Conditions: Recurrent Vulvovaginal Candidiasis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 438
Healthy volunteers: no

Brief summary:
Recurrent vulvovaginal candidiasis (RVVC), also known as recurrent yeast infections, is defined as at least 3 episodes of acute VVC in the past 12 months. Several properties of oteseconazole (VT-1161) suggest that it might be a safer and more effective treatment for RVVC than other oral anti-fungal medicines.

This study will evaluate the effectiveness and safety of oteseconazole (VT-1161) for the treatment of RVVC and consists of 2 parts. The first part of the study is a 2-week period for the treatment of the patient's current VVC episode with 3 150mg doses of fluconazole. The 2nd part consists of 12 weeks, when the patient will take either oteseconazole (VT-1161) 150 mg or a placebo (according to a random assignment), and then a 36-week follow-up period.

In addition, at participating sites, an amendment to the study allows US patients who complete the initial 48 weeks without experiencing a confirmed RVVC episode to continue in a 48-week observational extension period designed to evaluate the continued effectiveness of oteseconazole (VT-1161).

This study is identical to VMT-VT-1161-CL-012 (NCT03561701).

Detailed description:

Arms:
arm 1: Once daily for 7 days starting at Day 1, followed by once weekly for 11 weeks arm 2: Once daily for 7 days starting at Day 1, followed by once weekly for 11 weeks

Interventions: intervention 1: Oteseconazole (VT-1161) intervention 2: Placebo
Intervention descriptions: intervention 1: Oteseconazole (VT-1161) 150mg capsule intervention 2: matching placebo capsule

Protocol document:
Prot_000.pdf: 
PRS COVER PAGE for PROTOCOL 
TITLE: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of VT-1161 Oral Capsules in the 
Treatment of Subjects with Recurrent Vulvovaginal Candidiasis (VMT-VT-
1161-CL-011) 
DATE: 01 October 2019 
CLINICALTRIALS.GOV ID: NCT03562156 


PROPRIETARY INFORMATION: This document and the contents hereof are considered proprietary and confidential information of 
Mycovia Pharmaceuticals, Inc. Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without the 
prior written consent of Mycovia Pharmaceuticals, Inc. 
 
 
 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of VT-1161 Oral Capsules in the 
Treatment of Subjects with Recurrent Vulvovaginal Candidiasis 
 
 
 
Study Number: VMT-VT-1161-CL-011 
EudraCT Number:  2018-001269-18 
 
Version: 5 (Amendment 4) 
Country-Specific Amendment: U.S. Only  
 
Date of Issue: 01 October 2019 
Mycovia Pharmaceuticals, Inc 
4505 Emperor Boulevard, Suite 300 
Durham, NC USA 27703 
 
 
 
Confidentiality Statement 
This document and the information it contains are confidential and the proprietary property of 
Mycovia Pharmaceuticals, Inc. The information is not to be disclosed or transmitted to any party 
without the written approval of Mycovia Pharmaceuticals, Inc. or its agents, and any such 
unauthorized use or disclosure is expressly prohibited.  




PROPRIETARY INFORMATION: This document and the contents hereof are considered proprietary and confidential information of 
Mycovia Pharmaceuticals, Inc. Disclosure to unauthorized individuals or dissemination, publication or copying is prohibited without the 
prior written consent of Mycovia Pharmaceuticals, Inc. 
PROTOCOL SIGNATURE PAGE 
 
 
 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of VT-1161 Oral Capsules in the 
Treatment of Subjects with Recurrent Vulvovaginal Candidiasis 
 
 
Study Number: VMT-VT-1161-CL-011 
EudraCT Number:  2018-001269-18 
 
Version: 5 (Amendment 4) 
Country-Specific Amendment: U.S. Only  
 
 
 
 
 
Date of Issue: 01 October 2019 
 
Signatures of approval for protocol: 
Name 
Signature 
Date 
 
 
 


CONFIDENTIAL 
 
Mycovia Pharmaceuticals, Inc. 
 
Product: VT-1161  
Protocol Synopsis 
Protocol VMT-VT-1161-CL-011 
IND 111675 
Ver. 5 U.S. Only, 01 October 2019 
 
3 
This study is to be performed in accordance with Good Clinical Practice, the ethical principles that 
have their origin in the Declaration of Helsinki, Title 21 of the Code of Federal Regulations, 
Parts 11 (Electronic Records; Electronic Signatures), 50 (Protection of Human Subjects), 
54 (Financial Disclosure by Clinical Investigators), 56 (Institutional Review Boards), and 
312 (Investigational New Drug Application), and International Conference on Harmonisation 
E6(R2) (Guideline for Good Clinical Practice).  Regulatory authorities, if required by national law, 
must give a favorable opinion/approval of the study protocol and amendments, informed consent 
and assent (for those ages 12 to 17) documents, and investigational brochure. 
 
