Clinical trial NCT03734991
Conditions: Candida Vulvovaginitis
Sponsor: Scynexis, Inc.
Start date: 2019-01-04; Completion date: 2019-09-04
Enrollment: 376 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

Detailed description:
Subjects who meet all of the inclusion and none of the exclusion criteria will be enrolled into the study and will be randomized in a 2:1 ratio to either oral ibrexafungerp or ibrexafungerp matching placebo, as follows:

* Oral ibrexafungerp 300-mg dose BID for 1 day
* Oral ibrexafungerp matching placebo BID for 1 day

Subjects will receive their first dose of study drug at the site and will be dispensed the second dose for self-administration at home 12 hours after the first dose. Study Blinding, Randomization and Stratification: This is a randomized, double-blind study.

All site and sponsor personnel will be blinded to treatment assignment. Approximately 366 eligible subjects will be enrolled and randomized in a 2:1 ratio to one of the two study treatment groups. For the purpose of maintaining treatment blinding, all subjects randomized to the placebo group will receive matching ibrexafungerp placebo tablets.

Arms: arm 1: 300 mg orally every 12 hrs for 1 day (2 doses in 1 day) arm 2: Matching Placebo
Interventions: intervention 1: Ibrexafungerp intervention 2: Placebo
Intervention descriptions: intervention 1: Ibrexafungerp 300 mg BID for 1 day intervention 2: Matching placebo

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) 
vs. Placebo in Subjects with Acute Vulvovaginal Candidiasis 
SCYNEXIS Protocol Number SCY-078-303 
 
SCYNEXIS, Inc. 
1 Evertrust Plaza, 13th Floor 
Jersey City, NJ 07302 
 
Original Protocol Issue Date: 12 Oct 2018 (Version 1.0) 
 
US IND Number 107521 
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. 
NCT03734991


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1.0 
Contact Information 
 
   Contract Research Organization 
 
 
 
Study Medical Monitor 
David Angulo, MD 
 
 
Clinical Project Manager 
 
 
 
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-078-303 
 
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate 
the Efficacy and Safety of Oral Ibrexafungerp (SCY-078) vs. Placebo in Subjects with 
Acute Vulvovaginal Candidiasis 
SCYNEXIS, Inc. Approval: 
 
 
 
 
 
David Angulo, MD 
Chief Medical Officer 
One Evertrust Plaza, 13th Floor 
Jersey City, NJ 07302 
 
 
Date 
 


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Investigator Agreement Statement 
PROTOCOL ID: SCY-078-303 
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate 
the Efficacy and Safety of Oral Ibrexafungerp (SCY-078) vs. Placebo in Subjects with 
Acute 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 patient. 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..................................................................................................... 14 
6.0 Schematic of Study Design ...................................................................................... 22 
7.0 Background Information and Scientific Rationale .................................................. 23 
7.1 Background Information ...................................................................................... 23 
7.2 Rationale for the Study ........................................................................................ 28 
8.0 Study Objectives ...................................................................................................... 29 
8.1 Primary Objectives............................................................................................... 29 
8.2 Secondary Objectives........................................................................................... 29 
9.0 Study Endpoints ....................................................................................................... 29 
9.1 Primary Endpoints ............................................................................................... 29 
9.2 Secondary Endpoints ........................................................................................... 30 
10.0 Study Design .......................................................................................................... 30 
10.1 Overall Description of the Study ....................................................................... 30 
10.1.1 Study Visits ................................................................................................. 31 
10.1.2 Study Assessments ...................................................................................... 32 
10.2 Blinding, Randomization and Stratification ...................................................... 33 
10.3 Study Duration ................................................................................................... 34 
10.4 Number of Centers ............................................................................................. 34 
11.0 Study Population .................................................................................................... 34 
11.1 Inclusion Criteria ............................................................................................... 34 
11.2 Exclusion Criteria .............................................................................................. 35 
11.3 Discontinuation Criteria ..................................................................................... 36 


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11.4 Early Termination .............................................................................................. 37 
11.5 Replacement of Dropouts .................................................................................. 38 
12.0 Study Treatments ................................................................................................... 38 
12.1 Study Treatment Groups .................................................................................... 38 
12.2 Dietary Requirements ........................................................................................ 38 
12.3 Study Drugs ....................................................................................................... 38 
12.3.1 Ibrexafungerp SCY-078 Description .......................................................... 38 
12.3.2 Formulation, Packaging and Labelling ....................................................... 39 
12.3.3 Storage and Stability ................................................................................... 40 
12.4 Drug Accountability........................................................................................... 40 
12.5 Subject Compliance with Study Drug Dosing ................................................... 41 
13.0 Non-Study Treatments ........................................................................................... 41 
13.1 Prior and Concomitant Medications .................................................................. 41 
13.2 Prohibited Medications ...................................................................................... 41 
13.3 Medications to be Administered with Caution and Monitored as Appropriate . 42 
13.4 Study Restrictions .............................................................................................. 42 
14.0 Study Procedures ................................................................................................... 42 
14.1 Informed Consent............................................................................................... 42 
14.2 Assignment of Subject Number ......................................................................... 42 
14.3 Inclusion and Exclusion Criteria ........................................................................ 43 
14.4 Medical History and Demographics .................................................................. 43 
14.5 Abbreviated Physical Examination .................................................................... 43 
14.6 Urine Pregnancy Test ......................................................................................... 43 
14.7 Safety Laboratory Tests ..................................................................................... 43 
14.8 Rating of Vulvovaginal Symptoms by the Subject Using the VSS Scale ......... 44 
14.9 Vulvovaginal Samples for Identification of Other Pathogens and Vaginal pH . 44 
14.10 Vulvovaginal Samples for KOH and Fungal Culture ...................................... 45 
14.11 Rating of Vulvovaginal Signs by the Investigator Using the VSS Scale ........ 45 
14.12 Randomization ................................................................................................. 46 


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14.13 Study Drug and Subject Diary Dispensing ...................................................... 46 
14.14 Study Drug Dosing .......................................................................................... 46 
14.15 Subject Diary Completion................................................................................ 47 
14.16 Study Drug Collection and Treatment Compliance Evaluation ...................... 47 
14.17 Subject Diary Collection and Review .............................................................. 47 
14.18 Vital Signs ........................................................................................................ 47 
14.19 Prior and Concomitant Medication Review ..................................................... 47 
14.20 Adverse Event Monitoring ............................................................................... 48 
15.0 Study Schedule....................................................................................................... 49 
16.0 Safety Assessments and Monitoring ...................................................................... 52 
16.1 Definition of an Adverse Event ......................................................................... 52 
16.2 Definition of a Serious Adverse Event .............................................................. 53 
16.3 Events of Clinical Interest .................................................................................. 53 
16.4 Overdose ............................................................................................................ 54 
16.5 Pregnancy ........................................................................................................... 54 
16.6 Unexpected Adverse Event ................................................................................ 54 
16.7 Grading of Adverse Events ................................................................................ 55 
16.8 Causality Assessment......................................................................................... 55 
16.9 Adverse Event Collection Timeframe ............................................................... 55 
16.10 Serious Adverse Event Reporting Requirements ............................................. 56 
16.11 Adverse Event and Serious Adverse Event Follow-up .................................... 56 
16.12 Serious Adverse Event Reporting – Procedures for Investigators ................... 56 
16.13 Procedures for Emergency Unblinding ............................................................ 57 
17.0 Data Collection, Study Monitoring and Record Management ............................... 57 
17.1 Data Collection and Reporting........................................................................... 57 
17.2 Study Monitoring ............................................................................................... 57 
17.3 Investigator Study Files ..................................................................................... 58 
17.4 Retention of Records.......................................................................................... 58 
18.0 Analytical Plan ....................................................................................................... 59 


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18.1 Sample Size Determination................................................................................ 60 
18.2 Analysis Populations .......................................................................................... 60 
18.3 Subject Disposition, Discontinuation, and Baseline Data ................................. 60 
18.4 Handling of Missing Data, Dose Adjustments, and Early Withdrawals............ 61 
18.5 Prior and Concomitant Medications .................................................................. 61 
18.6 Efficacy .............................................................................................................. 61 
18.6.1 Efficacy Assessments.................................................................................. 61 
18.6.2 Efficacy Analyses ....................................................................................... 62 
18.7 Safety ................................................................................................................. 62 
18.7.1 Safety Assessments ..................................................................................... 62 
18.7.2 Analyses ...................................................................................................... 63 
19.0 Ethics and Protection of Human Patients............................................................... 63 
19.1 Ethical Conduct of the Study ............................................................................. 63 
19.2 Institutional Review Board/Ethics Committee Review ..................................... 63 
19.3 Informed Consent............................................................................................... 64 
19.4 Future Use of Samples ....................................................................................... 64 
19.5 Subject Privacy and Subject Confidentiality ..................................................... 64 
19.6 Study Termination ............................................................................................. 65 
19.7 Financial Disclosure........................................................................................... 65 
20.0 References .............................................................................................................. 66 
21.0 Appendices ............................................................................................................. 67 
Appendix A:  Prohibited Medications and Medications to be Administered with Caution
 
67 
Prohibited Medications ............................................................................................. 67 
Medications to be administered with Caution and Monitored as Appropriate ......... 68 
Appendix B:  Vulvovaginal Signs and Symptoms Scale .............................................. 69 
 
LIST OF FIGURES 
Figure 1 
Schematic of Study Design ........................................................................... 22 


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Figure 2 
Chemical Structure of Ibrexafungerp Citrate (formerly SCY-078) .............. 39 
LIST OF TABLES 
Table 1: Schedule of Visits and Procedures (Study SCY-078-303) .............................. 49 
 
 
 
 


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3.0 
Revision History 
Not applicable 
 
 


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4.0 
Abbreviations 
ABBREVIATION 
DEFINITION 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AVVC 
acute vulvovaginal candidiasis 
BID 
twice daily 
CD 
compact disk 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
Cmax 
maximum concentration 
CMH 
Cochran Mantel Haenszel 
CPK 
creatine phosphokinase 
CRO 
contract research organization 
CYP 
cytochrome P450 
DVD 
digital versatile disk 
EC 
Ethics Committee 
ECI 
event of clinical interest 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
FLU 
fluconazole 
FU 
follow-up 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GSI 
glucan synthesis inhibitor 


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ABBREVIATION 
DEFINITION 
IB 
Investigator´s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ID 
identification 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IV 
intravenous 
KOH 
potassium hydroxide 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
minimum inhibitory concentration 
mITT 
modified intent to treat 
OATP1B3 
organic anion-transporting polypeptide 1B3 
P-gp 
P-glycoprotein 
PI 
principal investigator 
PP 
per protocol 
QD 
once daily 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SOC 
standard of care 
TOC 
test of cure 
ULN 
upper limit of normal 
US 
United States 
VSS Scale 
Vulvovaginal Signs and Symptoms Scale 
VVC 
vulvovaginal candidiasis 


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ABBREVIATION 
DEFINITION 
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) vs. Placebo in Subjects with 
Acute Vulvovaginal Candidiasis 
Primary Objectives: 
• 
To evaluate the efficacy of oral ibrexafungerp versus placebo in subjects with acute 
vulvovaginal candidiasis (AVVC) by comparing the clinical outcomes of ibrexafungerp 
and placebo 
Secondary Objectives: 
• 
To evaluate the efficacy of oral ibrexafungerp versus placebo in subjects with AVVC based 
on mycological and clinical outcomes 
• 
To evaluate the safety and tolerability of oral ibrexafungerp versus placebo in subjects with 
AVVC 
Primary Endpoints: 
• 
Efficacy as measured by the percentage of subjects with clinical cure (complete resolution 
of signs and symptoms) at the test-of-cure (TOC) visit 
Secondary Endpoints: 
Efficacy as measured by: 
• 
The percentage of subjects with mycological eradication (negative culture for growth of 
Candida species) at the TOC visit 
• 
The percentage of subjects with clinical cure and mycological eradication (responder 
outcome) at the TOC visit. 
• 
The percentage of subjects with complete resolution of symptoms at the Follow-up (FU) 
visit. 
• 
The percentage of subjects with clinical improvement (partial or complete resolution of signs 
and symptoms with total composite score no greater than 1) at the TOC visit.  
• 
The absolute change in signs and symptoms score from Baseline to TOC and FU visits. 
 
Safety and tolerability as measured by: 
• 
Adverse events (AEs), vital signs, physical examination, treatment discontinuation and 
safety laboratory tests. 
Study Phase: 3 
Study Design: This is a Phase 3, randomized, multicenter, double-blind, placebo-controlled 
study to evaluate the efficacy and safety of oral Ibrexafungerp (SCY-078) compared to placebo 
in female subjects 12 years and older with AVVC.  Approximately 366 eligible subjects will be 
enrolled and randomized in a 2:1 ratio to either ibrexafungerp (300-mg dose twice a day [BID]) 
or matching placebo administered BID for 1 day. 


