference fluconazole arm.  Specifically, clinical cure was reported 
in 14 of 27 (52%) patients in the ibrexafungerp 600 mg dose arm and in 14 of 24 (58%) patients 
in the fluconazole arm.  The percentage of patients showing a signs and symptoms score of 0 or 
1 was also comparable, with 70% and 71% patients reporting this improvement in the 
ibrexafungerp 600 mg dose and fluconazole arms, respectively. The mycological eradication at 
this time point was 63% for both groups. 
At Day 25, the follow-up (FU) visit, the ibrexafungerp 600 mg dose showed a trend towards 
improved clinical and mycological outcomes when compared to the fluconazole arm. If patients 
continued to have signs and symptoms of VVC at the TOC visit or later, rescue antifungal 
medication could be prescribed. Seven patients treated with fluconazole received rescue 
antifungal medication, whereas one patient treated with ibrexafungerp 600 mg received rescue 
antifungal medication. The rate of patients with no signs and symptoms (score = 0) at the FU 
visit was 70% for the ibrexafungerp 600 mg dose versus 50% for the fluconazole arm. A similar 
difference was observed when performing the analysis using a signs and symptoms score of 0 or 
1, where this improvement was achieved by 81% of the subjects receiving ibrexafungerp 600 mg 


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dose versus 58% of the subjects receiving fluconazole. This demonstrates sustained symptom 
relief for at least 25 days and supports the monthly dosing proposed in this study  
The oral ibrexafungerp 600 mg dose was generally well tolerated, with self-limiting (generally 
one-day duration), mild to moderate gastrointestinal AEs being the most commonly reported. 
Nausea was reported in three (10%) subjects in the ibrexafungerp 600 mg dose arm compared to 
two (6%) subjects in the fluconazole arm. Diarrhea and loose stool were reported in five (17%) 
subjects in the ibrexafungerp 600 mg dose arm compared to one (3%) subject in the fluconazole 
arm. Abdominal pain was reported in one (3%) subject in the ibrexafungerp 600 mg dose arm 
compared to 5 (16%) subjects in the fluconazole arm. No vomiting, severe AEs or 
discontinuations due to AEs were reported in the ibrexafungerp 600 mg dose arm. 
Several drug-drug interaction studies have been conducted. Ketoconazole (a strong inhibitor of 
CYP3A) induces a significant (5-fold) increase in ibrexafungerp exposure, while diltiazem (a 
moderate inhibitor of CYP3A) induces a mild to moderate (< 3-fold) increase in ibrexafungerp 
exposure. Ibrexafungerp did not have any effect on rosiglitazone (a CYP2C8 substrate) exposure, 
had only a mild effect (less than a 0.5-fold increase) on the area under the curve of tacrolimus (a 
CYP3A and P-glycoprotein [P-gp] substrate) and had no effect on the maximum concentration 
(Cmax) of tacrolimus. 
Ibrexafungerp has the potential to be an important addition to the antifungal treatment arsenal by 
providing potent activity against the full spectrum of Candida species, including difficult-to-treat 
organisms, and by affording the added flexibility of both oral and IV formulations.  
For additional information on Ibrexafungerp (SCY-078), please refer to the Investigator’s 
Brochure (IB).  
7.2 
Rationale for the Study 
RVVC is a major unmet medical need in women and there is currently no approved drug for the 
prevention of recurrences.  This is a Phase 3 study of ibrexafungerp versus placebo being 
performed to evaluate the efficacy and safety of oral ibrexafungerp, a novel triterpenoid beta-
glucan synthase inhibitor with broad spectrum antifungal activity and demonstrated sustained 
relief in acute VVC when given once a month for the prevention of RVVC in female subjects 12 
years and older with RVVC.  
A Nested Sub-Study will be available to a subgroup of subjects who fail fluconazole therapy in 
the Acute Phase. Details of the Nested Sub-Study are provided in Section 21.3 (Appendix C). 
7.2.1 
Rationale for Study Indication and Population 
Considering the properties of ibrexafungerp as a potent antifungal compound with fungicidal 
activity against Candida spp., if ibrexafungerp is proven effective, it will represent an important 
treatment for subjects suffering from RVVC.  


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7.2.2 
Rationale for Selected Dosing Regimen 
Continued antifungal suppressive therapy is recommended for the treatment of RVVC. Previous 
studies have indicated that 6 months of continued suppressive azole therapy may be appropriate 
for the prevention of RVVC.6  
In this study, oral ibrexafungerp will be administered as a single-day treatment repeated every 4 
weeks (28 days [±3]) for a total of 6 single-day treatments. Each single-day treatment will 
consist of two doses of 300 mg each given 12 (±4) hours apart (total single-day dose = 600 mg). 
This dose level is the dose level used in the Phase 2b DOVE study in acute VVC, which was 
shown to be effective in achieving high clinical cure and mycological eradication rates. This 
dose level will be administered once every 4 weeks (28 days [±3]) for a total of 6 single-day 
treatments. The once-every-four-weeks dosing regimen was selected based on the fact that, in the 
DOVE study, the selected dose showed a sustained clinical benefit with high cure rates for up to 
25 days (last follow-up).   
7.2.3 
Rationale for Study Endpoints and Efficacy Outcomes 
In this study, recurrent VVC will be broken into three categories:  
• Mycologically Proven Recurrence: An episode of VVC with a total composite score ≥ 3 
on the VSS Scale and a culture positive for Candida spp. that required antifungal 
treatment. 
• Presumed Recurrence: An episode of VVC with a total composite score ≥ 3 on the VSS 
Scale that required antifungal treatment and for which there is a positive KOH microscopy 
but no positive fungal culture.  
• Suspected Recurrence: An episode of VVC that required treatment with an antifungal 
agent (including self-administration with over-the-counter antifungals) regardless of VSS 
composite score but for which there is no mycological evidence of disease, such as a 
positive potassium hydroxide (KOH) microscopy or fungal culture.  
The primary endpoint of the study will be the percentage of subjects with documented Clinical 
Success (defined as subjects having a TOC evaluation and no Mycologically Proven, Presumed 
or Suspected Recurrence of VVC) up to TOC (Week 24).  This criterion is meant to reflect real 
world practice, where patients may self-treat, and apply scientific rigor in assigning subjects with 
signs and symptoms of disease, regardless of culture result or missing data, as failures. 
The key secondary endpoint will be the percentage of subjects with no Mycologically Proven 
Recurrence at TOC (Week 24). The key secondary endpoint is based on recurrences that are 
symptomatic and required antifungal therapy. This criterion is aimed at reflecting the highest 
level of certainty in the diagnosis of a recurrence in a symptomatic subject seeking medical 
treatment. This endpoint is anticipated to objectively demonstrate the antifungal activity of 
ibrexafungerp. 
These endpoints are considered appropriate to identify the key clinical benefit intended with this 
preventive regimen. 


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7.2.4 
Rationale for the Study Design 
This Phase 3 trial is being conducted as a randomized, double-blind, placebo-controlled study. 
This design is deemed appropriate in consultation with regulatory agencies for this indication, 
considering that there are no approved therapies to prevent recurrences in subjects with RVVC.  
It is expected that the data generated from this study, along with supportive data from studies of 
ibrexafungerp in acute VVC, will provide substantive evidence of the safety and efficacy of the 
proposed dosing regimen of ibrexafungerp to seek regulatory approval for the prevention of 
RVVC. 
8.0 
Study Objectives 
8.1 
Primary Objective 
• To evaluate the efficacy of oral ibrexafungerp versus placebo in preventing recurrences of 
VVC in subjects with RVVC based on Clinical Success. 
8.2 
Key Secondary Objective 
• To evaluate the efficacy of oral ibrexafungerp versus placebo in preventing recurrences of 
VVC in subjects with RVVC based on Mycologically Proven Recurrences at TOC. 
8.3 
Other Secondary Objectives 
• To evaluate the efficacy of oral ibrexafungerp versus placebo in preventing recurrences 
(Mycologically Proven, Presumed or Suspected) of VVC in subjects with RVVC. 
• To evaluate the efficacy of oral ibrexafungerp versus placebo in preventing recurrences of 
VVC in subjects with RVVC based on the number of Recurrences (Mycologically Proven, 
Presumed or Suspected) of VVC. 
• To evaluate the efficacy of oral ibrexafungerp versus placebo in subjects with RVVC based 
on Quality-of-Life (QOL) outcomes. 
• To evaluate the safety and tolerability of oral ibrexafungerp in subjects with RVVC.  
9.0 
Study Endpoints 
9.1 
Primary Endpoint 
• Efficacy as measured by the percentage of subjects with documented Clinical Success 
(defined as subjects having a TOC evaluation and no Mycologically Proven, Presumed or 
Suspected Recurrence of VVC) up to TOC (Week 24). 


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9.2 
Key Secondary Endpoint 
• Efficacy as measured by the percentage of subjects with no Mycologically Proven 
Recurrence (defined as an episode of VVC with a total composite score ≥ 3 on the VSS Scale 
and a culture positive for Candida spp. that required antifungal treatment) at TOC 
(Week 24). 
9.3 
Other Secondary Endpoints 
Efficacy as measured by: 
• The percentage of subjects with no Mycologically Proven Recurrence at Week 4, Week 8, 
Week 12 and Week 36 (end of follow-up [EOFU]). 
• The time to the first Recurrence (Mycologically Proven, Presumed or Suspected) of VVC 
through EOFU. 
• The percentage of subjects with Mycological Eradication (negative fungal culture) at 
Week 12, Week 24 (TOC) and Week 36 (EOFU).  
• The percentage of subjects with no Mycologically Proven, Presumed or Suspected 
Recurrences at Week 4, Week 8, Week 12 and Week 36 (EOFU). 
• The percentage of subjects with no Mycologically Proven or Presumed Recurrences at 
Week 4, Week 8, Week 12, TOC (Week 24) and Week 36 (EOFU). 
• The proportion of subjects in three ordered categories related to the number of Recurrences 
(Mycologically Proven, Presumed or Suspected) of VVC from Baseline (Day 1) to TOC 
(Week 24) and Week 36 (EOFU). The three categories of recurrence are defined as (i) 0 to 1 
episodes, (ii) 2 to 3 episodes, and (iii) ≥ 4 episodes. 
• The absolute number of Mycologically Proven, Presumed or Suspected Recurrences from 
Baseline (Day 1) to TOC (Week 24) and Week 36 (EOFU). 
• Absolute improvement in QOL outcomes at Week 12, Week 24 (TOC) and Week 36 (EOFU) 
as measured by EQ-5D, SF-36 and FSDS).  
 
Safety and tolerability as measured by: 
• AEs, vital signs, treatment discontinuation and safety laboratory tests at TOC (Week 24). 
10.0 Study Design 
10.1 
Overall Description of the Study 
This study is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of oral ibrexafungerp (formerly “SCY-078”) compared to 
placebo in female subjects 12 years and older with RVVC. The primary objective of the study is 


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to evaluate the efficacy of oral ibrexafungerp versus placebo in preventing recurrences of VVC 
in subjects with RVVC based on Clinical Success.  
The study will consist of a Screening visit, an Acute Phase with open-label fluconazole and a 
Prevention of Recurrence Phase with randomized ibrexafungerp or placebo. Screening and the 
beginning of the Acute Phase (Day -14) may occur on the same day. Approximately 320 subjects 
are planned to be enrolled into the open-label Acute Phase of the study in order to randomize 
approximately 240 subjects into the double-blind Prevention of Recurrence Phase, which will 
consist of 6 monthly, single-day treatments with randomized study drug.  
A Nested Sub-Study will be made available to subjects who fail treatment with fluconazole  
during the Acute Phase and are not eligible for randomization into the Prevention of Recurrence 
Phase  (see Section 21.3 [Appendix C] for Sub-Study details). 
A summary of study visits is provided below. Further details of the study visits are provided in 
Section 10.1.1. 
• Screening (Days -16 to -14):  To be eligible for inclusion, subjects must have a history of 
at least three episodes of VVC in the past 12 months (including the current episode), a 
total composite score ≥ 4 on the VSS Scale, a positive potassium hydroxide (KOH) test, 
and a normal vaginal pH (≤ 4.5). Screening and the beginning of the Acute Phase 
(Day -14) may occur on the same day. 
• Acute Phase (Days -14 to -1): Eligible subjects will receive active treatment with open-
label oral fluconazole 150 mg, administered QD on Days -14, -11 and -8, for a total of 3 
doses.  
• Prevention of Recurrence Phase: The occurrence of a recurrence is the key efficacy 
parameter in this study. Subjects who have a culture-confirmed Candida spp. infection 
from the sample collected at Screening, achieve significant resolution of their 
vulvovaginal signs and symptoms (defined as a total composite score ≤ 2 on the VSS 
Scale) at Baseline (Day 1) and continue to meet all other eligibility criteria will be 
randomized into the Prevention of Recurrence Phase. Subjects who are not eligible for this 
study or the Nested Sub-Study will be discontinued. Subjects will be assessed for potential 
recurrences throughout the Study Treatment Period and the Follow-up Period.  
o Study Treatment Period (Baseline [Day 1] through Week 24 [TOC]): Subjects will 
be randomized at a 1:1 ratio to receive one of two study treatments (oral ibrexafungerp 
or placebo administered as a single-day treatment repeated every 4 weeks [28 days 
(±3)] for a total of 6 single-day treatments) in a double-blind manner. Each single-day 
treatment will consist of two doses of ibrexafungerp 300 mg each or placebo given 12 
(±4) hours apart (total single-day ibrexafungerp dose = 600 mg). Subjects will take the 
study drug on Day 1 (Baseline), Week 4, Week 8, Week 12, Week 16 and Week 20, 
regardless of recurrence or administration of antifungal medication. Subjects will be 
evaluated for potential recurrence, antifungal medication use and safety throughout 
this period. 
o Follow-up Period (Week 25 through Week 36 [EOFU]): Subjects will enter the 
Follow-up Period regardless of recurrence or rescue antifungal medication use. 
Subjects will continue to be evaluated for potential recurrence, antifungal medication 
use and safety throughout this period. 


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Efficacy and Safety 
Efficacy will be determined primarily by the percentage of subjects with documented Clinical 
Success (defined as subjects having a TOC evaluation and no Mycologically Proven, Presumed 
or Suspected recurrence of VVC) up to TOC (Week 24). The key secondary endpoint will be the 
percentage of subjects with no Mycologically Proven Recurrence (defined as an episode of VVC 
with a total composite score ≥ 3 on VSS Scale and a culture positive for Candida spp. that 
required antifungal treatment) at TOC (Week 24). Efficacy will also be assessed by other 
secondary efficacy and patient-reported outcomes (see Section 9.3). 
Safety and tolerability will be evaluated throughout the study by the following parameters: 
AEs, treatment discontinuations, vital signs and safety laboratory tests at TOC (Week 24).  
 
A summary description of the study visits and assessments is provided below. A schematic of the 
study design is available in Section 6.0. Detailed descriptions of study treatments and procedures 
are provided in Section 12.0 and Section 14.0, respectively.  
10.1.1 Study Visits 
Study visits will consist of scheduled on-site visits, phone contacts, and lab visits (Acute Phase 
only), as well as unscheduled visits. Whenever possible, on-site visits and phone contacts will be 
scheduled to occur on the date of dosing (or as close to the date of dosing as possible) to 
facilitate reminding subjects to take their study doses. This is applicable for the Baseline (Day 1), 
Week 4, Week 8, Week 12, Week 16 (phone contact), and Week 20 (phone contact) visits.  
If a subject is actively menstruating at an on-site study visit that requires a vaginal exam, the visit 
should be rescheduled as soon as the subject’s period ends but in no case more than 7 days after 
the initially scheduled visit. 
Phone contacts will be conducted to check for AEs, treatment compliance, potential recurrence, 
and concomitant medication use, including other antifungal agents. Unscheduled visits will be 
conducted anytime that there are symptoms indicating a potential recurrence or an AE. 
Subjects will be instructed to visit the study center for a proper evaluation of any potential 
recurrence before initiating any VVC treatment. Subjects participating in the study will be 
strongly discouraged from self-administering any treatment for a potential recurrence. 
An electronic dosing reminder system (e.g. text message) may be implemented for consenting 
subjects to facilitate study drug dosing compliance.  
10.1.1.1 
Screening (Days -16 to -14) 
At Screening, subjects who are experiencing vulvovaginal symptoms will be evaluated by the 
investigator, who will obtain a vulvovaginal sample for local KOH testing and vaginal pH 
determination prior to initiation of open-label fluconazole treatment. The vaginal samples will 
also be tested for fungal culture, species identification and susceptibility testing by the central 
laboratory, as well as to rule out other potential pathogens. The investigators and the subjects 
will rate the signs and symptoms of infection, respectively, on a standardized VSS Scale. Safety 


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procedures, including an abbreviated physical exam, vital signs, and a urine pregnancy test will 
also be performed.  
To be eligible for inclusion, subjects must have a history of at least three episodes of VVC in the 
past 12 months (including the current episode), a total composite score ≥ 4 on the VSS Scale, a 
positive KOH test, and a normal vaginal pH (≤ 4.5). Eligible subjects will move on to Day -14 to 
enter the Acute Phase of the study. The Screening and Day -14 visits may occur on the same day. 
10.1.1.2 
Acute Phase (Days -14 to -1) 
During the Acute Phase, study visits will be scheduled on Day -14 (which may be combined with 
the Screening visit), Day -11 and Day -8 (phone contacts). Eligible subjects will receive active 
treatment with oral fluconazole 150 mg QD on Days -14, -11 and -8.  
Fluconazole will be administered in an open-label fashion. Subjects will take their first dose of 
fluconazole at the site and self-administer the remaining doses at home. Subjects will be 
dispensed fluconazole supplies and subject diaries where they will rate their vulvovaginal 
symptoms and record dosing details, AEs and concomitant medication use.  
Safety procedures (abbreviated physical exam, vital signs, AE collection) will be conducted. On 
Days -4 to -2 subjects will have a laboratory visit, where safety labs will be collected to be 
reviewed on Day 1 (Baseline) to verify eligibility, prior to randomization.  
10.1.1.3 
Prevention of Recurrence Phase (Day 1 [Baseline] through Week 36 
[EOFU]) 
10.1.1.3.1 
Study Treatment Period (Day 1 [Baseline] through Week 24 [TOC])  
Baseline (Day 1) 
On Day 1, subjects will return their open-label fluconazole supplies. Treatment compliance will 
be evaluated, and subject diaries will be collected and reviewed. Vulvovaginal samples will be 
collected for fungal culture and pH. The investigator and the subject will rate the signs and 
symptoms of infection, respectively, on the VSS Scale. The subject’s QOL questionnaires will be 
administered. The results of the vaginal culture collected at Screening will be reviewed. 
Subjects with a culture-confirmed Candida spp. infection from the sample collected at Screening 
who achieve a significant resolution of their vulvovaginal signs and symptoms (total composite 
score ≤ 2 on the VSS Scale) and continue to meet all study eligibility criteria at Baseline (Day 1) 
will continue to the Prevention of Recurrence Phase, where they will be randomized at a 1:1 ratio 
to receive one of the following two study treatments in a double-blind manner: 
• Oral ibrexafungerp administered as a single-day treatment repeated every 4 weeks (28 
days [±3]) for a total of 6 single-day treatments (Baseline [Day 1], Week 4, Week 8, Week 
12, Week 16 and Week 20). Each single-day treatment will consist of two doses of 300 
mg each given 12 (±4) hours apart (total single-day dose = 600 mg).  
• Matching oral placebo administered as a single-day treatment repeated every 4 weeks (28 
days [±3]) for a total of 6 single-day treatments (Baseline [Day 1], Week 4, Week 8, Week 


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12, Week 16 and Week 20). Each single-day treatment will consist of two doses of 
placebo given 12 (±4) hours apart.  
Subjects will receive their first dose of study drug at the site and will be dispensed double-blind 
study drug and subject diaries, where they will rate their vulvovaginal symptoms on a weekly 
basis and at the time of each visit to the site, and will record dosing details, AEs and concomitant 
medication use during the study. Safety procedures (abbreviated physical exam, vital signs, AE 
collection and urine pregnancy test) will be conducted. 
Subjects who do not have a culture-confirmed Candida spp. infection at Screening, do not 
achieve a significant resolution of their signs and symptoms at Baseline (Day 1) and/or do not 
continue to meet all eligibility criteria will be discontinued from the study.  
A Nested Sub-Study will be made available to subjects who fail treatment with fluconazole 
during the Acute Phase and are not eligible for randomization into the Prevention of Recurrence 
Phase  (see Section 21.3, Appendix C for details about the Sub-Study). 
Day 2 through Week 23 
On-site study visits will be scheduled at Weeks 4, 8, and 12 and phone contacts will be 
conducted on Weeks 16 and 20 to check for potential recurrence, treatment compliance and 
antifungal medication use. During this period, subjects will self-administer their double-blind 
study drug at home. Study drug will be taken as a single-day treatment repeated every 4 weeks 
(28 days [±3]) for a total of 6 single-day treatments (i.e., at Week 4, Week 8, Week 12, Week 16 
and Week 20), regardless of recurrence or administration of antifungal medication, preferably 
with or immediately after a meal. 
Subjects will be assessed for potential recurrence at all visits during the Study Treatment Period 
following Baseline (Day 1), including phone contacts, scheduled visits and unscheduled visits. 
Anytime that there is suspicion of a recurrence (Mycologically Proven, Presumed or Suspected), 
all procedures for the assessment of the recurrence must be completed (see Section 10.1.1.3.3 for 
an overview and Section 14.18 for detailed procedures). Subjects participating in the study 
will be strongly discouraged from self-administering any treatment for a potential 
recurrence. Subjects will be instructed to visit the study center for a proper evaluation of their 
recurrence before initiating any VVC treatment. 
At Week 12, an abbreviated physical exam will be performed, blood samples will be drawn for 
safety laboratory tests and vulvovaginal samples will be collected for fungal culture and 
susceptibility testing  by the central laboratory. The investigator and the subject will rate the 
signs and symptoms of infection, respectively, on the VSS Scale. Subjects will complete their 
QOL questionnaires. Subjects will return their empty bottles of study drug and new bottle 
supplies will be provided. Subject diaries will be collected, reviewed and dispensed. 
Subjects will continue rating their vulvovaginal symptoms on a weekly basis and at the time of 
each scheduled or unscheduled visit to the site on their subject diaries and recording dosing 
details, AEs and concomitant medication use. AEs, concomitant medication use, treatment 
compliance and potential recurrence will be assessed at each study visit, including phone 
contacts. Subject diaries will be reviewed and vital signs will be determined at all on-site visits.   
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At Week 24 (TOC), subjects will return any remaining medication as well as empty bottles of the 
study drug and treatment compliance will be evaluated. Subjects will return their diaries and 
diaries will be reviewed. Safety procedures (abbreviated physical exam, vital signs, AEs, and 
concomitant medication use) will be performed.  
Vaginal samples will be obtained for fungal culture and for antifungal susceptibility testing by 
the central laboratory. Subjects will complete their QOL questionnaires.  
The investigator and the subject will rate the signs and symptoms of infection, respectively, on 
the VSS Scale and potential recurrence will be assessed (see Section 10.1.1.3.3). Subjects will 
continue to the FU Period regardless of recurrence or antifungal medication use. 
10.1.1.3.2 
Follow-up Period 
During the FU Period, an on-site study visit will be scheduled at Week 36 (EOFU) and phone 
contacts will be conducted at Weeks 28 and 32 to check for potential recurrence and antifungal 
medication use. Subjects will continue to rate their vulvovaginal symptoms on a weekly basis 
and at the time of each scheduled or unscheduled visit to the site and will continue to record use 
of any antifungal medication on their subject diaries.  
Subjects will be assessed for potential recurrence at all visits during the Follow-up Period, 
including phone contacts, scheduled visits and unscheduled visits. Anytime that there is 
suspicion of a recurrence, all procedures for the assessment of the recurrence must be completed 
(see Section 10.1.1.3.3 for an overview and Section 14.18 for detailed procedures). Subjects 
participating in the study will be strongly discouraged from self-administering any 
treatment for a potential recurrence. Subjects will be instructed to visit the study center for a 
proper evaluation of their recurrence before initiating any VVC treatment. 
At the EOFU (Week 36) visit, vaginal samples will be obtained for fungal culture and for 
antifungal susceptibility testing by the central laboratory. Subjects will complete their QOL 
questionnaires and subject diaries will be reviewed and collected. Safety procedures (vital signs, 
AEs, and concomitant medication use) will be performed. Blood samples will be drawn if needed 
to follow up on a laboratory abnormality.  
Subjects will continue to complete all FU visits regardless of recurrence or antifungal medication 
use.  
10.1.1.3.3 
Recurrence During the Prevention of Recurrence Phase 
The occurrence of a recurrence is the key efficacy parameter in this study. Randomized subjects 
will be assessed for potential recurrence at all visits during the Prevention of Recurrence Phase 
following Day 1 (Baseline) (i.e., from Day 2 through Week 36 [EOFU]), including phone 
contacts, scheduled visits and unscheduled visits, as well as in between visits. If during a phone 
contact or at any other time there is suspicion of a potential recurrence (any kind of recurrence, 
i.e., Mycologically Proven, Presumed or Suspected), subjects will be instructed to visit the study 
center for a proper evaluation of their recurrence before initiating any VVC treatment. 
Potential recurrences will be assessed based on clinical and mycological outcomes and need for 
other antifungal treatment. If a subject has symptoms suggestive of Candida infection (itching, 
burning, irritation) that in the opinion of the investigator may require antifungal therapy, the 
following procedures must be completed: 


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• Rate and document symptoms in the electronic case report form (eCRF), 
• Perform vaginal examination to rate signs and document in the eCRF,  
• Measure vaginal pH at the site and document results in the eCRF, 
• Collect vaginal sample for KOH testing and investigation of potential bacterial vaginosis 
and Trichomonas vaginalis infection at the site or by the local laboratory, and  
• Collect vaginal samples for fungal culture by the central laboratory.  
All of the procedures above should be completed prior to administration of rescue antifungal 
medication. Subjects participating in the study should be strongly discouraged from self-
administering any treatment for a potential recurrence. Ideally, if the severity of the symptoms 
allows based on the investigator’s judgment, the initiation of antifungal therapy should be 
delayed until results from the vaginal culture are available to confirm that the episode is due to 
Candida spp. and not to other cause of vaginitis.   
See Section 14.18 for a detailed description of procedures to be completed for potential 
recurrences. 
In this study, Recurrences of VVC will be broken into three categories: 
• Mycologically Proven Recurrence: An episode of VVC with a total composite score ≥ 3 
on the VSS Scale and a culture positive for Candida spp. that required antifungal 
treatment. 
• Presumed Recurrence: An episode of VVC with a total composite score ≥ 3 on the VSS 
Scale that required antifungal treatment and for which there is a positive KOH microscopy 
but no positive fungal culture.  
• Suspected Recurrence: An episode of VVC that required treatment with an antifungal 
agent (including self-administration with over-the-counter antifungals) regardless of VSS 
composite score but for which there is no mycological evidence of disease, such as a 
positive KOH microscopy or fungal culture.  
Subjects with a Mycologically Proven Recurrence should receive antifungal therapy.  
If a subject experiences one or more recurrences during the Study Treatment Period Phase (i.e., 
either a Mycologically Proven Recurrence, a Presumed Recurrence or a Suspected Recurrence), 
she will continue her scheduled study drug administration and will complete all scheduled visits 
until reaching EOFU. 
All antifungal therapy administered during the study should be documented in the electronic data 
capture (EDC) system, with the reason for use clearly indicated (i.e., Mycologically Proven 
Recurrence, Presumed Recurrence, Suspected Recurrence). 
10.1.2 Study Assessments 
The study will include efficacy, safety and tolerability assessments. 
Efficacy Assessments 
Efficacy assessments will be based on clinical evaluations, mycological testing and QOL. The 
primary efficacy endpoint of the study is the percentage of subjects with documented Clinical 
Success (defined as subjects having a TOC evaluation and no Mycologically Proven, Presumed 


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or Suspected Recurrence of VVC) up to TOC (Week 24).  The key secondary efficacy endpoint 
is the percentage of subjects with no Mycologically Proven Recurrence (defined as an episode of 
VVC with a total composite score ≥ 3 on the VSS Scale and a culture positive for Candida spp. 
that required antifungal treatment) at TOC (Week 24). Efficacy will also be assessed by other 
secondary efficacy and patient-reported outcomes (see Section 9.3). 
Clinical Evaluations 
The signs (edema, erythema and excoriation or fissures) and symptoms (itching, burning and 
irritation) of infection will be assessed by the investigator and the subject, respectively, on the 
VSS Scale (provided in Appendix B). The VSS Scale is a standardized, predefined scale where 
each sign and symptom will be given a numerical rating based on severity (absent = 0; mild = 1; 
moderate = 2; severe = 3) to calculate a total composite VSS score. The symptoms of infection 
will be rated by the subject on a weekly basis and at the time of each scheduled or unscheduled 
visit to the site throughout the Prevention of Recurrence Phase. Vaginal examinations will be 
conducted by the investigator to rate the subject’s signs of infection at protocol-specified visits 
and anytime that there is suspicion of a potential recurrence. 
Mycological Testing 
Mycological tests will include direct wet mount microscopic examination to visualize clue cells 
indicative of bacterial vaginosis or trichomonas, direct microscopic examination with 10% KOH 
to identify yeast, and fungal cultures. The direct wet mount and KOH examination will be 
performed locally at Screening for the determination of subject eligibility and then anytime that a 
recurrence is suspected. If the investigator suspects Herpes virus, Neisseria gonorrhoeae or 
Chlamydia trachomatis infection, a vaginal sample will be collected and sent to a designated central 
laboratory. Fungal cultures will be performed centrally at Screening and at protocol-specified 
time points for species identification and susceptibility testing. Fungal cultures will also be done 
anytime that a recurrence is suspected during the Prevention of Recurrence Phase and for 
antifungal susceptibility testing for subjects with positive cultures.  
Quality of Life 
QOL will be assessed by EQ-5D, SF-36 and FSDS at protocol-specified time points to assess 
improvement in QOL outcomes. 
Safety Assessments  
Safety procedures will include collection of AEs, treatment discontinuations, abbreviated 
physical examination, vital signs, safety laboratory tests and prior and concomitant medications. 
10.2 
Blinding, Randomization and Stratification 
This is a randomized, double-blind study. All site and sponsor personnel will be blinded to 
treatment assignment. 
Approximately 320 subjects are planned to be enrolled into the open-label Acute Phase of the 
study in order to randomize approximately 240 subjects at a 1:1 ratio to one of the two study 
treatment groups. All randomization of subjects will be managed electronically through an 
interactive voice response system (IWRS). 


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Subjects will be stratified at randomization based on the presence or absence of uncontrolled 
diabetes mellitus, defined as A1C levels ≥ 8.00% at Baseline (Uncontrolled diabetes mellitus: 
YES or NO), and by geographical region (USA or Ex-USA).  
10.3 
Study Duration 
Each subject is expected to complete the study within approximately 38 weeks. 
10.4 
Number of Centers 
Approximately 50 study centers are expected to participate in the study.  
11.0 Study Population 
The study population will include female subjects 12 years and older with RVVC. 
11.1 
Inclusion Criteria 
Subjects must fulfill all the following criteria at Screening and/or Baseline to be eligible for 
study admission: 
1. Subject is a postmenarchal female subject 12 years and older at Screening and is in good 
general health based on medical history, physical examination, vital sign measurements and 
safety laboratory tests performed at the Screening visit and prior to administration of the 
initial dose of study drug. 
2. Subject has a diagnosis of symptomatic VVC that meets the following criteria at Screening:  
a. A total composite score of ≥ 4 on the VSS Scale  
b. Positive microscopic examination with 10% KOH in a vaginal sample collected at 
Screening revealing yeast forms (hyphae/pseudohyphae) or budding yeasts 
c. Normal vaginal pH (≤ 4.5) 
d. A minimum of three episodes of VVC in the past 12 months, including the current 
episode, that required administration of antifungal medication. Besides the current 
episode, at least one of the previous episodes in the past 12 months is required to have 
been a physician-diagnosed episode of VVC, with at least one positive test confirming 
vaginal yeast infection (e.g., KOH, culture or fungal polymerase chain reaction)  
3. Subject meets the following criteria at Baseline (Day 1): 
a. Significant resolution of signs and symptoms of Candida infection (total composite score 
≤ 2 on the VSS Scale) 
b. Culture positive for Candida spp. in a vaginal sample collected at Screening 
c. Normal vaginal pH (≤ 4.5) 
4. Subject is able to take oral tablets and capsules. 


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5. Subject is not pregnant or lactating and is highly unlikely to become pregnant since she 
meets at least one of the following criteria:  
a. Subject is a female subject who is not of reproductive potential and is eligible without 
requiring the use of contraception. A female subject who is not of reproductive potential 
is defined as one who: (1) has reached natural menopause (defined as 6 months of 
spontaneous amenorrhea with serum follicle-stimulating hormone levels in the 
postmenopausal range as determined by the local laboratory, or 12 months of 
spontaneous amenorrhea); (2) has undergone bilateral oophorectomy and/or hysterectomy 
or (3) is 3 months post bilateral tubal ligation. Spontaneous amenorrhea does not include 
cases for which there is an underlying disease that causes amenorrhea (e.g. anorexia 
nervosa). 
b. Subject is a female subject who is of reproductive potential and is using an effective 
contraceptive method including intrauterine device, systemic hormonal contraceptives 
(i.e., implant, oral, injectable or patch) for at least 30 days before Baseline and agrees to 
continue using the contraceptive method through at least 10 days after the completion of 
study therapy. Subjects who are taking hormonal contraceptives must use a non-hormonal 
barrier method of contraception until 10 days after the last dose of study drug. Vasectomy 
in the male partner is also an acceptable contraceptive method as long as performed at 
least 3 months prior to Baseline. 
c. Subject is a female subject who is of reproductive potential and agrees to remain 
abstinent or use (or have her partner use) an acceptable barrier contraceptive method 
from the time of consent through 10 days after the completion of study therapy.  
Acceptable barrier methods of contraception for this study are: male condom, female 
condom and diaphragm. 
Note: Subjects must refrain from using any topical vaginal contraceptives such as 
spermicides or intra-vaginal hormonal contraceptive devices such as vaginal rings as 
these may interfere with the efficacy evaluations. 
Note: Women of childbearing potential must have a negative urine pregnancy test 
(sensitivity ≥25 mIU/human chorionic gonadotropin [hCG]) prior to enrollment at 
Screening and at Baseline (performed by the site’s local laboratory). 
6. Subject and/or parent/legal representative is able to understand and sign a written informed 
consent form (ICF), which must be obtained prior to treatment and any study-related 
procedures. For subjects under the legal age of consent, the subject’s parent or legal 
representative must also be willing and able to sign the subject’s ICF. 
7. Subject and/or parent/legal representative is able to understand and sign a consent or 
authorization form, which shall permit the use, disclosure and transfer of the subject’s 
personal health information (e.g., in the United States Health Information Portability and 
Accountability Act Authorization form).  
8. Subject and/or parent/legal representative is able to understand and follow all study-related 
procedures including study drug administration. 


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11.2 
Exclusion Criteria 
A subject will be excluded from participation in the study if she meets any of the following 
exclusion criteria:  
1. Subject has any vaginal condition other than RVVC that may interfere with the diagnosis or 
evaluation of response to therapy, such as suspected or confirmed concurrent causes of 
vulvovaginitis and/or cervicitis including bacterial vaginosis, Trichomonas, Herpes virus, 
Neisseria gonorrhoeae, Chlamydia, symptomatic human papillomavirus infection or other 
mixed infections. 
2. Subject received systemic and/or topical vaginal antifungal treatment, including prescription 
or over-the-counter products, within 28 days prior to the Day -14 visit. 
3. Subject is receiving or anticipates to require treatment with the prohibited medications 
(including prescription and over-the-counter medications, supplements, and herbal products) 
listed in Section 21.0 (Appendix A), during the following timeframes: 
a. 
Systemic and topical vaginal antifungal treatment other than study drug and rescue 
medication (if needed), as specified in the protocol, anytime during the study. 
b. 
Select CYP3A4/5 inducers during the 14 days prior to enrollment and during study 
treatment. 
c. 
Select strong CYP3A4/5 inhibitors during 48 hours prior to enrollment and during 
study treatment. 
d. 
Select P-gp substrates during the 48 hours prior to enrollment or during study treatment 
with ibrexafungerp. 
e. 
Topical vaginal corticosteroids from 7 days prior to the Screening visit to the Week 24 
(TOC) visit. 
4. Subject has active menstruation at the Screening visit. Note: The Screening visit may be 
rescheduled if required. 
5. Subject has a history of or an active cervical/vaginal cancer. 
6. Subject has a known hypersensitivity to fluconazole or any of the components of the 
fluconazole or ibrexafungerp formulations. 
7. Subject has a known human immunodeficiency virus infection and/or is receiving 
chemotherapy, has recently received immunosuppressive or systemic corticosteroid 
therapies, or has an illness that, in the judgment of the investigator, is serious enough to 
induce an immune deficiency. 
8. Subject has had any major illness within 30 days before Screening. 
9. Subject has participated in any other investigational study within at least 30 days (or 5.5 half-
lives of the investigational product, whichever is longer) before signing the ICF.  
10. Subject has received prior treatment with the study drug in a previous trial. 
11. Subject has any other condition or laboratory abnormality evidencing a major organ system 
disease that, in the judgment 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. 