 
Study Sponsor: 
Mycovia Pharmaceuticals, Inc. 
 
4505 Emperor Boulevard, Suite 300, Durham, NC USA 27703 
 
 
 
 
 
 
Sponsor Contact: 
Stephen Brand, Ph.D. 
 
Senior VP of Clinical Development 
 
4505 Emperor Boulevard, Suite 300, Durham, NC USA 27703 
 
 
 
 
 
 
 
 
 
Medical Responsible: 
Claude Hughes, M.D., Ph.D. 
Medical Consultant 
4505 Emperor Boulevard, Suite 300, Durham, NC USA 27703 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Mycovia Pharmaceuticals, Inc. 
 
Product: VT-1161  
Protocol Synopsis 
Protocol VMT-VT-1161-CL-011 
IND 111675 
Ver. 5 U.S. Only, 01 October 2019 
 
4 
Investigator’s Statement 
 
I have reviewed the protocol VMT-VT-1161-CL-011 entitled “A Phase 3, Randomized, Double-
Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of VT-1161 Oral Capsules 
in the Treatment of Subjects with Recurrent Vulvovaginal Candidiasis” and agree that it contains 
all the information necessary to conduct the study as required. I will conduct the study in 
accordance with the principles of International Conference on Harmonisation, Good Clinical 
Practice, and the Declaration of Helsinki. 
I will maintain as confidential all written and verbal information provided to me by the Sponsor, 
including but not limited to, the protocol, case report forms, Investigational Brochure, material 
supplied at investigator meetings, minutes of teleconferences, etc. I agree that such material will 
only be provided as necessary to site personnel involved in the conduct of the study, the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC), regulatory authorities, or 
agencies as required by local law. 
I will obtain written informed consent or assent (for those ages 12 to 17) from each prospective 
study subject or each prospective study subject’s legal representative prior to conducting any 
protocol-specified procedures. The consent and assent forms used will have the approval of the 
IRB/IEC. 
I will maintain adequate source documents and record all observations, treatments, and procedures 
pertinent to study subjects in their medical records. I will accurately complete the case report forms 
supplied by the Sponsor in a timely manner. I will ensure that my facilities and records are 
available for inspection by representatives of the Sponsor, the IRB/IEC, or other applicable 
regulatory authorities. I will ensure that my staff and I are available to resolve queries and meet 
with representatives of the Sponsor during regularly scheduled monitoring visits. 
I will notify the Sponsor within 24 hours of any serious adverse events. Following this notification, 
a written report describing the serious adverse event will be provided to the Sponsor within 1 
business day following the initial notification. 
I acknowledge that I am responsible for the overall study conduct, and I agree to personally 
conduct and/or supervise the study. I will ensure that all associates, colleagues, and employees 
assisting in the conduct of the study, are informed and trained as necessary about their obligations 
and that there are adequate mechanisms in place for the site staff to receive the appropriate 
information throughout the study. 
 
 
 
 
 
Name 
 
 
 
 
 
Signature 
 
Date 


CONFIDENTIAL 
 
Mycovia Pharmaceuticals, Inc. 
 
Product: VT-1161  
Protocol Synopsis 
Protocol VMT-VT-1161-CL-011 
IND 111675 
Ver. 5 U.S. Only, 01 October 2019 
 
5 
PROTOCOL SYNOPSIS 
Title of Study: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of VT-1161 Oral Capsules in the Treatment of Subjects with Recurrent Vulvovaginal 
Candidiasis 
Protocol Number: VMT-VT-1161-CL-011 
Interim Analysis: No 
Investigational Medicinal Product: VT-1161 capsules 
Non-Investigational Medicinal Product: Fluconazole tablets or capsules 
Planned Number of Sites: 60 to 80 
Planned Number of Subjects: 600 screened; 300 randomized 
Phase of Development: 3 
Introduction: 
VT-1161 is an orally-available inhibitor of fungal CYP51 that has shown high potency and selectivity in 
in vitro studies.  VT-1161 blocks the production of ergosterol, an essential component of the fungal cell 
membrane, which is critical to fungal growth.  In vitro and in vivo pharmacology studies have 
demonstrated that VT-1161 is highly active against Candida albicans, including fluconazole-resistant C. 
albicans, and non-albicans Candida species that cause vulvovaginal candidiasis (VVC).  VT-1161 is 
highly selective for fungal CYP51 relative to off-target human CYP enzymes, and data to date suggest 
that it may avoid the side-effect profile that limits the use of commonly prescribed azole antifungal 
agents. 
Oral VT-1161 has been evaluated in Phase 1 and 2 studies and shown to be safe, well tolerated, and 
highly effective in the treatment of vulvovaginal infections caused by Candida species.  For example, in 
a Phase 2b study in subjects with recurrent VVC (RVVC), subjects in the 12-week VT-1161 treatment 
group (150 mg VT-1161 once daily for 7 days followed by 150 mg VT-1161 once weekly for 11 weeks) 
showed a 4.8% recurrence rate through Week 48 compared with a 52% recurrence rate in the placebo 
group in the intent-to-treat analysis.  
RVVC, defined as 3 or more acute VVC episodes over a 12-month period, is experienced by 5 to 
7 million women each year in the US.  Candida albicans is the leading cause of recurrent vulvovaginal 
yeast infections in the United States.  However, there has been an increasing trend in the number of 
vaginal yeast infections attributable to non-albicans species such as C. glabrata and C. tropicalis.  In 
addition to the use of topical products to treat VVC, the majority of the women visiting healthcare 
professionals receive fluconazole for the treatment of each acute episode.  A smaller percentage are 
prescribed a fluconazole maintenance regimen although fluconazole is not currently approved for the 
treatment of RVVC.  Since some of the C. albicans and the majority of non-albicans isolates are resistant 
to fluconazole, the management of RVVC has become even more challenging.  
In both nonclinical studies and clinical trials conducted to date, VT-1161 has demonstrated a favorable 
safety and tolerability profile, with no discernable adverse effect on liver function.  In reproductive 
toxicity studies in pregnant rats or rabbits, VT-1161 was not teratogenic at any exposure studied.  In a 
recent CYP3A4 drug-drug interaction study utilizing midazolam as the substrate, no clinically significant 
inhibition and only weak induction of midazolam metabolism was observed.  These data are favorable 
when compared to other oral antifungal agents such as fluconazole.  
 