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Study Visits 
The study will consist of a Screening visit, a Baseline visit on Day 1 (these visits may occur on 
the same day), a TOC visit on Day 11 (±3) and a FU visit on Day 25 (±4). 
Screening  
At Screening, subjects who are experiencing vulvovaginal symptoms will be evaluated by the 
investigator, who will obtain a vaginal sample for potassium hydroxide (KOH) testing and 
vaginal pH determination by the local laboratory prior to randomization and initiation of 
treatment. The vaginal samples will also be evaluated locally for findings indicative of bacterial 
vaginosis and Trichomonas vaginalis. A vaginal sample for fungal culture and for species 
identification and susceptibility testing will be obtained and sent to a designated central 
laboratory. 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. The investigators and the subjects will rate the signs and symptoms of infection, 
respectively, on a standardized vulvovaginal signs and symptoms scale (the Vulvovaginal Signs 
and Symptoms [VSS] Scale). Safety procedures, including an abbreviated physical exam, vital 
signs, laboratory tests and a pregnancy test will also be performed.  
To be eligible for inclusion, subjects must have a minimum composite score of vulvovaginal 
signs and symptoms ≥4 with at least 2 signs or symptoms having a score of 2 (moderate) or 
greater in the VSS Scale at Baseline, a positive KOH test and a normal vaginal pH (≤4.5). 
The Screening and Baseline (Day 1) visits may occur on the same day. 
Baseline  
Eligible subjects will be randomized in a 2:1 ratio to one of the following two treatment groups: 
• 
Oral ibrexafungerp 300-mg dose BID for 1 day  
• 
Oral ibrexafungerp matching placebo BID for 1 day 
For the purpose of maintaining treatment blinding, all subjects randomized to the placebo group 
will receive matching ibrexafungerp placebo tablets. Subjects will receive their first dose of study 
drug at the site and will be dispensed study drug and subject diaries to rate their vulvovaginal 
symptoms of infection and to record dosing details, AEs and concomitant medication use from 
Day 1 until the TOC visit (Day 8-Day 14). Subjects will self-administer their second study drug 
dose at home 12 hours after the first dose.  
Assessment of Clinical Cure (TOC)  
At the TOC visit (Day 8-Day 14), subjects will return any remaining medication as well as empty 
bottles of the study drug and treatment compliance will be evaluated. 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 vaginal sample for fungal culture and for species 
identification and antifungal susceptibility testing will be obtained and sent to a designated 
central laboratory. An abbreviated physical exam, vital signs measurements and safety laboratory 
tests will also be performed.  
If the baseline vulvovaginal symptoms have not noticeably improved or have worsened and the 
investigator considers that rescue antifungal medication may be needed, a vaginal sample should 
also be obtained for KOH testing by the local laboratory. 
Follow up  


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At the FU visit, subjects will rate their symptoms of infection on the VSS Scale. Vulvovaginal 
samples for KOH testing and fungal culture should be obtained if there is persistence or 
recurrence of vulvovaginal symptoms. Only if symptoms are present, the investigator will 
perform a vulvovaginal examination to rate the subject´s signs of infection. 
All Visits 
AEs and prior/concomitant medications will be assessed and documented at all visits. 
Efficacy (Clinical and Mycological) and Safety Assessments 
Clinical Evaluation 
The signs (edema, erythema and excoriation or fissures) and symptoms (burning, itching and 
irritation) of infection will be assessed by the investigator and the subject, respectively, on the 
VSS Scale [provided in Appendix B of the protocol]). 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 microscopic examination with 10% KOH and fungal 
cultures. KOH will be performed locally at Screening for the determination of subject eligibility 
and at the TOC visit or FU visit if symptoms persist or recur. Vaginal samples will be collected 
at Screening, TOC visit and prior to the initiation of rescue antifungal medication during the 
study for fungal cultures and tested centrally. The central lab will determine growth of yeasts, 
species identification and susceptibility testing.  
Safety Assessments  
Safety procedures will include collection of AEs, treatment discontinuations, physical 
examination, vital signs, safety laboratory tests and prior and concomitant medications. 
Early Termination 
If the subject experiences persistence or worsening or recurrence of symptoms that per the 
investigator’s assessment (e.g., symptoms ≥3) warrant the use of rescue antifungal therapy, a 
vaginal examination with investigator’s rating of signs should be completed. Additionally, 
vulvovaginal samples should be obtained for KOH testing and pH measurements by the local 
laboratory, fungal culture by the central laboratory and investigation of other pathogens such as 
bacterial vaginosis and Trichomonas vaginalis by the local laboratory. If the KOH test is 
negative, the investigator should consider other causes for the persistence or worsening of the 
symptoms and antifungal rescue medication may not be indicated. 
If the investigator’s rating of the vulvovaginal signs and vaginal sample collection is not possible 
prior to the initiation of the rescue therapy, it should still be completed as soon as possible after 
rescue therapy is initiated. 
In addition to the vaginal examination, the symptoms that led to the use of rescue antifungal 
therapy should be documented in the eCRF and the following procedures should also be 
completed: 
• 
If rescue therapy is administered prior to or at the TOC visit, all TOC visit procedures should 
be completed and no additional visits will be needed.  The subject will be considered as 
early termination due to lack of efficacy prior to or at TOC. 


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• 
If rescue therapy is administered after the TOC visit but prior to or at the FU visit, all FU 
visit procedures should be completed and no additional visits will be needed.  The subject 
will be considered as early termination due to lack of efficacy after TOC but prior to or 
at FU. 
Oral fluconazole [one 150-mg dose] may be provided to study sites as rescue medication. 
However, at the investigator’s discretion other approved antifungal agents may be administered 
as rescue medication to a particular patient for whom fluconazole is not considered the optimal 
option.  All rescue antifungal medications should be documented in the eCRF. 
Target Population: The study population will include female subjects 12 years and older with 
AVVC. 
KEY Inclusion Criteria:  
Subjects must fulfill all of the following KEY criteria to be eligible for study admission: 
1. 
Subject is a postmenarchal female subject 12 years and older 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/or prior to administration of the initial 
dose of study drug. 
2. 
Subject has a diagnosis of symptomatic AVVC that meets the following criteria:  
a. 
Minimum composite vulvovaginal signs and symptoms score of  ≥4 with at least 2 
signs or symptoms having a score of 2 (moderate) or greater in the VSS Scale at 
Baseline 
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) 
3. 
Subject is able to take oral tablets. 


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KEY 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 AVVC 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 vaginalis, 
Herpes virus, Neisseria gonorrhoeae, Chlamydia trachomatis, symptomatic human 
papillomavirus or other mixed infections. 
2. Subject received systemic and/or topical (vaginal) antifungal treatment, including 
prescription or over-the-counter products, within 28 days of the Baseline visit. 
3. Subject has active menstruation at the Baseline visit. 
4. Subject has uncontrolled diabetes mellitus. 
5. Subject has a history of or an active cervical/vaginal cancer. 
6. Subject requires treatment with the prohibited medications (including prescription and over-
the-counter medications, supplements, and herbal products) listed in Section 21.0 (Appendix 
A) of the protocol, during the following timeframes: 
a. 
Systemic and/or topical (vaginal) antifungal treatment, including prescription or 
over-the-counter products, within 28 days prior to enrollment if administered for the 
treatment of VVC and during the study for all cases 
b. 
Select strong CYP3A4/5 inhibitors and CYP3A4/5 inducers during the 7 days prior 
to enrollment and during study treatment until the TOC visit  
c. 
Select P-gp substrates during the 48 hours prior to enrollment or during study 
treatment with SCY-078 
Study Drugs: Study drug will consist of ibrexafungerp (SCY-078) (150-mg tablets) and 
ibrexafungerp matching placebo tablets. 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 SCY-078 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. 
The placebo product matching SCY-078 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: 
Subjects who meet all of the inclusion and none of the exclusion criteria will be enrolled into the 
study and will be randomized in a 2:1 ratio to either oral ibrexafungerp or ibrexafungerp 
matching placebo, as follows:  
• 
Oral ibrexafungerp 300-mg dose BID for 1 day  
• 
Oral ibrexafungerp matching placebo BID for 1 day  


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Subjects will receive their first dose of study drug at the site and will be dispensed the second 
dose for self-administration at home 12 hours after the first dose. 
Study Blinding, Randomization and Stratification: This is a randomized, double-blind study. 
All site and sponsor personnel will be blinded to treatment assignment.  
Approximately 366 eligible subjects will be enrolled and randomized in a 2:1 ratio to one of the 
two study treatment groups. For the purpose of maintaining treatment blinding, all subjects 
randomized to the placebo group will receive matching ibrexafungerp placebo tablets. All 
randomization of subjects will be managed electronically through an interactive response system 
(voice or web-based). 
Eligible subjects will be stratified at randomization based on the presence or absence of a 
diagnosis of diabetes mellitus (diabetes mellitus: YES or NO). 
Study Evaluations: 
Efficacy Evaluations: 
The primary efficacy endpoint of the study is the percentage of subjects with clinical cure 
(complete resolution of signs and symptoms) at the TOC visit. Secondary efficacy endpoints 
include the percentage of subjects with mycological eradication (negative culture for growth of 
Candida species) at the TOC visit, the percentage of subjects with clinical cure and mycological 
eradication at the TOC visit, the percentage of subjects with complete resolution of symptoms at 
the FU visit, and the percentage of subjects with clinical improvement (partial or complete 
resolution of signs and symptoms with a total composite score no greater than 1) at the TOC 
visit.  
The following treatment outcome definitions will be used for the assessment of efficacy: 
Clinical Outcome 
• 
Clinical cure: Complete resolution of signs and symptoms of vulvovaginal infection without 
need for further antifungal treatment. Specifically, for complete resolution, any sign or 
symptom should be absent (score = 0) by the TOC visit. 
• 
Clinical failure: No response to therapy or incomplete resolution of signs and symptoms or 
need for additional vulvovaginal or systemic antifungal therapy. If the subject receives or 
self-administers topical drug therapy for the treatment of vulvovaginal irritation/pruritus 
such as topical analgesic or corticosteroid after completing treatment with the study drug and 
before the TOC visit, the subject is considered a clinical failure. 
Mycological Outcome 
• 
Mycological eradication: A subject with negative culture for Candida species. 
• 
Mycological persistence: A subject with a positive culture for Candida species. 
Safety Evaluations: 
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. An abbreviated physical examination, including general 
appearance and an overall examination of body systems, will be conducted at Screening and at 


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the TOC visit. Vital signs, including blood pressure (systolic and diastolic), heart rate, respiratory 
rate and body temperature will be measured at the Screening and TOC visits, and at unscheduled 
visits, if needed. Safety laboratory tests (hematology and blood chemistry) will be measured at 
Screening, at the TOC visit and at unscheduled visits, if needed. 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). 
Statistical Analyses: 
All statistical processing 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 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.  
All analyses will be presented by treatment group.  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 statistical analyses in detail will be provided as 
a separate document. The SAP will be finalized prior to unblinding of the study treatments. 
Sample Size Determination 
The primary endpoint of the study is the percentage of subjects achieving a clinical cure at the 
TOC visit. Assuming clinical cure rates of 50% and 30% for ibrexafungerp and placebo 
administered in a 2:1 ratio, respectively, approximately 282 subjects will provide 90% power to 
detect a difference between ibrexafungerp and placebo based on a Pearson’s Chi-squared test 
with a Type 1 error rate of 5%. Because it is expected that approximately 20% of subjects may 
not have a mycological culture-confirmed infection at Baseline and approximately 10% may 
withdraw early from the study, an additional 84 subjects are added for a total of 366 subjects 
(244 subjects randomized to ibrexafungerp and 122 subjects, to placebo). 
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 positive 
culture for Candida species at Baseline. 
Per-Protocol (PP) Population: All mITT subjects who have completed the study drug treatment 
AND who have a TOC evaluation. 
Safety Population: All randomized subjects who received at least one dose of study drug and 
who have at least one post-Baseline evaluation. 
Efficacy Analyses: 


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The efficacy analyses will be conducted using the mITT (primary analysis population), ITT and 
PP populations to evaluate SCY-078 vs. placebo. 
The primary endpoint, percentage of subjects with clinical cure at TOC, will be analyzed using 
a Cochran Mantel Haenszel (CMH) test adjusted for site; the p-value and 95% confidence 
intervals will be presented. Missing Day 8-Day 14 (TOC) data for the primary endpoint will be 
imputed as failures in the analysis. A sensitivity analysis will be performed where subjects with 
missing values will be removed from the analysis. All other data will be analyzed as is with no 
imputation. 
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. 
Safety Analyses: 
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. 
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 by treatment group for laboratory tests. 
 