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12. Subject is an employee of SCYNEXIS, Inc., the investigator or the contract research 
organization (CRO) involved in the study, or is an immediate family member (partner, 
offspring, parent, sibling, or sibling’s offspring) of an employee involved in the study. 
13. Subject is unlikely to comply with protocol requirements. 
11.3 
Discontinuation Criteria 
A subject may be discontinued from the study or study drug for any of the following reasons: 
• Withdrawal of consent by the subject and/or subject’s legal guardian; 
• Investigator or sponsor decision that withdrawal is in the subject’s best interest; 
• Occurrence of an AE that, in the opinion of the investigator, warrants discontinuation of 
the subject from the study drug; 
• Lost to follow-up (every attempt should be made to contact the subject). 
 
A subject will be discontinued from the study for any of the following reasons: 
• Absence of culture-confirmed Candida spp. infection from the sample collected at 
Screening as reviewed at Baseline (Day 1) 
• Failure to continue to meet all eligibility criteria at Baseline (Day 1)  
• Occurrence of pregnancy 
 
A subject will be discontinued from the study and will enter the Nested Sub-Study (see 
Section 21.3 [Appendix C]) for the following reason: 
• Positive fungal cultures at Screening with persistence of signs and symptoms of infection 
(total composite score ≥ 3 on the VSS Scale) at Baseline (Day 1), following treatment 
with open-label fluconazole 
Subjects with Recurrences (Mycologically Proven, Presumed or Suspected) of VVC will not be 
discontinued from the study but will receive rescue antifungal medication, continue their study 
drug administration (if during the Study Treatment Phase) and complete all their scheduled visits 
until reaching EOFU. 
The reason for a subject’s discontinuation of treatment or withdrawal from the study will be 
clearly documented in the source documents and on the electronic case report form (eCRF). At 
the time of discontinuation, all Week 24 (TOC) procedures should be performed for subjects 
who discontinue from the study on or before the Week 24 (TOC) visit and all Week 36 (EOFU) 
procedures should be performed for subjects who discontinue from the study after the TOC visit 
but on or before the EOFU visit.  
11.4 
Replacement of Discontinued Subjects 
Subjects who discontinue early from randomized treatment will not be replaced. 


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12.0 Study Treatments 
12.1 
Study Treatment Groups 
12.1.1 Acute Phase 
Subjects who meet all study eligibility criteria at Screening will enter the Acute Phase of the 
study and will receive oral fluconazole, as follows: 
• Oral fluconazole 150 mg QD on Days -14, -11 and -8  
The first dose of fluconazole will be administered on Day -14 at the study site, after all other 
visit procedures have been done. Subjects will self-administer the remaining doses at home. 
12.1.2 Prevention of Recurrence Phase 
Subjects who have a culture-confirmed VVC from the sample collected at Screening, achieve a 
significant resolution of the signs and symptoms of infection (total composite score ≤ 2 on the 
VSS Scale) at Baseline (Day 1) and continue to meet all study eligibility criteria will be 
randomized at a 1:1 ratio to one of the following two treatment groups:  
• Oral ibrexafungerp administered as a single-day treatment repeated every 4 weeks (28 
days [±3]) for a total of 6 single-day treatments (Baseline [Day 1], Week 4, Week 8, Week 
12, Week 16 and Week 20). Each single-day treatment will consist of two doses of 
300 mg each given 12 (±4) hours apart (total single-day dose = 600 mg) (see Table 1). 
• Matching oral placebo administered as a single-day treatment repeated every 4 weeks (28 
days [±3]) for a total of 6 single-day treatments (Baseline [Day 1], Week 4, Week 8, Week 
12, Week 16 and Week 20). Each single-day treatment will consist of two doses of 
placebo given 12 (±4) hours apart. 
 


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Table 1: 
Double-Blind Oral Ibrexafungerp Dosing Regimen  
Dosing Day  
Study Visit/Study Day 
Single-Day 
Doses 
Oral 
Tablets 
Total Daily 
Dose 
Dosing Day 1 
Week 1/ Study Day 1 (Baseline) 
300 mg AM 
300 mg PM 
2 x 150 mg 
2 x 150 mg 
600 mg 
Dosing Day 2 
Week 4/ Study Day 28 (±3) 
300 mg AM 
300 mg PM 
2 x 150 mg 
2 x 150 mg 
600 mg 
Dosing Day 3 
Week 8/ Study Day 56 (±3) 
300 mg AM 
300 mg PM 
2 x 150 mg 
2 x 150 mg 
600 mg 
Dosing Day 4 
Week 12/ Study Day 84 (±3) 
300 mg AM 
300 mg PM 
2 x 150 mg 
2 x 150 mg 
600 mg 
Dosing Day 5 
Week 16/ Study Day 112 (±3) 
300 mg AM 
300 mg PM 
2 x 150 mg 
2 x 150 mg 
600 mg 
Dosing Day 6 
Week 20/ Study Day 140 (±3) 
300 mg AM 
300 mg PM 
2 x 150 mg 
2 x 150 mg 
600 mg 
Subjects will receive their first dose of double-blind study drug at the site and will self-
administer the remaining doses at home.  Subjects must take the two doses of study drug 12 
hours apart (±4 hours), preferably with or immediately after a meal. An electronic dosing 
reminder system (e.g. text message) may be implemented for consenting subjects to facilitate 
study drug dosing compliance. 
12.2 
Dietary Requirements 
Double-blind study drug should be administered preferably with or immediately after a meal. In 
addition, it is recommended that each subject identifies and keeps their optimal routine to 
facilitate compliance (for example, administering the study drug at breakfast and at dinner on 
treatment days).  
12.3 
Study Drugs 
Study drug will consist of oral ibrexafungerp (150-mg tablets) and ibrexafungerp matching oral 
placebo tablets for the double-blind Prevention of Recurrence Phase, and oral fluconazole (150-
mg tablets or capsules) for the open-label Acute Phase. Study drug will be provided by the 
Sponsor. 
12.3.1 Ibrexafungerp (SCY-078) Description 
Study Drug Identifier: Ibrexafungerp (SCY-078) 
Empirical Formula: 
C50H75N5O11 (citrate salt) 
Molecular Weight: 
922.18 (citrate salt) 


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Physical Description: 
White to off-white solid 
Chemical Name: 
(1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[(2R)-2-amino-
2,3,3-trimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[5-(4-
pyridinyl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-
dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-
phenanthro[1,2-c]pyran-7-carboxylic acid, citrate salt] 
 
Figure 2 
Chemical Structure of Ibrexafungerp (SCY-078) Citrate 
12.3.2 Formulation, Packaging and Labelling 
Study drug will consist of fluconazole, ibrexafungerp (SCY-078) and ibrexafungerp-matching 
placebo.  
Ibrexafungerp citrate drug product for oral administration will be supplied as a tablet containing 
150 mg of ibrexafungerp active ingredient on a free-base basis. In addition to the active 
ingredient, the tablet formulation also contains silicified microcrystalline cellulose, 
crospovidone, mannitol, colloidal silicon dioxide, magnesium stearate (non-bovine) and 
butylated hydroxyanisole. 
Fluconazole drug product will be sourced commercially and will be provided as a tablet or 
capsule containing 150 mg of active ingredient.  
The placebo product matching ibrexafungerp will be supplied as an oral tablet matching the size 
and appearance of the active tablet. The tablet formulation contains silicified microcrystalline 
cellulose, crospovidone, mannitol, colloidal silicon dioxide, magnesium stearate (non-bovine) 
and butylated hydroxyanisole. 
Ibrexafungerp and matching placebo drug supplies will be packaged in bottles. Bottles will 
contain 12 oral tablets of either ibrexafungerp or matching placebo. Bottles will be supplied at 
Baseline (Day 1) and Week 12. For the purpose of blinding, the number and appearance of 
dosage units will be the same across both treatment groups. 


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Labels on the bottles containing double-blind study medication will include the following 
information and any other information required by applicable regulations:  
• Sponsor Name 
• Study Protocol Number 
• Place to write the subject number  
• Number of tablets per bottle 
• Dosing instructions 
• Storage conditions 
• Caution Statement: "Caution:  New Drug – Limited by Federal (United States) Law to 
Investigational Use Only” 
12.3.3 Storage and Stability 
The pharmacist or appropriate designee at each clinical research site will be responsible for the 
study drug. For long-term storage at the site, ibrexafungerp and matching placebo supplies 
(provided in bottles) and fluconazole supplies (provided in their original commercial packaging 
for each region [e.g., blister pack or bottle]) must be kept in a secure area (e.g., locked cabinet) 
and stored at room temperature. 
12.4 
Drug Accountability 
The investigator or designee will inventory and acknowledge receipt of all shipments of the 
study drug. An IWRS will be used to dispense study drugs to individual subjects during the 
Prevention of Recurrence Phase.  Drug accountability logs will be used to maintain accurate 
records of receipt, dispensing, administration to each subject and return of drug.  A study 
monitor will periodically check the supplies of investigational products held by the site to verify 
accountability of all study drugs. After drug accountability has been completed by the monitor, 
all unused study drug and all medication containers will be returned to the Sponsor or destroyed 
on site if the site has procedures in place for study drug destruction. 
Drug supplies will be maintained in a secure, limited-access storage area under the recommended 
storage conditions (see Section 12.3.3). 
The study drug supplied for this study is only for use in subjects properly consented and enrolled 
under this protocol. This is a double-blind study.  All site and sponsor personnel will be blinded 
to treatment assignment during the double-blind phase of the study. A study site designee (e.g. 
pharmacist, study nurse/coordinator) will: 
• Record the treatment in the appropriate drug accountability log 
• Report and document any study medication issues such as crushed or broken tablets or 
capsules  
o All product quality complaints should be reported to the Sponsor 
• Collect and count the number of fluconazole tablets/capsules remaining at the Baseline 
(Day 1) visit 


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• Collect and count the number of double-blind tablets remaining at the Week 12 and 
Week 24 (TOC) visits 
• Review subject diary and tablet/capsule count, record any unused or remaining drug in the 
drug accountability log and eCRF, and note any discrepancies and reason for 
discrepancies 
12.5 
Subject Compliance with Study Drug Dosing 
Compliance for open-label fluconazole treatment during the Acute Phase of the study will be 
reviewed at Baseline (Day 1). Treatment compliance with double-blind study drug will be 
reviewed at all study visits during the Study Treatment Period, including on-site visits and phone 
contacts.  
Subjects (or subject’s parent/legal representative, if applicable) will be instructed to have the 
assigned bottles or other containers of study medication (including empty bottles/containers) 
with them at these visits.  Compliance will be assessed based on remaining tablets/capsules as 
compared to what should have been taken and based on the subject diary where the subject will 
enter the details of study drug dosing.  Details of treatment including any missing dose will be 
recorded on the eCRF. Sites are encouraged to contact the medical monitor or Sponsor for 
concerns of compliance with the treatment regimen, especially for subjects who miss doses due 
to AEs related with tolerability.  
13.0 Non-Study Treatments 
13.1 
Prior and Concomitant Medications 
All medications (including prescription and over-the-counter medications, supplements, and 
herbal products) taken from 28 days before Screening through the Week 24 (TOC) visit will be 
recorded on the eCRF. Only the use of other antifungal medications, medications used to treat 
vaginal bacterial or parasitic infections, topical vaginal medications or medications to treat a 
study-drug related AE will be recorded after the TOC visit through the last study visit (Week 36 
[EOFU]).  Start and stop dates of concomitant medications will be recorded on the eCRF. Prior 
and concomitant medications will be reviewed and recorded at all scheduled and unscheduled 
study visits. 
Certain concomitant medications must be administered with caution or close monitoring as 
described in Appendix A Section 21.0. 
13.2 
Prohibited Medications 
Medications specifically not permitted in the inclusion and/or exclusion criteria (Section 11.1 
and Section 11.2, respectively) include the following: 
• Non-study systemic or topical vaginal antifungal therapy 
• Topical vaginal corticosteroids and topical vaginal contraceptives or intra-vaginal 
hormonal contraceptive devices 


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• Select strong CYP3A4/5 inhibitors, select CYP3A4/5 inducers and select P-gp substrates 
• Other investigational drug(s) 
See Section 21.0 (Appendix A) for the full list of prohibited medications. 
13.3 
Medications to be Administered with Caution and Monitored as 
Appropriate 
The following medications must be administered with caution and must be monitored as 
appropriate: 
• CYP3A4 substrates with a narrow therapeutic window, including but not limited to 
sirolimus, cyclosporine, tacrolimus and warfarin 
• Organic anion-transporting polypeptide 1B3 (OATP1B3) substrates 
See Section 21.0 (Appendix A) for the full list of medications to be administered with caution. 
13.4 
Study Restrictions 
There are no study restrictions other than those described in Sections 11.2 (Exclusion Criteria), 
Section 12.2 (Dietary Requirements) and Section 13.2 (Prohibited Medications). 
14.0 Study Procedures 
The following sections provide a description of the individual study procedures to be performed 
during the conduct of the study.  Detailed schedules of study assessments are provided in the 
Schedule of Visits and Procedures in Section 15.0. Study days and weeks are counted relative to 
the first dose of double-blind study drug (Baseline [Day 1]).  
Study visits will consist of scheduled on-site visits, phone contacts, and lab visits (Acute Phase 
only) and unscheduled visits. Screening will occur on Days -16 to -14. The Acute Phase will 
comprise Day -14 to Day -1 (+3). The Screening and Day -14 visits may occur on the same day.  
On-site study visits during the Prevention of Recurrence Phase (i.e., Baseline [Day 1], Week 4, 
Week 8, Week 12, Week 24 and Week 36) will have a window of ±3 days.  
Whenever possible, on-site visits and phone contacts will be scheduled to occur on the date of 
dosing (or as close to the date of dosing as possible) to facilitate reminding subjects to take their 
study doses. This is applicable for the Baseline (Day 1), Week 4, Week 8, Week 12, Week 16 
(phone contact), and Week 20 (phone contact) visits. An electronic dosing reminder system (e.g. 
text message) may be implemented for consenting subjects to facilitate study drug dosing 
compliance.  
If a subject is actively menstruating at an on-site study visit that requires a vaginal exam, the visit 
should be rescheduled as soon as the subject’s period ends but in no case more than 7 days after 
the initially scheduled visit. 
Phone contacts will be conducted to check for AEs, treatment compliance, potential recurrence, 
and concomitant medication use, including other antifungal agents. Unscheduled visits will be 


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conducted anytime that there are symptoms indicating a potential recurrence or an AE. If during 
a phone contact or at any other time there is suspicion of a potential recurrence (any kind of 
recurrence, i.e., Mycologically Proven, Presumed or Suspected), subjects will be strongly 
discouraged from self-administering any treatment and will be instructed to visit the study center 
for a proper evaluation of their recurrence before initiating any VVC treatment. 
14.1 
Informed Consent 
Every study subject must provide written informed consent at Screening, prior to participating in 
any Screening evaluations or any other study activities (see Section 19.3). For subjects under the 
legal age of consent, the subject’s parent or legal representative will also sign the subject’s ICF. 
Additional local regulatory requirements may be applicable for participation of subjects under 
the age of consent. At Screening, subjects will provide consent for participation in both this 
study and the Nested Sub-Study, and will enter either study based on the criteria met at Baseline. 
14.2 
Assignment of Subject Number 
At Screening, all subjects who have signed an ICF will receive a unique subject identification 
(ID) number. The subject numbers assigned to eligible subjects will be recorded in the eCRF.  
This number will be unique to each subject and will be used to identify the subject throughout 
the study. This number is different from the treatment bottle number. 
Subjects who are screen failures or who are not eligible for randomization into the Prevention of 
Recurrence Phase will be recorded as such in the eCRF. For subjects who sign an ICF (i.e., are 
assigned a subject number) but are NOT assigned a treatment assignment number because they 
do not meet all of the study eligibility criteria, the applicable Screening visit pages of the eCRF 
will be completed. The criteria that were not met for randomization will be documented in the 
eCRF.  
14.3 
Inclusion and Exclusion Criteria 
All inclusion and exclusion criteria for the study will be reviewed at Screening and at Baseline 
(Day 1) to ensure that the subject qualifies for the trial. 
14.4 
Medical History and Demographics 
During the Screening visit, a complete medical history for the prior year will be recorded for 
each subject.  The medical history will include previous and current medical diagnoses and 
major surgical procedures. Subject demographics such as age, sex, race and ethnicity will also be 
collected. 
14.5 
Abbreviated Physical Examination  
An abbreviated physical examination, including general appearance and an overall examination 
of body systems, will be conducted at Screening, Baseline (Day 1), Week 12 and Week 24 
(TOC). Abbreviated physical exams may also be conducted at unscheduled visits, if needed. 


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14.6 
Urine Pregnancy Test  
A urine pregnancy test will be performed at Screening, Baseline (Day 1) and unscheduled visits 
(if needed) by the local laboratory for all subjects of childbearing potential. The urine test will 
have a sensitivity to detect hCG levels of at least the 25 mIU/hCG threshold. Subjects must have 
a negative pregnancy test at Screening and Baseline (Day 1) before starting the study drug.  
14.7 
Vulvovaginal Samples 
The following vulvovaginal samples will be collected during the study: 
• Sample for direct microscopic examination with 10% KOH: to be collected at the 
Screening visit and any time that a subject experiences a potential recurrence (including 
both scheduled and unscheduled visits). The sample will be assessed by a local laboratory 
or at the site by the investigator or a qualified designee. The direct microscopic 
examination with KOH is intended for the visualization of yeasts.  
• Sample for fungal culture: to be collected at Screening, Baseline (Day 1), Week 12, 
Week 24 (TOC), Week 36 (EOFU) and any time that a subject experiences a potential 
recurrence (including both scheduled and unscheduled visits). The sample will be 
processed by a central laboratory for species identification. Positive cultures will also be 
tested for susceptibility against ibrexafungerp, fluconazole and additional antifungal 
agents, as deemed appropriate based on validated methods.  
• Sample for vaginal pH: to be collected at Screening, Baseline (Day 1) and any time that 
a subject experiences a potential recurrence. The sample will be assessed at the site by the 
investigator or a qualified designee. 
• Sample for identification of other pathogens: 
o Samples (e.g. wet mount) to rule out bacterial vaginosis and Trichomonas vaginalis 
will be collected at the Screening visit and any time that a subject experiences a 
potential recurrence (including both scheduled and unscheduled visits). Samples will 
be assessed by a local laboratory or at the site by the investigator or a qualified 
designee. 
o Samples to rule out Neisseria Gonorrhoeae, Chlamydia trachomatis or Herpes virus to 
be collected at the Screening visit and any time that a subject experiences a potential 
recurrence (including both scheduled and unscheduled visits) if any of these pathogens 
is suspected. Samples will be processed by a central laboratory.  
If during a phone contact or at any other time there is suspicion of a potential recurrence (any 
kind of recurrence, i.e., Mycologically Proven, Presumed or Suspected), subjects will be strongly 
discouraged from self-administering any treatment and will be instructed to visit the study center 
immediately for collection of vulvovaginal samples before initiating any VVC treatment. 
Procedures for collecting and processing local samples, as well as for shipping central laboratory 
vulvovaginal samples, will be described in the laboratory manual. 


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14.8 
Vulvovaginal Examination and Rating of Signs by the Investigator 
Using the VSS Scale 
The investigator (or qualified designee) will perform vulvovaginal examinations to rate the 
subject’s signs of infection at Screening, Baseline (Day 1), Week 12 and Week 24 (TOC). The 
signs of infection will also be rated at Week 4, Week 8 and Week 36 (EOFU) if symptoms are 
present and any time there is suspicion of a potential recurrence. A vulvovaginal examination 
should be scheduled immediately if there is suspicion of a potential recurrence based on a phone 
contact discussion or at any other time (see Section 14.18). The investigator should ensure that 
subjects rate their symptoms of infection at the site every time that the investigator performs a 
vulvovaginal examination for the rating of signs. 
Investigators will assess the signs of infection using the VSS Scale provided in Section 21.0 
[Appendix B]), a standardized, predefined scale where each sign of the vagina and/or vulva will 
be given a numerical rating based on severity, as follows: 
• Edema: absent = 0; mild = 1; moderate = 2; severe = 3 
• Erythema: absent = 0; mild = 1; moderate = 2; severe = 3 
• Excoriation or fissures: absent = 0; mild = 1; moderate = 2; severe = 3 
Other findings will be recorded using the most relevant medical term in the abbreviated physical 
examination page of the eCRF. 
If a subject is actively menstruating at the time of an on-site study visit that requires a 
vulvovaginal exam, the visit should be rescheduled as soon as the subject’s period ends but in no 
case more than 7 days after the initially scheduled visit. 
14.9 
Rating of Vulvovaginal Symptoms by the Subject Using the VSS Scale 
Subjects will be asked to rate their vulvovaginal symptoms at Screening, from Day -14 through 
Day -1 of the Acute Phase, and then from Day 1 (Baseline) through Week 36 (EOFU) of the 
Prevention of Recurrence Phase. Subjects will also assess their symptoms at unscheduled visits, 
if applicable.  
Subjects will rate their symptoms of infection using the VSS Scale (see Appendix B), where each 
vulvovaginal symptom will be given a numerical rating based on severity, as follows: 
• Itching: absent = 0; mild = 1; moderate = 2; severe = 3 
• Burning: absent = 0; mild = 1; moderate = 2; severe = 3 
• Irritation: absent = 0; mild = 1; moderate = 2; severe = 3 
From Baseline (Day 1) through the Week 36 (EOFU) visit, subjects will rate their symptoms and 
record their scores on the VSS Scale included in their subject diaries. Symptoms of infection will 
be rated on a weekly basis and at the time of each scheduled or unscheduled visit to the site.  
14.10 Dispensing and Dosing of Open-Label Fluconazole  
On Day -14, eligible subjects (or subjects’ legal representatives, if applicable) will be dispensed 
commercially sourced open-label fluconazole (see Section 12.3.2). All eligible subjects who 


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enter the Acute Phase of the study will receive oral fluconazole 150 mg QD on Days -14, -11 
and -8 (Section 12.1.1). The first dose of fluconazole will be administered at the site on Day -14, 
after all other visit procedures have been done. The remaining doses will be self-administered by 
the subjects at home. An electronic dosing reminder system (e.g. text message) may be 
implemented for consenting subjects to facilitate study drug dosing compliance.  
14.11 Dispensing, Completion, Review and Collection of Subject Diaries 
All subjects will receive subject diaries that they will complete once a week from Day -14 to 
Day -1 of the Acute Phase and from Day 1 (Baseline) through Week 36 (EOFU) of the 
Prevention of Recurrence Phase of the study.  
Diaries will be dispensed to all subjects on Day -14. At the Baseline (Day 1) visit of the study: 
• Subjects who do not meet criteria to enter the Prevention of Recurrence phase of the study 
or to enter the Nested Sub-Study will be discontinued from the study and will have their 
diaries collected at that visit.  
• Subjects who do not meet all criteria to enter the Prevention of Recurrence phase of the 
study but meet eligibility for the Nested Sub-Study will have their diaries e collected for 
review and redispensed at the Sub-Study Baseline visit (see Sub-Study details in Section 
21.3 [Appendix C]). 
• Subjects who are eligible to enter the Prevention of Recurrence Phase of the study will 
have their diaries collected and dispensed every three 4-week period, i.e., at Baseline 
(Day 1), Week 12, Week 24 (TOC), Week 36 (EOFU, diary collection only). 
Subject diaries will be reviewed at all on-site visits (Baseline [Day 1], Week 4, Week 8, 
Week 12, Week 24 [TOC], Week 36 [EOFU]) and unscheduled visits.  
The subject diaries will include the Vulvovaginal Signs and Symptoms (VSS) Scale so that 
subjects can rate their vulvovaginal symptoms (see Section 14.9 for symptom rating procedures 
and Section 21.2 [Appendix B] for the full VSS Scale). Subjects will record the date of study 
medication dosing, vulvovaginal symptoms rated on a weekly basis and at the time of each 
scheduled or unscheduled visit to the site, other medical concerns or complaints and concomitant 
medications used.  
The site will determine if any signs/symptoms or other medical concerns/complaints recorded on 
the diary should be reported as AEs. The information from the subject diary will be reviewed by 
the site and relevant findings will be included in the corresponding eCRFs modules (e.g. 
concomitant medications, AEs, etc.). 
14.12  Sample Collection for Safety Laboratory Tests  
Safety laboratory tests will be performed by a qualified central laboratory. Blood samples for 
safety laboratory tests will be collected at the Days -4 to -2 visit (Acute Phase, lab visit only) to 
determine subject eligibility. Lab results will be reviewed at Baseline (Day 1). Additional 
samples will be collected at Week 12 and at unscheduled visits, if needed. If indicated, these may 
be done at Week 36 to follow up on a laboratory abnormality. 


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The following laboratory parameters will be determined: 
Hematology 
 White blood cell (WBC) count  
 Hemoglobin 
 Red blood cell (RBC) count  
 Hematocrit 
 Platelet count 
 
 Differential WBC count will include percentages for lymphocytes, monocytes, 
eosinophils and basophils, and absolute counts for neutrophils, lymphocytes, atypical 
lymphocytes, monocytes, eosinophils and basophils. 
Blood Chemistry 
 Glucose 
 Hemoglobin A1C (glycosylated 
hemoglobin) 
 Total creatine phosphokinase (CPK) 
 Albumin 
 Aspartate aminotransferase (AST/SGOT) 
 Sodium 
 Alanine aminotransferase (ALT/SGPT) 
 Potassium 
 Gamma glutamyl transferase (GGT) 
 Alkaline Phosphatase 
 Bilirubin (total, direct and indirect) 
 Creatinine 
 Blood Urea Nitrogen (BUN) 
 Total protein  
14.13 Collection of Open-Label Fluconazole Supplies and Evaluation of 
Treatment Compliance 
Treatment compliance with open-label fluconazole dosing during the Acute Phase will be 
reviewed by the investigator or designee at Baseline (Day 1).  Subjects will be instructed to bring 
all fluconazole supplies (including empty bottles/containers) with them to assess medication 
compliance. Further details are available in Section 12.5. 
14.14 Assessment of Clinical Outcome following Fluconazole Treatment 
At the Baseline (Day 1) visit of the study, the investigator will assess the subject’s signs and 
symptoms of infection based on the VSS Scale ratings to determine if the subject achieved a 
significant resolution of all signs and symptoms of infection (total composite score ≤ 2 on the 
VSS Scale) and may enter the Prevention of Recurrence Phase or if the subject did not achieve a 
significant resolution of her signs and symptoms of infection but meets other criteria to enter the 
open-label, ibrexafungerp, Nested Sub-Study (see Section 21.3 [Appendix C] for details 
regarding the Sub-Study). Subjects who do not meet criteria for this study or the Sub-Study will 
be discontinued. 


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14.15 Randomization  
At Baseline (Day 1), subjects with a culture-confirmed Candida spp. infection from a sample 
collected at Screening who achieve a significant resolution of their signs and symptoms and 
continue to meet all study eligibility criteria will continue to the Prevention of Recurrence Phase, 
where they will be randomized at a 1:1 ratio to one of the two study treatment groups. Subjects 
will be stratified at randomization based on the presence or absence of uncontrolled diabetes 
mellitus, defined as A1C levels ≥ 8.00% at Baseline (Uncontrolled diabetes mellitus: YES or 
NO), and by geographical region (USA or Ex-USA). 
Subject randomization will be performed using an IWRS, which will assign a unique 
randomization number for each randomized subject corresponding to a study treatment. Only one 
randomization number and study drug treatment will be assigned to each eligible subject. 
14.16 Dispensing and Dosing of Blinded Study Drug  
At Baseline (Day 1), eligible subjects will be dispensed bottles containing double-blind study 
medication supplies for 12 weeks (see Section 12.3.2). At Week 12, subjects will return all their 
bottles of study drug (see Section 14.19) and will be dispensed new supplies for an additional 
12-week period.  
Study drug will be taken as a single-day treatment repeated every 4 weeks (28 days [±3]) for a 
total of 6 single-day treatments (Baseline [Day 1], Week 4, Week 8, Week 12, Week 16 and 
Week 20). The first dose of double-blind study drug will be administered at the study site 
(Baseline [Day 1]) and the remaining doses will be self-administered by the subjects at home, 
preferably with or immediately after a meal. 
Whenever possible, on-site visits and phone contacts will be scheduled to occur on the date of 
dosing to facilitate reminding subjects to take their study drug dose. It is recommended that each 
subject identifies and keeps their optimal routine to facilitate compliance (for example, 
administering the study drug after breakfast and after dinner on dosing days). An electronic 
dosing reminder system (e.g. text message) may be implemented for consenting subjects to 
facilitate study drug dosing compliance. Details of study treatment groups and dietary 
requirements for treatment administration are provided in Section 12.1.2 and Section 12.2, 
respectively. 
14.17 Assessment of Quality of Life 
QOL will be assessed at Day -14, Baseline (Day 1), Week 12, Week 24 (TOC) and Week 36 
(EOFU). Quality-of-life tools will include the Euro Quol 5 Dimensions (EQ-5D), Short Form 
Health Survey (SF-36) and Female Sexual Distress-Revised Scale (FSDS). 
14.18 Assessment of Potential Recurrence and Use of Rescue Antifungal 
Medication 
The occurrence of a recurrence is the key efficacy parameter in this study. Randomized subjects 
will be assessed for potential recurrence at all visits during the Prevention of Recurrence Phase 
following Day 1 (Baseline) (i.e., from Day 2 through Week 36 [EOFU]), including phone 


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contacts, scheduled visits and unscheduled visits, as well as in between visits. If during a phone 
contact or at any other time there is suspicion of a potential recurrence (any kind of recurrence, 
i.e., Mycologically Proven, Presumed or Suspected), subjects will be instructed to visit the study 
center for a proper evaluation of their recurrence before initiating any VVC treatment. 
14.18.1 Categories of Recurrences 
In this study, Recurrences of VVC will be broken into three categories: 
• Mycologically Proven Recurrence: An episode of VVC with a total composite score ≥ 3 
on the VSS Scale and a culture positive for Candida spp. that required antifungal 
treatment. 
• Presumed Recurrence: An episode of VVC with a total composite score ≥ 3 on the VSS 
Scale that required antifungal treatment and for which there is a positive KOH microscopy 
but no positive fungal culture.  
• Suspected Recurrence: An episode of VVC that required treatment with an antifungal 
agent (including self-administration with over-the-counter antifungals) regardless of VSS 
composite score but for which there is no mycological evidence of disease, such as a 
positive KOH microscopy or fungal culture.  
14.18.2 Procedures for Potential Recurrences 
Potential recurrences will be assessed based on clinical and mycological outcomes and need for 
other antifungal treatment. If a subject has symptoms suggestive of Candida infection (itching, 
burning, irritation) that in the opinion of the investigator may require antifungal therapy, the 
following procedures must be completed: 
• Rate and document symptoms in the eCRF (Section 14.9), 
• Perform vaginal examination to rate signs and document in the eCRF (Section 14.8), 
• Measure vaginal pH at the site and document results in the eCRF (Section 14.7), 
• Collect vaginal sample for KOH testing and investigation of potential bacterial vaginosis 
and Trichomonas vaginal infection at the site or by the local laboratory (Section 14.7),  
• Collect vaginal samples for fungal culture by the central laboratory (Section 14.7), and 
• Document any additional antifungal treatment used by the subjects (Section 14.21).  
All of the procedures above should be completed prior to administration of rescue antifungal 
medication. Subjects participating in the study should be strongly discouraged from self-
administering any treatment for a potential recurrence. Ideally, if the severity of the 
symptoms allows based on the investigator’s judgment, the initiation of antifungal therapy 
should be delayed until results from the vaginal culture are available to confirm that the episode 
is due to Candida spp. and not to other cause of vaginitis.  
 
The following steps should be followed for potential recurrences: 


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• If the vaginal culture results are positive for yeast and the subject remains symptomatic 
(VSS score ≥3), rescue antifungal therapy should be offered and the episode should be 
listed as a Mycologically Proven Recurrence. Rescue antifungal therapy should be 
documented in the eCRF. 
• If the vaginal culture results are negative for yeast, other causes of vaginitis (e.g. bacterial 
vaginitis or trichomoniasis) should be further investigated and rescue antifungal therapy 
may not be indicated.  Subjects with a diagnosis of vaginitis caused by pathogens other 
than yeast (e.g. bacterial vaginitis or trichomoniasis) may receive treatment for these 
conditions as indicated and the vaginitis episode should be listed as AE. 
• If the vaginal culture results are negative for yeast but the patient was given rescue 
antifungal therapy based on KOH results and symptoms (VSS score ≥3), the episode 
should be listed as a Presumed Recurrence. The rescue antifungal therapy administered 
should be documented in the eCRF. 
• Empiric administration of rescue antifungal therapy prior to collecting and documenting 
evidence that the vaginal symptoms are caused by Candida spp. infection is strongly 
discouraged. Subjects who receive empiric rescue antifungal therapy for a potential 
recurrence of VVC prior to documenting the Candida spp. infection should still have their 
vaginal evaluation including KOH and culture collected as soon as possible. These 
episodes should be listed as Suspected Recurrences. 
• If subjects experience a relapse of the VVC symptoms, they should be strongly 
discouraged from self-administering any treatment for VVC and instructed to visit the 
study site for evaluation of the episode and prescription of rescue therapy, if needed.   
• In the event that the subject self-administers, or another physician prescribes therapy for a 
recurrent episode of VVC, the subject should still be seen at the study site as soon as 
possible for an unscheduled visit, which should include collection of a vaginal swab for 
culture. 
14.18.3 Rescue Antifungal Therapy 
Subjects will be offered one dose of fluconazole 150 mg as rescue therapy. Other antifungal 
rescue therapy may be administered, per investigator’s discretion, based on the Candida species 
reported from the culture results. All antifungal therapy administered during the study should be 
documented in the EDC, with the reason for use clearly indicated (i.e., Mycologically Proven 
Recurrence, Presumed Recurrence or Suspected Recurrence). 
If a subject experiences one or more recurrences during the Study Treatment Period (i.e., a 
Mycologically Proven Recurrence, a Presumed Recurrence or a Suspected Recurrence), she will 
continue her scheduled study drug administration and will complete all scheduled visits until 
reaching EOFU. 


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14.19 Collection of Blinded Study Drug Supplies and Evaluation of 
Treatment Compliance 
Treatment compliance with double-blind study drug will be reviewed by the investigator or 
designee at all study visits during the Study Treatment Period, including both on-site visits and 
phone contacts.  Subjects (or subjects’ legal representatives, if applicable) will be instructed to 
bring all bottles (including empty bottles) of study medication with them at all visits to assess 
medication compliance. Empty bottles will be collected at Week 12 and Week 24 (TOC). Further 
details are available in Section 12.5. 
14.20 Vital Signs 
Vital signs, including blood pressure (systolic and diastolic), heart rate, respiratory rate and body 
temperature will be measured at all on-site scheduled and unscheduled visits. 
14.21 Prior and Concomitant Medication Review 
All medications (including prescription and over-the-counter medications, supplements, and 
herbal products) taken from 28 days before Screening through the Week 24 (TOC) visit will be 
recorded on the eCRF. Only the use of other antifungal medications, medications used to treat 
vaginal bacterial or parasitic infections, topical vaginal medications or medications to treat a 
study-drug related AE will be recorded after the TOC visit through the last study visit (Week 36 
[EOFU]).  Start and stop dates of concomitant medications will be recorded on the eCRF. Prior 
and concomitant medications will be reviewed and recorded at all scheduled and unscheduled 
study visits. 
See Section 13.0 for prohibited medications, medications to be administered with caution and 
further details for non-study treatments. 
14.22 Adverse Event Monitoring 
AEs will be recorded and reviewed at all scheduled and unscheduled study visits from the time 
the ICF is signed (Screening) through Week 24 (TOC). New AEs starting after Week 24 and 
until Week 36 will be recorded only if they led to the use of other antifungal medications or 
topical vaginal treatment, if they are a vaginal bacterial or parasitic infection, or if they are 
deemed related to the previously administered study drug. See Section 16.0 for further reference. 


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15.0 Study Schedule 
Detailed schedules of all study visits and procedures are presented in Schedule of Visits and Procedures (Table 2). 
 