CONFIDENTIAL 
 
Mycovia Pharmaceuticals, Inc. 
 
Product: VT-1161  
Protocol Synopsis 
Protocol VMT-VT-1161-CL-011 
IND 111675 
Ver. 5 U.S. Only, 01 October 2019 
 
6 
Objectives: 
Primary:  
• 
To evaluate the efficacy of oral VT-1161 in the treatment of RVVC through Week 48. 
Secondary:  
• 
To evaluate the safety and tolerability of oral VT-1161 in the treatment of RVVC through 
Week 48. 
• 
To evaluate the impact of oral VT-1161 treatment on patient reported outcomes through 
Week 48. 
Methodology: 
Study Design: 
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.  
The study will evaluate the efficacy and safety of oral VT-1161 capsules in the treatment of subjects with 
RVVC.  The impact of oral VT-1161 treatment will also be evaluated using data collected from patient 
reported outcome assessments. 
Subjects must have a history of RVVC, defined as at least 3 episodes of acute VVC in the past 12 months, 
as described below: 
• 
Subjects must have an acute VVC episode at the time of Screening, with a documented 
positive potassium hydroxide (KOH) or Gram stain performed at the investigative site 
• 
Subjects must also have had 2 or more additional episodes of acute VVC in the past 
12 months, with at least 1 of the episodes documented by a positive confirmatory laboratory 
test (i.e., culture, PCR, Affirm test, KOH test, Gram stain, a documented Papanicolaou (Pap) 
test, or other approved diagnostic tests) 
The study consists of two Phases: 1) an open-label Induction Phase for the treatment of the acute VVC 
episode with 3 sequential 150 mg oral doses (every 72 hours) of fluconazole, and 2) a Maintenance Phase 
in which subjects will be randomly assigned to receive VT-1161 or placebo for 7 daily doses followed 
by 11 weekly doses and will then enter a 36-week follow-up period. 
Once subjects have provided informed consent or assent (for those ages 12 to 17), the investigational site 
will evaluate all subjects by completing a review of pertinent medical history, obtaining vital signs, 
weight and height, electrocardiogram (ECG) and laboratory tests, reviewing clinical signs and symptoms 
of vulvovaginitis, performing a complete physical examination including speculum examination of the 
vagina, performing a KOH wet mount test or Gram stain from a vaginal smear to confirm the presence 
of yeast, and collecting vaginal swabs to establish a baseline culture for identification of fungal species.  
Patient reported outcome surveys (SF-36, EQ-5D-3L or EQ-5D-Y (for ages 12 to 17), WPAI:SHP, 
PHQ-9) for all regions and questions regarding their RVVC history (US only) will also be administered.  
Eligible subjects must have an acute VVC episode at Screening, defined as a total signs and symptoms 
score of ≥3 and a positive local KOH wet mount preparation or Gram stain from a vaginal smear 
revealing filamentous hyphae/pseudohyphae and/or budding yeast cells, and must meet other initial entry 
criteria.  Once eligibility is confirmed, subjects will enter the Induction Phase.  During the Induction 
Phase, the presenting acute VVC infection will be treated with 3 sequential 150 mg oral doses (every 
72 hours) of fluconazole.  Subjects will return approximately 14 days after the first dose of fluconazole 


CONFIDENTIAL 
 
Mycovia Pharmaceuticals, Inc. 
 