 


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6.0 
Schematic of Study Design 
 
 
 
Figure 1 
Schematic of Study Design 
SCREENING/ 
BASELINE (DAY 1) 
Randomization  
Ibrexafungerp (SCY-078) 
[300-mg dose BID for 1 day] 
 
Placebo 
TEST OF CURE (DAY 11 ± 3 or DAY 8 - DAY 14) 
FOLLOW UP (DAY 25 ± 4)  
TREATMENT DAYS (DAY 1) 


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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.3  
Current treatments for VVC include topical antifungals and the use of prescription oral antifungals 
such a single doses of fluconazole.  In two vaginal candidiasis studies conducted with fluconazole, 
the therapeutic cure rate, defined as the resolution of signs and symptoms of vaginal candidiasis 
along with negative KOH examination and negative culture for Candida, was achieved by 55% of 
subjects receiving single doses of fluconazole 150 mg.  The therapeutic cure rate is reduced to 
40% in subjects with a history of recurrent vaginitis4,5. Although a single dose of fluconazole is 
able to provide an acceptable therapeutic outcome for more than half of the treated individuals, the 
emergence of fluconazole resistance among C. albicans isolates and the frequency of cases caused 
by C. glabrata, a strain naturally less susceptible to fluconazole, signals the need for new 
therapeutic approaches.  
Additionally, recurrence of VVC after fluconazole therapy is not uncommon and these 
exacerbations often involve the same microorganism identified in the initial episode, suggesting 
that a small number of C. albicans remain as a reservoir in the vagina after completion of azole 
therapy, becoming the source of subsequent exacerbations. This may be explained by the fact that 
azoles are fungistatic, which means that they slow the growth of, but do not kill, the fungus and 
azoles are not active against certain species of Candida that cause VVC. 
New curative approaches are needed, particularly involving agents with fungicidal activity (i.e., 
that are able to kill the fungus) and activity against fluconazole-resistant strains, so that the 
causative yeasts can be eradicated. A new therapeutic approach with these characteristics would 
be expected to result in improved short-term and potentially long-term outcomes for this condition.   
This study aims to provide evidence of the efficacy and evaluate the safety of oral SCY-078 as a 
new class of antifungal agent with fungicidal activity against Candida spp. in the treatment of 
patients with VVC. 
The glucan synthesis inhibitor ibrexafungerp (formerly known as SCY-078) 
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. 
Ibrexafungerp (SCY-078) is a structurally distinct class of glucan synthesis inhibitor (GSI) that 
inhibits the synthesis of the fungal cell wall polymer β-(1,3)-D-glucan. Time-kill studies have 


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demonstrated that ibrexafungerp (SCY-078) has in vitro fungicidal activity against Candida spp. 
isolates similar to that observed with the echinocandins.  
Ibrexafungerp (SCY-078) is being developed as the first oral and intravenous (IV) GSI 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 (SCY-078) 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)6 and European 
Committee on Antimicrobial Susceptibility Testing methods. Overall, the epidemiological studies 
have demonstrated that ibrexafungerp (SCY-078) 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 SCY-078 for the treatment of invasive fungal infections.  
Activity against Candida spp. 
Ibrexafungerp (SCY-078) has been evaluated against >2000 Candida isolates, including all 
clinically relevant species with more than 300 C. albicans, more than 300 C. glabrata and more 
than 100 C. auris isolates tested. These in vitro studies have demonstrated the broad spectrum of 
anti-Candida activity of SCY-078. Additionally, ibrexafungerp (SCY-078) demonstrated in vitro 
activity against pre-formed biofilms, which is a relevant feature when addressing catheter-related 
Candida infections and, potentially, VVC. Studies conducted with azole- and echinocandin-
resistant strains have shown that ibrexafungerp (SCY-078) retains activity (i.e., no significant 
change in minimum inhibitory concentration [MIC] 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 (SCY-078) 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 (SCY-078) was evaluated in vitro against clinical isolates of echinocandin-resistant 
strains of Candida spp. containing mutations in the FKS gene. Overall, ibrexafungerp (SCY-078) 
was active against the majority of the echinocandin-resistant strains tested. Significantly, 
ibrexafungerp (SCY-078) 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 (SCY-078) 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 (SCY-078) did not select for mutations 
at positions S663 or S645. These results suggest that ibrexafungerp (SCY-078) inhibits glucan 
synthase in a manner different from that of echinocandins.  


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The in vitro studies also included several multidrug-resistant isolates. Consistent with the data 
described above, ibrexafungerp (SCY-078) was active against >70% of these isolates. 
ibrexafungerp (SCY-078) has also demonstrated a potent activity against life-threatening and 
multi-drug-resistant C. auris strains over 100 different C. auris isolates, at concentrations 
indicative of potential clinically relevant effect. C. auris has been recently highlighted as a clinical 
alert by the Centers for Disease Control and Prevention (CDC) because of the global emergence 
of this fungal infection with limited therapeutic options and high mortality.  
Activity against Aspergillus spp. 
The in vitro activity of ibrexafungerp (SCY-078) has been evaluated against >450 clinical 
Aspergillus isolates, including most clinically relevant species and azole-resistant strains. The 
results demonstrated potent activity of ibrexafungerp (SCY-078) against all of the strains tested.  
Murine models of invasive fungal infections  
The antifungal efficacy of ibrexafungerp (SCY-078) has been evaluated in several murine models 
of disseminated candidiasis and aspergillosis. In a disseminated C. albicans model, ibrexafungerp 
(SCY-078) was more active than fluconazole at all doses. Murine models of SCY-078 in 
disseminated candidiasis caused by C. glabrata and C. tropicalis indicated activity across multiple 
Candida species. The ibrexafungerp (SCY-078) area under the concentration-time curve (AUC) 
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 (SCY-078) following 
oral administration for up to 90 days. Reproductive and developmental toxicity studies have also 
been completed. The results from the non-clinical safety program provide adequate safety support 
for the doses and treatment duration intended in this study. 
The in vitro studies indicated that ibrexafungerp (SCY-078) 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 (SCY-078); therefore, the concurrent administration of ibrexafungerp (SCY-078) 
with such inhibitors is prohibited.  
Clinical experience  
To date, over 500 subjects and patients have received either oral or IV formulations of 
ibrexafungerp (SCY-078) in Phase 1 and Phase 2 studies.  
Ibrexafungerp (SCY-078) 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 


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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 (SCY-078) 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 (SCY-078) or fluconazole. 
Ibrexafungerp (SCY-078) was well tolerated, with an AE profile typical of this population and 
comparable to the Standard of Care (SOC). The results from this study also indicated that the 
higher dose of ibrexafungerp (SCY-078) tested (750 mg once daily  [QD]) is predicted to achieve 
the target exposure at steady state in the majority of patients.  
A Phase 2 proof-of-concept study (SCY-078-203) of oral ibrexafungerp (SCY-078) in patients 
with acute vulvovaginal candidiasis (AVVC) has also been completed. In this multicenter, 
randomized, active-controlled, evaluator-blinded study of oral ibrexafungerp (SCY-078) 
compared to oral fluconazole in adult female patients with AVVC, 96 patients with an acute, 
moderate to severe, symptomatic episode of vulvovaginal candidiasis were randomized in a 1:1:1 
ratio to receive either oral ibrexafungerp (SCY-078) 750 mg with a 1250 mg loading dose for three 
days, oral ibrexafungerp (SCY-078) 750 mg with a 1250 mg loading dose for five days or a single 
dose of oral fluconazole. Ibrexafungerp (SCY-078) was well tolerated, with the most common AEs 
being mild gastrointestinal events. The high clinical cure rates observed in this study are supportive 
of the clinically relevant antifungal activity of SCY-078 in this form of Candida infection.  
A Phase 2, Multicenter, Randomized, Double-Blind, Double-Dummy, Active-Controlled, Dose-
Finding Study to Compare the Safety and Efficacy of Oral SCY-078 (ibrexafungerp) vs. Oral 
Fluconazole in Subjects with Acute Vulvovaginal Candidiasis (DOVE) 
The primary objective of the study was dose selection for our Phase 3 pivotal program in VVC. 
This Phase 2b study was a randomized, multi-center, double-blind, active-controlled, dose-finding 
study designed to evaluate the safety, efficacy, tolerability and pharmacokinetics of five dose 
regimens of oral ibrexafungerp (SCY-078) in patients with moderate-to-severe acute VVC 
(defined as signs and symptoms score of 7 or greater), with oral fluconazole (FLU) 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 durations explored were 1 or 3 days. The maximum 
duration of treatment of 3 days was based on our previous Phase 2a study, SCY-078-203, 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 endpoint including both 
clinical cure and mycological eradication. In this Phase 2 study, response was also evaluated as 


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the percentage of subjects achieving a noticeable improvement in their signs and symptoms by 
achieving a composite sign and symptoms score of 0 or 1, absolute change in signs and symptoms 
from baseline and need for rescue antifungal therapy. 
All doses tested achieved meaningful clinical cure and mycological eradication rates and the dose 
that was considered to provide the best combination of attributes for this indication is the 
ibrexafungerp (SCY-078) 600-mg dose administered as 300 mg BID for 2 doses.  
At Day 10, the TOC visit, the 600-mg dose showed clinical and mycological response rates in-line 
with the reference fluconazole arm.  Specifically, the clinical cure was reported in 14 of 27 of 
patients (52%) in the 600-mg dose and in 14 of 24 of patients (58%) in the fluconazole arm.  The 
percentage of patients showing 0 or 1 signs and symptoms score was also comparable, with 70% 
and 71% of patients reporting this improvement in the ibrexafungerp (SCY-078) 600-mg dose and 
fluconazole arms, respectively. The mycological eradication at this timepoint was 63% for both 
groups. 
At Day 25, the follow-up (FU) visit, the ibrexafungerp (SCY-078) 600-mg dose showed a trend 
towards improved clinical and mycological outcomes when compared to the fluconazole arm.  If 
patients had persistence or recurrence of signs and symptoms of VVC, rescue antifungal 
medication could be prescribed. Seven (7) patients treated with fluconazole received rescue 
antifungal medication, whereas one patient treated with ibrexafungerp (SCY-078) 600 mg received 
rescue antifungal medication. The rate of patients with zero signs and symptoms at the FU visit 
was 70% for the ibrexafungerp (SCY-078) 600-mg dose versus 50% for the fluconazole arm. A 
similar difference was observed with the “0 or 1 signs and symptoms score” analysis, with 82% of 
patients achieving this improvement with the ibrexafungerp (SCY-078) 600-mg dose versus 58% 
with fluconazole. The mycological eradication at this timepoint was also numerically higher in the 
600-mg dose (48%) when compared to the fluconazole arm (38%). 
Oral ibrexafungerp (SCY-078) 600-mg dose was generally well tolerated, with self-limiting 
(generally one-day duration), mild to moderate gastrointestinal adverse events (AEs) being the 
most commonly reported. Nausea was reported in three patients (10%) in the ibrexafungerp (SCY-
078) 600-mg dose arm compared to two patients (6%) in the FLU arm. Diarrhea and loose stool 
was reported in five patients (17%) in the ibrexafungerp (SCY-078) 600-mg dose arm compared 
to one patient in the FLU arm (3%). Abdominal pain was reported in one patient (3%) in the 
ibrexafungerp (SCY-078) 600-mg dose arm compared to 5 patients (16%) in the FLU arm. No 
vomiting, severe AEs or discontinuations due to AEs were reported in the ibrexafungerp (SCY-
078) 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 (SCY-078) exposure, while 
diltiazem (a moderate inhibitor of CYP3A) induces a mild to moderate (<3-fold) increase in 
ibrexafungerp (SCY-078) exposure. Ibrexafungerp (SCY-078) did not have a clinically 


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meaningful effect on rosiglitazone (a CYP2C8 substrate) exposure, had only a mild effect (less 
than a 0.5-fold increase) on the AUC of tacrolimus (a CYP3A and P-glycoprotein [P-gp] substrate) 
and had no effect on the maximum concentration (Cmax) of tacrolimus. 
Ibrexafungerp (SCY-078) 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. 
SCY-078 through the remainder of this protocol will be referred to as ibrexafungerp from this 
point forward.  
For additional information on ibrexafungerp, please refer to the Investigator´s Brochure (IB).  
7.2 
Rationale for the Study 
This study is being performed to evaluate the efficacy and safety of one dosing regimen of 
ibrexafungerp as compared to placebo in female patients 12 years and older with acute 
vulvovaginal candidiasis (AVVC). The study design generally follows the FDA guidance 
regarding drug development for vulvovaginal candidiasis7 . 
Rationale for Study Indication and Population 
Considering the properties of ibrexafungerp as a potent antifungal compound, with fungicidal 
activity against Candida spp., it will represent an important non-azole alternative treatment for 
subjects suffering from AVVC.  
Subjects with AVVC are intended for this study to facilitate the identification of a clinically 
meaningful effect of ibrexafungerp in the intended population.   
Rationale for Selected Dose Levels and Dosing Regimens 
The ibrexafungerp selected dose of 300 mg BID for 1 day 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. 
Rationale for Study Endpoints 
The primary endpoint for the study is clinical cure (complete resolution of signs and symptoms) 
of the acute symptomatic episode at the TOC visit on Day 8-Day 14, which is in line with the FDA 
guidance on vulvovaginal candidiasis7. The secondary efficacy endpoints will include mycological 
eradication (negative culture for growth of Candida spp.) at the TOC visit, a composite endpoint 
of both clinical cure and mycological eradication at the TOC visit, complete resolution of 
symptoms at the Follow-up (FU) visit on Day 25 (±4), which are also in line with current 
guidelines. Additional endpoints are evaluated, including clinical improvement (partial or 
complete resolution of signs and symptoms with total composite score no greater than 1) at  the 