Table 2: 
Schedule of Visits and Procedures (Study SCY-078-304) 
 
Screena 
Acute Phase 
(Days -14 to -1 [+3 d]) 
Prevention of Recurrence 
Study Treatment Period 
(D1 to W24) 
Follow-up Period 
(W25 to W36) 
Unschc 
Study Week/Day 
 
Study Procedures 
D -16 
to -14 D-14a 
D -11 
& -8 
Phone 
D -4 to 
-2 
Lab 
W1/ 
D1 
(BL) 
W4/ 
D28 
(±3 d) 
W8/ 
D56 
(±3 d) 
W12/ 
D84 
(±3 d) 
W16/D112  
Phoneb 
W20/D140  
Phoneb 
W24/ 
D168 
(TOC) 
(±3 d) 
W28 & 
W32 
Phoneb 
W36 
(EOFU) 
(±3 d) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assignment of Subject ID number 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviated physical exam 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
If needed 
Urine pregnancy test 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
If needed 
Vulvovaginal sample for KOHd 
X 
 
 
 
 
If PRe 
If PRe If PRe 
 
 
If PRe 
 
If PRe 
If PRe 
Vulvovaginal sample for fungal 
cultured 
X 
 
 
 
X 
If PRe 
If PRe 
X 
 
 
X 
 
X 
If PRe 
Vulvovaginal sample for pHd 
X 
 
 
 
X 
If PRe 
If PRe If PRe 
 
 
If PRe 
 
If PRe 
If PRe 
Vulvovaginal sample for other 
pathogensd  
X 
 
 
 
 
If PRe 
If PRe If PRe 
 
 
If PRe 
 
If PRe 
If PRe 
Vulvovaginal examf and rating of 
signs by the investigator 
X 
 
 
 
X 
If PRe 
If PRe 
X 
 
 
X 
 
If PRe 
If PRe 
Rating of vulvovaginal symptoms 
by the subjectg 
X 
X-----------------X 
X ------------------------------------------------------------------------------------X 
X 
Open-label FLU dispensing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Open-label FLU dosingh 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Subject diary dispensing and 
collection 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 


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Screena 
Acute Phase 
(Days -14 to -1 [+3 d]) 
Prevention of Recurrence 
Study Treatment Period 
(D1 to W24) 
Follow-up Period 
(W25 to W36) 
Unschc 
Study Week/Day 
 
Study Procedures 
D -16 
to -14 D-14a 
D -11 
& -8 
Phone 
D -4 to 
-2 
Lab 
W1/ 
D1 
(BL) 
W4/ 
D28 
(±3 d) 
W8/ 
D56 
(±3 d) 
W12/ 
D84 
(±3 d) 
W16/D112  
Phoneb 
W20/D140  
Phoneb 
W24/ 
D168 
(TOC) 
(±3 d) 
W28 & 
W32 
Phoneb 
W36 
(EOFU) 
(±3 d) 
Subject diary completion 
 
  X----------------------------------------------------------------------------------------------------------------------------X 
 
Subject diary review 
 
 
 
 
X 
X 
X 
X 
 
 
X 
 
X 
X 
Sample collection for safety labs 
(hematology and blood chemistry) 
 
 
 
Xi 
 
 
 
X 
 
 
 
 
Xj 
If needed 
Open-label FLU collection and 
compliance evaluation 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Assessment of clinical outcome to 
FLU treatment 
 
 
 
 
Xk 
 
 
 
 
 
 
 
 
 
Randomization  
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Blinded study drug dispensing 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
Blinded study drug dosingl 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Quality-of-life assessmentm 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
Assessment for potential 
recurrence 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blinded study drug compliance 
evaluation  
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Blinded study drug collection  
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
Vital Signs 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
 
X 
X 
Prior & concomitant medication 
review 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event monitoring 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: BL = Baseline; d = day; D = Day; EOFU = end of follow-up; FLU = fluconazole; ID = identification; KOH = potassium hydroxide; Phone = Phone 
contact; PR = potential recurrence; Screen = Screening; TOC = test of cure; Unsch = unscheduled; VSS = vulvovaginal signs and symptoms; VVC = vulvovaginal 
candidiasis; W = Week; 
Note regarding visits: Whenever possible, on-site visits and phone contacts will be scheduled to occur on the date of dosing (or as close to the date of dosing as 
possible) to facilitate reminding subjects to take their study doses. This is applicable for the Baseline (Day 1), Week 4, Week 8, Week 12, Week 16 (phone contact), and 
Week 20 (phone contact) visits. Phone contacts will be conducted to check for adverse events, treatment compliance, potential recurrence, and concomitant medication 
use, including other antifungal agents. 


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Screena 
Acute Phase 
(Days -14 to -1 [+3 d]) 
Prevention of Recurrence 
Study Treatment Period 
(D1 to W24) 
Follow-up Period 
(W25 to W36) 
Unschc 
Study Week/Day 
 
Study Procedures 
D -16 
to -14 D-14a 
D -11 
& -8 
Phone 
D -4 to 
-2 
Lab 
W1/ 
D1 
(BL) 
W4/ 
D28 
(±3 d) 
W8/ 
D56 
(±3 d) 
W12/ 
D84 
(±3 d) 
W16/D112  
Phoneb 
W20/D140  
Phoneb 
W24/ 
D168 
(TOC) 
(±3 d) 
W28 & 
W32 
Phoneb 
W36 
(EOFU) 
(±3 d) 
a. 
Screening and Day-14 may occur on the same day. 
b. If there is suspicion of a potential recurrence, subjects will be strongly discouraged from self-administering any treatment and will be instructed to visit the study 
center for a proper evaluation of their recurrence before initiating any VVC treatment. 
c. 
Unscheduled visits should be conducted anytime that there are symptoms indicating a potential recurrence or an adverse event. If there is suspicion of a potential 
recurrence, subjects will be strongly discouraged from self-administering any treatment and will be instructed to visit the study center for a proper evaluation of 
their recurrence before initiating any VVC treatment. 
d. Vulvovaginal specimens will be obtained at the specified visits and anytime that a recurrence is suspected for local vaginal pH determination and KOH testing as 
well as to rule out bacterial vaginosis and Trichomonas vaginalis (wet-mount or other, process locally). Testing for Neisseria Gonorrhoeae, Chlamydia trachomatis 
or Herpes virus may also be conducted if these pathogens are suspected (central laboratory). Samples for fungal culture should also be collected for processing at a 
central laboratory. Susceptibility testing will be done centrally at Screening and for all positive cultures during the study. 
e. 
Only if there is suspicion of a potential recurrence. 
f. 
If a subject is actively menstruating at an on-site study visit that requires a vaginal exam, the visit should be rescheduled as soon as the subject’s period ends but in 
no case more than 7 days after the initially scheduled visit. 
g. From Baseline (Day 1) through the Week 36 (EOFU) visit, subjects will rate their symptoms and record their scores on the VSS Scale included in their subject 
diaries. Symptoms of infection will be rated on a weekly basis and at the time of each scheduled or unscheduled visit to the site. 
h. The first dose of fluconazole will be administered at the site on Day -14, after all other visit procedures have been done. The remaining doses will be self-
administered by the subjects at home.  
i. 
Conducted by the central lab. Results will be reviewed at Baseline (Day 1). 
j. 
Only if needed to follow up on a lab abnormality 
k. If the subject has a culture-confirmed Candida spp. infection from the sample collected at Screening, achieves a significant resolution of all signs and symptoms of 
infection (total composite score ≤ 2 on the VSS Scale) and meets other eligibility criteria for the study, she will enter the Prevention of Recurrence Phase. Subjects 
who fail treatment with open-label fluconazole in the Acute Phase but continue to meet all other eligibility criteria will enter the open-label ibrexafungerp Nested 
Sub-Study (see Section 21.3 [Appendix C]). Subjects who are not eligible for this study or the Nested Sub-Study will be discontinued. 
l. 
Oral ibrexafungerp or placebo administered as a single-day treatment repeated every 4 weeks (28 days [±3]) for a total of 6 single-day treatments (Baseline [Day 1], 
Week 4, Week 8, Week 12, Week 16 and Week 20). Each single-day treatment will consist of two doses of ibrexafungerp 300 mg each or placebo given 12 (±4) 
hours apart. Subjects will continue study drug treatment regardless of recurrence and/or administration of antifungal therapy. The first dose will be administered at 
the study site (Baseline [Day 1]) and the remaining doses will be self-administered by the subjects at home. Study drug should be administered preferably with or 


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Screena 
Acute Phase 
(Days -14 to -1 [+3 d]) 
Prevention of Recurrence 
Study Treatment Period 
(D1 to W24) 
Follow-up Period 
(W25 to W36) 
Unschc 
Study Week/Day 
 
Study Procedures 
D -16 
to -14 D-14a 
D -11 
& -8 
Phone 
D -4 to 
-2 
Lab 
W1/ 
D1 
(BL) 
W4/ 
D28 
(±3 d) 
W8/ 
D56 
(±3 d) 
W12/ 
D84 
(±3 d) 
W16/D112  
Phoneb 
W20/D140  
Phoneb 
W24/ 
D168 
(TOC) 
(±3 d) 
W28 & 
W32 
Phoneb 
W36 
(EOFU) 
(±3 d) 
immediately after a meal. 
m. Quality of Life tools will include: Euro Quol 5 Dimensions (EQ-5D), Short Form Health Survey (SF-36) and Female Sexual Distress-Revised Scale (FSDS) 
 


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16.0 Safety Assessments and Monitoring 
16.1 
Definition of an Adverse Event 
An AE is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom or disease 
temporally associated with the use of a study drug/study intervention, whether or not 
related to the study drug/study intervention. 
Any laboratory abnormality that is deemed to be clinically significant in the opinion of 
the investigator will be considered an AE and should be recorded in the eCRF, whether or 
not it is related to the study drug. 
Stable chronic conditions that are present prior to clinical trial enrollment and do not 
worsen are not considered AEs and will be accounted for in the subject’s medical history. 
The following can be considered AEs: 
• An exacerbation of a pre-existing illness 
• An increase in frequency or intensity of a pre-existing episodic event or condition 
• A condition detected or diagnosed after the initiation of treatment with study 
medication, even though it may have been present prior to the start of the study 
• Continuous persistent disease or symptoms present at Baseline (Day 1) that worsen 
after signing the informed consent or following the initiation of treatment with 
study medication 
The following are not considered AEs: 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction or 
transfusion); the condition that leads to the procedure is an AE 
• Pre-existing disease or conditions present or detected at the start of the study that 
do not worsen 
• Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalizations for cosmetic surgery or elective surgery or social/convenience 
admissions) 
• The disease being studied, or signs or symptoms associated with the disease, 
unless more severe than expected for the subject’s condition or a worsening of the 
disease being studied 
16.2 
Definition of a Serious Adverse Event 
A SAE is defined as an AE meeting one of the following outcomes: 
• Death 
• Life-threatening event 
• Inpatient hospitalization or prolongation of existing hospitalization 


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• Persistent or significant disability/incapacity or substantial disruption of the ability 
to conduct normal life functions 
• Congenital anomaly or birth defect 
Any other important medical event that may not result in one of the above outcomes may 
be considered a SAE when, based upon appropriate medical judgment, the event may 
jeopardize the participant and may require medical or surgical intervention to prevent one 
of the outcomes listed above. 
A life-threatening AE is any AE that places the subject, in the view of the investigator, at 
immediate risk of death from the AE as it occurred.  It does not include an AE that, had it 
occurred in a more severe form, might have caused death. 
16.3 
Events of Clinical Interest 
The following are considered events of clinical interest (ECIs) if they occur after dosing, 
and must be reported by the site when it becomes aware of the ECI: 
• ALT or AST > 8 x the upper limit of normal (ULN), confirmed by repeat testing 
• ALT or AST > 5 x ULN for more than 2 weeks or accompanied by total bilirubin 
> 2 x ULN   
16.4 
Overdose 
This refers to the administration of a quantity of a medicinal product given per 
administration or cumulatively, which is above the maximum recommended dose 
according to the authorized product information.  
An overdose can occur if a subject has taken, accidentally or intentionally, a drug 
administered in a dose exceeding the protocol-specified dose.  An overdose must be 
reported within 24 hours of the site becoming aware of the overdose if such overdose 
occurs with an associated SAE. If an overdose occurs without an associated SAE, the 
overdose must be reported within 5 working days and documented in the subject diary 
and in the subject medical record. 
16.5 
Pregnancy 
Female subjects who become pregnant should be immediately discontinued from the 
study and followed up to determine the outcome of the pregnancy.  The pregnancy must 
be reported to the Sponsor within 24 hours of the site becoming aware of the pregnancy 
using the pregnancy reporting form.  If the pregnancy ends for any reason before the 
anticipated date, the investigator should notify the Sponsor. At the completion of the 
pregnancy, the investigator will document the outcome of the pregnancy. The pregnancy 
itself is not to be reported as an AE or SAE. If the outcome of the pregnancy meets the 
criteria for immediate classification as an SAE (i.e., postpartum complication, 
spontaneous abortion, stillbirth, neonatal death or congenital anomaly), the investigator 
should follow the procedures for reporting an SAE. 


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16.6 
Unexpected Adverse Event 
An AE is considered “unexpected” if it is not listed in the IB or is of greater specificity or 
severity than those that have been observed with the particular study drug being tested. 
For example, under this definition, hepatic necrosis would be unexpected (by virtue of 
greater severity) if the IB referred only to elevated hepatic enzymes or hepatitis.  
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by 
virtue of greater specificity) if the IB listed only cerebral vascular accidents. 
"Unexpected," as used in this definition, also refers to AEs that are mentioned in the IB 
as occurring with a class of drugs or as anticipated from the pharmacological properties 
of the drug but are not specifically mentioned as occurring with the particular drug under 
investigation. 
16.7 
Study Monitoring 
Study progress will be monitored by the Sponsor or its representative as frequently as 
necessary to ensure adequate and accurate data collection, protocol compliance, and 
study conduct in accordance with accepted regulatory requirements. The principal 
investigator (PI) must make all the subject data available to the monitor for review during 
the planned site monitoring visits. Arrangements for monitoring visits will be made in 
advance, except in emergency cases. 
16.8 
Grading of Adverse Events 
The severity (or intensity) of an AE refers to the extent to which it affects the subject’s 
daily activities and will be classified by the investigator as mild, moderate or severe using 
the following criteria: 
• Mild:  Awareness of sign or symptom, but easily tolerated.  Not likely to require 
medical attention. 
• Moderate:  Discomfort enough to cause some interference with daily activity.  
May require medical intervention. 
• Severe:  Intense enough to disrupt daily activities.  Likely requires medical 
intervention. 
Clarification of the difference in meaning between “severe” and “serious” 
The term “severe” is often used to describe the intensity (severity) of a specific event (as 
in mild, moderate or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as 
“serious”, which is based on the outcome or action criteria usually associated with events 
that pose a threat to life or functioning.  Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations. 


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16.9 
Causality Assessment 
The investigator will assess causality (i.e., whether there is a reasonable possibility that 
the study drug caused the event) for all AEs and SAEs.  The relationship will be 
characterized using the following classification: 
• Related:  The temporal relationship of the AE with the study drug makes causality 
possible and as likely or more likely than due to another cause such as other drugs, 
a surgical intervention or an underlying disease. 
• Not related:  The temporal relationship of the AE with the study drug makes 
causality improbable and can be due to another cause such as other drugs, a 
surgical intervention or an underlying disease. 
16.10 Adverse Event Collection Timeframe 
AEs and SAEs will be recorded from the time the ICF is signed (Screening) through 
Week 24 (TOC). New AEs starting after Week 24 and until Week 36 will be recorded 
only if they led to the use of other antifungal medications or topical vaginal treatment, or 
if they are a vaginal bacterial or parasitic infection, or if they are deemed related to the 
previously administered study drug.  
All AEs reported by the subject or observed by members of the clinical staff will be 
evaluated by the PI or qualified designee. The PI will attempt, if possible, to establish a 
diagnosis based on presenting signs and symptoms.  The nature of the AE, time of onset 
relative to study drug administration, duration, severity, and relationship to treatment 
should be determined. Details of any corrective treatment must be recorded in the eCRF. 
The PI will determine whether any changes have occurred in baseline signs and 
symptoms. All AEs and SAEs will be collected in the eCRF. 
16.11 Serious Adverse Event Reporting Requirements 
All SAEs must be reported within 24 hours of the site becoming aware of the SAE.  Any 
event that is serious, study drug-related, and unexpected as assessed by the medical 
monitor or the Sponsor will be submitted to the regulatory authorities in accordance with 
national regulatory laws and regulations. The PI will be responsible for reporting all 
SAEs that require reporting to the local or central Institutional Review Board/Ethics 
Committee (IRB/EC) in accordance with its regulations and guidelines. 
16.12 Adverse Event and Serious Adverse Event Follow-up 
All AEs and SAEs will be followed up to resolution (the subject’s health has returned to 
her baseline status or all variables have returned to normal) or until an outcome is 
reached, stabilization occurs (the investigator does not expect any further improvement or 
worsening of the event) or the event is otherwise explained, regardless of whether the 
subject is still participating in the study. All appropriate therapeutic measures should be 
undertaken and recorded. Where appropriate, medical tests and examinations will be 
performed to document resolution of the event(s). 


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16.13 Serious Adverse Event Reporting – Procedures for Investigators 
Initial Reports and Follow-Up SAE Reports:  To report an SAE, the SAE eCRF form 
within the Electronic Data Capture (EDC) system must be completed. All SAEs, whether 
or not deemed drug-related or expected, must be reported by the investigator or qualified 
designee within 24 hours of first becoming aware of the event.  The investigator/qualified 
designee will enter the required information regarding the SAE into the appropriate form, 
which will automatically result in distribution of the information to the appropriate 
sponsor contact. 
If the EDC system is temporarily unavailable (> 24 hours), the event, including the 
investigator-determined causality to study drug, should be reported via a paper back-up 
SAE form to PPD Safety Surveillance (contact information, i.e., e-mail or fax will be 
available on the SAE form).  
Upon return of the availability of EDC system, the SAE information must be entered into 
the EDC system as soon as possible. The SAE form within the EDC system must be 
updated within 24 hours of knowledge/receipt of SAE follow-up information. 
16.14 Procedures for Emergency Unblinding 
This is a double-blind study. The Investigator should only be unblinded if it is necessary 
to determine treatment of emergency. The study personnel responsible for the treatment 
assignment can provide the information necessary to unblind the investigator (evaluator), 
in case of an emergency. If the evaluator is unblinded, the reason for unblinding should 
be documented in the comment page of the eCRF.  
17.0 Data Collection, Study Monitoring and Record 
Management 
17.1 
Data Collection and Reporting 
Data for this study will be collected using eCRFs. The investigator and study site staff 
will receive training regarding the completion of the eCRF. Visit-specific data should be 
entered into the eCRF and be ready for review as soon as possible, but no later than 5 
days after each visit/time point. 
All protocol-required information collected during the study must be entered by the 
investigator or designated representative in the source documents and eCRF. All data 
entry, modification or deletion will be recorded indicating the individual subject, original 
value, the new value, the reason for change, who made the change, and when the change 
was made.  All data changes will be clearly indicated with a means to locate prior values. 
The investigator will maintain a list of individuals who are authorized to enter or correct 
data on the eCRFs. 
The investigator or designated sub-investigator, following review of the data in the eCRF, 
will confirm the validity of each subject’s data by signing the eCRF. 


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17.2 
Investigator Study Files 
The PI is responsible for maintaining all study-related documents in study files. The 
Sponsor will notify the PI when retention of study files is no longer necessary. The 
following documents will be kept in the study files or be readily accessible: 
• original protocol and all amendments; 
• signed agreement or protocol; 
• signed and dated study staff roles and responsibilities log; 
• copy of the current curriculum vitae of the PI and of all sub-investigators; 
• IRB/EC membership list and all IRB/EC approvals for the protocol and 
amendments, informed consent documentation and all updates, advertisements, 
and written information provided to subjects; all IRB/EC correspondence; 
documentation that the Investigator’s Brochure and subsequent revisions have 
been submitted to the IRB/EC; documentation that all SAEs and any periodic 
safety reports have been submitted to the IRB/EC; and annual IRB/EC renewals 
(as required); 
• updated laboratory certification and the laboratory’s normal values (covering the 
entire time interval of the study for all laboratory tests conducted during the study); 
• all confirmations of investigational drug receipt, drug accountability logs and drug 
return records; 
• a CD or DVD containing final subject eCRF data; 
• all correspondence to or from the Sponsor or its designees; 
• blank informed consent form; 
• Investigator’s Brochure; 
• subject screening log; 
• subject list (contains subject initials and/or protocol-specific subject number); 
• all subjects’ original signed informed consents; and, 
• monitoring visit log. 
17.3 
Retention of Records 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing 
applications, or at least 2 years have elapsed since the formal discontinuation of the 
clinical development of the investigational product.  These documents should be retained 
for a longer period, however, if required by the applicable regulatory requirements or by 
an agreement with the Sponsor. 
The Sponsor will inform the PI/institution in writing of the need for record retention and 
will notify the PI/institution in writing when the trial-related records are no longer 
needed. 
An investigator who withdraws from the responsibility of maintaining study records or 
wishes to move them to a new location has the obligation to place them in safekeeping 
and to inform the Sponsor of their location. 


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18.0 Analytical Plan 
 
All statistical analysis will be performed using SAS® version 9.3 or later, unless 
otherwise stated.  All statistical tests will be two-sided and interpreted at a 5% 
significance level.  
Descriptive statistics (i.e., mean, standard deviation, median, minimum, maximum, etc.) 
will be provided for all continuous variables; frequencies and percentages will be 
tabulated for incidence and categorical variables.  For parameters measured over time, 
observed values and changes from baseline will be described for each time point. 
The Mycologically Proven Recurrence and Mycological Eradication rates will be 
described by baseline Candida species, when the number of isolates per species allows.  
The percentage of subjects with Mycologically Proven Recurrence will be described by 
number of VVC episodes in the 12 months prior to randomization.  
All analyses will be presented by treatment group, as appropriate.  Unless otherwise 
stated, data will be analyzed as is with no imputation.  No adjustment for multiplicity will 
be employed. 
A Statistical Analysis Plan (SAP) describing all final statistical analyses in detail will be 
provided as a separate document. The SAP will be finalized prior to the unblinding of the 
study treatments for analysis. 
18.1 
Sample Size Determination 
The primary endpoint of the study is the percentage of subjects with documented Clinical 
Success up to TOC (Week 24). Assuming response rates of 65% and 43% for 
ibrexafungerp and placebo, respectively; 90% power; and an alpha level of 0.05, 
approximately 240 subjects randomized at a 1:1 ratio are needed to declare a difference 
between ibrexafungerp and placebo at Week 24 based on Fisher’s Exact test.  
In order to be randomized, a subject should have achieved the proposed significant 
resolution of signs and symptoms (total composite score ≤2 on the VSS Scale) after 
receiving fluconazole therapy for an acute episode and have a positive culture for 
Candida spp. from the sample collected at Screening.  It is estimated that approximately 
320 subjects will need to enter the Acute Phase to provide 240 subjects randomized to the 
Prevention of Recurrence Phase.  Enrollment into the Acute Phase will be discontinued 
when approximately 240 subjects have been randomized. 
18.2 
Analysis Populations 
The study populations to be used in the analyses are defined as follows: 
• Intent-to-Treat (ITT) Population: All randomized subjects. 


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• Modified Intent-to-Treat (mITT) Population: All randomized subjects who 
have a confirmed mycological culture for yeast at Screening and a negative culture 
for yeast at Baseline (Day 1).  
• Per-Protocol (PP) Population: All ITT subjects who did not have major protocol 
deviations likely to affect study efficacy and who have available data at the TOC 
visit.  Note that subjects who discontinue due to a study-drug-related AE will be 
classified as failures for the analyses of efficacy under the PP population. 
• Safety Population: All randomized subjects who received at least one dose of 
study drug (ibrexafungerp or placebo) and who have at least one post-Baseline 
(Day 1) evaluation. 
18.3 
Subject Disposition, Discontinuation, and Baseline Data 
Subject disposition in terms of the number and percentage of subjects enrolled by site 
will be tabulated. The number of subjects randomized, number completing the study, and 
reasons for discontinuation will be summarized by treatment group. Subject 
demographics and baseline characteristics such as age, race, ethnicity, sex, weight, 
height, body mass index, region (if applicable) and other relevant parameters will be 
tabulated by treatment group.  
Baseline is defined as the last non-missing assessment prior to the date (and time if 
appropriate) of the first dose of study drug. Change from baseline is defined as: post-
baseline value – baseline value. 
18.4 
Handling of Missing Data, Dose Adjustments, and Early 
Withdrawals 
For the efficacy analyses, subjects who do not have a TOC (Week 24) assessment will be 
assigned as treatment failures. For subjects who withdraw from the study early, every 
effort will be made to collect TOC or EOFU visit information (as applicable) at the point 
of withdrawal.  Missing data will be further described in the SAP for early withdrawal 
subjects. 
18.5 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization 
Drug Dictionary terminology. The number and percentage of subjects taking each 
medication before and after the first dose of study drug will be tabulated by treatment 
group. Medications taken and stopped prior to the first dose of study drug will be 
considered prior medications. Medications started on or before the EOFU visit date with 
missing stop dates or stop dates after the first dose of study drug will be considered 
concomitant medications. 


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18.6 
Efficacy 
18.6.1 Efficacy Assessments 
Efficacy assessments will be based on clinical evaluations, mycological testing and QOL.  
The primary efficacy endpoint of the study is the percentage of subjects with 
documented Clinical Success (defined as subjects having a TOC evaluation and no 
Mycologically Proven, Presumed or Suspected Recurrence of VVC) up to TOC (Week 
24).  The key secondary efficacy endpoint is the percentage of subjects with no 
Mycologically Proven Recurrence (defined as an episode of VVC with a total composite 
score ≥ 3 on the VSS Scale and a culture positive for Candida spp. that required 
antifungal treatment) at TOC (Week 24).  
Other secondary efficacy endpoints will also be assessed (see Section 9.3). 
The following efficacy outcomes will be evaluated in the study: 
• Clinical Success: Subjects having a TOC evaluation and no Mycologically Proven, 
Presumed or Suspected Recurrence of VVC 
• Recurrence of VVC: In this study, Recurrences of VVC will be broken into three 
categories: 
o Mycologically Proven Recurrence: An episode of VVC with a total composite 
score ≥ 3 on the VSS Scale and a culture positive for Candida spp. that required 
antifungal treatment. 
o Presumed Recurrence: An episode of VVC with a total composite score ≥ 3 on 
the VSS Scale that required antifungal treatment and for which there is a positive 
KOH microscopy but no positive fungal culture.  
o Suspected Recurrence: An episode of VVC that required treatment with an 
antifungal agent (including self-administration with over-the-counter antifungals) 
regardless of VSS composite score but for which there is no mycological evidence 
of disease, such as a positive KOH microscopy or fungal culture.  
• Mycological Eradication: Negative fungal culture (no growth of Candida species). 
 
18.6.2 Efficacy Analyses 
The efficacy analyses will be conducted using the ITT (primary analysis population), 
mITT, and PP populations. The efficacy parameters will be evaluated comparing the 
ibrexafungerp treatment group versus the placebo group. 
The primary endpoint, the percentage of subjects with  documented Clinical Success up 
to TOC (Week 24), will be analyzed using a Cochran-Mantel-Haenszel (CMH) test 
adjusted for site; p-values and 95% confidence intervals will be presented. Subjects 
whose results are missing at TOC (Week 24) will be imputed as failures in the analysis. 
In the event that model convergence is an issue with a stratified analysis, alternative 


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methods for accounting for site, or an unstratified analysis will be considered.  A 
sensitivity analysis will be performed on the ITT population where subjects with missing 
values will be removed from the analysis.  
For other continuous efficacy endpoints, a two-way analysis of variance (ANOVA) 
model will be used including effects for treatment and site; p-values and 95% confidence 
intervals will be presented. For other categorical endpoints, the CMH test adjusted for 
site will be performed, and p-values and 95% confidence intervals will be presented. 
For the ordered categorical endpoint, a proportional odds model will be fitted accounting 
for the effects of treatment and site.  The proportional odds model will fit an ordered 
regression model for the ordinal dependent variable as described by McCullagh (1980).  
If the assumption of proportional odds is violated alternative analyses will be considered 
which require a weaker assumption. 
18.7 
Safety  
18.7.1 Safety Assessments 
Safety will be evaluated throughout the study, including the following parameters: AEs, 
treatment discontinuations, vital signs, safety laboratory tests and prior and concomitant 
medications. 
Safety procedures are described in Section 14.0 and safety assessments are described in 
Section 16.0. 
18.7.2 Analyses 
No formal statistical analysis is planned for the safety data. Safety analyses will be 
conducted using the safety population. AEs will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) Version 19.1 or higher. The incidence and severity 
of treatment-emergent AEs and SAEs and their relationship to treatment will be 
summarized by system organ class and preferred term. The percentage of subjects who 
discontinued study treatment and the reasons for discontinuation will be summarized by 
treatment group. 
 
Laboratory evaluations and vital signs will be summarized as observed values and as 
changes from Baseline by treatment group. In addition, shifts (with respect to the 
reference range) from Baseline will be presented for laboratory tests by treatment group. 
18.8 
Interim Analyses 
No interim analyses are planned for this study. 


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19.0 Ethics and Protection of Human Patients 
19.1 
Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, the ethical principles 
established by the Declaration of Helsinki (as amended in Fortaleza, Brazil, October 
2013), the International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines, the United States Code of Federal Regulations (CFR) sections that 
address clinical research studies, applicable European Union regulations and/or other 
national and local ethical and legal requirements, as applicable. 
19.2 
Institutional Review Board/Ethics Committee Review 
The PI or CRO must provide the IRB/EC with all appropriate materials, including a copy 
of the subject ICF. The study will not be initiated until the PI or CRO obtains written 
approval of the protocol and the subject ICF from the appropriate IRB/EC, and copies of 
these documents are received by the Sponsor. Appropriate reports on the progress of this 
study will be made by the PI to the IRB/EC, medical monitor, and Sponsor in accordance 
with applicable government regulations and in agreement with policy established by the 
Sponsor. 
19.3 
Informed Consent  
The ICH issued guidelines to provide protection for human subjects in clinical 
investigations. The ICH Tripartite Guideline for GCP establishes the general 
requirements for informed consent. Each subject will be provided with oral and written 
information in a language they can understand that describes the nature and duration of 
the study. Before undergoing screening, each subject must consent in writing to study 
participation. The patient will sign and personally date the subject ICF. The person 
rendering consent will also sign and personally date the subject ICF as the person who 
obtained the consent of the subject. In the case of a minor, according to the local 
definition (e.g., below 16 or 18 years of age), a parent or legal representative should also 
sign and date the ICF. Additional local regulatory requirements may be applicable for 
participation of subjects below the age of consent. The original signed subject ICF will be 
retained with the study center’s records. Each subject will receive a copy of her signed 
subject ICF. In addition, the PI, or his or her designee, must document in the case history 
that informed consent was obtained before study participation.  
19.4 
Future Use of Samples 
Biological samples collected during the study, including Candida spp. or other yeast 
isolates (see Section 14.7) may be maintained in repositories for potential future use. 
Future research of Candida isolates may include in vitro susceptibility testing of new or 
existing antifungals or analysis of mechanisms of resistance. All samples will be 
identified only by a coded number to maintain subject confidentiality.   


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19.5 
Subject Privacy and Subject Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified only by a coded number to maintain subject privacy and confidentiality. 
All records will be kept in a locked file cabinet. All computer entry and networking 
programs will be performed with coded numbers only. Clinical information will not be 
released without written permission of the subject, except as necessary for monitoring by 
the medical monitor, IRB/EC, the Food and Drug Administration (FDA), the Sponsor or 
where required by law. All local privacy laws must be followed.   
19.6 
 Study Termination 
The PI, the sponsor, the FDA, and the IRB/EC each reserve the right to terminate the 
study in the interest of subjects’ safety and welfare. The sponsor reserves the right to 
terminate the study at any time for administrative reasons. 
19.7 
Financial Disclosure 
The financial interests of all investigators from all participating clinical centers must be 
collected prior to study initiation and 1 year following the completion of the clinical trial. 


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20.0 References 
1. Sobel JD. Vaginal candidosis. Lancet 2007;369:1961–71. 
2. Hurley R, De Louvois J. Candida vaginitis. Postgrad Med J 1979;55:645–47. 
3. Foxman B, Marsh JV, Gillespie B, Sobel JD. Frequency and response to vaginal 
symptoms among white and African American women: results of a random digit 
dialing survey. J Womens Health 1998;7:1167–74 
4. Sobel JD. Recurrent vulvovaginal candidiasis. Am J Obstet Gynecol. 2016 
Jan;214(1):15-21. 
5. Sobel JD. Management of recurrent vulvovaginal candidiasis: unresolved issues. 
Curr Infect Dis Rep. 2006 Nov;8(6):481-6. 
6. Sobel JD, Wiesenfeld HC, Martens M, Danna P, Hooton TM, Rompalo A, 
Sperling M, Livengood C 3rd, Horowitz B, Von Thron J, Edwards L, Panzer H, 
Chu TC. Maintenance fluconazole therapy for recurrent vulvovaginal candidiasis. 
N Engl J Med. 2004 Aug 26;351(9):876-83. 
7. CLSI. 2008a. Reference method for broth dilution antifungal susceptibility testing 
of yeasts; approved standard – third edition. CLSI document M27-A3. Clinical 
and Laboratory Standards Institute, Wayne, PA. 
 
 


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21.0 Appendices 
21.1 
Appendix A:  Prohibited Medications and Medications to be 
Administered with Caution 
21.1.1 Prohibited Medications 
Other Investigational Drugs 
No investigational drugs other than the study drug are allowed within 30 days before 
Screening and throughout the study. 
Topical Vaginal Corticoids and Contraceptives 
No topical vaginal corticoids and topical vaginal contraceptives are allowed during the 
study.  Topical vaginal corticosteroids are prohibited from 7 days prior to the Screening 
visit to the Week 24 (TOC) visit. Subjects must refrain from using any topical vaginal 
contraceptives such as spermicides or intra-vaginal hormonal contraceptive devices such 
as vaginal rings as these may interfere with the efficacy evaluations. 
Other Systemic or Topical Vaginal Antifungals 
No systemic or topical vaginal antifungal treatment other than the study drug, including 
prescription or over-the-counter products, is allowed from 28 days prior to Day -14 and 
throughout the study unless used as rescue medication.  
CYP3A4/5 Inhibitors and Inducers 
The medications listed below are also prohibited: 
 
Strong CYP3A4/5 inhibitors and CYP3A4/5 inducers 
CYP 
Strong Inhibitorsa 
Inducersb 
3A4/5 
• 
boceprevir 
• 
clarithromycin 
• 
conivaptan 
• 
indinavir 
• 
lopinavir/ritonavir  
• 
mibefradil 
• 
nefazodone 
• 
nelfinavir 
• 
saquinavir 
• 
telaprevir  
• 
telithromycin 
 
• 
avasimibe 
• 
carbamazepine 
• 
phenytoin 
• 
rifampin 
• 
St. John’s wort 
• 
long-acting 
barbiturates 
a. The CYP3A4/5 inhibitors listed in this table are not permitted during the 48 hours prior to 
enrollment and during study treatment. 
b. The CYP3A4/5 inducers listed in this table are not permitted during the 14 days prior to 
enrollment and during study treatment. 
 


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P-glycoprotein (P-gp) substrates 
P-gp Drug Substratesa 
digoxin, colchicine, quinidine, vinblastine, talinolol, methotrexate, rifampin, dabigatran, 
fexofenadine 
a. 
The P-gp substrates listed in this table are not permitted during the 48 hours prior to 
enrollment and during study treatment with ibrexafungerp 
21.1.2 Medications to be administered with Caution and Monitored as 
Appropriate 
CYP3A4 substrates 
CYP 
Substrates 
3A4 
In vitro, ibrexafungerp was an inhibitor of CYP3A mediated metabolism of 
midazolam, but was only a weak inhibitor of metabolism of testosterone. The clinical 
significance of this inhibition is unknown; caution should be exercised when 
administering ibrexafungerp with drugs known to be CYP3A sensitive substrates with 
narrow therapeutic index, such as midazolam. 
Subjects receiving sirolimus, tacrolimus, warfarin, cyclosporine or amiodarone are 
permitted for enrollment in the study and these medications may be administered 
concomitantly with ibrexafungerp with close monitoring. Dosing adjustments and 
subsequent monitoring of sirolimus and warfarin should be undertaken in accordance 
with product prescribing information for the respective agents. 
OATP1B3 substrates 
OATP Substrate 
1B3 
In vitro, ibrexafungerp is an inhibitor of the OATP1B3 liver uptake transporter.  The 
clinical significance of this inhibition is unknown; however, there is a potential risk 
for increased exposure of the concomitant medications (arising from lowered hepatic 
clearance) when administering ibrexafungerp with drugs known to be OATP1B3 
selective substrates. Therefore, caution should be exercised when administering 
ibrexafungerp with drugs known to be OATP1B3 selective substrates such as 
telmisartan, including monitoring the subject for signs of overexposure associated 
with the concomitant medications as described in the product prescribing information. 
 