Product: VT-1161  
Protocol Synopsis 
Protocol VMT-VT-1161-CL-011 
IND 111675 
Ver. 5 U.S. Only, 01 October 2019 
 
7 
for evaluation. If the clinical signs and symptoms of the acute VVC infection have resolved (defined by 
a signs and symptoms score of <3), they will be randomized in a 2:1 ratio to receive either VT-1161 or 
a matching placebo regimen.  Day 1 (Baseline) is defined as the first day of investigational medicinal 
product (IMP) administration and subsequent study days are defined by the number of consecutive days 
thereafter. If the acute VVC has not resolved (defined by a signs and symptoms score of ≥3), the subject 
will be considered a screen failure and encouraged to see their physician for follow-up care. 
Study Duration: 
The planned study duration is expected to be approximately 26 months from screening of the first subject 
until last follow-up of the last subject. 
Subject Participation: 
The duration of individual subject participation will be approximately 50 weeks, including the 2-week 
Induction Phase.  See Table 1 for the Schedule of Assessments and Procedures which will be performed. 
After Screening, subjects will return to the clinic on Day 1 (Baseline), the start of the Maintenance Phase. 
Subjects will then have visits on Day 14 (±2 days), Weeks 6 (±7 days), 12 (±14 days), 18 (±14 days), 
24 (±14 days), 30 (±14 days), 36 (±14 days), 42 (±14 days) and 48 (±14 days) (end of study [EOS]). 
Subjects who return to the clinic with a recurrent acute VVC episode should be evaluated as per the 
unscheduled visit noted in the Schedule of Assessment and Procedures.  
Scoring of Vulvovaginal Signs and Symptoms: 
Vulvovaginal signs and symptoms will be evaluated at Screening and at each subsequent study visit. 
Each of the following vulvovaginal signs and symptoms will be scored and the individual scores 
combined, for a maximum score of 18 using the following scale: 
a. Signs: erythema, edema, and excoriation 
b. Symptoms: itching, burning, and irritation 
 
Scoring Scale: Each score should be graded on a scale of 0 to 3 as follows: 
0 = none (complete absence of any sign or symptom) 
1 = mild (slight) 
2 = moderate (present) 
3 = severe (marked, intense) 
Mycology Assessment: 
A local mycological assessment using KOH wet mount followed by microscopy or Gram stain will be 
evaluated at the Screening and at any study visit where a recurrent acute VVC episode is suspected. The 
investigative site is to use the same local mycology test (KOH or Gram stain) consistently for all subjects 
throughout the study.  In addition, a vaginal swab for culture testing will be obtained and sent to the 
central mycology laboratory at the Screening and each subsequent study visit. 
Plasma Pharmacokinetics: 
Blood samples for assay of VT-1161 plasma concentrations will be collected from subjects at Baseline, 
Day 14, and Weeks 12, 24, 36, 48 and unscheduled visits. 


CONFIDENTIAL 
 
Mycovia Pharmaceuticals, Inc. 
 
Product: VT-1161  
Protocol Synopsis 
Protocol VMT-VT-1161-CL-011 
IND 111675 
Ver. 5 U.S. Only, 01 October 2019 
 
8 
Safety: 
Subject safety will be monitored by collection of adverse events (AEs), changes in vital signs, physical 
and vaginal exam parameters, ECGs, and safety laboratory parameters, including pregnancy tests for 
women of childbearing potential (WOCBP). 
Concomitant Medications: 
The following prescription and over-the-counter drug products are prohibited during the study and will 
be considered a protocol deviation: 
1. Topical or oral antifungal drugs (with the exception of fluconazole when prescribed by the 
Investigator to treat a subject with a recurrent VVC episode; refer to Section 8.1.12 on treatment 
options if fluconazole is ineffective).  
2. Topical products applied to the vulva or vagina (e.g. antibiotic, antitrichomonal, corticosteroids, or 
anti-inflammatory agents). 
3. Oral antibacterial or antitrichomonal agents for the treatment of bacterial vaginosis, trichomonas, or 
other concomitant (urogenital) infection unless prescribed by the Investigator. 
4. Oral or injectable corticosteroid or immunosuppressive drugs for the duration of the study. Use of 
topical (no vulvar or vaginal steroids), inhaled, ophthalmic, collunarium/nasal, or intraarticular and 
intralesional steroids is permitted. 
5. Drugs with a narrow therapeutic index that are metabolized by CYP3A4 and sensitive to induction 
of CYP3A4 (carbamazepine, cyclosporine, fentanyl, quinidine, sirolimus and tacrolimus). 
6. Vaginal douches or benzalkonium chloride disinfectant during the study. 
Number of Subjects (Planned):  
Approximately 600 screened and 300 randomized subjects are planned for this study. Assuming a 20% 
discontinuation rate for the duration of the study, approximately 240 subjects are expected to complete 
the study. 
Criteria for Inclusion and Exclusion: 
Criteria for Inclusion: 
1) Subjects must be generally healthy, post-menarchal, non-pregnant females 12 years of age and older 
as of Screening. 
2) Subjects must have a history of recurrent VVC as defined by three (3) or more episodes of acute 
VVC in the past 12 months, including the episode confirmed at Screening, with at least one episode 
(not including the current episode) documented by a positive culture, PCR, Affirm test, KOH test, 
Gram stain or a documented Pap test in the prior 12 months revealing filamentous 
hyphae/pseudohyphae and/or budding yeast cells, or other approved diagnostic tests. 
3) Subjects must have an acute VVC episode at Screening, defined as: 
a. a total signs and symptoms score of ≥3 and  
b. a positive KOH wet mount preparation or Gram stain from a vaginal smear revealing 
filamentous hyphae/pseudohyphae and/or budding yeast cells. 
4) Subjects must have a composite vulvovaginal signs and symptoms score of <3 at the Baseline (Day 
1) Visit. 
5) Subjects must have a documented Pap test at Screening or within the timeline per current standard 
of care guidelines for the appropriate age requirement.  Results must be either “negative for 