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TOC visit, since this is considered a meaningful clinical improvement. The safety and tolerability 
of ibrexafungerp will also be evaluated as secondary objectives.  
Rationale for Study Design 
This trial is being conducted as a randomized, placebo-controlled, double-blind study. This design 
is considered an appropriate design for this indication and phase of investigation and will use 
matching ibrexafungerp placebo. The placebo-controlled design for this study is in line with the 
current regulatory guidance and is appropriate considering that acute VVC is not a life threatening 
infection, that delayed treatment is not expected to result in a complication of the VVC and that 
subjects enrolled will be closely followed up to be provided rescue therapy, when indicated, after 
failure of the assigned study drug has been determined. 
The data generated from this study will provide a characterization of the efficacy, safety and 
tolerability of ibrexafungerp in subjects with AVVC.  
8.0 
Study Objectives 
8.1 
Primary Objectives 
• To evaluate the efficacy of oral ibrexafungerp versus placebo in subjects with acute 
vulvovaginal candidiasis (AVVC) by comparing the clinical outcomes of ibrexafungerp and 
placebo  
8.2 
Secondary Objectives 
• To evaluate the efficacy of oral ibrexafungerp versus placebo in subjects with AVVC based on 
mycological and clinical outcomes 
• To evaluate the safety and tolerability of oral ibrexafungerp versus placebo in subjects with 
AVVC 
9.0 
Study Endpoints 
9.1 
Primary Endpoints 
• Efficacy as measured by the percentage of subjects with clinical cure (complete resolution of 
signs and symptoms) at the test-of-cure (TOC) visit 


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9.2 
Secondary Endpoints 
Efficacy as measured by: 
• The percentage of subjects with mycological eradication (negative culture for growth of 
Candida species) at the TOC visit 
• The percentage of subjects with clinical cure and mycological eradication (responder outcome) 
at the TOC visit. 
• The percentage of subjects with complete resolution of symptoms at the Follow-up (FU) visit. 
• The percentage of subjects with clinical improvement (partial or complete resolution of signs 
and symptoms with total composite score no greater than 1) at the TOC visit.  
• The absolute change in signs and symptoms score from Baseline to TOC and FU visits. 
 
Safety and tolerability as measured by: 
• Adverse events (AEs), vital signs, physical examination, treatment discontinuation and safety 
laboratory tests 
10.0 Study Design 
10.1 
Overall Description of the Study 
This is a Phase 3, randomized, multicenter, double-blind, placebo-controlled study to evaluate the 
efficacy and safety of oral ibrexafungerp compared to placebo in female subjects 12 years and 
older with AVVC. 
Approximately 366 eligible subjects will be enrolled and randomized in a 2:1 ratio to either 
ibrexafungerp (300-mg dose twice a day [BID]) or matching placebo administered BID for 1 day. 
The primary objective of this study is to evaluate the efficacy of oral ibrexafungerp in subjects 
with AVVC by comparing the clinical outcomes of ibrexafungerp and placebo. 
The study will consist of a Screening visit, a Baseline visit on Day 1 (these visits may occur on the 
same day), a TOC visit on Day 11 (±3) and a FU visit on Day 25 (±4). 
Efficacy and safety assessments will be conducted for the study. Efficacy will be determined 
primarily by the percentage of subjects with clinical cure (complete resolution of signs and 
symptoms) at the TOC visit. Efficacy will also be assessed by the percentage of subjects with 
mycological eradication (negative culture for growth of Candida species) at the TOC visit, the 
percentage of subjects with both clinical cure and mycological eradication at the TOC visit, the 
percentage of subjects with complete resolution of symptoms at the FU visit and the percentage of 
subjects with clinical improvement (partial or complete resolution of signs and symptoms with 
total composite score no greater than 1) at the TOC visit. Safety and tolerability will be evaluated 


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throughout the study, including the following parameters: AEs, vital signs, an abbreviated physical 
examination, treatment discontinuations and safety laboratory tests. 
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 
Screening (Day -1 [Day -2]) 
At Screening, subjects who are experiencing vulvovaginal symptoms will be evaluated by the 
investigator, who will obtain a vaginal sample for potassium hydroxide (KOH) testing and vaginal 
pH determination by the local laboratory prior to randomization and initiation of treatment. The 
vaginal samples will also be evaluated locally for findings indicative of bacterial vaginosis and 
Trichomonas vaginalis. A vaginal sample for fungal culture and for species identification and 
susceptibility testing will be obtained and sent to a designated central laboratory. 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. The investigators and the 
subjects will rate the signs and symptoms of infection, respectively, on a standardized vulvovaginal 
signs and symptoms scale (the Vulvovaginal Signs and Symptoms [VSS] Scale). Safety 
procedures, including an abbreviated physical exam, vital signs, laboratory tests and a pregnancy 
test will also be performed.  
To be eligible for inclusion, subjects must have a minimum composite score of vulvovaginal signs 
and symptoms ≥4 with at least 2 signs or symptoms having a score of 2 (moderate) or greater in 
the VSS Scale at Baseline, a positive KOH test and a normal vaginal pH (≤4.5). 
The Screening and Baseline (Day 1) visits may occur on the same day. 
 
Baseline (Day 1) 
Eligible subjects will be randomized in a 2:1 ratio to one of the following two treatment groups: 
• Oral ibrexafungerp 300-mg dose BID for 1 day  
• Oral ibrexafungerp matching placebo BID for 1 day 
For the purpose of maintaining treatment blinding, all subjects randomized to the placebo group 
will receive matching ibrexafungerp placebo tablets. Subjects will receive their first dose of study 
drug at the site and will be dispensed study drug and subject diaries to rate their vulvovaginal 
symptoms of infection and to record dosing details, AEs and concomitant medication use from 
Day 1 until the TOC visit (Day 8-Day 14). 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 


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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. 
 
Assessment of Clinical Cure (TOC [Day 11 ±3])  
At the TOC visit (Day 8-Day 14), subjects will return any remaining medication as well as empty 
bottles of the study drug and treatment compliance will be evaluated. 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 vaginal sample for fungal culture and for species 
identification and antifungal susceptibility testing will be obtained and sent to a designated central 
laboratory. An abbreviated physical exam, vital signs measurements and safety laboratory tests 
will also be performed.  
If the baseline vulvovaginal symptoms have not noticeably improved or have worsened and the 
investigator considers that rescue antifungal medication may be needed, a vaginal sample should 
also be obtained for KOH testing by the local laboratory. 
 
Follow up (Day 25 [±4])  
At the FU visit, subjects will rate their symptoms of infection on the VSS Scale. Vulvovaginal 
samples for KOH testing and fungal culture should be obtained if there is persistence or recurrence 
of vulvovaginal symptoms. Only if symptoms are present, the investigator will perform a 
vulvovaginal examination to rate the subject´s signs of infection. 
 
All Visits 
AEs and prior/concomitant medications will be assessed and documented at all visits. 
10.1.2 Study Assessments 
The study will include efficacy, safety and tolerability assessments. 
 
Efficacy Assessments 
The primary efficacy endpoint of the study is the percentage of subjects with clinical cure 
(complete resolution of signs and symptoms) at the TOC visit. Secondary efficacy endpoints 
include the percentage of subjects with mycological eradication (negative culture for growth of 
Candida species) at the TOC visit, the percentage of subjects with clinical cure and mycological 


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eradication at the TOC visit, the percentage of subjects with complete resolution of symptoms at 
the FU visit, and the percentage of subjects with clinical improvement (partial or complete 
resolution of signs and symptoms with a total composite score no greater than 1) at the TOC visit 
and the absolute change in signs and symptoms score from Baseline to TOC and FU visits..  
Clinical Evaluation 
The signs (edema, erythema and excoriation or fissures) and symptoms (burning, itching 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 score. 
 
Mycological Testing 
Mycological tests will include direct microscopic examination with 10% KOH and fungal cultures. 
KOH will be performed locally at Screening for the determination of subject eligibility and at the 
TOC visit or FU visit if symptoms persist or recur. Vaginal samples will be collected at Screening, 
TOC visit and when possible vaginal samples will also be collected prior to the initiation of rescue 
antifungal medication during the study for central lab fungal cultures. The central lab will culture 
samples for the presences of yeast, and process isolates for species identification and susceptibility 
testing.  
 
Safety Assessments  
Safety procedures will include collection of AEs, treatment discontinuations, 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 366 eligible subjects will be enrolled and randomized in a 2:1 ratio to one of the 
two study treatment groups. For the purpose of maintaining treatment blinding, all subjects 
randomized to the placebo group will receive matching ibrexafungerp placebo tablets. All 
randomization of subjects will be managed electronically through an interactive response system 
(voice or web-based). 
Eligible subjects will be stratified at randomization based on the presence or absence of a diagnosis 
of diabetes mellitus (diabetes mellitus: YES or NO). 


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10.3 
Study Duration 
Each subject is expected to complete the study within approximately 30 days.  
10.4 
Number of Centers 
Approximately 30 study centers are expected to participate in subject enrollment and treatment. 
11.0 Study Population 
The study population will include female subjects 12 years and older with AVVC. 
11.1 
Inclusion Criteria 
Subjects must fulfill all of the following criteria to be eligible for study admission: 
1. Subject is a postmenarchal female subject 12 years and older 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/or prior to administration of the initial dose of study 
drug. 
2. Subject has a diagnosis of symptomatic AVVC that meets the following criteria:  
a. 
Minimum composite vulvovaginal signs and symptoms score of  ≥4 with at least 2 signs 
or symptoms having a score of 2 (moderate) or greater in the VSS Scale at Baseline 
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) 
3. Subject is able to take oral tablets. 
4. 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). 


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b. Subject is a female subject who is of reproductive potential and is using an effective 
contraceptive method including intrauterine device, hormonal contraceptives (i.e., 
vaginal ring, 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. 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 methods 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. 
Subjects must refrain from using any topical vaginal contraceptives as these may 
have an impact on the signs and symptoms of VVC. 
Note: Women of childbearing potential must have a negative urine pregnancy test prior to 
enrollment (performed by the site’s local laboratory). 
5. Subject 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 to sign the subject’s 
ICF. Local regulations should be followed for consenting subjects under the age of consent. 
6. 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 US Health Information Portability and Accountability Act 
Authorization form).  
7. Subject and/or parent/legal representative is able to understand and follow all study-related 
procedures including study drug administration. 
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 AVVC 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 vaginalis, Herpes 
virus, Neisseria gonorrhoeae, Chlamydia trachomatis, symptomatic human papillomavirus or 
other mixed infections. 
2. Subject received systemic and/or topical (vaginal) antifungal treatment, including prescription 
or over-the-counter products, within 28 days of the Baseline visit. 