Sources: 
• FDA Draft Guidance for Industry.  Drug Interaction Studies – Study Design, Data 
Analysis, and Implications for Dosing and Labeling.  2012. 
• Drug interactions in infectious disease by Stephen C. Piscitelli, Keith Rodvold 
(2007) 
• UCSF-FDA Transportal 
 


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21.2 
Appendix B:  Vulvovaginal Signs and Symptoms Scale 
SIGNS: 
To be rated by the investigator during the vulvovaginal examination 
Sign 
Absent 
0 
Mild 
1 
Moderate 
2 
Severe 
3 
Edema 
 
 
 
 
Erythema  
 
 
 
 
Excoriation or 
fissures 
 
 
 
 
 
Definitions: 
Absent: none 
Mild: slight 
Moderate: definitely noticeable 
Severe: marked, intense 
 
SYMPTOMS: 
To be rated by the subject  
Symptom 
Absent 
0 
Mild 
1 
Moderate 
2 
Severe 
3 
Burning 
 
 
 
 
Itching 
 
 
 
 
Irritation 
 
 
 
 
 
Definitions: 
Absent: I have no discomfort (i.e., burning, itching, irritation) 
Mild: I have some discomfort (i.e., burning, itching, irritation), but it does not bother me 
much 
Moderate: I have discomfort (i.e., burning, itching, irritation), which is annoying, but not 
enough to affect what I am doing 
Severe: I have discomfort (i.e., burning, itching, irritation), which is annoying enough to 
affect what I am doing 
 


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21.3 
Appendix C: Protocol for Study SCY-078-304S 
Study Title: An exploratory, open-label, single-group ibrexafungerp sub-study to 
evaluate the efficacy and safety of oral ibrexafungerp in the treatment of acute VVC in 
patients with recurrent VVC that has not responded to oral fluconazole treatment 
This study is an exploratory, open-label, single-group sub-study to evaluate the efficacy 
and safety of oral ibrexafungerp (SCY-078) in the treatment of subjects with acute VVC 
who did not respond to oral fluconazole treatment. Subjects with a history of recurrent 
VVC (enrolled in the Main Study [Study SCY-078-304] with an acute VVC episode), 
who had a culture-confirmed VVC at Screening (Main Study) and failed to meet 
resolution of their vulvovaginal signs and symptoms after fluconazole treatment (as 
defined in the SCY-078-304 study protocol) will be eligible for this sub-study (SCY-078-
304S). These subjects will not be eligible for randomization into the Prevention of 
Recurrence Phase of the Main Study but will be offered open-label, one-day oral 
ibrexafungerp treatment for their unresolved VVC episode under this sub-study.  
The full study protocol for study SCY-078-304 is provided from Section 5.0 onwards. 
This Appendix C describes the protocol for this Nested Sub-Study (SCY-078-304S) and 
all references to “the study” in this appendix refer to this study SCY-078-304S, unless 
otherwise noted.  
21.3.1 Protocol Synopsis 
Title: An exploratory, open-label, single-group ibrexafungerp sub-study to evaluate the 
efficacy and safety of oral ibrexafungerp in the treatment of acute vulvovaginal candidiasis in 
patients with recurrent VVC that has not responded to oral fluconazole treatment 
STUDY OBJECTIVES: 
Primary Objective:  
• 
To evaluate the efficacy of a single-day dosing of oral ibrexafungerp in subjects with a 
history of RVVC who failed oral fluconazole therapy for the treatment of an acute VVC 
episode, based on Clinical Success. 
Secondary Objectives:  
• 
To evaluate the efficacy of a single-day dosing of oral ibrexafungerp in subjects with a 
history of RVVC who failed oral fluconazole therapy for the treatment of an acute VVC 
episode, based on mycological and clinical outcomes. 
• 
To evaluate the safety and tolerability of a single-day dosing of oral ibrexafungerp in 
subjects with a history of RVVC who failed  oral fluconazole therapy for the treatment of 
an acute VVC episode. 
STUDY ENDPOINTS: 
Primary Endpoint:  
• 
Efficacy as measured by the percentage of subjects with Clinical Success (at least 50% 
reduction from Baseline in the total composite VSS score with no additional antifungal 
therapy required based on investigator’s judgment) at the Test-of-Cure (TOC) visit. 


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Secondary Endpoints:  
Efficacy as measured by: 
• 
The percentage of subjects with Clinical Improvement (partial or complete resolution of 
signs and symptoms [total composite score ≤1 on the VSS Scale] with no additional 
antifungal therapy required based on investigator’s judgment) at the TOC visit. 
• 
The percentage of subjects with Clinical Cure (complete resolution of signs and symptoms 
[total composite score of 0 on the VSS Scale] with no additional antifungal therapy 
required based on investigator’s judgment) at the TOC visit. 
• 
The percentage of subjects with Mycological Eradication (negative culture for growth of 
Candida spp.) at the TOC visit. 
• 
The percentage of subjects with both Clinical Cure and Mycological Eradication at the 
TOC visit. 
• 
The percentage of subjects with Continued Clinical Success (sustained resolution of signs 
and symptoms in subjects who achieved Clinical Success at the TOC visit) at the FU visit. 
• 
The absolute change in total composite VSS score from Baseline to the TOC and FU visits. 
Safety and tolerability as measured by: 
• 
Adverse events (AEs), vital signs, treatment discontinuation and safety laboratory tests. 
STUDY DESIGN:  
This study is an exploratory, open-label, single-group nested sub-study to evaluate the efficacy 
and safety of oral ibrexafungerp (SCY-078) in the treatment of subjects with acute VVC who 
did not respond to oral fluconazole treatment. Subjects with a history of recurrent VVC 
(enrolled in the Main Study [study SCY 078 304] with an acute VVC episode), who had a 
culture-confirmed VVC at Screening (Main Study) and failed oral fluconazole will be eligible 
for this sub-study (SCY-078-304S). A subject will be considered to have failed oral 
fluconazole therapy if she did not achieve a significant resolution of the signs and symptoms of 
infection (defined as a total composite score ≤ 2 on the VSS Scale) at the Baseline Visit (Day 
1) following treatment with oral fluconazole 150 mg once daily (QD) on Days -14, -11 and -8.  
Eligible subjects must continue to meet all other applicable eligibility criteria of the Main 
Study (study SCY-078-304) to enter this study. Subjects who are eligible for this study will be 
offered open-label, one-day oral ibrexafungerp treatment for their unresolved VVC episode. 
Approximately 60 subjects are planned to enter the study. All eligible subjects will receive oral 
ibrexafungerp administered as a single-day treatment consisting of two 300-mg doses (total 
dose = 600 mg) given 12 hours apart (±4 hours).  
The study will consist of the following visits: 
• 
Baseline visit (Day 1): Subjects who meet all criteria for this study will receive the first 
dose of study drug, oral ibrexafungerp 300 mg, at the site and will self-administer the 
second 300-mg dose at home, 12 hours (±4 hours) after the first dose. At this visit, subjects 
will be provided with subject diaries to record the date and time of their second study drug 
dose and to rate their vulvovaginal symptoms of infection, AEs and concomitant 
medication use from the Baseline (Day 1) visit until the TOC visit (Day 11 ± 3). 
• 
TOC visit (Day 11 [±3]): At this visit, treatment compliance will be evaluated, and subject 
diaries will be returned and reviewed. The investigators and the subjects will rate the signs 
and symptoms of infection, respectively, on the VSS Scale (a standardized, predefined 
scale [see STUDY EVALUATIONS below]).  
If the baseline vulvovaginal signs and symptoms have not improved or have worsened, 
vulvovaginal samples for fungal culture, species identification and antifungal susceptibility 
testing will be obtained and sent to a designated central laboratory. Additional vaginal 


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samples will be obtained for a potassium hydroxide (KOH) testing by the local laboratory 
if symptoms persist or have worsened. An abbreviated physical exam, vital signs 
measurements and safety laboratory tests will also be performed. 
• 
FU visit (Day 25 [±4]): At the FU visit, subjects will rate their symptoms of infection on 
the VSS Scale. Vulvovaginal samples for pH determination, KOH testing and fungal 
culture should be obtained if there is persistence or worsening of vulvovaginal symptoms. 
Only if symptoms are present, the investigator will perform a vulvovaginal examination to 
rate the subject’s signs of infection. 
The study will include efficacy, safety and tolerability assessments. Efficacy assessments will 
be based on clinical evaluations (rating of signs and symptoms of infection) and mycological 
testing (direct microscopic examinations and fungal cultures). Safety and tolerability will be 
evaluated by AEs, vital signs, safety laboratory tests and study treatment discontinuations. See 
STUDY EVALUATIONS for further details. 
TARGET POPULATION: The study population will include female subjects 12 years and 
older with RVVC. 
INCLUSION CRITERIA:  
Subjects must fulfill all of the following criteria to be eligible for admission to this study: 
1. Subject meets the following criteria at Baseline (Day 1): 
a) Failure to achieve a significant resolution of the signs and symptoms of the Candida 
infection (total composite score ≥ 3 on the VSS Scale). 
b) Culture positive for Candida spp. in a vaginal sample collected at Screening (Main 
Study). 
c) Normal vaginal pH (≤ 4.5) 
2. Subject meets all other inclusion criteria in Section 11.1 of the Main Study (except 
Inclusion Criterion No. 3a, requiring a total composite score ≤ 2 on the VSS Scale). 
EXCLUSION CRITERIA: 
A subject will be excluded from participation in this study if she meets any of the exclusion 
criteria listed in Section 11.2 of the Main Study. 
STUDY DRUGS:  
The study drug administered during the study will be provided by the Sponsor and will consist 
of oral ibrexafungerp (150-mg tablets). The study drug will be supplied as ibrexafungerp 
citrate drug product, a tablet containing 150 mg of ibrexafungerp active ingredient on a free-
base basis for oral administration. In addition to the active ingredient, the tablet formulation 
also contains silicified microcrystalline cellulose, crospovidone, mannitol, colloidal silicon 
dioxide, magnesium stearate (non-bovine) and butylated hydroxyanisole.  
STUDY TREATMENT GROUPS:  
This is an open-label, single-group study. All subjects will receive oral ibrexafungerp 
administered as a single-day treatment (Baseline [Day 1]) consisting of two 300-mg doses 
(total dose = 600 mg) given 12 hours apart (±4 hours). The study drug should be administered 
preferably with or immediately after a meal.  
STUDY BLINDING, RANDOMIZATION AND STRATIFICATION:  This is an open-
label, single-group study. There will be no study-drug blinding, randomization or stratification.  
STUDY EVALUATIONS 
Efficacy Evaluations 


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Clinical Evaluation: The signs (edema, erythema and excoriation or fissures) and symptoms 
(itching, burning and irritation) of infection will be assessed by the investigator and the subject, 
respectively, on the VSS Scale. The VSS Scale is a standardized, predefined scale where each 
sign and symptom will be given a numerical rating based on severity (absent = 0; mild = 1; 
moderate = 2; severe = 3) to calculate a total composite score.  
Mycological Evaluations: Mycological tests will include direct wet mount microscopic 
examination (performed locally) to visualize clue cells indicative of bacterial vaginosis or 
trichomonas, direct microscopic examination with 10% KOH (performed locally) to identify 
yeast, and fungal cultures (performed at the central lab) for species identification and 
susceptibility testing.  
Safety and Tolerability Assessments 
Safety Evaluations: Safety will be evaluated throughout the study, including the following 
parameters: AEs, vital signs, safety laboratory tests and study treatment discontinuations. 
STATISTICAL ANALYSES: 
Sample Size Determination 
The primary endpoint of the study is the percentage of subjects with Clinical Success (at least 
50% reduction from Baseline in the total composite VSS score with no additional antifungal 
therapy required based on investigator’s judgment) at the TOC visit. As this is a single arm 
sub-study, a statement regarding the Clinical Success rate and 95% confidence interval will be 
produced.  It is estimated that 60 subjects will be included based upon published fluconazole 
failure rates.  With a study of this size, if the Clinical Success rate for ibrexafungerp were 50%, 
this would correspond to a 95% confidence interval spanning from 36.8% to 63.2%.  Given it 
is expected that the Clinical Success for ibrexafungerp in subjects who have already failed 
fluconazole will be low as these subjects had already failed to respond, a sub-study of this size 
is appropriate to assess the efficacy of ibrexafungerp in this patient population 
Analysis Populations 
The study populations to be used in the analyses are defined as follows: 
• 
Intent-to-Treat (ITT) Population: All ibrexafungerp-treated subjects. 
• 
Modified Intent-to-Treat (mITT) Population: All treated subjects who have a positive 
culture for Candida species at Baseline. 
• 
Safety Population: All randomized subjects who received at least one dose of study drug 
and who have at least one post-Baseline evaluation. 
Efficacy Analysis 
Efficacy assessments will be based on clinical evaluations, mycological testing and additional 
antifungal use.  
The primary efficacy endpoint, the percentage of subjects with Clinical Success (at least 50% 
reduction from Baseline in the total composite VSS score with no additional antifungal therapy 
required based on investigator’s judgment) at TOC will be assessed on the mITT population 
and will present the Clinical Success rate and the 95% confidence interval calculated using the 
method of Clopper and Pearson.  Missing data for the primary endpoint will be imputed as 
failure. In addition, the Clinical Success rate and 95% CI will be calculated where subjects 
with missing values will be removed from the analysis. All other efficacy data will be 
summarized, but not subject to formal statistical analysis. 
The following treatment outcome definitions will be used for the assessment of efficacy 
relative to Baseline: 
Clinical Outcomes 


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• 
Clinical Success: at least 50% reduction from Baseline in the total composite VSS score 
with no additional antifungal therapy required based on investigator’s judgment 
• 
Clinical Improvement: partial or complete resolution of signs and symptoms (total 
composite score ≤1 on the VSS Scale) with no additional antifungal therapy required based 
on investigator’s judgment 
• 
Clinical Cure: complete resolution of signs and symptoms (total composite score of 0 on 
the VSS Scale) with no additional antifungal therapy required based on investigator’s 
judgment 
• 
Continued Clinical Success: sustained resolution of signs and symptoms in subjects who 
achieved Clinical Success at the TOC visit 
• 
Clinical Failure: Persistence and/or worsening of signs and symptoms or need for 
additional antifungal therapy 
Mycological Outcomes 
• 
Mycological Eradication: negative culture for growth of Candida species.  
• 
Mycological Persistence: positive culture for growth of Candida species. 
 
Safety Analysis 
Safety will be evaluated throughout the study, including the following parameters: AEs, 
treatment discontinuations, physical examination, vital signs, safety laboratory tests, and prior 
and concomitant medications. 
No formal statistical analysis is planned for the safety data. Safety presentations will be 
conducted using the Safety Population. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 
19.1 or higher. The incidence and severity of treatment-emergent AEs and SAEs and their 
relationship to treatment will be summarized by system organ class and preferred term. The 
percentage of subjects who discontinued study treatment and the reasons for discontinuation 
will be summarized. 
Safety laboratory evaluations and vital signs will be summarized as observed values and as 
changes from Baseline. In addition, shifts (with respect to the reference range) from Baseline 
will be presented for laboratory tests. 
 
 
 


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21.3.2 Schematic of Study Design 
 
 
Continue with 
MAIN STUDY 
NO 
MAIN STUDY  
Screening 
(Days -16 to -14)  
Acute Phase 
Fluconazole Treatment 
(Days -14 to -1)  
Significant resolution of signs and 
symptoms at Baseline (Day 1)? 
YES 
Follow-up Period 
(Day 11 [± 3] to Day 25 [± 4])  
Enter Open-Label 
Sub- Study 
Ibrexafungerp  
300 mg BID for 1 day 
TOC 
(Day 11 [± 3]) 
SUB-STUDY  
Abbreviations: BID = twice a day; TOC 
= Test of Cure 
*Note: See Section 5.0 for Main Study 
details. 


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21.3.3 Background Information and Scientific Rationale  
Background information for VVC, recurrent VVC (RVVC) and ibrexafungerp is 
available in Section 7.1 of the Main Study (study SCY-078-304). 
Considering the properties of ibrexafungerp as a potent antifungal compound with 
fungicidal activity against Candida spp., enhanced activity in low pH, concentration in 
vaginal tissue and spectrum of activity encompassing fluconazole-resistant strains, if 
ibrexafungerp is proven effective, it will represent an important alternative treatment for 
subjects suffering from VVC. 
In order to evaluate the efficacy of ibrexafungerp in the treatment of VVC that is not 
responding to oral fluconazole treatment, subjects who fail to respond to fluconazole 
treatment given as 150 mg once a day on Days -14, -11 and -8, for a total of 3 doses in 
the Acute Phase of the Main Study (study SCY-078-304) will be entered into this study.  
A subject will be considered not to respond to oral fluconazole treatment if she had a 
culture-confirmed vulvovaginal Candida spp. infection at Screening (Main Study) but did 
not achieve a significant resolution of her signs and symptoms at Baseline (Day 1). In 
addition, subjects must continue to meet all other eligibility criteria for the Main Study to 
enter this study (see Section 21.3.7). 
Subjects will receive oral ibrexafungerp 300 mg twice a day (BID) for one day (i.e., 
ibrexafungerp administered as a single-day treatment consisting of two doses of 300 mg 
each [given 12 hours apart]) on Day 1 only (total dose = 600 mg).  
The ibrexafungerp selected dose of 300 mg BID for 1day showed meaningful clinical and 
mycological response rates in a Phase 2b study (DOVE) with adequate tolerability. This 
dose is in the range of doses that have been well tolerated in Phase 1 investigations and is 
the dose in ongoing Phase 3 studies in the treatment of acute VVC. 
The primary endpoint of the study is the percentage of subjects with Clinical Success 
(defined as at least 50% reduction from Baseline in the total composite Vulvovaginal 
Signs and Symptoms [VSS] score, with no additional antifungal therapy required based 
on investigator’s judgment) at the Test-of-Cure (TOC) visit. Secondary endpoints will 
include the percentage of subjects with Clinical Improvement (partial or complete 
resolution of signs and symptoms [total composite score ≤1 on the VSS Scale] with no 
additional antifungal therapy required based on investigator’s judgment), Clinical Cure 
(complete resolution of signs and symptoms [total composite score of 0 on the VSS 
Scale] with no additional antifungal therapy required based on investigator’s judgment), 
Mycological Eradication, and both Clinical Cure and Mycological Eradication at the 
TOC visit. The percentage of subjects with Continued Clinical Success (sustained 
resolution of signs and symptoms in subjects who achieved Clinical Success at the TOC 
visit) at the Follow-up (FU) visit, and the absolute change in total composite VSS score 
from Baseline to the TOC and FU visits will also be assessed as secondary endpoints. 
These endpoints are considered appropriate for this study population and design. 


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21.3.4 Study Objectives 
21.3.4.1 
 Primary Objective 
• To evaluate the efficacy of a single-day dosing of oral ibrexafungerp in subjects with 
a history of RVVC who failed oral fluconazole therapy for the treatment of an acute 
VVC episode, based on Clinical Success. 
21.3.4.2 
 Secondary Objectives 
• To evaluate the efficacy of a single-day dosing of oral ibrexafungerp in subjects with 
a history of RVVC who failed oral fluconazole therapy for the treatment of an acute 
VVC episode, based on mycological and clinical outcomes.  
• To evaluate the safety and tolerability of a single-day dosing of oral ibrexafungerp in 
subjects with a history of RVVC who failed oral fluconazole therapy for the treatment 
of an acute VVC episode. 
21.3.5 Study Endpoints 
21.3.5.1 
Primary Endpoint 
Efficacy as measured by: 
• The percentage of subjects with Clinical Success (at least 50% reduction from 
Baseline in the total composite VSS score with no additional antifungal therapy 
required based on investigator’s judgment) at the Test-of-Cure (TOC) visit.  
21.3.5.2 
Secondary Endpoints 
Efficacy as measured by: 
• The percentage of subjects with Clinical Improvement (partial or complete resolution 
of signs and symptoms [total composite score  ≤1 on the VSS Scale] with no 
additional antifungal therapy required based on investigator’s judgment) at the TOC 
visit. 
• The percentage of subjects with Clinical Cure (complete resolution of signs and 
symptoms [total composite score of 0 on the VSS Scale] with no additional antifungal 
therapy required based on investigator’s judgment) at the TOC visit. 
• The percentage of subjects with Mycological Eradication (negative culture for growth 
of Candida spp.) at the TOC visit. 
• The percentage of subjects with both Clinical Cure and Mycological Eradication at 
the TOC visit. 
• The percentage of subjects with Continued Clinical Success (sustained resolution of 
signs and symptoms in subjects who achieved Clinical Success at the TOC visit) at 
the FU visit. 


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• The absolute change in total composite VSS score from Baseline to the TOC and FU 
visits. 
 
Safety and tolerability as measured by: 
• Adverse events (AEs), vital signs, treatment discontinuation and safety laboratory 
tests. 
21.3.6 Study Design 
This Nested Sub-Study is an exploratory, open-label, single-group study to evaluate the 
efficacy and safety of oral ibrexafungerp in the treatment of acute episodes of VVC in 
subjects with a history of RVVC who have not responded to 3 doses of oral fluconazole 
treatment.  
A subject will be considered to have failed oral fluconazole therapy if she had a positive 
culture for Candida spp. at Screening (Main Study) but did not achieve a significant 
resolution of the signs and symptoms of infection (defined as a total composite score ≤ 2 
on the VSS Scale) at the Baseline Visit (Day 1) following treatment with oral fluconazole 
150 mg once daily (QD) on Days -14, -11 and -8.  Eligible subjects must continue to 
meet all other applicable eligibility criteria of the Main Study (study SCY-078-304) to 
enter this study.  
Approximately 60 subjects are planned to enter this study. All eligible subjects will 
receive oral ibrexafungerp administered as a single-day treatment consisting of two 
300-mg doses (total dose = 600 mg) given 12 hours apart (±4 hours).  
The study will consist of the following visits: 
• Baseline visit (Day 1): Single-day, open-label administration of two doses of oral 
ibrexafungerp 300 mg 
• TOC visit (Day 11 [±3]): Assessment of efficacy and safety 
• FU visit (Day 25 [±4]) 
The study will include efficacy, safety and tolerability assessments.  
21.3.6.1 
Study Visits 
Baseline Visit (Day 1): Study Drug Dosing 
Subjects who meet all criteria for this study will receive the first dose of study drug, oral 
ibrexafungerp 300 mg, at the site and will self-administer the second 300-mg dose at 
home, 12 hours (±4 hours) after the first dose. At this visit, subjects will be provided with 
subject diaries to record the date and time of their second study drug dose and to rate 
their vulvovaginal symptoms of infection, AEs and concomitant medication use from the 
Baseline (Day 1) visit until the TOC visit (Day 11 ± 3).  


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TOC Visit (Day 11 [± 3]): Assessment of Efficacy 
At the TOC visit (Day 11), treatment compliance will be evaluated, and subject diaries 
will be returned and reviewed. The investigators and the subjects will rate the signs and 
symptoms of infection, respectively, on the VSS Scale (see Section 21.2 [Appendix B] of 
the Main Study).  
If the baseline vulvovaginal signs and symptoms have not improved or have worsened, 
vulvovaginal samples for fungal culture, species identification and antifungal 
susceptibility testing will be obtained and sent to a designated central laboratory. 
Additional vaginal samples will be obtained for a potassium hydroxide (KOH) testing by 
the local laboratory if symptoms persist or have worsened. An abbreviated physical 
exam, vital signs measurements and safety laboratory tests will also be performed. 
Follow-Up (Day 25 [± 4]) 
At the FU visit, subjects will rate their symptoms of infection on the VSS Scale. 
Vulvovaginal samples for pH determination, KOH testing and fungal culture should be 
obtained if there is persistence or worsening of vulvovaginal symptoms. Only if 
symptoms are present, the investigator will perform a vulvovaginal examination to rate 
the subject’s signs of infection. 
Unscheduled Visits 
Unscheduled visits should be conducted anytime that there is indication of persistence or 
worsening of symptoms or an adverse event. If there is suspicion of persistence or 
worsening of symptoms, subjects will be strongly discouraged from self-administering 
any treatment and will be instructed to visit the study center for a proper evaluation 
before initiating any new VVC treatment. 
All visits 
AEs and prior/concomitant medications will be assessed and documented at all visits. 
21.3.6.2 
Study Assessments 
Efficacy Assessments 
Efficacy assessments will be based on clinical evaluations (rating of signs and symptoms 
of infection) and mycological testing (direct microscopic examinations and fungal 
cultures).  
• Clinical Evaluations: The signs (edema, erythema and excoriation or fissures) and 
symptoms (itching, burning and irritation) of infection will be assessed and rated 
by the investigator and the subject, respectively, on the VSS Scale (provided in 
Section 21.2 [Appendix B]). The VSS Scale is a standardized, predefined scale 
where each sign and symptom will be given a numerical rating based on severity 
(absent = 0; mild = 1; moderate = 2; severe = 3) to calculate a total composite VSS 
score. 


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• Mycological Evaluations: Mycological tests will include direct wet mount 
microscopic examination (performed locally) to visualize clue cells indicative of 
bacterial vaginosis or trichomonas, direct microscopic examination with 10% 
KOH (performed locally) to identify yeast and fungal cultures (performed at the 
central lab) for species identification and susceptibility testing. 
 
Safety and Tolerability Assessments 
Safety and tolerability will be evaluated by AEs, vital signs, safety laboratory tests and 
study treatment discontinuations. 
 
A detailed description of study procedures is available in Section 21.3.10. 
21.3.7 Study Population 
The population will include subjects enrolled in the Main Study who fail oral fluconazole 
treatment for their VVC episode. 
21.3.7.1 
Inclusion Criteria 
Subjects must fulfill all of the following criteria to be eligible for admission to this study: 
1. Subject meets the following criteria at Baseline (Day 1): 
a. Failure to achieve a significant resolution of the signs and symptoms of the Candida 
infection (total composite score ≥ 3 on the VSS Scale). 
b. Culture positive for Candida spp. in a vaginal sample collected at Screening (Main 
Study). 
c. Normal vaginal pH (≤ 4.5) 
2. Subject meets all other inclusion criteria in Section 11.1 of the Main Study (except 
Inclusion Criterion No. 3a, requiring a total composite score ≤ 2 on the VSS Scale). 
21.3.7.2 
Exclusion Criteria 
A subject will be excluded from participation in this study if she meets any of the 
exclusion criteria listed in Section 11.2 of the Main Study. 
21.3.7.3 
Discontinuation Criteria 
A subject may me be discontinued from this study for any of the following reasons: 
• Withdrawal of consent by the subject and/or subject’s legal guardian; 
• Investigator or sponsor decision that withdrawal is in the subject’s best interest; 


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• Occurrence of an AE that, in the opinion of the investigator, warrants 
discontinuation of the subject from the study drug; 
• Lost to follow-up (every attempt should be made to contact the subject). 
If the subject withdraws consent on or before the TOC (Day 11) visit, all TOC visit 
procedures should be performed at the early termination visit. If the subject withdraws 
consent on or before the FU (Day 25) visit, all FU visit procedures should be performed 
at the early termination visit. Once the subject has completed all assessments for the early 
termination visit, as appropriate, no further follow-up will be needed unless there is an 
ongoing study drug-related AE. All study drug-related AEs should be followed up until 
resolution. 
21.3.8 Study Treatments 
21.3.8.1 
Study Treatment Groups 
This is an open-label, single-group study. All subjects will receive oral ibrexafungerp 
administered as a single-day treatment (Baseline [Day 1]) consisting of two 300-mg 
doses (total dose = 600 mg) given 12 hours apart (±4 hours). The study drug should be 
administered preferably with or immediately after a meal.  
21.3.8.2 
Study Drug Description, Formulation, Packaging, Labelling and 
Storage 
The study drug administered during the study will be provided by the Sponsor and will 
consist of oral ibrexafungerp (150-mg tablets). The study drug will be supplied as 
ibrexafungerp citrate drug product, a tablet containing 150 mg of ibrexafungerp active 
ingredient on a free-base basis for oral administration. In addition to the active ingredient, 
the tablet formulation also contains silicified microcrystalline cellulose, crospovidone, 
mannitol, colloidal silicon dioxide, magnesium stearate (non-bovine) and butylated 
hydroxyanisole. 
The pharmacist or appropriate designee at each clinical research site will be responsible 
for the study drug. For long-term storage at the site, ibrexafungerp must be kept in a 
secure, limited-access storage area (e.g., locked cabinet) and stored at room temperature. 
 
Drug Accountability 
The investigator or designee will inventory and acknowledge receipt of all shipments of 
the study drug during the Sub-Study. Drug accountability logs will be used to maintain 
accurate records of receipt, dispensing, administration to each subject and return of drug.  
A study monitor will periodically check the supplies of investigational products held by 
the site to verify accountability of all study drugs. After drug accountability has been 
completed by the monitor, all unused study drug and all medication containers will be 
returned to the Sponsor or destroyed on site if the site has procedures in place for study 
drug destruction. 


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The study drug supplied for this study is only for use in subjects properly consented and 
enrolled under this protocol. A study site designee (e.g. pharmacist, study 
nurse/coordinator) will: 
• Record the treatment in the appropriate drug accountability log 
• Report and document any study medication issues such as crushed or broken 
tablets (all product quality complaints should be reported to the Sponsor) 
• Collect and count the number of tablets remaining at the TOC (Day 11) visit 
• Review subject diary and tablet count, and record any unused or remaining drug in 
the drug accountability log and eCRF and note any discrepancies and reason for 
discrepancies 
21.3.8.3 
Subject Compliance with Study Drug Dosing 
Subjects (or subject’s parent/legal representative, if applicable) will be instructed to have 
the assigned bottle of study medication (including empty containers) with them at the 
TOC (Day 11) visit.  Compliance will be assessed based on remaining tablets as 
compared to what should have been taken and based on the subject diary where the 
subject will enter the details of their second study drug dosing.  Details of treatment 
including any missed second dose will be recorded on the eCRF. Sites are encouraged to 
contact the medical monitor or Sponsor for concerns of compliance with the treatment 
regimen, especially for subjects who miss their second dose due to AEs related with 
tolerability. 
21.3.9 Non-Study Treatments 
21.3.9.1 
Prior and Concomitant Medications 
All medications (including prescription and over-the-counter medications, supplements, 
and herbal products) taken from Baseline (Day 1) through the TOC (Day 11) visit will be 
recorded on the eCRF. Only the use of other antifungal medications, medications used to 
treat vaginal bacterial or parasitic infections, topical vaginal medications or medications 
to treat a study-drug related AE will be recorded after the TOC (Day 11) visit through the 
last study visit (FU [Day 25] visit).  Start and stop dates of concomitant medications will 
be recorded on the eCRF. Prior and concomitant medications will be reviewed and 
recorded at all scheduled and unscheduled study visits. 
21.3.9.2 
Prohibited Medications and Medications to be Administered 
with Caution 
Certain medications are not permitted during the study or must be administered with 
caution. See Section 21.1 (Appendix A) of the Main Study for details. 


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21.3.10 Study Procedures 
The following sections provide a description of the individual study procedures to be 
performed during the conduct of the study.  Detailed schedules of study assessments are 
provided in the Schedule of Visits and Procedures in Sub-Study Table 1.  
Study days are counted relative to the first dose of study drug (Baseline [Day 1]). If a 
subject is actively menstruating at a study visit that requires a vaginal exam, the visit 
should be rescheduled as soon as the subject’s period ends but in no case more than 7 
days after the initially scheduled visit. Unscheduled visits will be conducted any time that 
there is persistence or worsening of symptoms. 
21.3.10.1 
Informed Consent 
At the Screening visit of the Main Study, subjects (or their legal representative, if 
applicable) will provide consent for participation in both the Main Study and this study, 
and will enter either study based on the criteria met at Baseline (Day 1) (see Section 11.1 
and Section 11.2 in the Main Study).  
21.3.10.2 
Assignment of Subject Number 
Subjects included in the study will maintain the same unique subject identification (ID) 
number provided at the Screening visit of the Main Study, except that an additional letter 
coding will be added to the ID number to identify subjects participating in this study. 
21.3.10.3 
Inclusion/Exclusion Criteria 
All study inclusion and exclusion criteria will be reviewed at Baseline (Day 1) to ensure 
that the subject qualifies for the trial. 
21.3.10.4 
Abbreviated Physical Exam 
An abbreviated physical examination, including general appearance and an overall 
examination of body systems, will be conducted at the Baseline (Day 1) visit, the TOC 
(Day 11) visit and any unscheduled visit, if needed. 
21.3.10.5 
Urine Pregnancy Test 
A urine pregnancy test based on the measurement of human chorionic gonadotropin with 
a sensitivity of at least 25 mIU/mL will be performed at the Baseline (Day 1) visit and at 
unscheduled visits, if needed, by the local laboratory for all subjects of childbearing 
potential. The subject must have a negative pregnancy test before taking the first dose of 
study drug.  
21.3.10.6 
Vulvovaginal Samples 
The following vulvovaginal samples will be collected during the study: 
• Sample for direct microscopic examination with 10% KOH: A vulvovaginal 
sample for KOH testing by the local laboratory will be obtained for all subjects at 


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the Baseline (Day 1) visit. If the Baseline (Day 1) vulvovaginal signs and 
symptoms have not improved or have worsened at the TOC (Day 11) and FU (Day 
25) visits, a vaginal sample should be obtained for KOH testing by the local 
laboratory. Vaginal samples for KOH should also be collected any other time that 
a subject experiences persistence or worsening of symptoms (i.e., at unscheduled 
visits, if needed). The sample will be assessed by a local laboratory or at the site by 
the investigator or a qualified designee.  
The direct microscopic examination with KOH is intended for the visualization of 
yeasts. If the KOH test is negative, the investigator should consider other causes 
for the persistence or worsening of the symptoms. 
• Sample for fungal culture: A fungal culture will be collected at the Baseline 
(Day 1) visit for all subjects. If the Baseline (Day 1) vulvovaginal signs and 
symptoms have not improved or have worsened at the TOC (Day 11) and FU (Day 
25) visits, a vaginal sample should be obtained for fungal culture. Vaginal samples 
for culture should also be collected any other time that a subject experiences 
persistence or worsening of symptoms (i.e., at unscheduled visits, if needed). The 
sample will be processed by a central laboratory for species identification. Positive 
cultures will also be tested for susceptibility against ibrexafungerp, fluconazole 
and additional antifungal agents, as deemed appropriate based on validated 
methods.. 
• Sample for vaginal pH: To be collected at the Baseline (Day 1) visit for all 
subjects and at the TOC (Day 11) and FU (Day 25) visits if vulvovaginal signs and 
symptoms have not improved or have worsened. Samples for pH should also be 
obtained any time that a subject experiences persistence or worsening of symptoms 
(i.e., unscheduled visits if needed). The sample will be assessed at the site by the 
investigator or a qualified designee. 
• Sample for identification of other pathogens: 
o Samples (e.g. wet mount) to rule out bacterial vaginosis and Trichomonas 
vaginalis will be collected at Baseline (Day 1) and any time that a subject 
experiences persistence or worsening of symptoms. Samples will be assessed 
by a local laboratory or at the site by the investigator or a qualified designee. 
o Samples to rule out Neisseria Gonorrhoeae, Chlamydia trachomatis or Herpes 
virus are to be collected at the Baseline (Day 1) visit, and then at the TOC (Day 
11) and FU (Day 25) visits if vulvovaginal signs and symptoms have not 
improved or have worsened. Samples should also be collected any time that 
there is persistence or worsening of symptoms if any of these pathogens is 
suspected. Samples will be processed by a central laboratory.  
Procedures for collecting and processing local samples, as well as for shipping central 
laboratory vulvovaginal samples, will be described in the laboratory manual. 


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21.3.10.7 
Vulvovaginal Examination and Rating of Vulvovaginal Signs by 
the Investigator Using the VSS Scale 
The investigator (or qualified designee) will perform vulvovaginal examinations to rate 
the subject’s signs of infection at the Baseline (Day 1) and TOC (Day 11) visits. The 
vulvovaginal examination will be repeated at the FU (Day 25) visit only if the subject 
presents symptoms. Otherwise, no additional vulvovaginal examination will be 
conducted, or signs rated. Vulvovaginal examinations may be conducted at unscheduled 
visits, if needed.  
If the subject experiences persistence or worsening of symptoms, a vaginal examination 
with rating of signs by the investigator should be completed.  
Investigators will assess the signs of infection using the VSS Scale provided in 
Section 21.2 (Appendix B) of the Main Study, a standardized, predefined scale where 
each sign of the vagina and/or vulva will be given a numerical rating based on severity, 
as follows: 
• Edema: absent = 0; mild = 1; moderate = 2; severe = 3 
• Erythema: absent = 0; mild = 1; moderate = 2; severe = 3 
• Excoriation or fissures: absent = 0; mild = 1; moderate = 2; severe = 3 
Other findings will be recorded using the most relevant medical term in the abbreviated 
physical examination page of the eCRF. 
If a subject is actively menstruating at the time of a study visit that requires a 
vulvovaginal exam, the visit should be rescheduled as soon as the subject’s period ends 
but in no case more than 7 days after the initially scheduled visit. 
21.3.10.8 
Rating of Vulvovaginal Symptoms by the Subject Using the VSS 
Scale  
Subjects will be asked to rate their vulvovaginal symptoms from Baseline (Day 1) 
through the TOC (Day 11) visit and at the FU (Day 25) visit. Subjects will also assess 
their symptom at unscheduled visits, as needed.  
If the subject experiences persistence or worsening of symptoms, a vaginal examination 
with rating of signs by the investigator should be completed. 
Subjects will rate their symptoms of infection using the VSS Scale (see Section 21.2 
[Appendix B] of the Main Study), where each vulvovaginal symptom will be given a 
numerical rating based on severity, as follows: 
• Itching: absent = 0; mild = 1; moderate = 2; severe = 3 
• Burning: absent = 0; mild = 1; moderate = 2; severe = 3 
• Irritation: absent = 0; mild = 1; moderate = 2; severe = 3 
Subjects will rate their symptoms and record their scores on the VSS Scale included in 
their subject diaries. 