CONFIDENTIAL 
 
Mycovia Pharmaceuticals, Inc. 
 
Product: VT-1161  
Protocol Synopsis 
Protocol VMT-VT-1161-CL-011 
IND 111675 
Ver. 5 U.S. Only, 01 October 2019 
 
9 
intraepithelial lesion or malignancy” or “ASCUS-atypical squamous cells of undetermined 
significance” (not applicable to subjects with a history of total hysterectomy). 
6) Subjects must be suitable candidates for oral therapy and be able to swallow capsules intact.  
7) Subjects must be willing and able to provide written informed consent or assent (for those ages 12 
to 17) and authorization for use of protected health information. 
8) Subjects must be willing and able to comply with protocol requirements, instructions, and protocol-
stated restrictions and be likely to complete the study as planned. 
9) Subjects of non-childbearing potential must meet the requirements defined below: 
a. Pre-menopausal with documentation of surgical sterilization (i.e., hysterectomy, bilateral tubal 
ligation, bilateral oophorectomy, or bilateral salpingectomy) at least 3 months prior to 
Screening.  
b. Post-menopausal defined as amenorrhea for at least 12 months following cessation of all 
exogenous hormonal treatments at Screening. 
10) Subjects of childbearing potential (includes ages 12-17) must use 1 of the following methods of 
contraception during the study through Week 48: 
OPTION 1 – Highly effective methods that can be used alone: 
i. Copper intrauterine device 
ii. Levonorgestrel-releasing intrauterine system 
iii. Progestin implant 
iv. Monogamous with a vasectomized male partner 
v. Abstinencea 
OPTION 2 – Acceptable first and second barrier methods to be used in combination: 
FIRST (Hormonal Contraception)b 
1. Estrogen & progestin oral contraceptives, transdermal patch or 
vaginal ring. 
2. Progestin only oral contraceptives or injection 
SECOND (Barrier Method) 
1. Diaphragm (with spermicide) 
2. Cervical cap (with spermicide) 
3. Male condom (with or without spermicide) 
 
In addition to OPTIONS 1 and 2, subjects of childbearing potential (includes ages 12-17) may also 
use 1 of the following methods of contraception after completing the Induction Phase on Study Day 
1 through Week 48: 
OPTION 3 (Day 1 – Week 48)c – Acceptable first and second barrier methods to be 
used in combination: 
FIRST (Barrier Method) 
1. Diaphragm (with spermicide) 
2. Cervical cap (with spermicide) 
SECOND (Barrier Method) 
1. Male condom (with or without spermicide) 
a Sexual abstinence is defined as refraining from heterosexual intercourse during the entire study period 
and where this is the usual life style of the subject. Periodic abstinence (calendar, symptothermal, 
postovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method are not considered to be acceptable methods of contraception. 
b Subjects who started taking a hormonal contraceptive less than 3 months prior to the first dose of 


CONFIDENTIAL 
 
Mycovia Pharmaceuticals, Inc. 
 
Product: VT-1161  
Protocol Synopsis 
Protocol VMT-VT-1161-CL-011 
IND 111675 
Ver. 5 U.S. Only, 01 October 2019 
 
10 
fluconazole must agree to use a double-barrier method (i.e. diaphragm plus spermicide or condom) 
through 3 months after starting the hormonal contraceptive.   
cBecause of the teratogenic risk associated with repeat dosing of fluconazole, OPTION 3 contraceptive 
methods cannot be used during Screening and the Induction Phase of the study [from Screening until 
Baseline (Day 1) of the study].   
 