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3. Subject has active menstruation at the Baseline visit. 
4. Subject has uncontrolled diabetes mellitus. 
5. Subject has a history of or an active cervical/vaginal cancer. 
6. Subject requires 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/or topical (vaginal) antifungal treatment, including prescription or over-the-
counter products, within 28 days prior to enrollment if administered for the treatment of 
VVC and during the study for all cases 
b. Select strong CYP3A4/5 inhibitors and CYP3A4/5 inducers during the 7 days prior to 
enrollment and during study treatment until the TOC visit 
c. 
Select P-gp substrates during the 48 hours prior to enrollment or during study treatment.  
7. Subject has a known hypersensitivity to any of the components of the formulation. 
8. Subject has a known human immunodeficiency virus infection and/or is receiving 
chemotherapy or has an illness that, in the judgment of the investigator, is serious enough to 
induce an immune deficiency. 
9. Subject has had any major illness within 30 days before Screening. 
10. Subject has participated in any other investigational study within at least 30 days (or 5.5 half-
lives of the investigational product) before signing the ICF.  
11. Subject has received prior treatment with ibrexafungerp in a previous trial. 
12. Subject has any other condition or laboratory abnormality 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. 
13. 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. 
14. 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 parent or legal representative; 
• 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; 


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• Lost to follow up (every attempt should be made to contact the subject) 
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). All TOC 
procedures should be performed for subjects who discontinue from the study before the TOC visit.  
11.4 
Early Termination  
With effective oral therapy, immediate relief of all symptoms is not expected and subjects should 
not expect immediate relief.  
If the subject experiences persistence or worsening or recurrence of symptoms that per the 
investigator’s assessment (e.g., symptoms ≥3) warrant the use of rescue antifungal therapy, a 
vaginal examination with investigator’s rating of signs should be completed. Additionally, 
vulvovaginal samples should be obtained for KOH testing and pH measurements by the local 
laboratory, fungal culture by the central laboratory and investigation of other pathogens such as 
bacterial vaginosis and Trichomonas vaginalis by the local laboratory.  
If the KOH test is negative, the investigator should consider other causes for the persistence or 
worsening of the symptoms as antifungal rescue medication may not be indicated. 
If the investigator’s rating of the vulvovaginal signs and vaginal sample collection is not possible 
prior to the initiation of the rescue therapy, it should still be completed as soon as possible after 
rescue therapy is initiated. 
In addition to the vaginal examination, the symptoms that led to the use of rescue antifungal 
therapy should be documented in the eCRF and the following procedures should also be 
completed: 
• If rescue therapy is administered prior to or at the TOC visit, all TOC visit procedures 
should be completed and no additional visits will be needed.  The subject will be considered 
as early termination due to lack of efficacy prior to or at TOC. 
• If rescue therapy is administered after the TOC visit but prior to or at the FU visit, all FU 
visit procedures should be completed and no additional visits will be needed.  The subject 
will be considered as early termination due to lack of efficacy after TOC but prior to or at 
FU. 
Oral fluconazole [one 150-mg dose] may be provided to study sites as rescue medication. 
However, at the investigator’s discretion other approved antifungal agent may be administered as 
rescue medication to a particular patient for whom fluconazole is not considered the optimal 
option.  All rescue antifungal medications should be documented in the eCRF. 
Details of study treatment groups and dietary requirements for treatment administration are 
provided in Section 12.1 and Section 12.2, respectively. 


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11.5 
Replacement of Dropouts 
Subjects who discontinue early from randomized treatment will not be replaced. 
12.0 Study Treatments 
12.1 
Study Treatment Groups 
Subjects who meet all of the inclusion and none of the exclusion criteria will be enrolled into the 
study and will be randomized in a 2:1 ratio to either oral ibrexafungerp or ibrexafungerp matching 
placebo, as follows:  
• Oral ibrexafungerp 300-mg dose  BID for 1 day  
• Oral ibrexafungerp matching placebo BID for 1 day  
For the purpose of maintaining treatment blinding, all subjects randomized to placebo will receive 
matching ibrexafungerp placebo tablets. Subjects will receive their first dose of study drug at the 
site and will be dispensed the second dose for self-administration at home 12 hours after the first 
dose. 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 subsequent dose, the subject can self-administer both doses 
at home to allow for a more convenient dosing schedule. 
12.2 
Dietary Requirements 
There are no dietary requirements or restrictions for the administration of the study drug. It is 
recommended that study drug be administered preferably with food and with approximately 
8 oz./240 mL of water. 
12.3 
Study Drugs 
Study drug will consist of ibrexafungerp (150-mg tablets) and ibrexafungerp matching placebo 
tablets. Study drug will be provided by the Sponsor. 
12.3.1 Ibrexafungerp (SCY-078) Description 
Study Drug Identifier: 
Ibrexafungerp 
Empirical Formula: 
C50H75N5O11 (citrate salt) 
Molecular Weight: 
922.18 (citrate salt) 
Physical Description: 
White to off-white solid 


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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 Citrate (formerly SCY-078) 
 
12.3.2 Formulation, Packaging and Labelling 
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. 
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. 
The ibrexafungerp and matching placebo drug supplies will be packaged in bottles. 
Bottles will contain 4 tablets of ibrexafungerp or matching placebo. 
For the purpose of blinding, the number and appearance of dosage units will be the same across 
both treatment groups. 
Labels on the bottles containing double-blind study medication information will any other 
information required by applicable regulations and may include the following information:  
• Product name (Ibrexafungerp 150mg Tablet (Active or Placebo)) 


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• Sponsor Name 
• Study Protocol Number 
• Place to write the subject number  
• Study drug kit number 
• Number of tablets per bottle 
• Dosing instructions 
• Storage conditions (e.g. room temperature 15°C – 30°C  or 15°C – 25°C  for EU) 
• 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, study drug supplies provided in bottles 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 Interactive Response System (voice or web-based) will be used to dispense study drugs 
to individual subjects.  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. At the conclusion of the study after final 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, except for a member of the sponsor personnel or a sponsor representative 
who will be involved in safety activities. 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  
o All product quality complaints should be reported to the Sponsor 


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• Collect and count the number of tablets remaining at the TOC visit (Day 8 - Day 14).  
• 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 
12.5 
Subject Compliance with Study Drug Dosing 
Subjects will be instructed to bring the assigned bottles of study medication (including empty 
bottles) with them to the TOC visit (Day 8 – Day 14) to assess treatment compliance. 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 study drug dosing (Section 14.13).  
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 problems 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 30 days before Baseline (Day 1) through the TOC visit (Day 8 - Day 
14) will be recorded on the subject´s diary and in the eCRF. 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). 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. 
13.2 
Prohibited Medications 
Medications specifically not permitted in the exclusion criteria (Section 11.2) include the 
following: 
• Non-study systemic or topical antifungal therapy 
• Topical vaginal corticoids 
• Topical (vaginal) contraceptives 
• Other investigational drug(s) 
• Select strong CYP3A4/5 inhibitors, CYP3A4/5 inducers and select P-gp substrates. 
See Section 21.0 (Appendix A) for the full list of prohibited medications. 


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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, including but not limited to sirolimus, tacrolimus warfarin, 
cyclosporine and amiodarone 
• 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 Table 1. 
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. 
Local regulations should be followed for consenting subjects under the age of consent. 
14.2 
Assignment of Subject Number 
At Screening, all subjects who have signed an ICF will receive a unique subject identification (ID) 
number, which will consist of a site number followed by a 2-digit sequentially assigned subject 
number starting at 01, at each site. 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 study drug kit number.  
Subjects who are screen failures or who are not eligible for randomization 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 inclusion/exclusion 


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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 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, at the TOC visit and at any unscheduled visit, if 
needed. 
14.6 
Urine Pregnancy Test  
A urine pregnancy test based on the measurement of human chorionic gonadotropin with a 
sensitivity of at least 25 international units per liter will be performed at Screening and at 
unscheduled visits, if needed, by the local laboratory for all subjects of childbearing potential. The 
pregnancy test results will be reviewed at Baseline (Day 1) before starting/dispensing study drug.  
14.7 
Safety Laboratory Tests  
Safety laboratory tests will be performed by a qualified central laboratory. Samples for safety 
laboratory tests will be collected at the Screening and the TOC visits 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 
 


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 
 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 
 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 
 Total protein  
14.8 
Rating of Vulvovaginal Symptoms by the Subject Using the VSS Scale 
Subjects will be asked to rate their vulvovaginal symptoms at Screening, from Day 1 through the 
TOC visit (Day 8-Day 14) and at the FU visit (Day 25 [(± 4]). Subjects will also assess their 
symptom at unscheduled visits, as needed.  
If the subject experiences persistence or worsening or recurrence of symptoms that per the 
investigator’s assessment (e.g. symptoms ≥3) warrant the use of rescue antifungal therapy, the 
rating of the symptoms that led to the use of rescue antifungal therapy must be documented in the 
eCRF and a vaginal examination with rating of signs by the investigator should be completed. If 
the investigator’s rating of the vulvovaginal signs and vaginal samples collection are not possible 
prior to the initiation of the rescue therapy, they should still be completed as soon as possible after 
rescue therapy is initiated.  
Subjects will rate their symptoms of infection using the VSS Scale, 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. 
14.9 
Vulvovaginal Samples for Identification of Other Pathogens and 
Vaginal pH  
A vulvovaginal specimen will be obtained at the Screening visit for local vaginal pH 
determination. This sample will also be tested by a local qualified laboratory to rule out bacterial 
vaginosis and Trichomonas vaginalis. Testing for Neisseria gonorrhoeae, Chlamydia trachomatis 


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or Herpes virus will also be conducted by a qualified laboratory (local or central laboratory), if 
clinically indicated. Vaginal samples will be tested for bacterial vaginosis, T. vaginalis, N. 
gonorrhoeae, C. trachomatis or Herpes virus at unscheduled visits only if needed.  This procedure 
should also be completed prior to the initiation of rescue therapy. If the vaginal samples collection 
is not possible prior to the initiation of rescue therapy, it should still be completed as soon as 
possible after rescue therapy is initiated.  If there is persistence or recurrence of vulvovaginal 
symptoms, additional vulvovaginal specimens will be collected at the TOC and at the FU visits.  
Procedures for collecting and shipping vulvovaginal samples to the central laboratory will be 
described in the laboratory manual. 
14.10 Vulvovaginal Samples for KOH and Fungal Culture 
At Screening, a vulvovaginal specimen will be obtained for direct microscopic examination with 
10% KOH. Subjects must have a positive KOH test at Screening to be randomized to one of the 
study treatment groups. The Screening KOH will be assessed at the site by the investigator or 
qualified designee. A vaginal sample will also be obtained at Screening and at the TOC visit for 
fungal culture and species identification by the central laboratory and for susceptibility testing 
against ibrexafungerp and additional antifungal agents (per CLSI M27-A3 guidelines). If there is 
persistence or recurrence of vulvovaginal symptoms, additional vulvovaginal specimens will be 
collected for KOH testing at the TOC and at the FU visits, and for fungal culture at the FU visit. 
Samples will also be obtained at any unscheduled visit, if needed.  
If the subject experiences persistence or worsening or recurrence of symptoms that per the 
investigator’s assessment (e.g. symptoms ≥3) warrant the use of rescue antifungal therapy, a 
vaginal examination with collection of samples for KOH (assess at the site) and culture should be 
completed prior to initiation of rescue therapy. If the KOH test is negative, the investigator should 
consider other causes for the persistence or worsening of the symptoms and antifungal rescue 
medication may not be indicated. If the collection of the vaginal culture is not possible prior to the 
initiation of the rescue therapy, it should still be collected as soon as possible after rescue therapy 
is given. 
14.11 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 Screening and TOC visits. The vulvovaginal examination will 
be repeated at the FU 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 or recurrence of symptoms that per the 
investigator’s assessment (e.g. symptoms ≥3) warrant the use of rescue antifungal therapy, a 


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vaginal examination with rating of signs by the investigator should be completed prior to initiation 
of rescue therapy. If the investigator’s rating of the vulvovaginal signs is not possible prior to the 
initiation of the rescue therapy, it should still be completed as soon as possible after rescue therapy 
is initiated. 
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. 
14.12 Randomization  
At Baseline (Day 1), subjects who meet all of the inclusion and none of the exclusion criteria will 
be randomized to one of the two study treatment groups. Subject randomization will be performed 
using an Interactive Response System (voice or web-based), 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. 
14.13 Study Drug and Subject Diary Dispensing 
At Baseline (Day 1), eligible subjects will be dispensed enough study medication to permit BID 
dosing of the assigned study medication (see Section 12.3.2 ) and a subject diary, where the subject 
will rate her vulvovaginal symptoms of infection and will record study drug dosing details, AEs 
and concomitant medication use daily from Day 1 through the TOC visit.  
14.14 Study Drug Dosing 
The first study drug dose will be preferably administered at the center and the second study drug 
dose will be self-administered by the subjects approximately 12 hours later at home on Baseline 
(Day 1). The 2 doses should be administered approximately 12 hours apart. 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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Details of study treatment groups and dietary requirements for treatment administration are 
provided in Section 12.1 and Section 12.2, respectively. 
14.15 Subject Diary Completion 
Subjects will complete their diaries from Day 1 through the TOC visit. The subject diaries will 
include the VSS Scale so that subjects can rate their vulvovaginal symptoms. Subjects will record 
study drug dosing details, daily vulvovaginal symptoms, other medical concerns or complaints, 
and concomitant medications used. Subjects will be instructed to return their subject diaries at the 
TOC visit (Day 8-Day 14).  
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 included as 
part of the eCRFs. 
14.16 Study Drug Collection and Treatment Compliance Evaluation  
Treatment compliance will be reviewed by the investigator or designee at the TOC (Day 8-Day 
14) visit. Subjects 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 12.5. 
14.17 Subject Diary Collection and Review 
Subject diaries will be collected and reviewed at the TOC visit. 
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 included as 
part of the eCRFs. 
14.18 Vital Signs 
Vital signs, including blood pressure (systolic and diastolic), heart rate, respiratory rate and body 
temperature will be measured at Screening and at the TOC visit  as well as at unscheduled study 
visits, if needed. 
14.19 Prior and Concomitant Medication Review 
All medications (including prescription and over-the-counter medications, supplements, and 
herbal products) taken from 30 days before Baseline (Day 1) through the TOC visit (Day 8-Day 
14) will be recorded on the subject’s diary and eCRF. Only the use of antifungal medications, 
vaginal (topical) medications, antibiotics for any reason or any other medications to treat an AE 