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21.3.10.9 
Single-Day Study Drug Dosing and Dispensing 
At the Baseline (Day 1) visit, subjects will receive their first dose of study drug 
(ibrexafungerp 300 mg) at the site and will be given study drug to self-administer their 
second dose (ibrexafungerp 300 mg) at home, approximately 12 hours later on the same 
day. The two doses should be administered approximately 12 (±4) hours apart. Study 
drug should be administered preferably with or immediately after a meal. 
21.3.10.10 
Dispensing, Completion, Collection and Review of Subject 
Diaries 
Subject diaries will be provided to all subjects at the Baseline (Day 1) visit for them to 
complete on a daily basis until the TOC (Day 11) visit. The subject diaries will include 
the VSS Scale so that subjects can rate their vulvovaginal symptoms  (see 
Section 21.3.10.7 and Section 21.3.10.8 for sign and symptom rating procedures, 
respectively, and Section 21.2 [Appendix B] for the full VSS Scale). Subjects will also 
record other medical concerns or complaints, concomitant medications used, adverse 
events and second dose of study drug details. Subjects will be instructed to return their 
subject diaries at the TOC (Day 11) visit, when they will be collected and reviewed. 
The site will determine if any signs/symptoms or other medical concerns/complaints 
recorded on the diary should be reported as AEs. The information from the subject diary 
will be reviewed by the site and relevant findings included in the corresponding eCRFs 
modules (e.g. concomitant medications, AEs, etc.). 
21.3.10.11 
Study Drug Collection and Treatment Compliance 
Treatment compliance will be reviewed by the investigator or designee at the TOC (Day 
11) visit. Subjects (or subjects’ legal representatives, if applicable) will be instructed to 
bring all bottles (including empty bottles) of study medication with them to the visit to 
assess treatment compliance. Further details are available in Section 21.3.8.3. 
21.3.10.12 
Assessment of Efficacy 
Efficacy outcomes (Section 21.3.14.5.1) will be assessed by the investigator at the TOC 
(Day 11) and FU (Day 25) visits and any time there is suspicion of persistence or 
worsening of symptoms. Efficacy will be evaluated based on the following procedures: 
• Vulvovaginal examination and rating of VVC signs on the VSS Scale by the 
investigator (see Section 21.3.10.7) 
• Rating of vulvovaginal symptoms on the VSS Scale by the subject (see 
Section 21.3.10.8) 


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• Collection of vaginal samples for the following tests (see Section 21.3.10.6): 
o pH measurement (local) 
o 10% KOH testing for identification of yeasts (local) 
o Fungal culture for identification of species and susceptibility testing (central) 
o Additional tests for identification of other potential pathogens (local or central, 
depending on pathogen) 
• Recording of any additional antifungal medication used by the subject (see 
Section 21.3.10.15) 
All of the procedures above should be completed prior to administration of any new 
antifungal medication. If there is suspicion of persistence or worsening of symptoms, 
subjects will be strongly discouraged from self-administering any treatment and will 
be instructed to visit the study center for a proper evaluation before initiating any 
new VVC treatment. Ideally, if the severity of the symptoms allows based on the 
investigator’s judgment, the initiation of antifungal therapy should be delayed until 
results from the vaginal culture are available to confirm that the episode is due to 
Candida spp. and not to other cause of vaginitis. 
21.3.10.13 
 Sample Collection for Safety Laboratory Tests 
Safety laboratory tests will be performed by a qualified central laboratory. Blood samples 
for safety laboratory tests will be collected at the TOC (Day 11) visit and at any 
unscheduled visit, if needed. If indicated, these may be done more frequently as 
follow- up to a laboratory abnormality. 
The following laboratory parameters will be determined: 
Hematology 
 White blood cell (WBC) count  
 Hemoglobin 
 Red blood cell (RBC) count  
 Hematocrit 
 Platelet count 
 
 Differential WBC count will include percentages for lymphocytes, monocytes, 
eosinophils and basophils, and absolute counts for neutrophils, lymphocytes, atypical 
lymphocytes, monocytes, eosinophils and basophils. 


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Blood Chemistry 
 Glucose 
 Total creatine phosphokinase (CPK) 
 Albumin 
 Aspartate aminotransferase (AST/SGOT) 
 Sodium 
 Alanine aminotransferase (ALT/SGPT) 
 Potassium 
 Gamma glutamyl transferase (GGT) 
 Alkaline Phosphatase 
 Bilirubin (total, direct and indirect) 
 Creatinine 
 Blood urea Nitrogen (BUN) 
 Total protein  
21.3.10.14 
Vital Signs 
Vital signs, including blood pressure (systolic and diastolic), heart rate, respiratory rate 
and body temperature will be measured at the Baseline (Day 1) and TOC (Day 11) visits 
as well as at unscheduled study visits, if needed. 
21.3.10.15 
Prior and Concomitant Medication Review 
All medications (including prescription and over-the-counter medications, supplements, 
and herbal products) taken from Baseline (Day 1) through the TOC visit (Day 11) will be 
recorded on the subject’s diary and eCRF. Only the use of other antifungal medications, 
medications used to treat vaginal bacterial or parasitic infections, topical vaginal 
medications or any other medications to treat a study drug-related AE will be recorded 
after the TOC visit through the last study visit (FU [Day 25]). Start and stop dates of 
concomitant medications will be recorded in the eCRF. Prior and concomitant 
medications will be reviewed and recorded at all scheduled and unscheduled study visits. 
See Section 21.1 (Appendix A) of the Main Study for prohibited medications, 
medications to be administered with caution and further details for non-study treatments. 
21.3.10.16 
Adverse Event Monitoring 
AEs will be recorded and reviewed at all scheduled and unscheduled study visits from the 
time the Informed Consent Form is signed in the Main Study through Follow up (Day 
25). Subjects will record any AE on their study diary from Baseline (Day 1) through the 
TOC visit (Day 11).  
21.3.11 Study Schedule 
Detailed schedules of all study visits and procedures are presented in the Schedule of 
Visits and Procedures (Sub-Study Table 1). 
 


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Sub-Study Table 1: Schedule of Visits and Procedures (Study SCY-078-304S) 
Visit 
Baseline 
(Treatment)  
Test of Cure 
Follow-up 
Unscheduled 
Visitsa 
Day 
(allowable window) 
 
Study Procedures 
Day 1 
Day 11 (±3) 
Day 25 
(± 4) 
Informed Consentb 
 
Assignment of Subject Number  
X 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
Abbreviated physical exam 
Xc 
X 
 
If needed 
Urine pregnancy testd 
Xc 
 
 
If needed 
Vulvovaginal sample for KOHe 
X 
If needed 
If needed 
If needed 
Vulvovaginal sample for fungal culturee 
Xc 
If needed 
If needed 
If needed 
Vulvovaginal sample for pHe 
Xc 
If needed 
If needed 
If needed 
Vulvovaginal sample for other pathogense 
X 
 
 
If needed 
Vulvovaginal examf and rating of signs by 
the investigator 
Xc 
X 
If 
symptomsg 
If needed 
Rating of vulvovaginal symptoms by the 
subject 
Xc-----------------X 
X 
If needed 
Study drug dosing and dispensing 
Xh 
 
 
 
Subject diary dispensingi 
X 
 
 
 
Subject diary completion 
X -----------------X 
 
 
Study drug collection and review 
 
X 
 
 
Subject diary collection and review 
 
X 
 
 
Assessment of efficacy 
 
X 
X 
 
Sample collection for safety labs 
(hematology and blood chemistry) 
 
Xj 
 
If needed 
Vital Signs 
Xc 
X 
 
If needed 
Prior & concomitant medication review 
Xc 
X 
X 
X 
Adverse event monitoringk 
Xc 
X 
X 
X 
Abbreviations: KOH = potassium hydroxide; VSS = vulvovaginal signs and symptoms 
a. 
Unscheduled visits should be conducted anytime that there is indication of persistence or worsening of 
symptoms or an adverse event. If there is suspicion of persistence or worsening of symptoms, subjects 
will be strongly discouraged from self-administering any treatment and will be instructed to visit the 
study center for a proper evaluation before initiating any new VVC treatment. 
b. Informed consent will be obtained for both the Main Study and this Sub-Study at the Screening visit of 
the Main Study. 
c. 
These procedures are conducted as part of the Baseline (Day 1) visit for the Main Study and do not need 
to be repeated for the purpose of this study. 
d. Results should be reviewed prior to the administration of the first dose of study drug. 
e. 
Vulvovaginal specimens will be obtained at the Baseline (Day 1) visit for all subjects and at the TOC 
(Day 11) and FU (Day 25) visits if vulvovaginal symptoms have not improved or have worsened. 
Samples will be collected for pH determination and KOH testing as well as to rule out bacterial vaginosis 
and Trichomonas vaginalis (wet-mount or other, process locally at the site or at a local qualified lab). 
Testing for Neisseria Gonorrhoeae, Chlamydia trachomatis or Herpes virus may also be conducted if 
these pathogens are suspected (central laboratory). Samples for fungal culture should also be collected for 
processing at a central laboratory. Susceptibility testing will be done centrally for all positive cultures 
during the study. Samples should also be obtained any time that a subject experiences persistence or 
worsening of symptoms (i.e., unscheduled visits if needed). 
f. 
If a subject is actively menstruating at a study visit that requires a vaginal exam, the visit should be 
rescheduled as soon as the subject’s period ends but in no case more than 7 days after the initially 


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Visit 
Baseline 
(Treatment)  
Test of Cure 
Follow-up 
Unscheduled 
Visitsa 
Day 
(allowable window) 
 
Study Procedures 
Day 1 
Day 11 (±3) 
Day 25 
(± 4) 
scheduled visit. 
g. Vulvovaginal examinations will be repeated at the FU visit only if the subject presents symptoms. 
Otherwise, no additional vulvovaginal examination will be conducted, or signs rated.  
h. Subjects will receive their first dose of study drug at the site at the Baseline (Day 1) visit and will be given 
study drug to self-administer their second dose at home. The two doses should be administered 
approximately 12 (±4) hours apart, preferably with or immediately after a meal. 
i. 
Subject diaries will be used to rate vulvovaginal symptoms of infection on the VSS Scale and record 
second dose of study drug details, adverse events and concomitant medication use. 
j. 
Conducted by the central lab. 
k. Recorded from the time the Informed Consent Form is signed in the Main Study. 
 
 
 


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21.3.12 Safety Assessments and Monitoring 
21.3.12.1 
Definitions, Grading, Causality and Other General Details for 
Adverse Events 
All specifications for AE definitions, grading, causality, reporting and other general 
details for safety assessment and monitoring that are provided in Section 16.0 of the Main 
Study protocol are applicable to this Nested Sub-Study except if in conflict with any of 
the sections provided below. 
21.3.12.2 
Events of Clinical Interest 
The following are considered events of clinical interest (ECIs) if they occur after dosing, 
and must be reported by the site when it becomes aware of the ECI: 
• 
ALT or AST > 8 x the upper limit of normal (ULN), confirmed by repeat testing 
• 
ALT or AST > 5 x ULN for more than 2 weeks or accompanied by total 
bilirubin > 2 x ULN   
21.3.12.3 
Adverse Event Collection Timeframe 
AEs and serious AEs (SAEs) will be recorded from Baseline (Day 1) through the Follow 
up (Day 25) visit. Subjects will record any AE on their study diary from Baseline (Day 1) 
through the TOC visit (Day 11). 
All AEs reported by the subject or observed by members of the clinical staff will be 
evaluated by the principal investigator (PI) or qualified designee. The investigator will 
attempt, if possible, to establish a diagnosis based on presenting signs and symptoms.  
The nature of the AE, time of onset relative to study drug administration, duration, 
severity, and relationship to treatment should be determined. Details of any corrective 
treatment must be recorded in the eCRF. The PI will determine whether any changes 
have occurred in baseline signs and symptoms. All AEs and SAEs will be collected in the 
eCRF. 
21.3.12.4 
Procedures for Emergency Unblinding 
This is an open-label study. No procedures for emergency unblinding are required. 
21.3.13 Data Collection, Study Monitoring and Record Management 
See Section 17.0 of the Main Study protocol for data collection, study monitoring and 
record management details. 
21.3.14 Analytical Plan 
All statistical processing will be performed using SAS® version 9.3 or later, unless 
otherwise stated.   


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Descriptive statistics (i.e., mean, standard deviation, median, minimum, maximum, etc.) 
will be provided for all continuous variables; frequencies and percentages will be 
presented for incidence and categorical variables.  For parameters measured over time, 
observed values and changes from Baseline will be described for each time point. 
The Clinical Cure and Mycological Eradication rates will be described by baseline 
Candida species, when the number of isolates per species allows.  
A Statistical Analysis Plan (SAP) describing all statistical analyses in detail will be 
provided as a separate document. The SAP will be finalized before full review of the data 
from this sub-study to avoid bias. 
21.3.14.1 
Sample Size Determination 
The primary endpoint of the study is the percentage of subjects with Clinical Success (at 
least 50% reduction from Baseline in the total composite VSS score with no additional 
antifungal therapy required based on investigator’s judgment) at the TOC visit. As this is 
a single arm sub-study, a statement regarding the  Clinical Success rate and 95% 
confidence interval will be produced.  It is estimated that 60 subjects will be included 
based upon published fluconazole failure rates.  With a study of this size, if the Clinical 
Success rate for ibrexafungerp were 50%, this would correspond to a 95% confidence 
interval spanning from 36.8% to 63.2%.  Given it is expected that the Clinical Success for 
ibrexafungerp in subjects who have already failed fluconazole will be low as these 
subjects had already failed to respond, a sub-study of this size is appropriate to assess the 
efficacy of ibrexafungerp in this patient population. 
21.3.14.2 
Analysis Populations 
The study populations to be used in the analyses are defined as follows: 
• Intent-to-Treat (ITT) Population: All ibrexafungerp-treated subjects. 
• Modified Intent-to-Treat (mITT) Population: All treated subjects who have a 
positive culture for Candida species at Baseline. 
• Safety Population: All randomized subjects who received at least one dose of 
study drug and who have at least one post-Baseline evaluation. 
21.3.14.3 
Handling of Missing Data and Early Withdrawals 
For the efficacy analyses, subjects who do not have a TOC (Day 11) assessment will be 
assigned as treatment failures. For subjects who withdraw from the study early, every 
effort will be made to collect TOC (Day 11) visit information at the point of withdrawal. 
21.3.14.4 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization 
Drug Dictionary terminology. The number and percentage of subjects taking each 
medication before and after the first dose of study drug will be tabulated by treatment 
group. Medications taken and stopped prior to the first dose of study drug will be 


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considered prior medications. Medications started on or before the EOFU visit date with 
missing stop dates or stop dates after the first dose of study drug will be considered 
concomitant medications. 
21.3.14.5 
Efficacy 
21.3.14.5.1 Efficacy Assessments 
The primary efficacy endpoint of the study is the percentage of subjects with Clinical 
Success (at least 50% reduction from Baseline in the total composite VSS score with no 
additional antifungal therapy required based on investigator’s judgment) at the Test-of-
Cure (TOC) visit.  
Secondary efficacy endpoints include the percentage of subjects with Clinical 
Improvement at the TOC visit, the percentage of subjects with Clinical Cure at the TOC 
visit, the percentage of subjects with Mycological Eradication at the TOC visit, the 
percentage of subjects with both Clinical Cure and Mycological Eradication at the TOC 
visit, the percentage of subjects with Continued Clinical Success at the FU visit, and the 
absolute change in total composite VSS score from Baseline to the TOC and FU visits. 
The following treatment outcome definitions will be used for the assessment of efficacy 
relative to baseline: 
Clinical Outcomes 
• 
Clinical Success: at least 50% reduction from Baseline in the total composite VSS 
score with no additional antifungal therapy required based on investigator’s judgment 
• Clinical Improvement: partial or complete resolution of signs and symptoms (total 
composite score  ≤1 on the VSS Scale) with no additional antifungal therapy required 
based on investigator’s judgment 
• Clinical Cure: complete resolution of signs and symptoms (total composite score of 0 
on the VSS Scale) with no additional antifungal therapy required based on 
investigator’s judgment 
• Continued Clinical Success: sustained resolution of signs and symptoms in subjects 
who achieved Clinical Success at the TOC visit 
• Clinical Failure: persistence and/or worsening of signs and symptoms or need for 
additional antifungal therapy 
Mycological Outcomes 
• Mycological Eradication: negative culture for growth of Candida species.  
• Mycological Persistence: positive culture for growth of Candida species. 
21.3.14.5.2 Efficacy Analyses 
The primary endpoint, the percentage of subjects with Clinical Success at TOC, will be 
assessed on the mITT population and will present the Clinical Success rate and the 95% 
confidence interval calculated using the method of Clopper and Pearson.1  Missing data 
for the primary endpoint will be imputed as failure. In addition, the Clinical Success rate 


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and 95% confidence interval will be calculated where subjects with missing values will 
be removed from the analysis. 
All other efficacy data will be summarized, but not subject to formal statistical analysis. 
21.3.14.6 
Safety 
21.3.14.6.1 Safety Assessments 
Safety will be evaluated throughout the study, including the following parameters: AEs, 
treatment discontinuations, physical examination, vital signs, safety laboratory tests, and 
prior and concomitant medications. 
AEs will be recorded and reviewed at all scheduled and unscheduled study visits from the 
time the Informed Consent Form is signed in the Main Study. An abbreviated physical 
examination, including general appearance and an overall examination of body systems, 
will be conducted at Baseline (Day 1), at the TOC (Day 11) visit, and at unscheduled 
visits, if needed. Vital signs, including blood pressure (systolic and diastolic), heart rate, 
respiratory rate and body temperature will be measured at the Baseline (Day 1) and TOC 
(Day 11) visits, and at unscheduled visits, if needed. Safety laboratory tests (hematology 
and blood chemistry) will be measured at the TOC (Day 11) visit and at unscheduled 
visits, if needed. All prior and concomitant medications taken before Baseline (Day 1) 
through the TOC (Day 11) visit will be recorded. Only the use of other antifungal 
medications, medications used to treat vaginal bacterial or parasitic infections, topical 
vaginal medications, or any other medications to treat a study drug related AE will be 
recorded after the TOC (Day 11) visit through the last study visit (FU [Day 25]). 
Safety procedures are described in Section  21.3.10 and safety assessments are described 
in Section 21.3.12. 
21.3.14.6.2 Safety Analyses 
No formal statistical analysis is planned for the safety data. Safety presentations will be 
conducted using the Safety Population. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 19.1 or higher. The incidence and severity of treatment-emergent AEs and SAEs 
and their relationship to treatment will be summarized by system organ class and 
preferred term. The percentage of subjects who discontinued study treatment and the 
reasons for discontinuation will be summarized. 
Safety laboratory evaluations and vital signs will be summarized as observed values and 
as changes from Baseline. In addition, shifts (with respect to the reference range) from 
Baseline will be presented for laboratory tests. 
21.3.15 Ethics and Protection of Human Patients 
All ethical and other protocol-specified details for the protection of human subjects 
discussed in the Main Study (Section 19.0) are applicable to this Nested Sub-Study. 


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21.3.16 References 
1. Clopper CJ, Pearson ES.  The use of confidence or fiducial limits illustrated in the 
case of the binomial. Biometrika 1934 Dec;26(4):404-413. 

SAP_001.pdf: 
 
Confidential 
 
 
 
 
 
 
 
 
 
SCYNEXIS, Inc. 
 
SCY-078-304 
 
 
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study 
to Evaluate the Efficacy and Safety of Oral Ibrexafungerp (SCY-078) 
Compared to Placebo in Subjects with Recurrent Vulvovaginal Candidiasis 
 
14Jan, 2022 
 
Statistical Analysis Plan 
 
Final Version 1.0 
 
Prepared by: 
 
PPD 
Unit 1101, Henderson Metropolitan,  
No. 155 Tianjin Road, Huangpu District, 
Shanghai 200001, China 
 
 
 


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II
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... VI 
1. 
INTRODUCTION ............................................................................................................ 1 
2. 
OBJECTIVES ................................................................................................................... 3 
2.1. PRIMARY OBJECTIVES ........................................................................................................ 3 
2.2. KEY SECONDARY OBJECTIVE: ............................................................................................ 3 
2.3. OTHER SECONDARY OBJECTIVES: ...................................................................................... 3 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 3 
3.1. OVERALL STUDY DESIGN AND PLAN .................................................................................. 3 
3.2. STUDY ENDPOINTS ............................................................................................................. 4 
3.2.1. 
Primary Endpoints ...................................................................................................... 4 
3.2.2. 
Key Secondary Endpoint: ........................................................................................... 4 
3.2.3. 
Other Secondary Endpoints: ....................................................................................... 4 
3.3. TREATMENTS ...................................................................................................................... 5 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 6 
4.1. SAMPLE SIZE ...................................................................................................................... 6 
4.2. RANDOMIZATION, STRATIFICATION AND BLINDING ........................................................... 7 
4.3. ANALYSIS SET .................................................................................................................... 7 
4.4. HANDING OF MISSING DATA ................................................................................................ 8 
4.4.1. 
Non-Responder Imputation (NRI) for Categorical Responses ................................... 8 
4.4.2. 
Last Observation Carried Forward (LOCF) .............................................................. 8 
5. 
SUBJECT DISPOSITION ............................................................................................... 8 
5.1. DISPOSITION ....................................................................................................................... 8 
5.2. PROTOCOL DEVIATIONS ..................................................................................................... 9 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 10 
6.1. DEMOGRAPHICS ................................................................................................................ 10 
6.2. BASELINE CHARACTERISTICS ........................................................................................... 10 
6.3. MEDICAL HISTORY ........................................................................................................... 11 
6.4. INCLUSION AND EXCLUSION CRITERIA ............................................................................. 12 
7. 
TREATMENTS AND MEDICATIONS ....................................................................... 12 
7.1. PRIOR AND CONCOMITANT MEDICATIONS ........................................................................ 12 
7.1.1. 
Prior Medications ..................................................................................................... 13 
7.1.2. 
Concomitant Medications ......................................................................................... 13 
7.1.3. 
Rescue Antifungal Medications................................................................................. 13 
7.2. STUDY TREATMENTS ........................................................................................................ 13 
7.2.1. 
Acute Phase ............................................................................................................... 13 
7.2.1.1. 
Exposure of Fluconazole ....................................................................................... 13 
7.2.1.2. 
Treatment Compliance of Fluconazole .................................................................. 14 
7.2.2. 
Prevention of Recurrence Phase ............................................................................... 14 
7.2.2.1. 
Study Participation Calculation and Extent of Exposure ...................................... 14 


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7.2.2.2. 
Treatment Compliance .......................................................................................... 15 
8. 
EFFICACY ANALYSIS................................................................................................. 16 
8.1. PRIMARY ENDPOINT ......................................................................................................... 16 
8.1.1. 
Primary Analysis ....................................................................................................... 16 
8.2. SECONDARY EFFICACY ENDPOINTS .................................................................................. 17 
8.2.1. 
Clinical Response...................................................................................................... 17 
8.2.2. 
Mycological outcomes .............................................................................................. 19 
8.2.3. 
Quality of Life Analysis ............................................................................................. 19 
8.2.3.1. 
Euro Quol 5 Dimensions 5-Level Version ............................................................. 19 
8.2.3.2. 
Short Form Health Survey ..................................................................................... 20 
8.2.3.3. 
Female Sexual Distress Scale ................................................................................ 21 
8.2.4. 
Composite Score of the Vulvovaginal Signs and Symptoms ..................................... 21 
9. 
SAFETY ANALYSIS ..................................................................................................... 23 
9.1. ADVERSE EVENTS ............................................................................................................. 23 
9.1.1. 
Treatment-Emergent Adverse Events ........................................................................ 24 
9.1.2. 
Relationship of Adverse Events to Study Treatment ................................................. 24 
9.1.3. 
Severity of Adverse Event.......................................................................................... 25 
9.1.4. 
Adverse Events Leading to Treatment Discontinuation............................................ 25 
9.1.5. 
Adverse Events Leading to Study Discontinuation ................................................... 25 
9.1.6. 
Death ......................................................................................................................... 26 
9.2. CLINICAL LABORATORY EVALUATIONS ........................................................................... 26 
9.2.1. 
Pregnancy ................................................................................................................. 26 
9.2.2. 
Events of Clinical Interest ......................................................................................... 26 
9.3. VITAL SIGN MEASUREMENTS ........................................................................................... 26 
9.4. ABBREVIATED PHYSICAL EXAMINATION .......................................................................... 27 
9.5. VAGINAL SAMPLES – PH, KOH AND OTHER PATHOGEN RESULTS ................................... 27 
10. 
INTERIM ANALYSIS ................................................................................................... 27 
11. 
CHANGES IN THE PLANNED ANALYSIS .............................................................. 27 
12. 
REFERENCES ................................................................................................................ 29 
13. 
APPENDICES ................................................................................................................. 30 
13.1. 
APPENDIX 1: SCHEDULE OF ASSESSMENTS .................................................................... 30 
13.2. 
APPENDIX 2: STANDARD EQ-5D-5L VALUE SETS ........................................................ 33 
13.3. 
APPENDIX 3: SF-36 SCORING ALGORITHM ............................................................ 34 
13.4. 
APPENDIX 4: SAP FOR THE NESTED SUB-STUDY SCY-078-304S ................................. 37 
13.4.1. 
Title ........................................................................................................................ 37 
13.4.2. 
Objectives .............................................................................................................. 37 
13.4.2.1. 
Primary Objectives ............................................................................................. 37 
13.4.2.2. 
Secondary Objectives ......................................................................................... 37 
13.4.3. 
Investigational Plan ............................................................................................... 37 
13.4.3.1. 
Overall Study Design and Plan .......................................................................... 37 
13.4.3.2. 
Study Endpoints .................................................................................................. 38 
13.4.3.2.1. Primary Endpoints ............................................................................................. 38 
13.4.3.2.2. Secondary Efficacy Endpoints ........................................................................... 38 


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13.4.3.3. 
Treatments .......................................................................................................... 39 
13.4.4. 
General Statistical Considerations ........................................................................ 40 
13.4.4.1. 
Sample Size ......................................................................................................... 40 
13.4.4.2. 
Randomization, Stratification and Blinding ....................................................... 40 
13.4.4.3. 
Analysis Set ........................................................................................................ 40 
13.4.4.4. 
Handing of missing data .................................................................................... 40 
13.4.5. 
Subject Disposition ................................................................................................ 41 
13.4.5.1. 
Disposition ......................................................................................................... 41 
13.4.5.2. 
Protocol Deviations............................................................................................ 41 
13.4.6. 
Demographics and Baseline Characteristics ........................................................ 42 
13.4.6.1. 
Demographics .................................................................................................... 42 
13.4.6.2. 
Baseline Characteristics .................................................................................... 42 
13.4.6.3. 
Medical History .................................................................................................. 43 
13.4.6.4. 
Inclusion and Exclusion Criteria ....................................................................... 43 
13.4.7. 
Treatments and Medications ................................................................................. 44 
13.4.7.1. 
Prior and Concomitant Medications .................................................................. 44 
13.4.7.1.1. Prior Medications .............................................................................................. 44 
13.4.7.1.2. Concomitant Medications .................................................................................. 45 
13.4.7.1.3. Rescue Antifungal Medications ......................................................................... 45 
13.4.7.2. 
Study Treatments ................................................................................................ 45 
13.4.7.2.1. Study Participation Calculation and Extent of Exposure .................................. 45 
13.4.7.2.2. Treatment Compliance ...................................................................................... 46 
13.4.8. 
Efficacy Analysis.................................................................................................... 47 
13.4.8.1. 
Primary Endpoint ............................................................................................... 47 
13.4.8.1.1. Primary Analysis ............................................................................................... 48 
13.4.8.2. 
Secondary Efficacy Endpoints ............................................................................ 48 
13.4.8.2.1. Clinical Outcome – Clinical Cure ..................................................................... 48 
13.4.8.2.2. Mycological outcomes ....................................................................................... 49 
13.4.8.2.3. Overall Outcome................................................................................................ 50 
13.4.8.2.4. Symptom Outcome ............................................................................................. 50 
13.4.8.2.5. Clinical Improvement ........................................................................................ 51 
13.4.8.2.6. Composite Score of the Vulvovaginal Signs and Symptoms .............................. 51 
13.4.9. 
Safety Analysis ....................................................................................................... 52 
13.4.9.1. 
Adverse Events ................................................................................................... 52 
13.4.9.1.1. Treatment-Emergent Adverse Events ................................................................ 53 
13.4.9.1.2. Relationship of Adverse Events to Study Treatment .......................................... 53 
13.4.9.1.3. Severity of Adverse Event .................................................................................. 54 
13.4.9.1.4. Adverse Events Leading to Treatment Discontinuation .................................... 54 
13.4.9.1.5. Adverse Events Leading to Study Discontinuation ............................................ 54 
13.4.9.1.6. Death ................................................................................................................. 54 
13.4.9.2. 
Clinical Laboratory Evaluations ........................................................................ 54 
13.4.9.2.1. Pregnancy .......................................................................................................... 55 
13.4.9.2.2. Events of Clinical Interest ................................................................................. 55 
13.4.9.3. 
Vital Sign Measurements .................................................................................... 55 
13.4.9.4. 
Physical Examination ......................................................................................... 55 
13.4.9.5. 
Vaginal Samples – pH, KOH and Other Pathogen Results ............................... 56 


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13.4.10. 
Interim Analysis.................................................................................................. 56 
13.4.11. 
Changes in the Planned Analysis ....................................................................... 56 
13.4.12. 
Appendices – Nested Sub-study .......................................................................... 57 
13.4.12.1. Appendix S1: Schedule of Assessments of the Nested Sub-Study ....................... 57 


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List of Abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase  
ANCOVA 
analysis of covariance 
ANOVA 
Analysis of variance 
AST 
aspartate aminotransferase  
BL 
baseline 
BMI 
body mass index 
CI 
confidence interval 
CLSI 
Clinical and Laboratory Standards Institute 
CMH 
Cochran Mantel Haenszel 
CRF 
case report form 
eCRF 
electronic case report form 
EOFU 
end of follow-up  
EQ-5D 
Euro Quol 5 Dimensions 
EQ-5D-5L Euro Quol 5 Dimensions 5-Level Version 
FLU 
fluconazole 
FSDS 
Female Sexual Distress Scale 
FUP 
follow-up 
ICF 
Informed Consent Form 
ID 
identification 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
Interactive web-based response system 
KOH 
potassium hydroxide 
LOCF 
last observation carried forward 
LS 
least squares 
MCS 
Mental Component Summary Score 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
minimum inhibitory concentration 
MIC50 
minimum inhibitory concentration required to inhibit the growth of 50% of 
organisms 
MIC90 
minimum inhibitory concentration required to inhibit the growth of 90% of 
organisms 
mITT 
modified intent to treat 
MMRM 
Mixed-Effect Model for Repeated Measure 
NRI 
non-responder imputation 
PAE 
prior adverse event 
PCS 
Physical Component Summary Score 
PI 
principal investigator 
PP 
per protocol 
PR 
potential recurrence 
PT 
preferred term 
QD 
once a day  
QOL 
Quality of Life 
RVVC 
recurrent vulvovaginal candidiasis 


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SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SE 
Standard error 
SF-36 
Short Form Health Survey 
SOC 
system organ class 
SS 
safety set 
TEAE 
Treatment emergent adverse event 
TOC 
test of cure 
UK 
unknown 
ULN 
upper limit of normal 
UNK 
unknown 
VAS 
Visual analogue scale 
VSS Scale 
vulvovaginal signs and symptoms scale 
VVC 
vulvovaginal candidiasis 
WHO-DD 
World Health Organization Drug Dictionary Enhanced 
 
 


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1. Introduction 
Vulvovaginal candidiasis (VVC) is a common fungal infection caused by Candida spp. and is a 
significant morbidity condition in women from all social classes. VVC can be an acute, chronic, 
recurrent, or persistent condition that can involve the vulva, vagina, and adjacent crural areas. It 
affects about 70%-75% of women on at least one occasion over a lifetime. Approximately 40%–
50% of women will experience a recurrence and 5% to 8% of adult women have a recurrent 
vulvovaginal candidiasis (RVVC). 
Current treatments for VVC include topical antifungals and the use of prescription oral antifungals 
such a single dose of fluconazole. There are no currently approved products to prevent recurrence 
of VVC in patients with RVVC. The entity of RVVC has been defined as at least three 
symptomatic episodes in the previous 12 months, although some investigators define it as four 
attacks in a year. This is an entirely arbitrary differentiation, not based on any data or study and it 
is likely that women identified by both definitions are identical. 
C. albicans is responsible for the majority of infections in women with RVVC and the majority 
remain susceptible to azoles implying that the host, along with the pathogen, contributes to the 
pathophysiology of RVVC.  
RVVC is likely a multifactorial disease including genetic predisposition to enhanced vaginal 
colonization where, in the presence of secondary triggering mechanisms, the carrier state is 
transformed into a proinflammatory state by a host’s hyperactive local immune response. Long-
term antifungal suppressive therapy may help control the host’s mucosal reaction by keeping the 
vaginal fungal load at markedly reduced levels. Several long-term maintenance regimens using 
either topical azoles or oral azoles (e.g., ketoconazole, itraconazole, and fluconazole) have been 
studied showing benefit in preventing recurrences of VVC. Although there have been few 
comparative studies, the best results were obtained with long-term maintenance therapy using once 
weekly fluconazole 150 mg for 6 months. The most important limitation of the suppressive therapy 
with fluconazole is exactly that: suppression of growth rather than eradication of the yeast. Even 
though yeast organisms are dramatically reduced in number, below the level of detection by 
conventional culture technique, they persist in low numbers in the vaginal lumen, triggering the 
VVC episode upon discontinuation of fluconazole. A fungicidal drug and regimen may be able to 
address this significant limitation of current therapies for RVVC and may be associated with a 
more sustained benefit after discontinuation of therapy. 
Ibrexafungerp (formerly known as SCY-078) is a member of a new class of antifungal agents and 
is an orally active, semi-synthetic, triterpenoid derivative of the natural product enfumafungin. 
Time-kill studies have demonstrated that ibrexafungerp (SCY-078) has in vitro fungicidal activity 
against Candida spp. isolates similar to that observed with the echinocandins. In addition, the 
safety and efficacy of ibrexafungerp (SCY-078) have been proved through many non-clinical 
programs and phase I/II studies.  


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This study aims to demonstrate the efficacy and define the safety of a 6-month dosing regimen of 
oral ibrexafungerp to prevent recurrences in subjects with RVVC. 
 