Criteria for Exclusion: 
1) Subjects must not have the presence of concomitant vulvovaginitis caused by other pathogens (e.g., 
bacterial vaginosis, Trichomonas vaginalis, Chlamydia trachomatis, or Neisseria gonorrhoeae) at 
Screening visit and at the Day 1 visit if an infection is suspected. 
2) Subjects must not have an active HPV infection as evidenced by visible condylomas on 
vulvovaginal examination at Screening and Day 1 visits. 
3) Subjects must not have the presence or a history of another vaginal or vulvar condition(s) that in the 
Investigator’s opinion would confound the interpretation of clinical response. 
4) Subjects must not have a history of cervical cancer.  
5) Subjects must not use any systemic (e.g., oral or injectable) corticosteroid therapy during the study 
or within 30 days prior to Screening, nor use of topical vulvar or vaginal steroids during the study 
or within 7 days prior to Screening. However, use of topical (no vulvar or vaginal steroids), inhaled, 
ophthalmic, collunarium/nasal, intraarticular and intralesional steroids is permitted.  
6) Subjects must not use any systemic (e.g., oral or injectable) or topical (applied to the vulva or vaginal 
area) antifungal, antibacterial, or antitrichomonal drugs or vaginal douches during the study (unless 
prescribed by the Investigator) or within 7 days prior to Screening. 
7) Subjects must not be using drugs with a narrow therapeutic index that are metabolized by CYP3A4 
and sensitive to induction of CYP3A4 during the study (carbamazepine, cyclosporine, fentanyl, 
quinidine, sirolimus and tacrolimus). 
8) Subjects must not use any vaginal estrogen replacement therapy, ospemifene, Vitamin E gel 
capsules (vaginally) or lubricants within 7 days prior to Screening. 
9) Subjects must not have a condition that would require treatment during the study with concomitant 
topical (applied to vulva and vagina) or systemic antimicrobial therapy for any reason. 
10) Subjects must not have received an immunosuppressive medication (e.g. cyclosporine, tacrolimus, 
methotrexate, 6-mercaptopurine, mycophenolate, etc.), or radiation therapy within 3 months prior 
to Screening or have a medical condition where it would be likely that the subject may need to use 
these therapies during the study. 
11) Subjects must not have evidence of any clinically significant major organ disease or current 
clinically significant infection or any other conditions (with the exception of acute VVC) that may 
affect the clinical assessment of RVVC per investigator judgment. 
12) Subjects must not have any comorbid condition that in the opinion of the Investigator would 
preclude the safe participation of the subject in the study or would prevent the subject from meeting 
the study requirements. 
13) Subjects must not have any condition that in the opinion of the investigator could impact drug 
absorption (e.g. gastrectomy, Roux-en-Y gastric bypass surgery, gastric bands or staples, etc.), 
distribution, or elimination. 
14) Subjects must not have poorly controlled diabetes mellitus (HbA1c ≥8.5% at Screening).  
15) Subjects must not have moderate or severe hepatic and/or renal disease (defined in Appendix B and 
Appendix C). 


CONFIDENTIAL 
 
Mycovia Pharmaceuticals, Inc. 
 
Product: VT-1161  
Protocol Synopsis 
Protocol VMT-VT-1161-CL-011 
IND 111675 
Ver. 5 U.S. Only, 01 October 2019 
 
11 
16) Subjects must not have a laboratory abnormality that in the opinion of the Investigator is likely to 
introduce additional risk to the subject or might interfere with data interpretation. The specific 
findings listed below are excluded at Screening (a single repeat laboratory evaluation is allowed for 
eligibility determination, except for HIV, HbsAg and antibodies to hepatitis C virus): 
a. Serum alanine aminotransferase (ALT) ≥2.0x the upper limit of normal (ULN) of the reference 
range.  
b. Serum aspartate aminotransferase (AST) ≥2.0x the ULN of the reference range.  
c. Serum total bilirubin ≥1.5x the ULN of the reference range, unless the elevation is consistent 
with Gilbert’s Syndrome.  
d. Electrocardiographic QTc interval >470 msec as corrected by the Fridericia formula, or any 
clinically significant electrocardiographic abnormality. 
e. Positive test for antibodies to human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HbsAg), or antibodies to hepatitis C virus. 
17) Subjects of childbearing potential must not be pregnant (positive pregnancy test at Screening), 
lactating, or planning to become pregnant during the study period. 
18) Subjects must not have planned surgery or other medical procedures that in the Investigator’s 
opinion would impact compliance with the protocol. 
19) Subjects must not have active substance abuse (e.g., drugs of any kind, including alcohol) or any 
other medical, psychiatric or social condition that in the Investigator’s opinion would preclude 
compliance with the protocol.   
20) Subjects must not have received VT-1161 study medication in a previous study. 
21) Subjects must not have received any IMP in a clinical trial within 5 half-lives of that IMP prior to 
Screening (if unknown, 60 days prior to Screening). 
22) Subjects must not have a known history of intolerance or hypersensitivity to azole antifungal drugs 
(e.g., fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole), or any excipients 
of the capsule formulation. 
Induction Phase Treatment: Fluconazole 150 mg tablets or capsules 
Dose and Mode of Administration:  
Oral administration of 3 sequential doses (every 72 hours) of fluconazole 150 mg starting at Screening 
(Day -14). 
Maintenance Phase Test Product: VT-1161 150 mg capsules 
Dose and Mode of Administration:  
Oral administration of VT-1161 within 30 minutes after ingestion of the subject’s main meal of the day 
(as determined by the subject and kept consistent throughout the duration of the study).  Approximately 
240 mL (approx. 8oz) of water is to be consumed with each dose of IMP. 
Starting at Baseline (Day 1), loading doses of 150 mg (1 capsule) once daily for 7 days, followed by 
doses of 150 mg (1 capsule) once weekly for 11 weeks. 
Duration of Administration: 12 weeks 
 