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will be recorded after the TOC visit through the last study visit (FU). 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 13.0 for prohibited medications, medications to be administered with caution and 
further details for non-study treatments. 
14.20 Adverse Event Monitoring 
AEs will be recorded and reviewed at all scheduled and unscheduled study visits from the time the 
ICF is signed. Subjects will record any AE in their study diary from Baseline (Day 1) through the 
TOC visit (Day 8-Day 14). 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 1). 
Table 1: 
Schedule of Visits and Procedures (Study SCY-078-303) 
Visit 
V1 
Screeninga 
V2 
Baselinea 
V3 
TOC 
V4 
Follow-up 
Unscheduled Visits 
Day 
(allowable window) 
D-1 (-2) 
D1 
D11 (±3) 
D25 (± 4) 
 
Study Procedures 
 
 
 
 
 
Informed consentb 
X 
 
 
 
 
Assignment of Subject ID 
number 
X 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
Medical history and 
demographics 
X 
 
 
 
 
Abbreviated physical exam 
X 
 
X 
 
If needed 
Urine pregnancy test c 
X 
 
 
 
If needed 
Safety labs d 
X 
 
X 
 
If needed 
Rating of vulvovaginal 
symptoms by the subjecte 
X 
X------------ X 
X 
If needed 
Vulvovaginal sample for other 
pathogens and pHe 
X 
 
If symptoms 
If symptoms 
If needed 
Vulvovaginal sample for KOHe  
X 
 
If symptoms 
If symptoms 
If needed 
Vulvovaginal sample for fungal 
culturee  
X 
 
X 
If symptoms 
If needed 


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Visit 
V1 
Screeninga 
V2 
Baselinea 
V3 
TOC 
V4 
Follow-up 
Unscheduled Visits 
Day 
(allowable window) 
D-1 (-2) 
D1 
D11 (±3) 
D25 (± 4) 
 
Study Procedures 
 
 
 
 
 
Rating of vulvovaginal signs by 
the investigator e  
X 
 
X 
If symptomsf 
If needed 
Randomization  
 
X 
 
 
 
Study drug and subject diaryg 
dispensing   
 
X 
 
 
 
Study drug dosingh 
 
X 
 
 
 
Subject diary completion 
 
X---------------X 
 
 
Study drug collection and 
treatment compliance evaluation  
 
 
X 
 
 
Subject diary collection and 
review 
 
 
X 
 
 
Vital Signs 
X 
 
X 
 
If needed 
Prior & concomitant medication 
review 
X 
X 
X 
X 
X 
AE monitoring 
X 
X 
X 
X 
X 
Abbreviations: AE=adverse event; D=day; TOC=test of cure; V=visit 
a. 
Screening and Baseline may occur on the same day. 
b. 
For subjects under the legal age of consent, the subject’s parent or legal representative will also sign the subject’s ICF. 
c. 
Results should be reviewed prior to randomization at Baseline (Day 1). 
d. 
Hematology and blood chemistry. Safety laboratory tests will be performed by a qualified central laboratory. 
e. 
If the subject experiences persistence or worsening or recurrence of symptoms, after the baseline visit, that per the investigator’s assessment (e.g. 
symptoms ≥3) warrant the use of rescue antifungal therapy, the symptoms that led to the use of rescue antifungal therapy must be documented in the eCRF and 
a vaginal examination with rating of signs by the investigator should be completed. Additionally, vulvovaginal samples should be obtained for KOH testing 


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and pH measurement (both at the site), fungal culture (central laboratory) and investigation of other pathogens such as bacterial vaginosis and Trichomonas 
vaginalis (at the site). If the investigator’s rating of the vulvovaginal signs and vaginal samples collection are not possible prior to the initiation of the rescue 
therapy, they should still be completed as soon as possible after rescue therapy is initiated. 
f. 
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.  
g. 
 Subject diaries will be used to rate vulvovaginal symptoms of infection and record study drug dosing details, AEs and concomitant medication use.  
h. 
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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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 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) 


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• 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 
• 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 if new compared to Baseline, 
confirmed by repeat testing 
• 
ALT or AST > 3 x ULN and total bilirubin >2 x ULN if new compared to 
Baseline, confirmed by repeat testing 
• ALT or AST > 3 x ULN, confirmed by repeat test, with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (> 5%) 


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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. Considering the dosing schedule in this 
study, one dose administered at the site and one dose administered at home approximately 
12 hours later, overdose is not expected.  If accidently the 2 doses of study drug are 
administered together, this should be recorded in the dosing section of the eCRF but will 
not require additional reporting unless associated with a SAE. An overdose must be 
reported within 24 hours of the site becoming aware of the overdose if such overdose 
occurs with an associated SAE.  
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.  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. 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. 
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. 


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16.7 
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. 
16.8 
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. 
16.9 
Adverse Event Collection Timeframe 
All AEs and SAEs will be recorded from the time informed consent is obtained through 
the FU visit (end of study).   


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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 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. 
16.10 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. 
16.11 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). 
16.12 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 the Safety Surveillance team via (contact information, i.e., e-mail or fax will 
be available on the SAE form).  


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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. 
16.13 Procedures for Emergency Unblinding 
This is a double-blind, double-dummy 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. 
17.2 
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 PI must make all the 


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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. 
17.3 
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 
IB 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. 
17.4 
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. 


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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. 
18.0 Analytical Plan  
All statistical processing 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 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.  
All analyses will be presented by treatment group.  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 statistical analyses in detail will be 
provided as a separate document. The SAP will be finalized prior to unblinding of the study 
treatments. 


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18.1 
Sample Size Determination 
The primary endpoint of the study is the percentage of subjects achieving a clinical cure at 
the TOC visit. Assuming clinical cure rates of 50% and 30% for ibrexafungerp and placebo 
administered in a 2:1 ratio, respectively, approximately 282 subjects will provide 90% 
power to detect a difference between ibrexafungerp and placebo based on a Pearson’s Chi-
squared test with a Type 1 error rate of 5%. Because it is expected that approximately 20% 
of subjects may not have a mycological culture-confirmed infection at Baseline and 
approximately 10% may withdraw early from the study, an additional 84 subjects are added 
for a total of 366 subjects (244 subjects randomized to ibrexafungerp and 122 subjects, to 
placebo). 
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. 
Modified Intent-to-Treat (mITT) Population: All randomized subjects who have a 
positive culture for Candida species at Baseline. 
Per-Protocol (PP) Population: All mITT subjects who have completed the study drug 
treatment AND who have a TOC evaluation. 
Safety Population: All randomized subjects who received at least one dose of study drug 
and who have at least one post-Baseline 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. 


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18.4 
Handling of Missing Data, Dose Adjustments, and Early 
Withdrawals 
For the efficacy analyses, subjects who do not have a TOC (Day 8-Day 14) assessment will 
be assigned as treatment failures. For subjects who withdraw from the study early, every 
effort will be made to collect TOC visit information at the point of withdrawal. 
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 FU visit date with 
missing stop dates or stop dates after the first dose of study drug will be considered 
concomitant medications. 
18.6 
Efficacy 
18.6.1 Efficacy Assessments 
The primary efficacy endpoint of the study is the percentage of subjects with clinical cure 
(complete resolution of signs and symptoms) at the TOC visit. Secondary efficacy 
endpoints include the percentage of subjects with mycological eradication (negative culture 
for growth of Candida species) at the TOC visit, the percentage of subjects with clinical 
cure and mycological eradication at the TOC visit, the percentage of subjects with complete 
resolution of symptoms at the FU visit, and the percentage of subjects with clinical 
improvement (partial or complete resolution of signs and symptoms with a total composite 
score no greater than 1) at the TOC visit and the absolute change in signs and symptoms 
score from Baseline to TOC and FU visits.  
The following treatment outcome definitions will be used for the assessment of efficacy 
relative to baseline: 
Clinical Outcome 
• Clinical cure: Complete resolution of signs and symptoms of vulvovaginal infection 
without need for further antifungal treatment. Specifically, for complete resolution, any 
sign or symptom should be absent (score = 0) by the TOC visit. 
• Clinical failure: No response to therapy or incomplete resolution of signs and 
symptoms or need for additional vulvovaginal or systemic antifungal therapy. If the 


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subject receives or self-administers topical drug therapy for the treatment of 
vulvovaginal irritation/pruritus such as topical analgesic or corticosteroid after 
completing treatment with the study drug and before the TOC visit, the subject is 
considered a clinical failure. 
Mycological Outcome 
• Mycological eradication: A subject with negative culture for Candida species.  
• Mycological persistence: A subject with a positive culture for Candida species. 
18.6.2 Efficacy Analyses 
The efficacy analyses will be conducted using the mITT (primary analysis population), ITT 
and PP populations to evaluate ibrexafungerp vs. placebo. 
The primary endpoint, percentage of subjects with clinical cure at TOC, will be analyzed 
using a Cochran Mantel Haenszel (CMH) test adjusted for site; the p-value and 95% 
confidence intervals will be presented. Missing Day 8-Day 14 (TOC) data for the primary 
endpoint will be imputed as failures in the analysis. A sensitivity analysis will be performed 
where subjects with missing values will be removed from the analysis. All other data will 
be analyzed as is with no imputation. 
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. 
 
18.7 
Safety  
18.7.1 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. An abbreviated physical examination, including 
general appearance and an overall examination of body systems, will be conducted at 
Screening and at the TOC visit. Vital signs, including blood pressure (systolic and 
diastolic), heart rate, respiratory rate and body temperature will be measured at the 
Screening and TOC visits, and at unscheduled visits, if needed. Safety laboratory tests 


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(hematology and blood chemistry) will be measured at Screening, at the TOC visit and at 
unscheduled visits, if needed. 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). 
Safety procedures are described in Section 14.0 and safety assessments are described in 
Section 16.0. 
18.7.2 Analyses 
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. 
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 by treatment group for laboratory tests. 
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 US 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 


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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 Good Clinical Practice 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. Local regulations should be followed for consenting subjects under the age 
of consent and original signed assent, when applicable, will be retained with the study 
center’s records with the subject’s ICF. 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. isolates (see 
Section 14.8 and Section 14.10) ,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.   
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.   


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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. Diflucan prescribing information. Pfizer. Revised November 2014. 
5. Sobel JD, Management of recurrent vulvovaginal candidiasis: unresolved issues. Curr 
Infect Dis Rep. 2006 Nov;8(6):481-6. 
6. 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. 
7. Vulvovaginal  Candidiasis:  Developing  Drugs  for  Treatment – Guidance  for 
Industry. FDA. Revised July 2016. 
 
 
 


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21.0 Appendices 
Appendix A:  Prohibited Medications and Medications to be 
Administered with Caution 
Prohibited Medications 
The use of any topical vaginal corticoids and topical vaginal contraceptives is prohibited 
during the study.  No systemic or topical vaginal antifungal treatment other than the study 
drug is allowed during the study unless used as rescue medication after the subject has been 
documented as not responding to study drug. No investigational drugs other than the study 
drug are allowed within 30 days before Screening and for the entire duration of the study.  
In addition, the medications listed below are also prohibited. 
 
Strong CYP3A4/5 inhibitors and CYP3A4/5 inducers 
CYP 
Strong Inhibitorsa 
Inducersa 
3A4/5 
 
• boceprevir 
• clarithromycin 
• conivaptan 
• indinavir 
• lopinavir  
• mibefradil 
 
 
• nefazodone 
• nelfinavir 
• ritonavir 
• saquinavir 
• telaprevir  
• telithromycin 
 
• avasimibe 
• carbamazepine 
• phenytoin 
• rifampin 
• St. John’s wort 
• long-lasting 
barbiturates 
a. The CYP3A4/5 inhibitors and CYP3A4/5 inducers listed in this table are not permitted during 
the 7 days prior to enrollment and during study treatment until TOC. 
 