 


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2. Objectives 
2.1. Primary Objectives 
• 
To evaluate the efficacy of oral ibrexafungerp versus placebo in preventing recurrences of 
vulvovaginal candidiasis (VVC) in subjects with recurrent VVC (RVVC) based on 
Clinical Success. 
2.2. Key Secondary Objective:  
• 
To evaluate the efficacy of oral ibrexafungerp versus placebo in preventing recurrences of 
VVC in subjects with RVVC based on Mycologically Proven Recurrences at Test of Cure 
(TOC).  
2.3. Other Secondary Objectives:  
• 
To evaluate the efficacy of oral ibrexafungerp versus placebo in preventing recurrences 
(Mycologically Proven, Presumed or Suspected) of VVC in subjects with RVVC.  
• 
To evaluate the efficacy of oral ibrexafungerp versus placebo in preventing recurrences of 
VVC in subjects with RVVC based on the number of Recurrences (Mycologically Proven, 
Presumed or Suspected) of VVC.  
• 
To evaluate the efficacy of oral ibrexafungerp versus placebo in subjects with RVVC 
based on Quality of Life (QOL) outcomes.  
• 
To evaluate the safety and tolerability of oral ibrexafungerp in subjects with RVVC.  
3. Investigational Plan 
3.1. Overall Study Design and Plan 
This study is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of oral ibrexafungerp (formerly “SCY-078”) compared to placebo 
in female subjects 12 years and older with RVVC. The primary objective of the study is to evaluate 
the efficacy of oral ibrexafungerp versus placebo in preventing recurrences of VVC in subjects 
with RVVC based on Clinical Success.  
The study will consist of a Screening visit, an Acute Phase with open-label fluconazole and a 
Prevention of Recurrence Phase with randomized ibrexafungerp or placebo. Screening and the 
beginning of the Acute Phase (Day -14) may occur on the same day. Approximately 320 subjects 
are planned to be enrolled into the open-label Acute Phase of the study in order to randomize 
approximately 240 subjects into the double-blind Prevention of Recurrence Phase, which will 
consist of 6 monthly, single-day treatments with the randomized study drug.  
A Nested Sub-Study will be made available to subjects who fail treatment with fluconazole during 
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The schedule of study assessments is presented in Appendix 1. 
3.2. Study Endpoints 
3.2.1. Primary Endpoints 
• 
Efficacy as measured by the percentage of subjects with documented Clinical Success 
(defined as subjects having a TOC evaluation and no Mycologically Proven, Presumed or 
Suspected Recurrences of VVC) up to Week 24 (TOC).  
3.2.2. Key Secondary Endpoint:  
• 
Efficacy as measured by the percentage of subjects with no Mycologically Proven 
Recurrence (defined as an episode of VVC with a total composite score ≥ 3 on the 
Vulvovaginal Signs and Symptoms [VSS] Scale and a culture positive for Candida spp. 
that required antifungal treatment) up to Week 24 (TOC).  
3.2.3. Other Secondary Endpoints:  
Efficacy as measured by:  
• 
The percentage of subjects with no Mycologically Proven Recurrence up to Week 4, Week 
8, Week 12, and Week 36 (end of follow-up [EOFU]); 
• 
The time to the first Recurrence (Mycologically Proven, Presumed or Suspected) of VVC 
through EOFU; 
• 
The percentage of subjects with Mycological Eradication (negative fungal culture) at 
Week 12, Week 24 (TOC) and Week 36 (EOFU); 
• 
The percentage of subjects with no Mycologically Proven, Presumed or Suspected 
Recurrences up to Week 4, Week 8, Week 12 and Week 36 (EOFU); 
• 
The percentage of subjects with no Mycologically Proven or Presumed Recurrences up to 
Week 4, Week 8, Week 12, Week 24 (TOC) and Week 36 (EOFU); 
• 
The proportion of subjects in four ordered categories related to the number of Recurrences 
(Mycologically Proven, Presumed or Suspected) of VVC from Baseline (Day 1) to Week 
24 (TOC) and Week 36 (EOFU). The three categories of recurrence are defined as (i) 0 
episode, (ii) 1 episode, (iii) 2 to 3 episodes, and (iv) ≥ 4 episodes; 
• 
The absolute number of Mycologically Proven, Presumed or Suspected Recurrences from 
Baseline (Day 1) to Week 24 (TOC) and Week 36 (EOFU); 
• 
Absolute improvement in QOL outcomes at Week 12, Week 24 (TOC) and Week 36 
(EOFU) as measured by EQ-5D, SF-36 and FSDS; 
Safety and tolerability as measured by:  
• 
Adverse events (AEs), vital signs, treatment discontinuation and safety laboratory tests. 


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3.3. Treatments   
Acute Phase  
Subjects who meet all study eligibility criteria at screening will enter the Acute Phase of the study 
and will receive oral fluconazole, as follows:  
• 
Oral fluconazole 150 mg QD on Days -14, -11 and -8 
The first dose of fluconazole will be administered on Day -14 at the study site, after all other visit 
procedures have been done. Subjects will self-administer the remaining doses at home.   
Prevention of Recurrence Phase  
Subjects who have a culture-confirmed Candida spp. infection from the sample collected at 
screening, achieve significant resolution of their vulvovaginal signs and symptoms on fluconazole 
(defined as a total composite score ≤ 2 on the VSS Scale) at Baseline (Day 1) and continue to meet 
all other eligibility criteria will be entered into the Prevention of Recurrence Phase and randomized 
at a 1:1 ratio to one of the following two treatment groups: 
• 
Oral ibrexafungerp administered as a single-day treatment repeated every 4 weeks (28 
days [±3]) for a total of 6 single-day treatments (Baseline [Day 1], Week 4, Week 8, Week 
12, Week 16 and Week 20). Each single-day treatment will consist of two doses of 300 
mg each given 12 (±4) hours apart (total single-day dose = 600 mg); 
• 
Matching oral placebo administered as a single-day treatment repeated every 4 weeks (28 
days [±3]) for a total of 6 single-day treatments (Baseline [Day 1], Week 4, Week 8, Week 
12, Week 16 and Week 20). Each single-day treatment will consist of two doses of placebo 
given 12 (±4) hours apart.  
Subjects will receive their first dose of double-blind study drug at the site and will self-administer 
the remaining doses at home. Subjects must take the two doses of study drug 12 hours apart (±4 
hours), preferably with or immediately after a meal. Subjects will record study drug dosing details 
in their study diary. 
A Nested Sub-Study will be made available to subjects who fail treatment with fluconazole during 
the Acute Phase and are not eligible for randomization into the Prevention of Recurrence Phase. 
All eligible subjects will receive oral ibrexafungerp administered as a single-day treatment 
consisting of two 300-mg doses (total dose = 600 mg) given 12 hours apart (±4 hours) at Baseline 
(Day 1). A detailed analysis plan for the Nested Sub-study will be provided in the Appendix 4. 
 
 


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4. General Statistical Considerations 
Continuous data will be described using descriptive statistics (i.e. n, mean, standard deviation 
(SD), median, minimum, and maximum). Categorical data will be described using the subject 
count and percentage in each category. For the summary statistics of all numerical variables unless 
otherwise specified, minimum and maximum will be displayed to the same level of precision as 
reported. Mean and median will be displayed to one level of precision greater than the data 
collected. Standard deviation / standard error will be displayed to two levels of precision greater 
than the data collected. P-values will be rounded to three decimal places. If a p-value is less than 
0.001 it will be reported as “<0.001.” If a p-value is greater than 0.999 it will be reported as 
“>0.999.” Data will be displayed in all listings sorted by treatment group.  
Subjects will be identified in the listings by the subject identification number concatenated with 
the investigator number. 
When count data are presented, the percentage will be suppressed when the count is zero in order 
to draw attention to the non-zero counts. A row denoted “Missing” will be included in count 
tabulations where specified on the shells to account for dropouts and missing values. The 
denominator for all percentages will be the number of subjects in that treatment within the analysis 
set of interest, unless otherwise specified. 
Unless otherwise specified, baseline will be defined as the last non-missing assessment prior to or 
on the date (and time if appropriate) of the first dose of study drug. Change from baseline is defined 
as post-baseline value – baseline value. 
The study day will be calculated as follows:  
If the assessment date occurs on or after the date of the first dose of study drug: 
Study day = assessment date – first dose date + 1. 
If the date of interest occurs before the date of the first dose of study drug: 
Study day = assessment date – first dose date 
There is no study day 0. 
All analyses will be conducted using SAS Version 9.3 or higher. All statistical tests will be two-
sided and interpreted at a 5% significance level. 
This statistical analysis plan is created for the main study. Regarding the detailed description of 
the statistical analysis of the nested sub-study, please refer to the Appendix 4. 
4.1. Sample Size 
The primary endpoint of the study is the percentage of subjects with documented Clinical Success 
up to Week 24 (TOC). Assuming response rates of 65% and 43% for ibrexafungerp and placebo, 
respectively; 90% power; and an alpha level of 0.05, approximately 240 subjects randomized at a 


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1:1 ratio are needed to declare a difference between ibrexafungerp and placebo at Week 24 based 
on Fisher’s Exact test.  
In order to be randomized, a subject should have achieved the proposed significant resolution of 
signs and symptoms (total composite score ≤2 on the VSS Scale) after receiving fluconazole 
therapy for an acute episode and have a positive culture for Candida spp. from the sample collected 
at screening. It is estimated that approximately 320 subjects will need to enter the Acute Phase to 
provide 240 subjects randomized to the Prevention of Recurrence Phase. Enrolment into the Acute 
Phase will be discontinued when approximately 240 subjects have been randomized.  
4.2. Randomization, Stratification and Blinding 
Approximately 320 subjects are planned to be enrolled into the open-label Acute Phase of the 
study in order to randomize approximately 240 subjects at a 1:1 ratio to one of the two study 
treatment groups.  
An interactive web-based response system (IWRS) will be used to administer the randomization 
schedule. Biostatistics will generate the randomization schedule using SAS® software Version 9.3 
or later (SAS Institute Inc, Cary, North Carolina) for IWRS, which will link sequential subject 
randomization numbers to treatment codes. 
Neither the subjects nor the investigators will be aware of the treatment assignment for the subjects. 
The study drugs will be identical in number and appearance. Blinding will be maintained 
throughout the study by use of active or placebo dosage forms of similar appearance. 
A subject’s treatment assignment will not be broken until the end of the study unless medical 
treatment of the subject depends on knowing the study treatment the subject received. In the event 
that the blind needs to be broken because of a medical emergency, the investigator may unblind 
an individual subject’s treatment allocation. As soon as possible, the investigator should first 
contact the medical monitor to discuss the medical emergency and the reason for revealing the 
actual treatment received by that subject. No investigator is in full rights to unblind a subject on 
medical reasons without prior consultation with the sponsor or medical monitor. 
Eligible subjects will be stratified at randomization based on the presence or absence of 
uncontrolled diabetes mellitus, defined as A1C levels ≥ 8.00% at Baseline (Uncontrolled diabetes 
mellitus: YES or NO), and by geographical region (USA or Ex-USA).  
4.3. Analysis Set 
Intent-to-Treat (ITT) Set: All randomized subjects who received at least one dose of study drug 
(ibrexafungerp or placebo). 
Modified Intent-to-Treat (mITT) Set: All randomized subjects who received at least one dose of 
study drug (ibrexafungerp or placebo), who have a confirmed mycological culture for yeast at 
Screening and a negative culture for yeast at Baseline (Day 1).  


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Per-Protocol (PP) Set: All mITT subjects who did not have major protocol deviations likely to 
affect study efficacy and who have available data at the TOC visit. Note that subjects who 
discontinue due to a study-drug-related AE will be classified as failures for the analyses of efficacy 
under the PP population.  
Safety Set (SS): All randomized subjects who received at least one dose of study drug 
(ibrexafungerp or placebo) and who have at least one post-baseline evaluation. 
4.4. Handing of missing data 
4.4.1. Non-Responder Imputation (NRI) for Categorical Responses 
For clinical responses which described in section 8.1, and 8.2.1, a subject who has not previously 
experienced a failure response of the endpoint of interest and does not have the required assessment 
of potential recurrence data at Week 4 (or Week 8, Week 12, Week 24 (TOC) and Week 36 
(EOFU)) for any reason will be considered as failure in the analysis of the specified time point. If 
one or more of the required assessments of potential recurrence are not completed within Week 4 
(or Week 8, Week 12, Week 24 (TOC) and Week 36 (EOFU)), the subject will be considered as 
failure. Randomized and took at least 1 study treatment patients without at least 1 post-baseline 
observation will also be defined as failure for the NRI analysis. 
For mycological outcome, subjects will be considered a non-responder for the NRI analysis if their 
mycological outcome cannot be determined due to early termination before the specified visit or 
missing mycological data at the specific visit. Randomized subjects without at least 1 post-baseline 
observation will also be defined as non-responder for the NRI analysis. 
Randomized subjects without study treatment will be excluded from all analysis. 
The NRI may be applied at any time point specified for analysis. 
4.4.2. Last Observation Carried Forward (LOCF) 
A LOCF analysis will be performed on health outcome variables, including EQ-5D Summary 
Index and EQ VAS, all 8 scale scores and 2 overall scores of SF-36, and FSDS total score. The 
last non-missing post-baseline observation will be carried forward to the corresponding endpoint 
for evaluation. For patients that take rescue therapy, their last non-missing observation up to the 
date of the rescue medication will be carried forward to the corresponding endpoint for evaluation.  
Randomized patients without at least 1 postbaseline observation will not be included for 
evaluation. 
5. Subject Disposition 
5.1. Disposition 
A flowchart diagram includes the number of subjects who screened, subjects who screen failed 
before acute phase, subjects who entered acute phase, subjects who discontinued after acute phase, 


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subjects who entered the nested sub-study, subjects who entered the prevention of recurrence 
phase, will be presented.  
For subjects who entered the nested sub-study, the following categories should be presented: 
subjects in each analysis set (ITT, mITT, SS), subjects who completed TOC visit, subjects who 
completed the study, subjects who discontinued from the study, and the reasons for study 
discontinuation. 
For subjects who entered the prevention of recurrence phase, the following categories should be 
presented: subjects in each analysis set (ITT, mITT, PP, SS), subjects who completed TOC visit, 
subjects who completed the study, subjects who discontinued from the study, and the reasons for 
study discontinuation. 
A disposition table of subjects includes the number and percentage of subjects for the following 
categories: subjects in each analysis set (ITT, mITT, PP, SS), subjects who completed TOC visit, 
subjects who completed the study, subjects who discontinued from the study, and the reasons for 
study discontinuation will be presented by the ITT and mITT sets. All percentages will be based 
on the number of subjects in each corresponding set. 
The reason for study discontinuation may include any of the following: Absence of culture-
confirmed Candida spp. infection from the sample reviewed at Baseline, Adverse Event, Lost to 
Follow-up, Physician Decision, Pregnancy, Study Terminated by Sponsor, Withdrawal by Parent  
or Guardian, Withdrawal by Subject, Other, Death, Trial Screen Failure. 
Subject disposition data will be presented in a listing. 
5.2. Protocol Deviations 
The investigator may not deviate from the protocol without a formal protocol amendment having 
been established and approved by an appropriate IRB, except when necessary to eliminate 
immediate hazards to the subject or when the change(s) involve(s) only logistical or administrative 
aspects of the study. 
Significant protocol deviations will be defined in the significant protocol deviations rules 
document. Each significant deviation will be assigned a rule number. As the study is ongoing, 
additional significant protocol deviations can also be spontaneously identified or defined by the 
sponsor and/or the project team during the regularly planned study deviation review meetings and 
the significant protocol deviations rules document can be updated.  
All protocol deviations will be reviewed and assessed as to significance and severity for the 
purposes of analysis prior to the database lock. 
All major protocol deviations (i.e. resulting in exclusion of the subjects from one or more analysis) 
will be summarized using the ITT and mITT sets.  
Major protocol deviations will also be presented in a listing. 
 


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6. Demographics and Baseline Characteristics 
6.1. Demographics 
A summary of the following demographics will be presented for the subjects in ITT set and mITT 
set, respectively.  
• 
Age (years); 
• 
Age group (<18 years, 18 -<36 years, 36 -<50 years, 50 -<65 years, ≥65 years); 
• 
Sex (Female); 
• 
Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, and Other); 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino); 
• 
Country [USA (United States), BGR (Bulgaria), RUS (Russia), POL (Poland)]; 
• 
Geographical location (USA, EX-USA); 
• 
BMI (kg/m²); 
• 
BMI group (Underweight <18.5 kg/m², Normal 18.5-<25 kg/m², Overweight 25-<30 
kg/m², Obese 30-<40 kg/m² and Morbidly Obese ≥40 kg/m²); 
• 
BMI group (≤35 kg/m² and >35 kg/m²). 
The age collected in CRF will be used for analysis if it is non-missing. If the age is not collected 
in the CRF, the age in years is calculated using the date of the informed consent and date of birth.  
Age (years) = [(Informed Consent Date – Date of Birth + 1) / 365.25]. 
BMI is calculated as 
BMI = (body weight in kilograms) / (height in meters)2. 
Demographics for all subjects in the ITT set will be presented in a listing.  
6.2. Baseline Characteristics 
A summary of the following baseline characteristics will be presented for subjects in the ITT and 
mITT sets, respectively. 
• 
Number of recurrent VVC episodes in the prior year; 
• 
Uncontrolled diabetes mellitus (Yes or No); 
• 
Candida species at screening (by Genus species); 
• 
Candida species at baseline (by Genus species); 
• 
Composite score of the vulvovaginal signs and symptoms at screening; 


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• 
Severity of VVC at screening (the composite score of the vulvovaginal signs and 
symptoms at screening ‘4 - 7’, ‘8 - 12’, and ‘>=13’); 
• 
Severity of VVC at screening (the composite score of the vulvovaginal signs and 
symptoms at screening <7, >=7); 
• 
Total score of Female Sexual Distress Scale at baseline; 
• 
Categorical responses of the 5 EQ-5D dimensions, EQ VAS score, and EQ-5D index score 
at baseline; 
• 
SF-36 PCS and MCS; 
• 
Fertility Status (Surgically Sterile/Infertile, Post-Menopausal, Potentially Able to Bear 
Children); 
• 
Method of Birth Control (Barrier Methods Only, Oral Contraceptives, Depo 
Contraceptives (Implants/Injectables), IUD, Abstinence, Vaginal Ring, Vasectomized 
Partner, None, Other); 
A separate summary table will be presented to include MIC range, mode, MIC50, and MIC90 by 
treatment group and geographical region (USA or Ex-USA) for the following MIC results from 2 
different methods, CLSI and EUCAST, respectively: 
• 
MIC results for SCY-078 and fluconazole (FLU) at 24 hours against candida species 
isolates obtained at Screening for all subjects in the ITT, mITT and PP sets; 
• 
MIC results for SCY-078 and fluconazole (FLU) at 48 hours against candida species 
isolates obtained at Screening for all subjects in the ITT, mITT and PP sets. 
• 
MIC results for SCY-078 and fluconazole (FLU) at 24 hours against candida species 
isolates obtained at Baseline for all subjects in the ITT set; 
• 
MIC results for SCY-078 and fluconazole (FLU) at 48 hours against candida species 
isolates obtained at Baseline for all subjects in the ITT set. 
Baseline characteristics for all subjects in ITT set will be presented in a listing.  
6.3. Medical History 
Medical history will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA; Version 19.1 or higher). A frequency summary (number and percentage) of subjects 
with at least one medical history will be presented by system organ class (SOC), and preferred 
term (PT), with SOCs sorted in alphabetical order and PTs within each SOC in descending order 
of frequency for all subjects in the ITT and mITT sets. 
In addition, A summary of other vulvovaginal conditions (Selected SOC and PTs) will be 
presented by SOC, and PT for subjects in the mITT set. 
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6.4. Inclusion and Exclusion Criteria 
Prior to both screening and randomization, the investigator will assess if the subject fulfills all of 
the inclusion and none of the exclusion criteria outlined in the protocol (sections 11.1 and 11.2). 
The specific inclusion criterion not met or exclusion criterion which was met will be recorded in 
the eCRF. 
7. Treatments and Medications 
7.1. Prior and Concomitant Medications 
All prior and concomitant medications taken from 28 days before screening through the Week 24 
(TOC) visit will be recorded. Only the use of other antifungal medications, medications used to 
treat vaginal bacterial or parasitic infections, topical vaginal medications or medications to treat a 
study-drug related AE will be recorded after the TOC visit through the last study visit (Week 36 
(EOFU)). 
A summary with the number and percentage of subjects who took medications will be presented 
by WHO therapeutic drug class and generic drug name for those subjects who discontinued before 
entering the prevention of recurrence phase or the nested sub-study. In addition, a by-subject listing 
of medications will be provided. 
For the purpose of inclusion in prior and/or concomitant medication tables, incomplete medication 
start and stop dates will be imputed as follows: 
Missing start dates (where UK, UKN and UNKN indicate unknown or missing day, month and 
year respectively):  
• 
UK-MMM-YYYY: Assume 01-MMM-YYYY. If the month and year are the same as the 
first dose of study drug month and year, then assume the date of first dose of study drug; 
• 
UK-UKN-YYYY: If the year is prior to the year of first dose of study drug, assume 01-
JAN-YYYY of the collected year. If the year is the same as the first dose of study drug 
year, then assume the date of first dose of study drug; 
• 
UK-UKN- UNKN: Assume date of first dose of study drug. 
Missing stop dates for concomitant medications data will be handled as follows (where UK, UKN 
and UNKN indicate unknown or missing day, month and year respectively):  
• 
UK-MMM-YYYY: Assume the last day of the month; 
• 
UK-UKN-YYYY: Assume 31-DEC-YYYY; 
• 
UK-UKN- UNKN: Assume ongoing and leave it missing. 
All prior and concomitant medications will be coded using the current version of the World Health 
Organization Drug Dictionary Enhanced (WHO-DD) and summarized by treatment group based 
on the ITT and mITT sets. 


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7.1.1. Prior Medications 
Prior medications are defined as medications taken and stopped prior to the first dose of study 
drug. The number and percentage of subjects who took prior medications will be presented by 
WHO therapeutic drug class and generic drug name. 
In addition, a summary of the following will be presented for subjects in the ITT set: 
• 
Antibiotic use 30 days before baseline visit; 
• 
Systemic steroid use 30 days before baseline visit; 
• 
Antifungal medications use 1 year prior to baseline visit. 
7.1.2. Concomitant Medications 
Concomitant medications are defined as medications started on or before the EOFU visit date with 
missing stop dates or stop dates after the first dose of study drug. 
A summary showing the number and percentage of subjects who took concomitant medications 
will be presented by WHO therapeutic drug class and generic drug name.  
A by-subject listing of prior and concomitant medications will be provided. 
7.1.3. Rescue Antifungal Medications 
The number and percentage of subjects who took rescue antifungal medication, prior or on TOC 
visit, after TOC visit but before or on EOFU visit, will be presented for the ITT and mITT sets. 
A by-subject listing of rescue antifungal medications will be provided. 
7.2. Study Treatments 
Please refer to Section 3.3 for the details of the study treatment. 
Data related to the study treatment will be presented in a listing. 
7.2.1. Acute Phase 
7.2.1.1. 
Exposure of Fluconazole 
The duration of treatment of fluconazole (days) is calculated as (last dose date of fluconazole – 
first dose date of fluconazole + 1).  
The actual fluconazole dose taken across the acute phase will be calculated as the number of 
fluconazole dispensed minus the number of fluconazole returned. If the fluconazole bottle was not 
returned, the dose diary data will be considered for the actual fluconazole dose calculation. When 
subject answered no dose missing, we can assume the actual fluconazole dose is 3 tablets. When 
subject answered only 1 dose missing, we can assume the actual fluconazole dose is 2 tablets. 
When subject answered 2 doses missing, we can assume the actual fluconazole dose is 1 tablet. 
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The actual fluconazole dose is missing when subject didn’t answer at least one missing dose 
question. 
The duration of treatment of fluconazole, and the actual fluconazole doses will be summarized 
descriptively for all screened subjects.  
All this exposure information of fluconazole will be presented in a listing. 
7.2.1.2. 
Treatment Compliance of Fluconazole 
Treatment compliance of fluconazole is defined as the ratio of the actual fluconazole dose to the 
planned dose, in terms of percentage. Treatment compliance of fluconazole will be summarized 
descriptively based on all screened subjects. 
Treatment compliance = the actual fluconazole dose / the planned dose (3 tablets) *100%. 
The treatment compliance will be classified as 0%, 33.3%, 66.7%, and 100%. This categorical data 
will be summarized with the frequency and percentage of subjects based on all screened subjects. 
Non-compliance with dose regimen (example 2 tablets taken as a single dose) will be captured 
based on investigator’s review of subject diary. 
7.2.2. Prevention of Recurrence Phase 
7.2.2.1. 
Study Participation Calculation and Extent of Exposure 
The duration of study treatment (days) is calculated as (treatment end date – treatment start date + 
1). The treatment start date is the date of first dose of study treatment. For patients who have 
completed or discontinued study treatment, the treatment end date is the date of last dose of study 
treatment recorded on end of Study page. 
The duration of study participation (days) is calculated as date of Study Completion/Termination 
recorded on the End of Study page – Inform consent date + 1. If the date of Study 
Completion/Termination on the End of Study page is missing, or if a subject is lost to follow-up, 
the latest available visit date will be used.  
The cumulative study drug doses taken across the Prevention of Recurrence phase is defined as 
the total number of study drug dispensed minus the total number of study drug returned. If any of 
study drug bottle not returned, the missing doses as recorded in the Dosing page of eCRF will be 
considered for the cumulative study drug doses calculation. For the specified drug dispensation 
period, the cumulative study doses for that period can be calculated as (6 – the number of times 
subjects answered dose missing) × 2 tablets each time. For example, when subject answered only 
1 dose missing, we can assume the cumulative study drug dose for the specified period is 5 times 
× 2 tablets each time = 10 tablets. The cumulative study drug dose will set to be missing when 
subject didn’t answer at least one missing dose question. 


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The duration of study treatment, the duration of study participation, the cumulative study drug 
doses by treatment will be summarized descriptively. 
All this exposure information will be presented in a listing. 
7.2.2.2. 
Treatment Compliance 
Treatment compliance of study drug is defined as the ratio of the actual study dose to the planned 
dose, in terms of percentage. Treatment compliance will be summarized descriptively. 
Treatment compliance = the cumulative study drug dose / the planned dose (24 tablets) *100%. 
The treatment compliance will be classified as <80% and 80% to 100%. This categorical data will 
be summarized with the frequency and percentage of subjects by treatment group. 
Non-compliance with dose regimen (example only 1 tablet taken as a single dose) will be captured 
based on investigator’s review of subject diary. 
 


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8. Efficacy Analysis 
The primary efficacy and secondary efficacy endpoints will be performed on the ITT, mITT and 
PP sets. The ITT analyses will be considered primary; the mITT and PP analyses will be considered 
supportive of the primary analyses on the ITT population. The denominator for all percentages 
will be the number of subjects in that treatment within the analysis set of interest, unless otherwise 
specified. 
8.1. Primary Endpoint 
The primary efficacy endpoint is defined as the proportion of ITT subjects who have documented 
Clinical Success (defined as subjects having a TOC evaluation and no Mycologically Proven, 
Presumed or Suspected Recurrences of VVC) up to Week 24 (TOC). 
Clinical success will be assessed according to the following definitions: 
• 
Clinical success: Subjects having a TOC evaluation and no Mycologically Proven, 
Presumed or Suspected Recurrences of VVC prior to or at the TOC visit. 
• 
Clinical failure: Mycologically Proven, Presumed or Suspected Recurrences of VVC prior 
to or at the TOC visit. For the subject who early terminated before TOC visit, the subject 
is considered a clinical failure. 
Recurrence of VVC: In this study, Recurrence of VVC will be broken into three categories:  
• 
Mycologically Proven Recurrence: An episode of VVC with a total composite score ≥ 3 
on the VSS Scale and a culture positive for Candida spp. that required antifungal 
treatment.  
• 
Presumed Recurrence: An episode of VVC with a total composite score ≥ 3 on the VSS 
Scale that required antifungal treatment and for which there is a positive KOH microscopy 
but no positive fungal culture. 
• 
Suspected Recurrence: An episode of VVC that required treatment with an antifungal 
agent (including self-administration with over-the-counter antifungals) regardless of VSS 
composite score but for which there is no mycological evidence of disease, such as a 
positive KOH microscopy or fungal culture. It also includes an episode of VVC that 
requires antifungal treatment and have a total VSS composite score lower than 3 
regardless of mycological results. 
8.1.1. Primary Analysis 
The primary efficacy analysis will be performed on the ITT set at the TOC visit and will compare 
the proportion of subjects, in the treatment and placebo groups, who have documented Clinical 
Success up to Week 24 (TOC). 
The number and percentage of subjects with documented clinical success up to the TOC visit will 
be presented by treatment group. Meanwhile, the number and percentage of subjects with clinical 


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failure will be presented by the recurrence categories. A Cochran Mantel Haenszel (CMH) test 
adjusted for Country and uncontrolled diabetes mellitus (Yes or No) at baseline will be performed 
to assess the statistical significance of a difference between treatment groups in the primary 
efficacy analysis. Mathematically stated: 
H0: Clinical Success Rate up to Week 24 (TOC) Oral ibrexafungerp 300-mg dose = Clinical Success 
Rate up to Week 24 (TOC) Placebo 
H1: Clinical Success Rate up to Week 24 (TOC) Oral ibrexafungerp 300-mg dose  Clinical Success 
Rate up to Week 24 (TOC) Placebo 
The p-value, relative risk and 95% confidence interval (CI) will be presented in the ibrexafungerp 
300-mg treatment arm compared to the placebo arm. Subjects who have one or more of the 
required assessments of potential recurrence not completed prior to or at Week 24 (TOC) visit or 
subjects who withdraw from the study early will be imputed using the imputation rules described 
in Section 4.4.1. 
A sensitivity analysis using the ITT set will be performed where subjects with the imputed clinical 
outcome will be removed from the analysis. 
Subgroup analyses will be performed in the ITT set depending on BMI category (≤35 kg/m² or 
>35 kg/m²), geographic region (USA and EX-USA), Race (White, Black or African American, 
Asian, American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, and Other), 
Uncontrolled diabetes mellitus (Yes or No), Ethnicity (Hispanic or Latino, Not Hispanic or 
Latino), Number of recurrent VVC episodes in the prior year (<4 times, =>4 times) and Candida 
species at screening (by Genus species), severity of VVC at screening (2 categorizations of the 
composite score of the vulvovaginal signs and symptoms at screening will be used to evaluate the 
severity of VVC at screening: <7, >=7 and ‘4 - 7’, ‘8 - 12’, and ‘>=13’). 
The same inferential analysis employing the same methods as for the primary analysis will be 
performed for the mITT set and PP set to assess clinical success rate up to the Week 24 (TOC). 
Subjects whose results are missing at Week 24 (TOC) and subjects who withdraw from the study 
early will be imputed using the imputation rules described in Section 4.4.1. No adjustment of type 
I error will be performed as these analyses are considered supportive to the primary analysis. 
8.2. Secondary Efficacy Endpoints 
8.2.1. Clinical Response 
The same inferential analysis employing the same methods as for the primary analysis will be 
performed for ITT, mITT, and PP sets to assess below endpoints. 
• 
The percentage of subjects with no Mycologically Proven Recurrence (defined as an 
episode of VVC with a total composite score ≥ 3 on the Vulvovaginal Signs and Symptoms 
[VSS] Scale and a culture positive for Candida spp. that required antifungal treatment) up 
to Week 4, Week 8, Week 12, Week 24 (TOC), and Week 36 (end of follow-up [EOFU]);  


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• 
The percentage of subjects with no Mycologically Proven, Presumed or Suspected 
Recurrences up to Week 4, Week 8, Week 12 and Week 36 (EOFU); 
• 
The percentage of subjects with no Mycologically Proven or Presumed Recurrences up to 
Week 4, Week 8, Week 12, Week 24 (TOC) and Week 36 (EOFU); 
For each specified timepoint, any clinical assessment outcomes at or before the specified visit will 
be counted. The imputation rules described in Section 4.4.1 will be used for the NRI analyses. 
Analysis of time to first recurrence (Mycologically Proven, Presumed or Suspected) and time to 
first Mycologically proven recurrence of VVC through EOFU will use Kaplan-Meier method to 
estimate the median recurrence time and its 2-sided 95% CIs based on the ITT, mITT, and PP sets. 
The time to first recurrence (Mycologically Proven, Presumed or Suspected) and time to first 
Mycologically proven recurrence of VVC is defined as time (days) from first dose of study drug 
to the first recurrence (Mycologically Proven, Presumed or Suspected) and first Mycologically 
proven recurrence of VVC, respectively. Subjects who completed the study will be censored at the 
last visit date if no previously recurrence of VVC experienced. Subjects who discontinued early 
will be censored at the last available assessment if no previously recurrence of VVC experienced. 
Subjects who missed any required assessment of potential recurrence will be censored at the last 
available assessment before the first missed assessment if no previously recurrence of VVC 
experienced. If there was no post-baseline assessment of potential recurrence, subjects will be 
censored at the first dose date of study treatment. 
Kaplan-Meier curves for time to the first recurrence (Mycologically Proven, Presumed or 
Suspected) of VVC and time to first Mycologically proven recurrence will be provided by 
treatment group based on the ITT, mITT, and PP sets. 
The summary of the absolute number of recurrences from Baseline (Day 1) to Week 24 (TOC) 
and Week 36 (EOFU) will be presented by recurrence categories and overall, a two-way analysis 
of variance (ANOVA) model including effects for treatment group and Country will be performed. 
For individual treatment group and ibrexafungerp 300-mg BID comparison versus placebo, the 
least squares mean, associate standard error (SE), 95% confidence interval and corresponding p-
value will be presented. Additionally, same analysis will be performed to only include those 
subjects who completed the specified visit based on the ITT set. 
For the below ordered categorical endpoint, a proportional odds model will be fitted accounting 
for the effects of treatment, Country, and uncontrolled diabetes mellitus (Yes or No) at baseline. 
The proportional odds model will fit an ordered regression model for the ordinal dependent 
variable as described by McCullagh (1980). If the assumption of proportional odds is violated, 
alternative analyses will be considered which require a weaker assumption. The p-value, relative 
risk and 95% CI will be presented in the ibrexafungerp 300-mg treatment group compared to the 
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• 
The proportion of subjects in four ordered categories related to the number of Recurrences 
(Mycologically Proven, Presumed or Suspected) of VVC from Baseline (Day 1) to Week 
24 (TOC) and Week 36 (EOFU). The four categories of recurrence are defined as (i) 0 
episode, (ii) 1 episode, (iii) 2 to 3 episodes, and (iv) ≥ 4 episodes 
8.2.2. Mycological outcomes 
The percentage of subjects with mycological eradication (negative culture for growth of Candida 
species) at Baseline, Week 12, Week 24 (TOC) and Week 36 (EOFU) visits will be analyzed based 
on ITT, mITT, and PP sets using the same inferential analysis employing the same methods as for 
the primary analysis as noted in Section 8.1.1. The subjects with missing specified visit data for 
the mycological outcome will be imputed as mycological persistence using the NRI method 
described in Section 4.4.1. 
Mycological outcomes will be assessed at the specified visit according to the following definitions.  
• 
Mycological Eradication: A subject with negative culture for Candida species; 
• 
Mycological Persistence: A subject with a positive culture for Candida species. 
In addition, a sensitivity analysis will be conducted based on the ITT set where subjects with the 
imputed mycological outcome using the NRI method at the specified visit will be removed from 
the analysis. 
In addition, a summary table will be presented to include MIC range, mode, MIC50, and MIC90, 
based on the ITT, mITT, and PP sets by treatment group and geographical region (USA or Ex-
USA) for the following MIC results from 2 different methods, CLSI and EUCAST, respectively: 
• 
MIC results for SCY-078 and fluconazole (FLU) at 24 hours against candida species 
isolates obtained at Week 12, Week 24 (TOC) and Week 36 (EOFU); 
• 
MIC results for SCY-078 and fluconazole (FLU) at 48 hours against candida species 
isolates obtained at Week 12, Week 24 (TOC) and Week 36 (EOFU) visits. 
8.2.3. Quality of Life Analysis 
Quality of life will be assessed at Day -14, Baseline (Day 1), Week 12, Week 24 (TOC) and Week 
36 (EOFU). Quality-of-life tools will include the Euro Quol 5 Dimensions 5-Level Version (EQ-
5D-5L), Short Form Health Survey (SF-36) and Female Sexual Distress-Revised Scale (FSDS). 
8.2.3.1. 
Euro Quol 5 Dimensions 5-Level Version 
The EQ-5D-5L essentially consists of 2 parts: the EQ-5D descriptive system and the EQ visual 
analogue scale (EQ VAS). The descriptive system comprises five dimensions: mobility, selfcare, 
usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no 
problems, slight problems, moderate problems, severe problems, unable to/extreme problems.  The 
EQ VAS records the patient’s self-rated health on a scale from 0-100 where 100 is the 'best 
imaginable health state' and 0 is the 'worst imaginable health state'. Additionally, an EQ-5D 
summary index will be calculated to reflect how good or bad a health state, which is defined by 


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combining one level from each of the five dimensions, is according to the preferences of the 
general population of a country/region. The EQ-5D index value is derived by applying a formula 
that attaches values (weights) to each of the levels in each dimension. The index values will be 
selected from the value sets which can be obtained from EuroQol office, refer to Appendix 2 for 
the samples of the value sets for this study. The value sets contain the index values for all possible 
EQ-5D health states for each country/region. If a standard EQ-5D-5L value set is not available for 
a specified country/region, it should discuss with client to select an EQ-5D-5L value set for a 
country/region that most closely approximates the country/region investigated. No missing 
dimension will be imputed. 
A summary of the number and percentage of subjects by categorical responses of the 5 EQ-5D 
dimensions will be presented by treatment and by visit. 
EQ-5D Summary Index and EQ VAS will be summarized by treatment and by visit descriptively. 
Change from Baseline to Week 12, Week 24 (TOC) and Week 36 (EOFU) in EQ-5D Summary 
Index and EQ-5D VAS will be analyzed and reported using an Mixed-Effect Model for Repeated 
Measure (MMRM) analysis model, using the ITT, mITT, and PP sets (one such analysis for all 
post-baseline data, grouped by time point), will be used to compare the difference between 
treatment groups. The model will include treatment group, Country, visit, uncontrolled diabetes 
mellitus (Yes or No) and the treatment-by-visit interaction as classification variables and the 
baseline value as covariate. An unstructured covariance matrix will be used. Based on this 
modeling, a point estimate, associate SE, 95% CI, and corresponding p-value will be provided for 
least squares (LS) mean treatment difference versus placebo at all scheduled timepoints. Degrees 
of freedom will be calculated using the Kenward-Roger procedure. 
In addition, an analysis of covariance (ANCOVA) model will be used having treatment group, 
Country and uncontrolled diabetes mellitus (Yes or No) as classification variables, and the baseline 
value as the continuous covariate as a sensitivity analysis, including and excluding the imputed 
values as the LOCF approach described in section 4.2, respectively, for change from baseline of 
EQ-5D Summary Index and EQ VAS and for each scheduled timepoints. For each treatment and 
treatment comparison versus placebo, the least squares mean, associate standard error (SE), 95% 
confidence interval and corresponding p-value will be presented.  
8.2.3.2. 
Short Form Health Survey 
A score will be calculated for each of the 8 scales in SF-36. Each scale score ranges from 0 to 100, 
with higher score reflecting less disability. The partially missing scores may be imputed as 
described in Appendix 3 and used in the summary and analysis. 2 overall scores will be further 
derived: Physical Component Summary score (PCS) and Mental Component Summary score 
(MCS). The summary scores range from 0 to 100, with higher scores indicating better levels of 
function and/or better health. See scoring algorithm in Appendix 3. All 8 scale scores and 2 overall 
scores will be summarized by visit. Change from Baseline in scale scores, PCS, and MCS will be 
analyzed and reported using the same MMRM and ANCOVA model as specified for the change 
in EQ-5D Summary Index in Section 8.2.3.1. 