 
 


CONFIDENTIAL 
 
Mycovia Pharmaceuticals, Inc. 
 
Product: VT-1161  
Protocol Synopsis 
Protocol VMT-VT-1161-CL-011 
IND 111675 
Ver. 5 U.S. Only, 01 October 2019 
 
12 
Maintenance Phase Reference Product: Matching Placebo capsules 
Dose and Mode of Administration:  
Oral administration of placebo within 30 minutes after ingestion of the subject’s main meal of the day 
(as determined by the subject and kept consistent throughout the duration of the study).  Approximately 
240 mL (approx. 8oz) of water is to be consumed with each dose of IMP. 
Starting at Baseline (Day 1), loading doses of placebo once daily for 7 days, followed by doses of placebo 
(1 capsule) once weekly for 11 weeks. 
Duration of Administration: 12 weeks 
Study Populations: 
Intent-to-Treat (ITT) Population: All randomized subjects. 
Safety Population: All randomized subjects who received at least 1 dose of IMP.  
Per Protocol Population (PP): All randomized subjects who had the following:  
• 
Had no deviations to inclusion/exclusion criteria that could impact treatment outcome. 
• 
Were compliant with the assigned study treatment, defined as ≥80% compliance during the daily 
dosing phase and ≥50% compliance during the weekly dosing phase. 
• 
Had the Week 48 visit completed within the acceptable time window (±14 days). 
• 
Had no major protocol violations that would impact treatment outcome. 
Modified ITT: All randomized subjects who had the following: 
• 
Positive KOH or Gram stain at Screening. 
• 
Positive culture at Screening. 
• 
Negative culture at Baseline. 
Criteria for Evaluation:  
Efficacy: 
Clinical and mycological assessments will be conducted as outlined in Table 1. 
Schedule 
of 
Assessments and Procedures. 
All efficacy analyses will be performed on the ITT, PP, and mITT Populations. 
The primary efficacy outcome measure is the proportion of subjects with one or more culture-verified 
acute VVC episodes during the Maintenance Phase (post-randomization through Week 48) in the ITT 
population. An acute VVC episode during the Maintenance Phase (considered a recurrent episode) is 
defined as a positive culture for Candida species and a clinical signs and symptoms score of ≥3.  
The key secondary efficacy outcome measures include the following: 
a. Time to first recurrence of a culture-verified acute VVC episode with signs and symptoms score ≥3 
during the Maintenance Phase. 
b. The proportion of subjects with at least one positive culture for Candida during the Maintenance 
Phase. 


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c. The proportion of subjects with at least one culture-verified acute VVC episode with signs and 
symptoms of ≥3 post randomization through Week 24. 
d. Change from Screening through Week 48 in the SF-36 mental component score (MCS). 
e. Change from Screening through Week 48 in the SF-36 patient reported outcome survey total score. 
 