P-glycoprotein (P-gp) substrates 
P-gp Drug Substratesa 
digoxin, colchicine 
a. The P-gp substrates listed in this table are not permitted during the 48 hours prior to 
enrollment or during study treatment 
 
 


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Medications to be administered with Caution and Monitored as Appropriate 
CYP3A4 substrates 
CYP 
Substrates 
3A4 
In vitro, ibrexafungerp (SCY-078) 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 (SCY-078) with drugs known to be CYP3A sensitive 
substrates with narrow therapeutic index, such as midazolam and cyclosporine. 
Subjects receiving sirolimus, tacrolimus, warfarin, cyclosporine or amiodarone are 
permitted for enrollment in the study and these medications may be administered 
concomitantly with ibrexafungerp (SCY-078) 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 (SCY-078) 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 (SCY-078) with drugs 
known to be OATP1B3 selective substrates. Therefore, caution should be exercised 
when administering ibrexafungerp (SCY-078) 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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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 
 
 
 
 
 


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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 

SAP_001.pdf: 
 
Confidential 
 
 
 
 
 
 
 
 
 
SCYNEXIS, Inc. 
 
SCY-078-303 
 
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Efficacy and Safety of Oral Ibrexafungerp (SCY-078) 
vs. Placebo in Subjects with Acute Vulvovaginal Candidiasis 
 
16Oct, 2019 
 
Statistical Analysis Plan 
 
Final Version 1.0 
 
 
 
 
 
 


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 II
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... IV 
1. 
INTRODUCTION ............................................................................................................ 1 
2. 
OBJECTIVES ................................................................................................................... 2 
2.1. PRIMARY OBJECTIVES ........................................................................................................ 2 
2.2. SECONDARY OBJECTIVES ................................................................................................... 2 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 2 
3.1. OVERALL STUDY DESIGN AND PLAN .................................................................................. 2 
3.2. STUDY ENDPOINTS ............................................................................................................. 2 
3.2.1. 
Primary Endpoints ...................................................................................................... 2 
3.2.2. 
Secondary Efficacy Endpoints .................................................................................... 2 
3.3. TREATMENTS ...................................................................................................................... 3 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 4 
4.1. SAMPLE SIZE ...................................................................................................................... 4 
4.2. RANDOMIZATION, STRATIFICATION AND BLINDING ........................................................... 5 
4.3. ANALYSIS SET .................................................................................................................... 5 
4.4. HANDING OF MISSING DATA ................................................................................................ 6 
5. 
SUBJECT DISPOSITION ............................................................................................... 6 
5.1. DISPOSITION ....................................................................................................................... 6 
5.2. PROTOCOL DEVIATIONS ..................................................................................................... 6 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................... 8 
6.1. DEMOGRAPHICS .................................................................................................................. 8 
6.2. BASELINE CHARACTERISTICS ............................................................................................. 8 
6.3. MEDICAL HISTORY ............................................................................................................. 9 
6.4. INCLUSION AND EXCLUSION CRITERIA ............................................................................... 9 
7. 
TREATMENTS AND MEDICATIONS ......................................................................... 9 
7.1. PRIOR AND CONCOMITANT MEDICATIONS .......................................................................... 9 
7.1.1. 
Prior Medications ....................................................................................................... 9 
7.1.2. 
Concomitant Medications ......................................................................................... 10 
7.1.3. 
Rescue Antifungal Medications................................................................................. 10 
7.2. STUDY TREATMENTS ........................................................................................................ 10 
7.2.1. 
Study Participation Calculation and Extent of Exposure ......................................... 10 
7.2.2. 
Treatment Compliance .............................................................................................. 11 
8. 
EFFICACY ANALYSIS................................................................................................. 12 
8.1. PRIMARY ENDPOINT ......................................................................................................... 12 
8.1.1. 
Primary Analysis ....................................................................................................... 13 
8.2. SECONDARY EFFICACY ENDPOINTS .................................................................................. 14 
8.2.1. 
Mycological outcomes .............................................................................................. 14 
8.2.2. 
Overall Outcome ....................................................................................................... 15 
8.2.3. 
Symptom Outcome .................................................................................................... 15 


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8.2.4. 
Clinical Improvement................................................................................................ 16 
8.2.5. 
Composite Score of the Vulvovaginal Signs and Symptoms ..................................... 16 
9. 
SAFETY ANALYSIS ..................................................................................................... 18 
9.1. ADVERSE EVENTS............................................................................................................. 18 
9.1.1. 
Treatment-Emergent Adverse Events ........................................................................ 19 
9.1.2. 
Relationship of Adverse Events to Study Treatment ................................................. 19 
9.1.3. 
Severity of Adverse Event.......................................................................................... 19 
9.1.4. 
Adverse Events Leading to Treatment Discontinuation............................................ 20 
9.1.5. 
Adverse Events Leading to Study Discontinuation ................................................... 20 
9.1.6. 
Death ......................................................................................................................... 20 
9.2. CLINICAL LABORATORY EVALUATIONS ........................................................................... 20 
9.2.1. 
Pregnancy ................................................................................................................. 21 
9.2.2. 
Events of Clinical Interest ......................................................................................... 21 
9.3. VITAL SIGN MEASUREMENTS ........................................................................................... 21 
9.4. PHYSICAL EXAMINATION ................................................................................................. 21 
9.5. VAGINAL SAMPLES – PH, KOH AND OTHER PATHOGEN RESULTS ................................... 22 
10. 
INTERIM ANALYSIS ................................................................................................... 22 
11. 
CHANGES IN THE PLANNED ANALYSIS .............................................................. 22 
12. 
REFERENCES................................................................................................................ 23 
13. 
APPENDICES ................................................................................................................. 24 


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  IV
List of Abbreviations 
AE 
adverse event 
ANOVA 
analysis of variance 
AVVC 
acute vulvovaginal candidiasis 
BID 
twice daily 
BMI 
body mass index 
CFR 
code of Federal Regulations 
CMH 
Cochran Mantel Haenszel 
CRF 
case report form 
eCRF 
electronic case report form 
eDISH 
evaluation of drug induced serious hepatotoxicity 
FU 
follow-up 
ICF 
Informed Consent Form 
ID 
identification 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
Interactive web-based response system 
IVRS 
interactive voice response system 
KOH 
potassium hydroxide 
mBOCF 
modified baseline observation carried forward 
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 
NRI 
non-responder imputation 
PI 
principal investigator 
PP 
per protocol 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
system organ class 
SS 
safety set 
TOC 
test of cure 
UK 
unknown 
UNK 
unknown 
VSS Scale 
vulvovaginal signs and symptoms scale 
VVC 
vulvovaginal candidiasis 
 
 


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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 75% of women on at least one occasion over a lifetime. 
Current treatments for VVC include topical antifungals and the use of prescription oral antifungals 
such a single dose of fluconazole. According to previous clinical studies, a single dose of 
fluconazole is able to provide an acceptable therapeutic outcome for more than half of the treated 
individuals, but the emergence of fluconazole resistance among C. albicans isolates and the 
frequency of cases caused by C. glabrata, a strain naturally less susceptible to fluconazole, signals 
the need for new therapeutic approaches. 
Additionally, recurrence of VVC after fluconazole therapy is not uncommon and these 
exacerbations often involve the same microorganism identified in the initial episode, suggesting 
that a small number of C. albicans remain as a reservoir in the vagina after completion of azole 
therapy, becoming the source of subsequent exacerbations. 
New curative approaches are needed, particularly involving agents with fungicidal activity (i.e., 
that are able to kill the fungus) and activity against fluconazole-resistant strains, so that the 
causative yeasts can be eradicated. A new therapeutic approach with these characteristics would 
be expected to result in improved short-term and potentially long-term outcomes for this condition. 
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.  
This study aims to provide evidence of the efficacy and evaluate the safety of oral SCY-078 as a 
new class of antifungal agent with fungicidal activity against Candida spp. in the treatment of 
subjects with acute vulvovaginal candidiasis (AVVC). 
 
 


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2. Objectives 
2.1. Primary Objectives 
To evaluate the efficacy of oral ibrexafungerp versus placebo in subjects with AVVC by 
comparing the clinical outcomes of ibrexafungerp and placebo. 
2.2. Secondary Objectives 
• 
To evaluate the efficacy of oral ibrexafungerp versus placebo in subjects with AVVC 
based on mycological and clinical outcomes 
• 
To evaluate the safety and tolerability of oral ibrexafungerp versus placebo in subjects 
with AVVC 
3. Investigational Plan 
3.1. Overall Study Design and Plan 
This is a Phase 3, randomized, multicenter, double-blind, placebo-controlled study to evaluate the 
efficacy and safety of oral ibrexafungerp compared to placebo in female subjects 12 years and 
older with AVVC. 
Approximately 366 eligible subjects will be enrolled and randomized in a 2:1 ratio to either 
ibrexafungerp (300-mg dose twice a day [BID]) or matching placebo administered BID for 1 day. 
The primary objective of this study is to evaluate the efficacy of oral ibrexafungerp in subjects 
with AVVC by comparing the clinical outcomes of ibrexafungerp and placebo. 
The study will consist of a Screening visit, a Baseline visit on Day 1 (these visits may occur on the 
same day), a TOC visit on Day 11 (±3) and a FU visit on Day 25 (±4). 
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 clinical cure (complete resolution of signs 
and symptoms) at the test-of-cure (TOC) visit. 
3.2.2. Secondary Efficacy Endpoints 
Efficacy as measured by: 
• 
The percentage of subjects with mycological eradication (negative culture for growth of 
Candida species) at the TOC visit; 
• 
The percentage of subjects with clinical cure and mycological eradication (responder 
outcome) at the TOC visit; 


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• 
The percentage of subjects with complete resolution of symptoms at the Follow-up (FU) 
visit; 
• 
The percentage of subjects with clinical improvement (partial or complete resolution of 
signs and symptoms with total composite score no greater than 1) at the TOC visit; 
• 
The absolute change in signs and symptoms score from Baseline to TOC and FU visits. 
Safety and tolerability as measured by: 
• 
Adverse events (AEs); 
• 
Vital signs; 
• 
Physical examination; 
• 
Treatment discontinuation; 
• 
Safety laboratory tests. 
3.3. Treatments   
At Baseline (Day 1), eligible subjects will be randomized in a 2:1 ratio to one of the following two 
treatment groups: 
• 
Oral ibrexafungerp 300-mg dose BID for 1 day 
• 
Oral ibrexafungerp matching placebo BID for 1 day 
For the purpose of maintaining treatment blinding, all subjects randomized to the placebo group 
will receive matching ibrexafungerp placebo tablets. 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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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. 
4.1. Sample Size 
The primary endpoint of the study is the percentage of subjects achieving a clinical cure at the 
TOC visit. Assuming clinical cure rates of 50% and 30% for ibrexafungerp and placebo 
administered in a 2:1 ratio, respectively, approximately 282 subjects will provide 90% power to 
detect a difference between ibrexafungerp and placebo based on a Pearson’s Chi-squared test with 
a Type 1 error rate of 5%. Because it is expected that approximately 20% of subjects may not have 
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from the study, an additional 84 subjects are added for a total of 366 subjects (244 subjects 
randomized to ibrexafungerp and 122 subjects, to placebo). 
4.2. Randomization, Stratification and Blinding 
Approximately 366 eligible subjects will be enrolled and randomized in a 2:1 ratio to one of the 
following two study treatment groups: 
• 
 Oral ibrexafungerp 300-mg dose BID for 1 day 
• 
Oral ibrexafungerp matching placebo BID for 1 day 
An interactive response system (voice or web-based) 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/IVRS, which will link sequential 
subject randomization numbers to treatment codes. The block size 6 will be used in the 
randomization schedule.  
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 a diagnosis 
of diabetes mellitus (diabetes mellitus: YES or NO). 
4.3. Analysis Set 
Intent-to-Treat (ITT) Set: All randomized subjects who signed the consent form and received at 
least one dose of study drug. 
Modified Intent-to-Treat (mITT) Set: All randomized subjects who have a positive culture for 
Candida species at baseline and taking at least one dose of study drug. 
Per-Protocol (PP) Set: All mITT subjects who meet all of the following criteria: 
• 
Completed the study drug treatment; 
• 
Have a TOC evaluation that includes documentation of signs, 
symptoms and collection of a vaginal culture; 
• 
No major protocol deviation. 