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8.2.3.3. 
Female Sexual Distress Scale 
The Female Sexual Distress Scale (FSDS) is a validated instrument that measures sexually related 
personal distress in women. The FSDS is a 13-item self-administered questionnaire that addresses 
different aspects of sexual distress. Every item requires an answer that is then rated as 0–4 (never 
[0], rarely [1], occasionally [2], frequently [3], or always [4]). The total score ranges from 0 to 52, 
and provides a measure of sexual distress, with a higher score corresponding to a higher level of 
sexual distress. No missing dimension will be imputed. 
FSDS total score will be summarized by treatment and by visit descriptively. Change from 
Baseline in FSDS total score will be analyzed and reported using the same MMRM and ANCOVA 
model as specified for the change in EQ-5D Summary Index in Section 8.2.3.1. 
In addition, FSDS total score will be classified as ‘<11’ and ‘>=11’. This categorical data will be 
summarized with the frequency and percentage of subjects by treatment group at each scheduled 
visit. In addition, this categorical data will be summarized in shift tables comparing the results at 
post-treatment study scheduled visits with those at the baseline visit. 
8.2.4. Composite Score of the Vulvovaginal Signs and Symptoms 
The composite score of the vulvovaginal signs and symptoms and Change from Baseline values 
to Week4, Week 8, Week 12, Week 24 (TOC), and Week 36 (EOFU) will be summarized by 
treatment and by visit descriptively.  
The composite score of the vulvovaginal signs and symptoms will be classified as ‘0’, ‘1’, ‘2’, and 
‘>=3’. This categorical data will be summarized with the frequency and percentage of subjects by 
treatment group at each scheduled visit. When there are multiple values within a visit, the worst 
value will be taken (worst being the maximum value of the composite score of the vulvovaginal 
signs and symptoms). All analysis will be performed based on the ITT, mITT, and PP sets. The 
similar analyses will be performed for below 2 categorizations of the composite score of the 
vulvovaginal signs and symptoms: <7, >=7 and ‘4 - 7’, ‘8 - 12’, and ‘>=13’. 
A listing will be provided to present the signs and symptoms score and mycological outcome for 
all subjects in the ITT set. Assessments that are not done will be presented in the data listing with 
a missing value. 
Signs of VVC will be defined as the presence of erythema, edema, or excoriation. Symptoms of 
VVC will be defined as itching, burning, or irritation. 
Each vulvovaginal sign will be objectively scored based on severity as follows: 
0 = none (complete absence of any signs or symptoms); 
1 = mild (slight); 
2 = moderate (present); 
3 = severe (marked, intense). 


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Each vulvovaginal symptom will be objectively scored based on severity as follows: 
0 = none (I have no discomfort); 
1 = mild (I have some discomfort, but it does not bother me much); 
2 = moderate (I have discomfort, which is annoying, but not enough to affect what I am 
doing); 
3 = severe (I have discomfort, which is annoying enough to affect what I am doing). 
The composite score of the vulvovaginal signs and symptoms will be calculated according to the 
following rules and this scale has a total possible score of 18. 
• 
If all items of the vulvovaginal signs and symptoms have been scored, the composite score 
is calculated as the sum of the individual scores of all 3 items of signs and 3 items of 
symptoms; 
• 
If any sign or symptom is not done, the composite score will not be calculated and treated 
as a missing data except at Week 4, Week 8, and Week 36 (EOFU); 
• 
Subjects who have no suspicion of a potential recurrence are not required per protocol to 
have a vaginal examination at Week 4, Week 8, and Week 36 (EOFU), therefore signs are 
not considered missing when subjects are free of symptoms and there is not suspicion of 
a potential recurrence. For subjects who do not present symptoms and have no suspicion 
of a potential recurrence at Week 4, Week 8, and Week 36 (EOFU), the total sign score 
and the composite score of the vulvovaginal signs and symptoms at Week 4, Week 8, and 
Week 36 (EOFU) will be calculated as zero. Otherwise, the composite score will not be 
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9. Safety Analysis 
Safety analyses will be performed on all subjects in the safety set, unless otherwise specified. 
Analyses will be based on adverse events, vital signs, clinical laboratory assessments, and 
abbreviated physical examination findings. Safety analyses in general will be descriptive and will 
be presented in tabular format with the appropriate summary statistics by treatment group. 
Individual subject listings will be provided to support the tables. 
9.1. Adverse Events 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated with the 
use of a study drug/study intervention, whether or not related to the study drug/study intervention. 
A prior adverse event (PAE) is defined as adverse event whose start date is before the date of the 
first dose of study treatment. For subjects who didn’t take study treatment, all AEs will be 
identified as PAE. A Summary of the total number of PAE and the number and percentage of 
subjects with at least one PAE will be provided by SOC and PT based on all screened patients. 
Besides, a subject listing will be presented for all the prior adverse events. 
A TEAE is defined as any event does not present before exposure to study drug or any event 
already present that worsens in either intensity or frequency after exposure to study drug. 
For the purpose of inclusion in TEAE tables, incomplete AE start and end dates will be imputed 
as follows: 
Incomplete onset dates (where UK and UNK indicate unknown or missing day and month 
respectively): 
• 
UK-MMM-YYYY: If the month and year are different from the month and year of the 
date of first dose, assume 01-MMM-YYYY. If the month and year are the same as the 
month and year for the date of first dose, and the end date (after any imputation) is on or 
after the date of first dose, then assume the date of first dose. If the month and year are the 
same as the date of first dose, and the end date (after any imputation) is prior to the date 
of first dose, then assume the end date for the start date.  
• 
DD-UNK-YYYY/UK-UNK-YYYY: If the year is different from the year of the date of 
first dose, assume 01-JAN-YYYY of the collected year. If the year is the same as the date 
of first dose year, and the end date (after any imputation) is on or after the date of first 
dose, then assume the date of first dose. If the year is the same as the date of first dose, 
and the end date (after any imputation) is prior to the date of first dose, then assume the 
end date for the start date.  
Incomplete end dates (where UK and UNK indicate unknown or missing day and month 
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• 
UK-MMM-YYYY: Assume the last day of the month; 
• 
DD-UNK-YYYY/UK-UNK-YYYY: Assume 31-DEC-YYYY. 
The missing onset dates will be imputed as the date of first dose of study drug. The missing end 
date will be imputed as the subject’s last visit date. 
All adverse events will be classified by SOC and PT according to the Medical Dictionary for 
Regulatory Activities (MedDRA, Version 19.1 or higher). 
An overview summary of the number and percentage of subjects with any TEAE, serious TEAE, 
treatment-related TEAE, treatment-related serious TEAE, TEAE leading to study treatment 
discontinuation, TEAE leading to study discontinuation, and AE leading to death will be provided 
by treatment group and study period (prior or on TOC visit, after TOC visit but prior or on EOFU 
visit, and entire study).  
All AEs will be presented in a listing. 
9.1.1. Treatment-Emergent Adverse Events 
Summaries of the total number of TEAEs and the number and percentage of subjects with at least 
one TEAE will be provided by treatment and study period (prior or on TOC visit, after TOC visit 
but prior or on EOFU visit, and entire study). Treatment-emergent AEs will be presented by SOC 
and PT. At each level of subject summarization, a subject is counted once if the subject reported 
one or more events. Percentages will be calculated out of the number of subjects in the safety set.  
The summary of TEAEs will be presented in alphabetical order of SOC. Within each SOC, PTs 
will be sorted in descending order from the PT with the highest total frequency (that is, summed 
across all treatment groups) to the PT with the lowest total frequency. If the total frequency for 
any two or more PTs is equal, the PTs will be presented in alphabetical order.  
The summarization described above will also be repeated for the following: 
• 
Serious Adverse Events; 
• 
Treatment-Related Adverse Events; 
• 
Treatment-Related Serious Adverse Events; 
• 
Adverse Events Leading to Dose Interruption. 
The adverse events with a missing relationship will be considered as “Treatment Related” in the 
tables. 
9.1.2. Relationship of Adverse Events to Study Treatment 
A summary of TEAEs by relationship to study treatment will be presented in a table. The 
investigator will provide an assessment of the relationship of the event to the study treatment. The 
possible relationships are “Not Related” and “Related”. In the TEAE relationship table, if subject 
reports multiple occurrences of the same TEAE, only the most closely related occurrence will be 


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presented. Treatment-emergent AEs that are missing a relationship will be presented in the 
summary table as “Related” but will be presented in the data listing with a missing relationship. 
Percentages will be calculated based on the number of subjects in the safety set. 
The TEAE data will be categorized and presented by SOC, PT, and relationship in a manner similar 
to that described in Section 9.1.1. 
Additionally, the TEAE data will be categorized and presented by SOC, PT, relationship, and 
duration (1 day, 2 days, >=3 days). The duration is calculated as the TEAE end date minus the 
TEAE start date, then add 1 day. At each combination level of relationship and duration, a subject 
is counted once if the subject reported one or more events. Percentages will be calculated out of 
the number of subjects in the safety set. 
Treatment-emergent SAEs by relationship to study treatment will also be presented in a table. 
Treatment-emergent SAEs that are missing a relationship will be presented in the table as 
“Related” but will be presented in the data listing with a missing relationship. 
9.1.3. Severity of Adverse Event 
A summary of TEAEs by severity will be presented in a table. The severity that will be presented 
represents the most extreme severity captured on the CRF page. The possible severities are “Mild”, 
“Moderate”, and “Severe”.  
In the TEAE severity table, if a subject reported multiple occurrences of the same TEAE, only the 
most severe will be presented. An additional row “Missing” must be added for the missing severity. 
Percentages will be calculated out of the number of subjects in the safety set. 
The TEAE data will be categorized and presented by SOC, PT, and severity in a manner similar 
to that described in Section 9.1.1. 
Additionally, the TEAE data will be categorized and presented by SOC, PT, severity, and 
relationship. At each combination level of severity and relationship, a subject is counted once if 
the subject reported one or more events. Percentages will be calculated out of the number of 
subjects in the safety set. 
Treatment-emergent SAEs by severity will also be presented in a table.  
9.1.4. Adverse Events Leading to Treatment Discontinuation 
A summary of the TEAEs with an action taken with study treatment of “Drug Withdrawn” will be 
presented by treatment in a manner similar to that described in Section 9.1.1. 
Any TEAEs leading to treatment discontinuation will be presented in a listing for all subjects. 
9.1.5. Adverse Events Leading to Study Discontinuation 
All subjects who have an AE with the answer to “Caused Study Discontinuation” is “Yes” will be 
presented in a listing. 


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9.1.6. Death 
All subjects who have an AE with an outcome of “Death Related to Adverse Event” will be 
presented in a listing. 
9.2. Clinical Laboratory Evaluations 
Summary tables will be presented for laboratory test results (hematology and blood chemistry) by 
treatment at Screening and the scheduled post-treatment visits for subjects in the safety set. 
All relevant clinical laboratory tests in chemistry and hematology will be classified as Low, 
Normal, and High according to the normal ranges. This categorical data will be summarized in 
shift tables comparing the extreme results at post-treatment study scheduled visits with those at 
the baseline visit. Extreme post-baseline results will also be summarized. When there are multiple 
values within a visit for a particular laboratory variable, the worst value will be taken (worst being 
the smallest value for criteria below a certain threshold or the largest value for criteria above a 
certain threshold). If a subject has a value below the threshold and above the threshold, the value 
furthest from the threshold will be chosen. 
Plots of average clinical laboratory parameters may be presented. 
In data listings, laboratory values will be compared to normal ranges; out-of-range values will be 
identified. 
9.2.1. Pregnancy 
Female subjects of child-bearing potential will have urine pregnancy tests conducted at baseline 
(Day 1) visit and at the unscheduled visits, if needed. Only subjects with negative pregnancy test 
results will be enrolled. Any subjects with positive pregnancy test results at any time during the 
study will be presented in a listing. 
9.2.2. Events of Clinical Interest 
The frequency and percentage of subjects with the following elevations will be summarized at any 
post-baseline visit: 
• 
ALT or AST > 8  the upper limit of normal (ULN); 
• 
ALT or AST > 5  ULN for more than 2 weeks or accompanied by total bilirubin > 2  
ULN. 
A listing will be provided for the above elevations, including the actual measurement of ALT, 
AST, and total bilirubin, and their reference high limits.  
9.3. Vital Sign Measurements 
Summary tables will be presented for vital sign data, including systolic blood pressure (mmHg), 
diastolic blood pressure (mmHg), body temperature (C), respiratory rate (bpm), and pulse rate 
(bpm), by treatment for subjects in the safety set. Observed results at the scheduled visits and 


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changes from baseline to the scheduled post-treatment visits will be presented. All vital sign data 
by subject will be presented in a listing. 
9.4. Abbreviated Physical Examination 
An abbreviated physical examination, including general appearance and an overall examination of 
body systems, will be conducted at Screening, Baseline (Day 1), Week 12 and Week 24 (TOC). 
Abbreviated physical exams may also be conducted at unscheduled visits, if needed. 
The abbreviated physical examinations will be classified as Normal, and Abnormal at baseline. 
The post-baseline examinations will be classified as “Changes from baseline” or “No change from 
baseline”. This categorical data will be summarized with the frequency and percentage of subjects 
by body system at each scheduled visit. 
All abbreviated physical examination data will be presented in a listing for all subjects. 
9.5. Vaginal Samples – pH, KOH and Other Pathogen Results 
Please refer to the section 14.7 of the protocol for the details of the Vaginal samples collection.  
The KOH testing results will be classified as Positive (Yeast Only), Positive (Yeast and other 
pathogens), Negative (Yeast and other pathogens), and Positive (Other pathogens only). This 
categorical data will be summarized with the frequency and percentage of subjects at the scheduled 
post-baseline visits by treatment group. 
The proportion of subjects with Chlamydia, Gonorrhea, and Herpes will be summarized at the 
scheduled visits by treatment group. 
All vaginal sample testing data will be presented in a listing. 
10. Interim Analysis 
No interim analysis is planned for this study. 
11. Changes in the Planned Analysis 
The following have changed from the protocol: 
• 
For the continuous efficacy endpoints except for the absolute number of Mycologically 
Proven, Presumed or Suspected Recurrences from Baseline (Day 1) to Week 24 (TOC) 
and Week 36 (EOFU), a Mixed-Effect Model for Repeated Measure (MMRM) analysis 
model and an analysis of covariance (ANCOVA) model are recommended rather than a 
two-way ANOVA model. Baseline value will be considered as possible contributor to any 
observed differences. Additionally, other variables may be considered during blinded data 
review. 
• 
Add the randomization stratification factor, uncontrolled diabetes mellitus (Yes or No), as 
justification factor in the efficacy analyses models. 


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• 
For efficacy analyses, Country is recommended rather than site to be used as the 
justification factor. 
• 
In protocol, it stated that the safety and tolerability as measured by AEs, vital signs, 
treatment discontinuation and safety laboratory tests at TOC (Week 24). The texts “at TOC 
(Week 24)” is removed since all safety data captured in this study will be taken into 
account for analysis. 
• 
Intent-to-treat (ITT) Set definition was changed to be “All randomized subjects who 
signed the consent form and received at least one dose of study drug (ibrexafungerp or 
placebo).” 
• 
Modified Intent-to-treat (mITT) Set definition was changed to be “All randomized 
subjects who signed the consent form and received at least one dose of study drug 
(ibrexafungerp or placebo), who have a confirmed mycological culture for yeast at 
Screening and a negative culture for yeast at Baseline (Day 1).” 
• 
The number of recurrence episodes will be classified to 4 order categories for analysis 
rather than 3 categories as mentioned in the protocol. Updated based on client’s request. 
 
 


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12. References 
Sobel, JD. Vaginal candidosis. Lancet 2007; 369:1961–71. 
William G. Cochran (December 1954). "Some Methods for Strengthening the Common χ2 
Tests". Biometrics. 10 (4): 417–451. 
Gelman, Andrew (February 2005). "Analysis of variance? why it is more important than ever". 
The Annals of Statistics. 33 (1): 1–53. 
Derogatis, L. R., Rosen, R., Leiblum, S., Burnett, A., & Heiman, J. (2002). The Female Sexual 
Distress Scale (FSDS): Initial validation of a standardized scale for assessment of sexually 
related personal distress in women. Journal of Sex & Marital Therapy, 28, 317-330.  
Brazier J, Roberts J, Deverill M. The estimation of a preference-based measure of health from 
the SF-36. Journal of health economics. 2002 Mar 1;21(2):271-92. 
Dolan P. Modeling valuations for EuroQol health states. Medical care. 1997 Nov 1;35(11):1095-
108. 
 
 


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13. Appendices 
13.1. 
Appendix 1: Schedule of Assessments 
 
Screena 
Acute Phase 
(Days -14 to -1 [+3 d]) 
Prevention of Recurrence 
Study Treatment Period 
(D1 to W24) 
Follow-up Period 
(W25 to W36) 
Unschc 
Study Week/Day 
 
Study Procedures 
D -16 
to -14 D-14a 
D -11 
& -8 
Phone 
D -4 to 
-2 
Lab 
W1/ 
D1 
(BL) 
W4/ 
D28 
(±3 d) 
W8/ 
D56 
(±3 d) 
W12/ 
D84 
(±3 d) 
W16/D112  
Phoneb 
W20/D140  
Phoneb 
W24/ 
D168 
(TOC) 
(±3 d) 
W28 & 
W32 
Phoneb 
W36 
(EOFU) 
(±3 d) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assignment of Subject ID number 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviated physical exam 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
If needed 
Urine pregnancy test 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
If needed 
Vulvovaginal sample for KOHd 
X 
 
 
 
 
If PRe 
If PRe If PRe 
 
 
If PRe 
 
If PRe 
If PRe 
Vulvovaginal sample for fungal 
cultured 
X 
 
 
 
X 
If PRe 
If PRe 
X 
 
 
X 
 
X 
If PRe 
Vulvovaginal sample for pHd 
X 
 
 
 
X 
If PRe 
If PRe If PRe 
 
 
If PRe 
 
If PRe 
If PRe 
Vulvovaginal sample for other 
pathogensd  
X 
 
 
 
 
If PRe 
If PRe If PRe 
 
 
If PRe 
 
If PRe 
If PRe 
Vulvovaginal examf and rating of 
signs by the investigator 
X 
 
 
 
X 
If PRe 
If PRe 
X 
 
 
X 
 
If PRe 
If PRe 
Rating of vulvovaginal symptoms 
by the subjectg 
X 
X-----------------X 
X ------------------------------------------------------------------------------------X 
X 
Open-label FLU dispensing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Open-label FLU dosingh 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Subject diary dispensing and 
collection 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
Subject diary completion 
 
  X---------------------------------------------------------------------------------------------------------------------------- 
 
Subject diary review 
 
 
 
 
X 
X 
X 
X 
 
 
X 
 
X 
X 
Sample collection for safety labs 
(hematology and blood chemistry) 
 
 
 
Xi 
 
 
 
X 
 
 
 
 
Xj 
If needed 


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Screena 
Acute Phase 
(Days -14 to -1 [+3 d]) 
Prevention of Recurrence 
Study Treatment Period 
(D1 to W24) 
Follow-up Period 
(W25 to W36) 
Unschc 
Study Week/Day 
 
Study Procedures 
D -16 
to -14 D-14a 
D -11 
& -8 
Phone 
D -4 to 
-2 
Lab 
W1/ 
D1 
(BL) 
W4/ 
D28 
(±3 d) 
W8/ 
D56 
(±3 d) 
W12/ 
D84 
(±3 d) 
W16/D112  
Phoneb 
W20/D140  
Phoneb 
W24/ 
D168 
(TOC) 
(±3 d) 
W28 & 
W32 
Phoneb 
W36 
(EOFU) 
(±3 d) 
Open-label FLU collection and 
compliance evaluation 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Assessment of clinical outcome to 
FLU treatment 
 
 
 
 
Xk 
 
 
 
 
 
 
 
 
 
Randomization  
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Blinded study drug dispensing 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
Blinded study drug dosingl 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Quality-of-life assessmentm 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
Assessment for potential 
recurrence 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blinded study drug compliance 
evaluation  
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Blinded study drug collection  
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
Vital Signs 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
 
X 
X 
Prior & concomitant medication 
review 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event monitoring 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: BL = Baseline; d = day; D = Day; EOFU = end of follow-up; FLU = fluconazole; ID = identification; KOH = potassium hydroxide; Phone = Phone 
contact; PR = potential recurrence; Screen = Screening; TOC = test of cure; Unsch = unscheduled; VSS = vulvovaginal signs and symptoms; VVC = vulvovaginal 
candidiasis; W = Week; 
Note regarding visits: Whenever possible, on-site visits and phone contacts will be scheduled to occur on the date of dosing (or as close to the date of dosing as 
possible) to facilitate reminding subjects to take their study doses. This is applicable for the Baseline (Day 1), Week 4, Week 8, Week 12, Week 16 (phone contact), and 
Week 20 (phone contact) visits. Phone contacts will be conducted to check for adverse events, treatment compliance, potential recurrence, and concomitant medication 
use, including other antifungal agents. 
a. 
Screening and Day-14 may occur on the same day. 
b. If there is suspicion of a potential recurrence, subjects will be strongly discouraged from self-administering any treatment and will be instructed to visit the study 
center for a proper evaluation of their recurrence before initiating any VVC treatment. 
c. 
Unscheduled visits should be conducted anytime that there are symptoms indicating a potential recurrence or an adverse event. If there is suspicion of a potential 
recurrence, subjects will be strongly discouraged from self-administering any treatment and will be instructed to visit the study center for a proper evaluation of 


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Screena 
Acute Phase 
(Days -14 to -1 [+3 d]) 
Prevention of Recurrence 
Study Treatment Period 
(D1 to W24) 
Follow-up Period 
(W25 to W36) 
Unschc 
Study Week/Day 
 
Study Procedures 
D -16 
to -14 D-14a 
D -11 
& -8 
Phone 
D -4 to 
-2 
Lab 
W1/ 
D1 
(BL) 
W4/ 
D28 
(±3 d) 
W8/ 
D56 
(±3 d) 
W12/ 
D84 
(±3 d) 
W16/D112  
Phoneb 
W20/D140  
Phoneb 
W24/ 
D168 
(TOC) 
(±3 d) 
W28 & 
W32 
Phoneb 
W36 
(EOFU) 
(±3 d) 
their recurrence before initiating any VVC treatment. 
d. Vulvovaginal specimens will be obtained at the specified visits and anytime that a recurrence is suspected for local vaginal pH determination and KOH testing as 
well as to rule out bacterial vaginosis and Trichomonas vaginalis (wet-mount or other, process locally). Testing for Neisseria Gonorrhoeae, Chlamydia trachomatis 
or Herpes virus may also be conducted if these pathogens are suspected (central laboratory). Samples for fungal culture should also be collected for processing at a 
central laboratory. Susceptibility testing will be done centrally at Screening and for all positive cultures during the study. 
e. 
Only if there is suspicion of a potential recurrence. 
f. 
If a subject is actively menstruating at an on-site study visit that requires a vaginal exam, the visit should be rescheduled as soon as the subject’s period ends but in 
no case more than 7 days after the initially scheduled visit. 
g. From Baseline (Day 1) through the Week 36 (EOFU) visit, subjects will rate their symptoms and record their scores on the VSS Scale included in their subject 
diaries. Symptoms of infection will be rated on a weekly basis and at the time of each scheduled or unscheduled visit to the site. 
h. The first dose of fluconazole will be administered at the site on Day -14, after all other visit procedures have been done. The remaining doses will be self-
administered by the subjects at home.  
i. 
Conducted by the central lab. Results will be reviewed at Baseline (Day 1). 
j. 
Only if needed to follow up on a lab abnormality 
k. If the subject has a culture-confirmed Candida spp. infection from the sample collected at Screening, achieves a significant resolution of all signs and symptoms of 
infection (total composite score ≤ 2 on the VSS Scale) and meets other eligibility criteria for the study, she will enter the Prevention of Recurrence Phase. Subjects 
who fail treatment with open-label fluconazole in the Acute Phase but continue to meet all other eligibility criteria will enter the open-label ibrexafungerp Nested 
Sub-Study (see Section Error! Reference source not found. [Appendix C]). Subjects who are not eligible for this study or the Nested Sub-Study will be 
discontinued. 
l. 
Oral ibrexafungerp or placebo administered as a single-day treatment repeated every 4 weeks (28 days [±3]) for a total of 6 single-day treatments (Baseline [Day 1], 
Week 4, Week 8, Week 12, Week 16 and Week 20). Each single-day treatment will consist of two doses of ibrexafungerp 300 mg each or placebo given 12 (±4) 
hours apart. Subjects will continue study drug treatment regardless of recurrence and/or administration of antifungal therapy. The first dose will be administered at 
the study site (Baseline [Day 1]) and the remaining doses will be self-administered by the subjects at home. Study drug should be administered preferably with or 
immediately after a meal. 
m. Quality of Life tools will include: Euro Quol 5 Dimensions (EQ-5D), Short Form Health Survey (SF-36) and Female Sexual Distress-Revised Scale (FSDS) 
 


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13.2. 
Appendix 2: Standard EQ-5D-5L Value Sets 
An EQ-5D summary index is derived by applying a formula that attaches values (weights) to each 
of the levels in each dimension. The index is calculated by deducting the appropriate weights from 
1, the value for full health. Below is a part of the value sets for your reference. The full value sets 
used for this study will be saved in a excel file and used as an external data to import into the study 
database for EQ-5D index value selection. 
 
Health State 
Country/Region 
5L Profile 
Russia 
Poland 
USA 
Bulgaria 
11111 
 
 
1.000 
 
11112 
 
 
0.876 
 
11113 
 
 
0.844 
 
11114 
 
 
0.700 
 
11115 
 
 
0.550 
 
11121 
 
 
0.861 
 
11122 
 
 
0.820 
 
11123 
 
 
0.809 
 
11124 
 
 
0.669 
 
11125 
 
 
0.524 
 
11131 
 
 
0.827 
 
11132 
 
 
0.806 
 
11133 
 
 
0.800 
 
11134 
 
 
0.661 
 
11135 
 
 
0.517 
 
11141 
 
 
0.682 
 
…… 
 
 
 
 
 
 


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13.3. 
Appendix 3: SF-36 SCORING ALGORITHM 
The SF-36 is a validated generic QOL questionnaire that measures 8 health dimensions: physical 
functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, 
and mental health. The General Health question will be examined, and two overall scores will be 
calculated. The Physical Health summary measure is an aggregate of the physical functioning, 
role-physical, bodily pain and general health scales. The Mental Health summary measure is an 
aggregate of the vitality, social functioning, role-emotional, and mental health scales. The SF-36 
demonstrates acceptable validity and reliability and has been used in osteoarthritis (OA), low back 
pain, and cancer pain.  
The SF-36 consists of 11 sections. Some of the sections consist of multiple items. To specify 
scoring formulas, the 11 sections will be denoted by Question 1 to Question 11 according to the 
order in the questionnaire; and the individual items by their alphabetic order. For example, the first 
item in section 3 is represented as Question 3a. 
Each item on the 36-item short-form health survey (SF-36) will be answered by a patient. Some 
of the answers will then be re-coded so that across all questions, a higher score will indicate a 
better health state. Question 2 (Compared to one year ago, how would you rate your health in 
general now) is not used in the calculation of domain scores. Questions 3, 4, 5, 9b, 9c, 9f, 9g, 9i, 
10, 11a, 11c will be scored as recorded; the other scores will be transformed as follows: 
• Question 1: 
Original Response 
1 
2 
3 
4 
5 
Re-coded Response 
5 
4.4 
3.4 
2 
1 
• Questions 6, 9a, 9d, 9e, 9h, 11b, 11d: 
Original Response 
1 
2 
3 
4 
5 
Re-coded Response 
5 
4 
3 
2 
1 
• Question 7: 
Original Response 
1 
2 
3 
4 
5 
6 
Re-coded Response 
6 
5.4 
4.2 
3.1 
2.2 
1 
• Question 8 (if question 7 is answered): 
Original Response to #8 
1 
1 
2 
3 
4 
5 
Original Response to #7 
1 
2-6 
1-6 
1-6 
1-6 
1-6 
Re-coded Response 
6 
5 
4 
3 
2 
1 
• Question 8 (if question 7 is NOT answered): 
Original Response 
1 
2 
3 
4 
5 
Re-coded Response 
6 
4.75 
3.5 
2.25 
1 
 


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The raw score for the following 8 domains will be calculated by summing the re-coded scores for 
the set of questions listed in the table below if all of the questions within that domain are answered.  
If < 50% of the questions within a domain are answered, the raw score will not be calculated. 
 
Domain 
Questions 
Physical functioning 
3a-3j 
Role limitations due to physical health 
4a-4d 
Bodily pain 
7-8  
General health 
1, 11a-d 
Vitality 
9a, 9e, 9g, 9i 
Social functioning 
6, 10  
Role limitations due to emotional problems  
5a – 5c 
Mental health 
9b, 9c, 9d, 9f, 9h  
 
If ≥50% but not all of the questions are answered, the non-missing questions are re-coded (if 
necessary, per above) and then summed. An average score is calculated for those non-missing 
scores and that average score is imputed as the score to be used for the value of the missing 
questions. The raw score is then calculated as the sum of all of the question scores. For example, 
for the vitality domain, if questions 9a, 9e, and 9g are answered but question 9i is missing, the 
algorithm will proceed as follows from left to right: 
Question 
Patient-
Recorded 
Response 
Response 
after 
Re-coding 
Average of  
non-missing 
scores  
= (4+2+5)/3 
=3.6666… 
Average imputed 
for missing 
responses 
Raw Score = 
4+2+5+3.6666 
= 14.6666 
9a 
2 
4 
4 
9e 
4 
2 
2 
9g 
5 
5 
5 
9i 
Missing 
Missing 
3.6666… 
 
After the raw score is calculated, the raw score is converted into a normalized score (on a scale of 
0 to 100) using the following transformation: 
Normalized score =    (Raw Score – Lowest Possible Raw Score)   x 100 
                                                                    Possible Raw Score Range 
The normalized domain scores will then be standardized using means and SDs from the 1998 
general U.S. population by the following formula: 
Standardized score =     Normalized Score – a  
                                 b 
The lowest possible raw score, possible raw score range, (a) mean values and (b) SDs values from 
the 1998 general U.S. population for each domain are as follows: 
 


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Domain 
Lowest 
Possible 
Raw Score 
Possible 
Raw Score 
Range 
a 
b 
Physical functioning 
10 
20 
83.29094 
23.75883 
Role limitations due to 
physical health 
4 
16 
82.50964 
25.52028 
Bodily pain 
2 
10 
71.32527 
23.66224 
General health 
5 
20 
70.84570 
20.97821 
Vitality 
4 
16 
58.31411 
20.01923 
Social functioning 
2 
8 
84.30250 
22.91921 
Role limitations due to 
emotional problems  
3 
12 
87.39733 
21.43788 
Mental health 
5 
20 
74.98685 
17.75604 
 
The two raw component scores will be calculated based on multiplying each standardized domain 
score by a weights (factor score coefficients) derived from the 1990 general U.S. population, and 
then adding the 8 domains together. The constants to use for the two component scores are as 
follows: 
Domain 
Physical 
Component Summary 
Mental 
Component Summary 
Physical functioning 
0.42402 
-0.22999 
Role limitations due to 
physical health 
0.35119 
-0.12329 
Bodily pain 
0.31754 
-0.09731 
General health 
0.24954 
-0.01571 
Vitality 
0.02877 
0.23534 
Social functioning 
-0.00753 
0.26876 
Role limitations due to 
emotional problems  
-0.19206 
0.43407 
Mental health 
-0.22069 
0.48581 
 
The norm-based scores for the two component summaries will then be calculated by multiplying 
the raw component score by 10 and adding 50. 
The norm-based scores for the 8 domains will be calculated by multiplying the standardized 
domain score by 10 and adding 50. 
The norm-based scores will be used in the analyses. 
 


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13.4. 
Appendix 4: SAP for the Nested Sub-Study SCY-078-304S 
13.4.1. Title 
An exploratory, open-label, single-group ibrexafungerp sub-study to evaluate the efficacy and 
safety of oral ibrexafungerp in the treatment of acute vulvovaginal candidiasis in patients with 
recurrent VVC that has not responded to oral fluconazole treatment. 
13.4.2. Objectives 
13.4.2.1. Primary Objectives 
• 
To evaluate the efficacy of a single-day dosing of oral ibrexafungerp in subjects with a 
history of RVVC who failed oral fluconazole therapy for the treatment of an acute VVC 
episode, based on Clinical Success.  
13.4.2.2. Secondary Objectives 
• 
To evaluate the efficacy of a single-day dosing of oral ibrexafungerp in subjects with a 
history of RVVC who failed oral fluconazole therapy for the treatment of an acute VVC 
episode, based on mycological and clinical outcomes.  
• 
To evaluate the safety and tolerability of a single-day dosing of oral ibrexafungerp in 
subjects with a history of RVVC who failed oral fluconazole therapy for the treatment of 
an acute VVC episode.  
13.4.3. Investigational Plan 
13.4.3.1. Overall Study Design and Plan 
This study is an exploratory, open-label, single-group nested sub-study to evaluate the efficacy 
and safety of oral ibrexafungerp (SCY-078) in the treatment of subjects with acute VVC who did 
not respond to oral fluconazole treatment. Subjects with a history of recurrent VVC (enrolled in 
the Main Study [study SCY 078 304] with an acute VVC episode), who had a culture-confirmed 
VVC at Screening (Main Study) and failed oral fluconazole will be eligible for this sub-study 
(SCY-078-304S). A subject will be considered to have failed oral fluconazole therapy if she did 
not achieve a significant resolution of the signs and symptoms of infection (defined as a total 
composite score ≤ 2 on the VSS Scale) at the Baseline Visit (Day 1) following treatment with oral 
fluconazole 150 mg once daily (QD) on Days -14, -11 and -8. Eligible subjects must continue to 
meet all other applicable eligibility criteria of the Main Study (study SCY-078-304) to enter this 
study. Subjects who are eligible for this study will be offered open-label, one-day oral 
ibrexafungerp treatment for their unresolved VVC episode.  


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Approximately 60 subjects are planned to enter the study. All eligible subjects will receive oral 
ibrexafungerp administered as a single-day treatment consisting of two 300-mg doses (total dose 
= 600 mg) given 12 hours apart (±4 hours).  
The study will consist of a Baseline visit on Day 1, a TOC visit on Day 11 (±3) and a FU visit on 
Day 25 (±4). 
The schedule of study assessments is presented in Appendix S1. 
13.4.3.2. Study Endpoints 
13.4.3.2.1. 
Primary Endpoints 
• 
Efficacy as measured by the percentage of subjects with Clinical Success (at least 50% 
reduction from Baseline in the total composite VSS score with no additional antifungal 
therapy required based on investigator’s judgment) at the Test-of-Cure (TOC) visit.  
13.4.3.2.2. 
Secondary Efficacy Endpoints 
Efficacy as measured by: 
• 
The percentage of subjects with Clinical Improvement (partial or complete resolution of 
signs and symptoms [total composite score ≤1 on the VSS Scale] with no additional 
antifungal therapy required based on investigator’s judgment) at the TOC visit; 
• 
The percentage of subjects with Clinical Cure (complete resolution of signs and symptoms 
[total composite score of 0 on the VSS Scale] with no additional antifungal therapy 
required based on investigator’s judgment) at the TOC visit; 
• 
The percentage of subjects with Mycological Eradication (negative culture for growth of 
Candida spp.) at the TOC visit; 
• 
The percentage of subjects with both Clinical Cure and Mycological Eradication at the 
TOC visit; 
• 
The percentage of subjects with Continued Clinical Success (sustained resolution of signs 
and symptoms in subjects who achieved Clinical Success at the TOC visit) at the FU visit; 
• 
The absolute change in total composite VSS score from Baseline to the TOC and FU visits. 
Safety and tolerability as measured by: 
• 
Adverse events (AEs); 
• 
Vital signs; 
• 
Physical examination; 
• 
Treatment discontinuation; 
• 
Safety laboratory tests. 