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Safety Set (SS): All randomized subjects who received at least one dose of study drug and who 
have at least one post-baseline evaluation. 
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 do not meet the clinical response criteria for 
categorical responses or 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. 
5. Subject Disposition 
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, PP, SS), subjects who completed TOC visit, 
subjects who completed the study (without need for antifungal treatment), subjects who completed 
the study (with need for antifungal treatment at FU visit), 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: lack of efficacy and/or use 
of antifungal therapy prior to TOC; use of antifungal therapy after TOC (but prior to FU visit); 
adverse event; lack of efficacy after TOC; lost to follow-up; physician decision; pregnancy; study 
terminated by sponsor; study subject withdrawal by parent or guardian; withdrawal by subject; 
other; death, and 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 


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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 will be summarized using the ITT and mITT sets.  
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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); 
• 
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. 
• 
Diabetes mellitus (Yes or No); 
• 
Candida species at baseline (by Genus species); 
• 
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 CLSI MIC range, mode, MIC50, and MIC90, 
based on the ITT and mITT sets by treatment group for the following MIC results: 


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• 
MIC results for SCY-078 and fluconazole (FLU) at 24 hours against candida species 
isolates obtained at Baseline; 
• 
MIC results for SCY-078 at 48 hours against candida species isolates obtained at Baseline. 
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 19.0 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 the following will be presented by system organ class (SOC), and 
preferred term (PT) for subjects in the mITT set: 
• 
History of recurrent VVC as evidence by applicable PT; 
• 
Other vulvovaginal conditions (Selected SOC and Preferred Terms). 
A by-subject listing of medical history will be provided. 
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 11.1 and 11.2). The specific inclusion 
criterion not met or exclusion criterion which was met will be recorded in the eCRF. This 
information will be presented in a listing. 
7. Treatments and Medications 
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). 
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. 
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. 


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In addition, a summary of the following will be presented for subjects in the mITT set: 
• 
Antibiotic use 30 days before baseline visit; 
• 
Systemic steroid use 30 days before baseline visit. 
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. 
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. 
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. 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 actual 
doses by treatment will be summarized by summary statistics.  


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All this exposure information will be presented in a listing. 
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 by treatment group. 
Non-compliance with dose regimen (example all four tablets taken as a single dose) will be 
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8. Efficacy Analysis 
The primary efficacy and secondary efficacy endpoints will be performed on the modified intent-
to-treat set (mITT), the intent-to-treat set (ITT) and the per-protocol (PP) set. The mITT analyses 
will be considered primary; the ITT and PP 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. 
8.1. Primary Endpoint 
The primary efficacy endpoint is defined as the proportion of mITT subjects who have a clinical 
cure (complete resolution of signs and symptoms) at the test-of-cure (TOC) visit. 
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); 
• 
Clinical failure: No response to therapy or incomplete resolution of signs and 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 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 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). 


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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 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. 
8.1.1. Primary Analysis 
The primary efficacy analysis will be performed on the mITT set at the TOC visit and will compare 
the proportion of subjects, in the treatment and placebo groups, who have a clinical cure at the 
TOC visit. 
The number and percentage of subjects with clinical cure at the TOC visit will be presented by 
treatment group. A Cochran Mantel Haenszel (CMH) test adjusted for site and diabetes mellitus 
diagnosis (Yes or No) will be performed to assess the statistical significance of a difference 
between treatment groups in the primary efficacy analysis. Mathematically stated: 
H0: TOC Clinical Cure Rate Oral ibrexafungerp 300-mg dose = TOC Clinical Cure Rate Placebo 
H1: TOC Clinical Cure Rate Oral ibrexafungerp 300-mg dose  TOC Clinical Cure Rate Placebo 
The p-value, odds ratio and 95% confidence interval will be presented in the ibrexafungerp 300-
mg treatment arm compared to the placebo arm. Missing data for clinical outcome will be imputed 
using the NRI method described in Section 4.4. Additional summarizations will be performed by 
Candida Species of the baseline yeast, and the same inferential analysis will be performed, as 
appropriate. 
The same inferential analysis employing the same methods as for the primary analysis will be 
performed for the ITT set and PP set to assess clinical cure at TOC visit. Missing data for clinical 
outcome will be imputed using the NRI method described in Section 4.4. No adjustment of type I 
error will be performed as these analyses are considered supportive to the primary analysis. 
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. 
Two subgroup analyses will be performed depending on Body Mass Index category (≤35 kg/m² or 
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Analysis of time to resolution of signs and symptoms after initiation of study drug will use Kaplan-
Meier method to estimate the median resolution time and its 2-sided 95% confidence intervals 
(CIs) based on the ITT, mITT, and PP sets. The time to resolution of signs and symptoms after 
initiation of study drug is defined as time (days) from first dose of study medication to the first 
resolution of signs and symptoms. Subjects who discontinued early will be censored at the last 
available assessment. 
Kaplan-Meier curves for time to resolution of signs and symptoms after initiation of study drug 
will be provided by treatment group based on the ITT, mITT, and PP sets. 
Summary of the number and percentage of subjects with continued clinical response at the Follow-
up (FU) visit, which defined as continued absence of signs and symptoms in subjects who achieved 
Clinical Cure at the TOC visit, will be provided by treatment based on the ITT, mITT, and PP sets. 
8.2. Secondary Efficacy Endpoints 
8.2.1. Mycological outcomes 
The percentage of subjects with mycological eradication (negative culture for growth of Candida 
species) at the TOC visit will be analyzed by Candida Species of the baseline yeast and overall, 
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 TOC visit data for the mycological outcome will 
be imputed as mycological persistence using the NRI method described in Section 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; 
• 
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. 
In addition, a sensitivity analysis will be conducted based on the mITT set where subjects with the 
imputed mycological outcome using the NRI method at the TOC visit will be removed from the 
analysis. 
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. 
The change of mycological outcomes will be summarized in shift tables comparing the testing 
results at TOC visit with those at FU visit. 
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In addition, a summary table will be presented to include CLSI MIC range, mode, MIC50, and 
MIC90, based on the ITT and mITT sets by treatment group for the following MIC results: 
• 
MIC results for SCY-078 and fluconazole (FLU) at 24 hours against candida species 
isolates obtained at TOC visit; 
• 
MIC results for SCY-078 at 48 hours against candida species isolates obtained at TOC 
visit. 
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. 
8.2.2. Overall Outcome 
The percentage of subjects with clinical cure and mycological eradication (overall outcome) at the 
TOC visit will be analyzed by Candida Species of the baseline yeast and overall, using the same 
inferential analysis employing the same methods as for the primary analysis as noted in Section 
8.1.1. 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 clinical failure or mycological persistence. 
The analyses for overall outcome will only be conducted for the mITT and PP sets. The overall 
outcomes will be listed with baseline species referenced aside in a listing. 
8.2.3. Symptom Outcome 
The percentage of subjects with complete resolution of symptoms at the Follow-up (FU) visit will 
be analyzed by Candida Species of the baseline yeast and overall, 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 Follow-Up data for the symptom outcome will be imputed as symptom 
persistence using the NRI method described in Section 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 


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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 
considered a symptom persistence.  
In addition, a sensitivity analysis will be conducted based on the mITT set where the subjects with 
the imputed symptom outcome using the NRI method at the FU visit will be removed from the 
analysis. 
8.2.4. Clinical Improvement 
The 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 analyzed using the same inferential analysis 
employing the same methods as for the primary analysis as noted in Section 8.1.1. 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 4.4. The composite 
score will be calculated as the rules described in Section 8.1. 
In addition, a sensitivity analysis will be conducted based on the mITT set where the subjects with 
the imputed clinical improvement outcome using the NRI method at the TOC visit will be removed 
from the analysis. 
8.2.5. Composite Score of the Vulvovaginal Signs and Symptoms 
The following secondary efficacy endpoints will be analyzed using an analysis of covariance 
(ANCOVA) model having treatment group, site and diabetes mellitus diagnosis (Yes or No) as 
classification variables, and the baseline value as the continuous covariate.   
• 
The change in signs and symptoms score from Baseline to TOC visit; 
• 
The change in signs and symptoms score from Baseline to FU visit. 
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.  
A descriptive summary will be presented for the followings based on the mITT and PP sets: 
• 
The change in total sign score from baseline to TOC and FU visits; 
• 
The change in total symptom score from baseline to TOC and FU visits; 
• 
The change in signs and symptoms score from TOC to FU visit. 


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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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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 by treatment group. 
Individual subject listings will be provided to support the tables. 
9.1. Adverse Events 
All AE summaries will be restricted to treatment-emergent AEs (TEAEs) only. A TEAE is defined 
as any event 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: 
Missing 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.  
Missing 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. 
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.  


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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. 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 a 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. 
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”.  


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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” has to 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. 
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 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 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. 


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In data listings, laboratory values will be compared to normal ranges; out-of-range and clinically 
significant laboratory values will be identified. 
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.  
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 x the upper limit of normal (ULN); 
• 
ALT or AST > 5 x ULN if new compared to Baseline; 
• 
ALT or AST > 3 x ULN and total bilirubin >2 x ULN if new compared to Baseline; 
• 
ALT or AST > 3 x ULN. 
If subjects meet the criterion ALT or AST > 3 x ULN, the additional summary of the frequency 
and percentage of subjects with ALT or AST > 3 x ULN, confirmed by repeat test, and with the 
appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (> 5%) will be provided. 
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 
changes from baseline to the TOC visit will be presented. All vital sign data by subject will be 
presented in a listing. 
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 


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baseline”. This categorical data will be summarized with the frequency and percentage of subjects 
by body system at each scheduled visit. 
Any abnormalities noted during the physical examination will be presented in a listing for all 
subjects. 
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 pH testing results will be summarized descriptively at the scheduled post-baseline visits by 
treatment group. 
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 by-subject 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 secondary efficacy endpoint “Change from Baseline in Composite Score of the 
Vulvovaginal Signs and Symptoms” described in Section 8.2.5, an analysis of covariance 
(ANCOVA) model is 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, diabetes mellitus diagnosis (Yes or No), as 
justification factor in the efficacy analyses models. 
 
 


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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. 
 
 


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13. Appendices 
Appendix 1: Schedule of Assessments 
Visit 
V1 
Screeninga 
V2 
Baselinea 
V3 
TOC 
V4 
Follow-up 
Unscheduled Visits 
Day 
(allowable window) 
D-1 (-2) 
D1 
D11 (±3) 
D25 (± 4) 
 
Study Procedures 
 
 
 
 
 
Informed consentb 
X 
 
 
 
 
Assignment of Subject ID number 
X 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
Medical history and demographics 
X 
 
 
 
 
Abbreviated physical exam 
X 
 
X 
 
If needed 
Urine pregnancy test c 
X 
 
 
 
If needed 
Safety labs d 
X 
 
X 
 
If needed 
Rating of vulvovaginal symptoms by the 
subjecte 
X 
X------------ X 
X 
If needed 
Vulvovaginal sample for other pathogens 
and pHe 
X 
 
If symptoms 
If symptoms 
If needed 
Vulvovaginal sample for KOHe  
X 
 
If symptoms 
If symptoms 
If needed 
Vulvovaginal sample for fungal culturee  
X 
 
X 
If symptoms 
If needed 
Rating of vulvovaginal signs by the 
investigator e  
X 
 
X 
If symptomsf 
If needed 
Randomization  
 
X 
 
 
 
Study drug and subject diaryg dispensing   
 
X 
 
 
 
Study drug dosingh 
 
X 
 
 
 
Subject diary completion 
 
X---------------X 
 
 
Study drug collection and treatment 
compliance evaluation  
 
 
X 
 
 


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Visit 
V1 
Screeninga 
V2 
Baselinea 
V3 
TOC 
V4 
Follow-up 
Unscheduled Visits 
Day 
(allowable window) 
D-1 (-2) 
D1 
D11 (±3) 
D25 (± 4) 
 
Study Procedures 
 
 
 
 
 
Subject diary collection and review 
 
 
X 
 
 
Vital Signs 
X 
 
X 
 
If needed 
Prior & concomitant medication review 
X 
X 
X 
X 
X 
AE monitoring 
X 
X 
X 
X 
X 
Abbreviations: AE=adverse event; D=day; TOC=test of cure; V=visit 
a. 
Screening and Baseline may occur on the same day. 
b. 
For subjects under the legal age of consent, the subject’s parent or legal representative will also sign the subject’s ICF. 
c. 
Results should be reviewed prior to randomization at Baseline (Day 1). 
d. 
Hematology and blood chemistry. Safety laboratory tests will be performed by a qualified central laboratory. 
e. 
If the subject experiences persistence or worsening or recurrence of symptoms, after the baseline visit, that per the investigator’s assessment (e.g. symptoms ≥3) 
warrant the use of rescue antifungal therapy, the symptoms that led to the use of rescue antifungal therapy must be documented in the eCRF and a vaginal examination with 
rating of signs by the investigator should be completed. Additionally, vulvovaginal samples should be obtained for KOH testing and pH measurement (both at the site), fungal 
culture (central laboratory) and investigation of other pathogens such as bacterial vaginosis and Trichomonas vaginalis (at the site). If the investigator’s rating of the 
vulvovaginal signs and vaginal samples collection are not possible prior to the initiation of the rescue therapy, they should still be completed as soon as possible after rescue 
therapy is initiated. 
f. 
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.  
g. 
 Subject diaries will be used to rate vulvovaginal symptoms of infection and record study drug dosing details, AEs and concomitant medication use.  
h. 
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