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13.4.3.3. Treatments   
All eligible subjects will receive oral ibrexafungerp administered as a single-day treatment 
consisting of two 300-mg doses (total dose = 600 mg) given 12 hours apart (±4 hours). Subjects 
will receive their first dose of study drug at the site. The second study drug dose will be self-
administered by the subjects approximately 12 hours later at home on Baseline (Day 1). If 
administering the first dose at the study center would complicate the administration of the second 
dose 12 hours later (e.g. first dose at 3 p.m. will require second dose at 3 a.m.), the subject can 
self-administer both doses at home to allow for a more convenient dosing schedule (e.g., 8 p.m. 
and 8 a.m.). Subjects will record study drug dosing details in their study diary. 
 


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13.4.4. General Statistical Considerations 
Please refer to Section 4 of the main study above for the details of general statistical considerations. 
13.4.4.1. Sample Size 
The primary endpoint of the study is the percentage of subjects with Clinical Success (at least 50% 
reduction from Baseline in the total composite VSS score with no additional antifungal therapy 
required based on investigator’s judgment) at the TOC visit. As this is a single arm sub-study, a 
statement regarding the Clinical Success rate and 95% confidence interval will be produced. It is 
estimated that 60 subjects will be included based upon published fluconazole failure rates. With a 
study of this size, if the Clinical Success rate for ibrexafungerp were 50%, this would correspond 
to a 95% confidence interval spanning from 36.8% to 63.2%. Given it is expected that the Clinical 
Success for ibrexafungerp in subjects who have already failed fluconazole will be low as these 
subjects had already failed to respond, a sub-study of this size is appropriate to assess the efficacy 
of ibrexafungerp in this patient population. 
13.4.4.2. Randomization, Stratification and Blinding 
This is an open-label, single-group study. There will be no study-drug blinding, randomization or 
stratification.  
13.4.4.3. Analysis Set 
Intent-to-Treat (ITT) Set: All ibrexafungerp-treated subjects.  
Modified Intent-to-Treat (mITT) Set: All treated subjects who have a positive culture for Candida 
species at Baseline.  
Safety Set: All randomized subjects who received at least one dose of study drug and who have at 
least one post-Baseline evaluation.  
13.4.4.4. Handing of missing data 
For categorical response endpoints including clinical outcome, mycological outcome, symptom 
outcome, and clinical improvement, subjects will be considered a non-responder for the non-
responder imputation (NRI) analysis if they are missing categorical response data at the specific 
visit. Randomized subjects without at least 1 post-baseline observation will also be defined as 
non-responder for the NRI analysis such that subjects who have a missing value at the TOC visit 
or FU visit will be assigned as treatment failures, i.e., non-responders or positive mycological 
outcome for the corresponding visit. Randomized subjects without study treatment will be 
excluded from all analysis. 


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13.4.5. Subject Disposition 
13.4.5.1. Disposition 
A disposition of subjects includes the number and percentage of subjects for the following 
categories: subjects in each analysis set (ITT, mITT, SS), subjects who completed TOC visit, 
subjects who completed the study, subjects who discontinued from the study, and the reasons for 
study discontinuation will be presented by the ITT and mITT sets. All percentages will be based 
on the number of subjects in each corresponding set. 
The reason for study discontinuation may include any of the following: Absence of culture-
confirmed Candida spp. infection from the sample reviewed at Baseline, Adverse Event, Lost to 
Follow-up, Physician Decision, Pregnancy, Study Terminated by Sponsor, Withdrawal by Parent  
or Guardian, Withdrawal by Subject, Other, Death, Trial Screen Failure. 
Subject disposition data will be presented in a listing. 
13.4.5.2. Protocol Deviations 
The investigator may not deviate from the protocol without a formal protocol amendment having 
been established and approved by an appropriate IRB, except when necessary to eliminate 
immediate hazards to the subject or when the change(s) involve(s) only logistical or administrative 
aspects of the study. 
Significant protocol deviations will be defined in the significant protocol deviations rules 
document. Each significant deviation will be assigned a rule number. As the study is ongoing, 
additional significant protocol deviations can also be spontaneously identified or defined by the 
sponsor and/or the project team during the regularly planned study deviation review meetings and 
the significant protocol deviations rules document can be updated.  
All protocol deviations will be reviewed and assessed as to significance prior to the database lock. 
The list of protocol deviations (significant or minor) that are additionally considered major 
clinically relevant for the purposes of analysis will also be identified prior to the database lock.   
All major protocol deviations (i.e. resulting in exclusion of the subjects from one or more analysis) 
will be summarized using the ITT and mITT sets.  
Major protocol deviations will also be presented in a listing. 
 


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13.4.6. Demographics and Baseline Characteristics 
13.4.6.1. Demographics 
A summary of the following demographics will be presented for the subjects in ITT set and mITT 
set, respectively.  
• 
Age (years); 
• 
Age group (<18 years, 18 -<36 years, 36 -<50 years, 50 -<65 years, >=65 years); 
• 
Sex (Female); 
• 
Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, and Other); 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino); 
• 
Country [USA (United States), BGR (Bulgaria), RUS (Russia), POL (Poland)]; 
• 
Geographical location (USA, EX-USA); 
• 
BMI (kg/m²); 
• 
BMI group (Underweight <18.5 kg/m², Normal 18.5-<25 kg/m², Overweight 25-<30 
kg/m², Obese 30-<40 kg/m² and Morbidly Obese ≥40 kg/m²); 
• 
BMI group (≤35 kg/m² and >35 kg/m²). 
The age collected in CRF will be used for analysis if it is non-missing. If the age is not collected 
in the CRF, the age in years is calculated using the date of the informed consent and date of birth.  
Age (years) = [(Informed Consent Date – Date of Birth + 1) / 365.25]. 
BMI is calculated as 
BMI = (body weight in kilograms) / (height in meters)2. 
Demographics for all subjects in the ITT set will be presented in a listing.  
13.4.6.2. Baseline Characteristics 
A summary of the following baseline characteristics will be presented for subjects in the ITT and 
mITT sets, respectively. 
• 
Number of recurrent VVC episodes in the prior year; 
• 
Uncontrolled diabetes mellitus (Yes or No); 
• 
Candida species at screening (by Genus species); 
• 
Candida species at baseline (by Genus species); 
• 
Composite score of the vulvovaginal signs and symptoms at screening; 


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• 
Severity of VVC at screening (the composite score of the vulvovaginal signs and 
symptoms at screening ‘4 - 7’, ‘8 - 12’, and ‘>=13’); 
• 
Severity of VVC at screening (the composite score of the vulvovaginal signs and 
symptoms at screening <7, >=7); 
• 
Fertility Status (Surgically Sterile/Infertile; Post-Menopausal; Potentially Able to Bear 
Children); 
• 
Method of Birth Control (Barrier Methods Only; Oral Contraceptives; Depo 
Contraceptives (Implants/Injectables); IUD; Abstinence; Vaginal Ring; Vasectomized 
Partner; None; Other); 
A separate summary table will be presented to include MIC range, mode, MIC50, and MIC90, 
based on the mITT set by treatment and geographical region (USA or Ex-USA) for the following 
MIC results from 2 different methods, CLSI and EUCAST, respectively: 
• 
MIC results for SCY-078 and fluconazole (FLU) at 24 hours against candida species 
isolates obtained at Baseline; 
• 
MIC results for SCY-078 and fluconazole (FLU) at 48 hours against candida species 
isolates obtained at Baseline. 
Baseline characteristics for all subjects in ITT set will be presented in a listing.  
13.4.6.3. Medical History 
Medical history will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA; Version 19.1 or higher). A frequency summary (number and percentage) of subjects 
with at least one medical history will be presented by system organ class (SOC), and preferred 
term (PT), with SOCs sorted in alphabetical order and PTs within each SOC in descending order 
of frequency for all subjects in the ITT and mITT sets. 
In addition, A summary of other vulvovaginal conditions (Selected SOC and Preferred Terms) will 
be presented by system organ class (SOC), and preferred term (PT) for subjects in the mITT set. 
A by-subject listing of medical history will be provided. 
13.4.6.4. Inclusion and Exclusion Criteria 
Prior to enrollment, the investigator will assess if the subject fulfills all of the inclusion and none 
of the exclusion criteria outlined in the protocol (sections 21.3.7.1 and 21.3.7.2). The specific 
inclusion criterion not met or exclusion criterion which was met will be recorded in the eCRF. 


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13.4.7. Treatments and Medications 
13.4.7.1. Prior and Concomitant Medications 
All prior and concomitant medications taken before Baseline (Day 1) through the TOC visit will 
be recorded. Only the use of antifungal medications, vaginal (topical) medications, antibiotics for 
any reason or any other medications to treat an AE will be recorded after the TOC visit through 
the last study visit (FU). 
For the purpose of inclusion in prior and/or concomitant medication tables, incomplete medication 
start and stop dates will be imputed as follows: 
Missing start dates (where UK, UKN and UNKN indicate unknown or missing day, month and 
year respectively):  
• 
UK-MMM-YYYY: Assume 01-MMM-YYYY. If the month and year are the same as the 
first dose of study drug month and year, then assume the date of first dose of study drug; 
• 
UK-UKN-YYYY: If the year is prior to the year of first dose of study drug, assume 01-
JAN-YYYY of the collected year. If the year is the same as the first dose of study drug 
year, then assume the date of first dose of study drug; 
• 
UK-UKN- UNKN: Assume date of first dose of study drug. 
Missing stop dates for concomitant medications data will be handled as follows (where UK, UKN 
and UNKN indicate unknown or missing day, month and year respectively):  
• 
UK-MMM-YYYY: Assume the last day of the month; 
• 
UK-UKN-YYYY: Assume 31-DEC-YYYY; 
• 
UK-UKN- UNKN: Assume ongoing and leave it missing. 
All prior and concomitant medications will be coded using the current version of the World Health 
Organization Drug Dictionary Enhanced (WHO-DD) and summarized by treatment group based 
on the ITT and mITT sets. 
13.4.7.1.1. 
Prior Medications 
Prior medications are defined as medications taken and stopped prior to the first dose of study 
drug. The number and percentage of subjects who took prior medications will be presented by 
WHO therapeutic drug class and generic drug name. 
In addition, a summary of the following will be presented for subjects in the mITT set: 
• 
Antibiotic use 30 days before baseline visit; 
• 
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13.4.7.1.2. 
Concomitant Medications 
Concomitant medications are defined as medications started on or before the FU visit date with 
missing stop dates or stop dates after the first dose of study drug. 
A summary showing the number and percentage of subjects who took concomitant medications 
will be presented by WHO therapeutic drug class and generic drug name.  
A by-subject listing of prior and concomitant medications will be provided. 
13.4.7.1.3. 
Rescue Antifungal Medications 
The number and percentage of subjects who took rescue antifungal medication, prior or on TOC, 
after TOC but before FU, at FU visit will be presented for the ITT and mITT sets. 
A by-subject listing of rescue antifungal medications will be provided. 
13.4.7.2. Study Treatments 
Please refer to Section 13.4.3.3 for the details of the study treatment. 
Data related to the study treatment will be presented in a listing. 
13.4.7.2.1. 
Study Participation Calculation and Extent of Exposure 
The duration of study treatment (hours) is calculated as (the date time of the second dose – the date 
time of the first dose + 1) / 3600 only for subjects who got both 2 study treatments. For subjects 
who only got 1 or none study treatment, the duration of study treatment will be missing. 
The duration of study participation (days) is calculated as date of Study Completion/Termination 
recorded on the End of Study page – first dose date + 1. If the date of Study 
Completion/Termination on the End of Study page is missing, or if a subject is lost to follow-up, 
the latest available visit date will be used.  
The cumulative doses taken across the treatment period is defined as the number of study drug 
dispensed minus the number of study drug returned. If the study drug bottle was not returned, the 
dose diary data will be considered for the cumulative dose calculation. When subject answered no 
dose missing, we can assume the cumulative dose is 4. When subject answered only 1 dose 
missing, we can assume the cumulative dose is 2. When subject answered 2 doses missing, we can 
assume the cumulative dose is 0 tablet. The cumulative dose is missing when subject didn’t answer 
at least one missing dose question. 
The duration of study participation, the number of drug administrations and the cumulative doses 
by treatment will be summarized by summary statistics.  
All this exposure information will be presented in a listing. 


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13.4.7.2.2. 
Treatment Compliance 
Treatment compliance is defined as the ratio of total study dose to the planned dose, in terms of 
percentage. Treatment compliance will be summarized descriptively. 
Treatment compliance = the cumulative dose / the planned dose (4 tablets) *100%. 
The treatment compliance will be classified as 0, 25%, 50%, 75%, and 100%. This categorical data 
will be summarized with the frequency and percentage of subjects. 
Non-compliance with dose regimen (example all four tablets taken as a single dose) will be 
captured based on investigator’s review of subject diary. 
 


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13.4.8. Efficacy Analysis 
The primary efficacy and secondary efficacy endpoints will be performed on the modified intent-
to-treat set (mITT), and the intent-to-treat set (ITT). The mITT analyses will be considered 
primary; the ITT analyses will be considered supportive of the primary analyses on the mITT 
population. The denominator for all percentages will be the number of subjects in that treatment 
within the analysis set of interest, unless otherwise specified. 
13.4.8.1. Primary Endpoint 
The primary efficacy endpoint is defined as the percentage of subjects with Clinical Success (at 
least 50% reduction from Baseline in the total composite VSS score with no additional antifungal 
therapy required based on investigator’s judgment) at the test-of-cure (TOC) visit. 
Clinical success will be assessed at the TOC Visit (Day 11) according to the following definitions: 
• 
Clinical success: At least 50% reduction from Baseline in the total composite VSS score 
with no additional antifungal therapy required based on investigator’s judgment prior to 
or at the TOC visit; 
• 
Clinical failure: less than 50% reduction from baseline in the total composite VSS score 
or need for additional antifungal therapy. For the subject who early terminated before TOC 
visit and received additional vulvovaginal or systemic antifungal therapy or topical vaginal 
drug therapy for the treatment of vulvovaginal irritation/pruritus prior to or at the early 
termination visit, the subject is considered a clinical failure. 
Signs of VVC will be defined as the presence of erythema, edema, or excoriation. Symptoms of 
VVC will be defined as itching, burning, or irritation. 
Each vulvovaginal sign will be objectively scored based on severity as follows: 
0 = none (complete absence of any signs or symptoms); 
1 = mild (slight); 
2 = moderate (definitely present); 
3 = severe (marked, intense). 
Each vulvovaginal symptom will be objectively scored based on severity as follows: 
0 = none (I have no discomfort); 
1 = mild (I have some discomfort, but it does not bother me much); 
2 = moderate (I have discomfort, which is annoying, but not enough to affect what I am 
doing); 
3 = severe (I have discomfort, which is annoying enough to affect what I am doing). 
The composite score of the vulvovaginal signs and symptoms will be calculated according to the 
following rules and this scale has a total possible score of 18. 


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• 
If all items of the vulvovaginal signs and symptoms have been scored, the composite score 
is calculated as the sum of the individual scores of all 3 items of signs and 3 items of 
symptoms; 
• 
If any sign or symptom is not done, the composite score will not be calculated and treated 
as a missing data except at FU visit; 
• 
Subjects who are free of symptoms are not required per protocol to have a vaginal 
examination at FU visit, therefore signs are not considered missing. For subjects who do 
not present symptoms and have no sign rated at the FU visit, the composite score of the 
vulvovaginal signs and symptoms at the FU visit will be calculated as zero. 
13.4.8.1.1. 
Primary Analysis 
The primary efficacy analysis will be performed on the mITT set at the TOC visit. The number 
and percentage of subjects with clinical success at the TOC visit will be presented. The 95% 
confidence interval of the clinical success rate will be calculated using the method of Clopper and 
Pearson. Missing data for clinical outcome will be imputed using the NRI method described in 
Section 13.4.4.4. Additional summarizations will be performed by Candida Species of the baseline 
yeast, but not subject to formal statistical analysis. 
The same analysis employing the same methods as for the primary analysis will be performed for 
the ITT set to assess clinical success at TOC visit. Missing data for clinical outcome will be 
imputed using the NRI method described in Section 13.4.4.4. 
A sensitivity analysis using the mITT set will be performed where subjects with the imputed 
clinical outcome using the NRI method at TOC visit will be removed from the analysis. 
Summary of the number and percentage of subjects with continued clinical success at the Follow-
up (FUP) visit, which defined as continued clinical success in subjects who achieved Clinical 
Success at the TOC visit, will be provided based on the ITT, and mITT sets. 
13.4.8.2. Secondary Efficacy Endpoints 
13.4.8.2.1. 
Clinical Outcome – Clinical Cure 
A summary with the number and percentage of subjects with clinical cure at the TOC visit will be 
presented by Candida Species of the baseline yeast and overall. Clinical outcomes will be assessed 
at the TOC Visit (Day 11) according to the following definitions: 
• 
Clinical cure: Complete resolution of signs and symptoms of vulvovaginal infection 
without need for further antifungal treatment and topical vaginal drug therapy for the 
treatment of vulvovaginal irritation/pruritus prior to or at the TOC visit. Specifically, for 
complete resolution, any sign or symptom should be absent (score = 0); 
• 
Not clinical cure: No response to therapy or incomplete resolution of signs and symptoms 
or use of additional vulvovaginal or systemic antifungal therapy or topical vaginal drug 


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therapy for the treatment of vulvovaginal irritation/pruritus prior to or at the TOC visit. 
For the subject who early terminated before TOC visit and received additional 
vulvovaginal or systemic antifungal therapy or topical vaginal drug therapy for the 
treatment of vulvovaginal irritation/pruritus prior to or at the early termination visit, the 
subject is considered a not clinical cure. 
13.4.8.2.2. 
Mycological outcomes 
A summary with the number and percentage of subjects with mycological eradication (negative 
culture for growth of Candida species) at the TOC visit will be performed by Candida species of 
the baseline yeast and overall. The subjects with missing TOC visit data for the mycological 
outcome will be imputed as mycological persistence using the NRI method described in Section 
13.4.4.4. 
Mycological outcomes will be assessed at the specified visit according to the following definitions.  
• 
Mycological Eradication: A subject with negative culture for Candida species without 
need for further antifungal treatment prior to the TOC visit. For subjects who are free of 
symptoms and have no vulvovaginal specimens obtained at the TOC visit, the subject will 
be considered as mycological eradication; 
• 
Mycological Persistence: A subject with a positive culture for Candida species or use of 
additional vulvovaginal or systemic antifungal therapy prior to the TOC visit. For the 
subject who early terminated before TOC visit and received additional vulvovaginal or 
systemic antifungal therapy prior to the early termination visit, the subject is considered a 
mycological persistence. 
The same analysis will be done for the percentage of subjects with mycological eradication 
(negative culture for growth of Candida species) at the FU visit. For subjects who are free of 
symptoms and have no vulvovaginal specimens obtained at the FU visit, the subject will be 
considered as mycological eradication at the FU visit. 
The change of mycological outcomes will be summarized in shift tables comparing the testing 
results at TOC visit with those at FU visit. 
The analyses for mycological outcome will only be conducted for the mITT set.  
In addition, a summary table will be presented to include MIC range, mode, MIC50, and MIC90, 
based on the ITT and mITT sets by treatment group and geographical region (USA or Ex-USA) 
for the following MIC results from 2 different methods, CLSI and EUCAST, respectively: 
• 
MIC results for SCY-078 and fluconazole (FLU) at 24 hours against candida species 
isolates obtained at TOC visit; 
• 
MIC results for SCY-078 and fluconazole (FLU) at 48 hours against candida species 
isolates obtained at TOC visit. 


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Frequency cross-tabulations of mycological persistence at baseline versus mycological eradication 
at TOC visit will be presented by treatment group by candida species isolates obtained at baseline 
based on mITT set. 
13.4.8.2.3. 
Overall Outcome 
A summary with the number and percentage of subjects with clinical cure and mycological 
eradication (overall outcome) at the TOC visit will be performed by Candida Species of the 
baseline yeast and overall. The subjects who cannot determine the overall outcome at the TOC 
visit will be removed from the analysis and no missing data will be imputed for both clinical 
outcome and mycological outcome. 
Overall outcomes will be assessed at the TOC Visit (Day 11) according to the following 
definitions: 
• 
Overall Success: A subject with the achievement of both a clinical cure and mycological 
eradication; 
• 
Overall Failure: A subject with either not clinical cure or mycological persistence. 
The analyses for overall outcome will only be conducted for the mITT set. The overall outcomes 
will be listed with baseline species referenced aside in a listing. 
13.4.8.2.4. 
Symptom Outcome 
A summary with the number and percentage of subjects with complete resolution of symptoms at 
the Follow-up (FUP) visit will be performed by Candida Species of the baseline yeast and overall. 
The subjects with missing Follow-Up data for the symptom outcome will be imputed as symptom 
persistence using the NRI method described in Section 13.4.4.4. 
Symptom outcomes will be assessed at the FU Visit according to the following definitions: 
• 
Symptom Resolution: All symptoms are absent (score = 0) without need for further 
antifungal treatment or topical vaginal drug therapy for the treatment of vulvovaginal 
irritation/pruritus prior to or at FU visit; 
• 
Symptom Persistence: No response to therapy or incomplete resolution of symptoms or 
use of additional vulvovaginal or systemic antifungal therapy or topical vaginal drug 
therapy for the treatment of vulvovaginal irritation/pruritus prior to or at FU visit. For the 
subject who early terminated before the FU visit and received additional vulvovaginal or 
systemic antifungal therapy or topical vaginal drug therapy for the treatment of 
vulvovaginal irritation/pruritus prior to or at the early termination visit, the subject is 
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13.4.8.2.5. 
Clinical Improvement 
A summary with the number and percentage of subjects with clinical improvement (partial or 
complete resolution of signs and symptoms with total composite score no greater than 1 without 
need for further antifungal treatment and topical vaginal drug therapy for the treatment of 
vulvovaginal irritation/pruritus prior to or at TOC visit) at the TOC visit will be performed. For 
the subject who early terminated before the TOC visit and received additional vulvovaginal or 
systemic antifungal therapy or topical vaginal drug therapy for the treatment of vulvovaginal 
irritation/pruritus prior to or at the early termination visit, the subject is considered no clinical 
improvement. The subjects with missing TOC visit data for clinical improvement outcome will be 
imputed as no clinical improvement using the NRI method described in Section 13.4.4.4. The 
composite score will be calculated as the rules described in Section 13.4.8.1. 
13.4.8.2.6. 
Composite Score of the Vulvovaginal Signs and Symptoms 
The composite score of the vulvovaginal signs and symptoms and Change from Baseline values 
to test of cure visit and follow up visit will be summarized by treatment and by visit descriptively.  
The composite score of the vulvovaginal signs and symptoms will be classified as ‘0’, ‘1’, ‘2’, and 
‘>=3’. This categorical data will be summarized with the frequency and percentage of subjects at 
each scheduled visit. When there are multiple values within a visit, the worst value will be taken 
(worst being the maximum value of the composite score of the vulvovaginal signs and symptoms). 
All analysis will be performed based on the ITT and mITT sets. The similar analyses will be 
performed for below 2 categorizations of the composite score of the vulvovaginal signs and 
symptoms: <7, >=7 and ‘4 - 7’, ‘8 - 12’, and ‘>=13’. 
A listing will be provided to present the signs and symptoms score and mycological outcome for 
all subjects in the ITT set. Assessments that are not done will be presented in the data listing with 
a missing value. 
 


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13.4.9. Safety Analysis 
Safety analyses will be performed on all subjects in the safety set. Analyses will be based on 
adverse events, vital signs, clinical laboratory assessments, and physical examination findings. 
Safety analyses in general will be descriptive and will be presented in tabular format with the 
appropriate summary statistics. 
Individual subject listings will be provided to support the tables. 
13.4.9.1. Adverse Events 
All AE summaries will be restricted to treatment-emergent AEs (TEAEs) only. A TEAE is defined 
as any event does not present before exposure to study drug or any event already present that 
worsens in either intensity or frequency after exposure to study drug. 
For the purpose of inclusion in TEAE tables, incomplete AE start and end dates will be imputed 
as follows: 
Incomplete onset dates (where UK and UNK indicate unknown or missing day and month 
respectively): 
• 
UK-MMM-YYYY: If the month and year are different from the month and year of the 
date of first dose, assume 01-MMM-YYYY. If the month and year are the same as the 
month and year for the date of first dose, and the end date (after any imputation) is on or 
after the date of first dose, then assume the date of first dose. If the month and year are the 
same as the date of first dose, and the end date (after any imputation) is prior to the date 
of first dose, then assume the end date for the start date.  
• 
DD-UNK-YYYY/UK-UNK-YYYY: If the year is different from the year of the date of 
first dose, assume 01-JAN-YYYY of the collected year. If the year is the same as the date 
of first dose year, and the end date (after any imputation) is on or after the date of first 
dose, then assume the date of first dose. If the year is the same as the date of first dose, 
and the end date (after any imputation) is prior to the date of first dose, then assume the 
end date for the start date.  
Incomplete end dates (where UK and UNK indicate unknown or missing day and month 
respectively):  
• 
UK-MMM-YYYY: Assume the last day of the month; 
• 
DD-UNK-YYYY/UK-UNK-YYYY: Assume 31-DEC-YYYY. 
The missing onset dates will be imputed as the date of first dose of study drug. The missing end 
date will be imputed as the subject’s last visit date. 
All adverse events will be classified by SOC and PT according to the Medical Dictionary for 
Regulatory Activities (MedDRA, Version 19.1 or higher). 


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An overview summary of the number and percentage of subjects with any TEAE, serious TEAE, 
treatment-related TEAE, treatment-related serious TEAE, TEAE leading to study treatment 
discontinuation, TEAE leading to study discontinuation, and AE leading to death will be provided 
by treatment group.  
All AEs will be presented in a listing. 
13.4.9.1.1. 
Treatment-Emergent Adverse Events 
Summaries of the total number of TEAEs and the number and percentage of subjects with at least 
one TEAE will be provided. Treatment-emergent AEs will be presented by SOC and PT. At each 
level of subject summarization, a subject is counted once if the subject reported one or more events. 
Percentages will be calculated out of the number of subjects in the safety set.  
The summary of TEAEs will be presented in alphabetical order of SOC. Within each SOC, PTs 
will be sorted in descending order from the PT with the highest total frequency (that is, summed 
across all treatment groups) to the PT with the lowest total frequency. If the total frequency for 
any two or more PTs is equal, the PTs will be presented in alphabetical order.  
The summarization described above will also be repeated for the following: 
• 
Serious Adverse Events; 
• 
Treatment-Related Adverse Events; 
• 
Treatment-Related Serious Adverse Events; 
• 
Adverse Events Leading to Dose Interruption. 
The adverse events with a missing relationship will be considered as “Treatment Related” in the 
tables. 
13.4.9.1.2. 
Relationship of Adverse Events to Study Treatment 
A summary of TEAEs by relationship to study treatment will be presented in a table. The 
investigator will provide an assessment of the relationship of the event to the study treatment. The 
possible relationships are “Not Related” and “Related”. In the TEAE relationship table, if subject 
reports multiple occurrences of the same TEAE, only the most closely related occurrence will be 
presented. Treatment-emergent AEs that are missing a relationship will be presented in the 
summary table as “Related” but will be presented in the data listing with a missing relationship. 
Percentages will be calculated based on the number of subjects in the safety set. 
The TEAE data will be categorized and presented by SOC, PT, and relationship in a manner similar 
to that described in Section 9.1.1. 
Treatment-emergent SAEs by relationship to study treatment will also be presented in a table. 
Treatment-emergent SAEs that are missing a relationship will be presented in the table as 
“Related” but will be presented in the data listing with a missing relationship. 


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13.4.9.1.3. 
Severity of Adverse Event 
A summary of TEAEs by severity will be presented in a table. The severity that will be presented 
represents the most extreme severity captured on the CRF page. The possible severities are “Mild”, 
“Moderate”, and “Severe”.  
In the TEAE severity table, if a subject reported multiple occurrences of the same TEAE, only the 
most severe will be presented. An additional row “Missing” must be added for the missing severity. 
Percentages will be calculated out of the number of subjects in the safety set. 
The TEAE data will be categorized and presented by SOC, PT, and severity in a manner similar 
to that described in Section 9.1.1. 
Additionally, the TEAE data will be categorized and presented by SOC, PT, severity, and 
relationship. At each combination level of severity and relationship, a subject is counted once if 
the subject reported one or more events. Percentages will be calculated out of the number of 
subjects in the safety set. 
Treatment-emergent SAEs by severity will also be presented in a table.  
13.4.9.1.4. 
Adverse Events Leading to Treatment Discontinuation 
A summary of the TEAEs with an action taken with study treatment of “Drug Withdrawn” will be 
presented by treatment in a manner similar to that described in Section 9.1.1. 
Any TEAEs leading to treatment discontinuation will be presented in a listing for all subjects. 
13.4.9.1.5. 
Adverse Events Leading to Study Discontinuation 
All subjects who have an AE with the answer to “Caused Study Discontinuation” is “Yes” will be 
presented in a listing. 
13.4.9.1.6. 
Death 
All subjects who have an AE with an outcome of “Death Related to Adverse Event” will be 
presented in a listing. 
13.4.9.2. Clinical Laboratory Evaluations 
Summary tables will be presented for laboratory test results (hematology and blood chemistry) at 
Screening and TOC visit for subjects in the safety set. 
All relevant clinical laboratory tests in chemistry and hematology will be classified as Low, 
Normal, and High according to the normal ranges. This categorical data will be summarized in 
shift tables comparing the extreme results at TOC visit with those at the screening visit. Extreme 
post-baseline results will also be summarized. When there are multiple values within a visit for a 
particular laboratory variable, the worst value will be taken (worst being the smallest value for 
criteria below a certain threshold or the largest value for criteria above a certain threshold). If a 


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subject has a value below the threshold and above the threshold, the value furthest from the 
threshold will be chosen. 
Plots of average clinical laboratory parameters may be presented. 
In data listings, laboratory values will be compared to normal ranges; out-of-range laboratory 
values will be identified. 
13.4.9.2.1. 
Pregnancy 
Female subjects of child-bearing potential will have urine pregnancy tests conducted at screening 
and at any timepoints during the study, if needed. Only subjects with negative pregnancy test 
results will be enrolled. Any subjects with positive pregnancy test results at any time during the 
study will be presented in a listing.  
13.4.9.2.2. 
Events of Clinical Interest 
The frequency and percentage of subjects with the following elevations will be summarized at any 
post-baseline visit: 
• 
ALT or AST > 8  the upper limit of normal (ULN); 
• 
ALT or AST > 5  ULN for more than 2 weeks or accompanied by total bilirubin > 2  
ULN. 
A listing will be provided for the above elevations, including the actual measurement of ALT, 
AST, and total bilirubin, and their reference high limits. 
13.4.9.3. Vital Sign Measurements 
Summary tables will be presented for vital sign data, including systolic blood pressure (mmHg), 
diastolic blood pressure (mmHg), body temperature (C), respiratory rate (bpm), and pulse rate 
(bpm), for subjects in the safety set. Observed results at the scheduled visits and changes from 
baseline to the TOC visit will be presented. All vital sign data by subject will be presented in a 
listing. 
13.4.9.4. Physical Examination 
The abbreviated physical examinations will be conducted at Screening and at the TOC visit. 
The abbreviated physical examination comprises a routine medical examination including general 
appearance and an overall examination of body systems. 
All abbreviated physical examinations will be classified as Normal, and Abnormal at baseline. For 
post-baseline examinations will be classified as “Changes from baseline” or “No change from 
baseline”. This categorical data will be summarized with the frequency and percentage of subjects 
by body system at each scheduled visit. 
All abbreviated physical examination data will be presented in a listing for all subjects. 


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13.4.9.5. Vaginal Samples – pH, KOH and Other Pathogen Results 
Vaginal samples will be obtained for pH testing, KOH testing, fungal culture, and other pathogens 
(Chlamydia, Gonorrhea, and Herpes) at the screening visit and other times during the study when 
persistence or recurrence of vulvovaginal symptoms occurs. Subjects with other pathogens other 
than Candida, suspected at screening will be excluded from the study. 
The KOH testing results will be classified as Positive (Yeast Only), Positive (Yeast and other 
pathogens), Negative (Yeast and other pathogens), and Positive (Other pathogens only). This 
categorical data will be summarized with the frequency and percentage of subjects at the scheduled 
post-baseline visits. 
The proportion of subjects with Chlamydia, Gonorrhea, and Herpes will be summarized at the 
scheduled visits. 
All vaginal sample testing data will be presented in a listing. 
13.4.10. 
Interim Analysis 
No interim analysis is planned for this study. 
13.4.11. 
Changes in the Planned Analysis 
For the clinical failure definition, the texts “less than 50% reduction from baseline in the total 
composite VSS score” was used to replace “persistence and/or worsening of signs and symptoms” 
we have in the protocol. 
 


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13.4.12. 
Appendices – Nested Sub-study 
13.4.12.1. Appendix S1: Schedule of Assessments of the Nested Sub-Study 
Visit 
Baseline 
(Treatment)  
Test of Cure 
Follow-up 
Unscheduled 
Visitsa 
Day 
(allowable window) 
 
Study Procedures 
Day 1 
Day 11 (±3) 
Day 25 
(± 4) 
Informed Consentb 
 
Assignment of Subject Number  
X 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
Abbreviated physical exam 
Xc 
X 
 
If needed 
Urine pregnancy testd 
Xc 
 
 
If needed 
Vulvovaginal sample for KOHe 
X 
If needed 
If needed 
If needed 
Vulvovaginal sample for fungal culturee 
Xc 
If needed 
If needed 
If needed 
Vulvovaginal sample for pHe 
Xc 
If needed 
If needed 
If needed 
Vulvovaginal sample for other pathogense 
X 
 
 
If needed 
Vulvovaginal examf and rating of signs by 
the investigator 
Xc 
X 
If 
symptomsg 
If needed 
Rating of vulvovaginal symptoms by the 
subject 
Xc-----------------X 
X 
If needed 
Study drug dosing and dispensing 
Xh 
 
 
 
Subject diary dispensingi 
X 
 
 
 
Subject diary completion 
X -----------------X 
 
 
Study drug collection and review 
 
X 
 
 
Subject diary collection and review 
 
X 
 
 
Assessment of efficacy 
 
X 
X 
 
Sample collection for safety labs 
(hematology and blood chemistry) 
 
Xj 
 
If needed 
Vital Signs 
Xc 
X 
 
If needed 
Prior & concomitant medication review 
Xc 
X 
X 
X 
Adverse event monitoringk 
Xc 
X 
X 
X 
Abbreviations: KOH = potassium hydroxide; VSS = vulvovaginal signs and symptoms 
a. 
Unscheduled visits should be conducted anytime that there is indication of persistence or worsening of 
symptoms or an adverse event. If there is suspicion of persistence or worsening of symptoms, subjects 
will be strongly discouraged from self-administering any treatment and will be instructed to visit the 
study center for a proper evaluation before initiating any new VVC treatment. 
b. Informed consent will be obtained for both the Main Study and this Sub-Study at the Screening visit of 
the Main Study. 
c. 
These procedures are conducted as part of the Baseline (Day 1) visit for the Main Study and do not need 
to be repeated for the purpose of this study. 
d. Results should be reviewed prior to the administration of the first dose of study drug. 
e. 
Vulvovaginal specimens will be obtained at the Baseline (Day 1) visit for all subjects and at the TOC 
(Day 11) and FU (Day 25) visits if vulvovaginal symptoms have not improved or have worsened. 
Samples will be collected for pH determination and KOH testing as well as to rule out bacterial vaginosis 
and Trichomonas vaginalis (wet-mount or other, process locally at the site or at a local qualified lab). 
Testing for Neisseria Gonorrhoeae, Chlamydia trachomatis or Herpes virus may also be conducted if 
these pathogens are suspected (central laboratory). Samples for fungal culture should also be collected for 
processing at a central laboratory. Susceptibility testing will be done centrally for all positive cultures 
during the study. Samples should also be obtained any time that a subject experiences persistence or 
worsening of symptoms (i.e., unscheduled visits if needed). 
f. 
If a subject is actively menstruating at a study visit that requires a vaginal exam, the visit should be 


SCYNEXIS, Inc. 
  Statistical Analysis Plan, Final Version 1.0 
SCY-078-304S 
 
 
 
58
Visit 
Baseline 
(Treatment)  
Test of Cure 
Follow-up 
Unscheduled 
Visitsa 
Day 
(allowable window) 
 
Study Procedures 
Day 1 
Day 11 (±3) 
Day 25 
(± 4) 
rescheduled as soon as the subject’s period ends but in no case more than 7 days after the initially 
scheduled visit. 
g. Vulvovaginal examinations will be repeated at the FU visit only if the subject presents symptoms. 
Otherwise, no additional vulvovaginal examination will be conducted, or signs rated.  
h. Subjects will receive their first dose of study drug at the site at the Baseline (Day 1) visit and will be given 
study drug to self-administer their second dose at home. The two doses should be administered 
approximately 12 (±4) hours apart, preferably with or immediately after a meal. 
i. 
Subject diaries will be used to rate vulvovaginal symptoms of infection on the VSS Scale and record 
second dose of study drug details, adverse events and concomitant medication use. 
j. 
Conducted by the central lab. 
k. Recorded from the time the Informed Consent Form is signed in the Main Study.