Safety: 
All safety analyses will be performed on the Safety Population.  AEs will be collected throughout the 
study.  Physical and vaginal examination findings and vital signs will be recorded at Screening and 
throughout the study per Table 1. 
Schedule 
of 
Assessments 
and 
Procedures.  
ECGs and safety laboratory tests (hematology, chemistry, and urinalysis) will be obtained throughout 
the study. All concomitant medications taken during the period from 30 days prior to Screening through 
the Week 48 (EOS) visit will be recorded in the case report form (CRF).  Pertinent and all major medical 
conditions will be recorded on the Medical History CRF.  
Subject who want to discontinue from the study should be encouraged to remain in the study for all 
remaining visits through Week 48 for safety and efficacy assessments.  All subjects who discontinue 
early from the study should have all EOS procedures performed on the day of discontinuation.  
Statistical Methods and Data Analysis:  
A statistical analysis plan will be finalized before 50% of subjects are enrolled. 
Efficacy Analysis: 
The primary statistical objective of this study is to determine if there are differences in the proportions 
of subjects with one or more episodes of culture-verified acute VVC in those receiving VT-1161 
compared to those receiving placebo during the Maintenance Phase. 
A sample size of 68 active subjects and 34 placebo subjects provides at least 95% power to detect a 
treatment difference of 35% between the VT-1161 treatment group and the placebo treatment group in 
percentage of subjects with at least one or more culture-verified acute VVC episodes during the 
Maintenance Phase (post randomization through Week 48).   (PASS 2008: Fisher’s exact test, two-sided 
alpha=0.05, and assuming 50% of placebo subjects have recurrence). Based on an estimated 20 % 
discontinuation rate, approximately 128 total subjects (85 active, 43 placebo) will be necessary for 
randomization to arrive at approximately 102 evaluable subjects.    
Safety Analysis: 
AEs will be coded using the Medical Dictionary for Regulatory Activities® dictionary.  The number and 
percentage of subjects reporting treatment-emergent AEs will be tabulated by system organ class, 
preferred term, and greatest severity with a breakdown by treatment group.  Mean changes from pre-
treatment in vital signs, ECG, and clinical laboratory variables will be summarized by treatment group. 
Pharmacokinetics: 
No formal statistical hypothesis testing related to pharmacokinetics will be conducted.  VT-1161 
concentrations will be presented by visit with descriptive statistics.  The pharmacokinetic data will be 


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Protocol VMT-VT-1161-CL-011 
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used in a cross-population pharmacokinetic analysis that will be presented in a separate report. 
Patient Reported Outcomes:  
The SF-36, EQ-5D-3L or EQ-5D-Y (for ages 12 to 17), WPAI:SHP, and PHQ-9 patient reported outcome 
surveys will be administered at Screening, Week 24 (EOT) and Week 48 (EOS) for all regions. At 
Screening, subjects will also be required to answer questions regarding their RVVC history (US only). 




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a. 
All medication taken 30 days prior to Screening and all non-pharmacologic treatments received 72 hours prior to Screening will be recorded through the EOS 
visit. 
b. SF-36, EQ-5D-3L or EQ-5D-Y (for ages 12 to 17), WPAI:SHP, and PHQ-9 patient reported outcome surveys. 
c. 
Weight only. 
d. Vital signs include sitting heart rate, blood pressure, temperature, and respiratory rate.  
e. 
Limited physical examination, i.e. vaginal speculum examination plus a symptom directed physical examination. 
f. 
PK Samples should be collected before the weekly dosing of study drug (placebo/VT-1161). 
g. Serum chemistry (creatinine, BUN, AST, ALT, alkaline phosphatase, total bilirubin, conjugated bilirubin, albumin, total protein, total carbon dioxide, glucose, 
sodium, potassium, chloride, calcium, and phosphorus, creatine phosphokinase [CK], cholesterol, and triglycerides). Testing for HbA1c is performed at 
Screening. Cultures to test for Chlamydia trachomatis and Neisseria gonorrhoeae will be taken at Screening and sent to the central lab. Testing for bacterial 
vaginosis will be done locally at Screening. An OSOM® Rapid test or similar test will be performed for Trichomonas vaginalis locally at Screening. 
h. For WOCBP, a local lab urine pregnancy test will be performed at every study visit.  A central lab serum pregnancy test will also be performed at Screening, 
Baseline, and Weeks 12, 24, and 48. 
i. 
IMP is to be administered within 30 minutes after the subject’s main meal of the day (as determined by the subject) at approximately the same time of the day 
consistently throughout the study. Approximately 240 mL (approx. 8 oz.) of water is to be consumed with each dose of IMP. Remind subject to bring IMP to 
each visit to ensure compliance.  
j. 
All procedures listed are to be completed only for unscheduled visits where a recurrent VVC episode is suspected. If the unscheduled visit is for repeat 
procedures (i.e., ECG, safety labs, etc.), only those specific procedures need to be performed, along with collection of any changes in medical treatments or 
medications and collection of any AEs. 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .................................................................................................2 
PROTOCOL SYNOPSIS ................................................................................................................5 
TABLE OF CONTENTS ...............................................................................................................17 
LIST OF TABLES .........................................................................................................................21 
LIST OF APPENDICES ................................................................................................................22 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..................................................23 
1 
INTRODUCTION ......................................................................................................25 
1.1 
Background Information .............................................................................................25 
1.1.1 
Vulvovaginal Candidiasis ...........................................................................................25 
1.2 
VT-1161 ......................................................................................................................28 
1.2.1 
Non-Clinical Pharmacology .......................................................................................29 
1.2.2 
Clinical Studies ...........................................................................................................32 
1.3 
Study Rationale ...........................................................................................................41 
1.3.1 
Rationale for Induction Phase Treatment ...................................................................41 
1.3.2 
Dosing Regimen for VT-1161 and Matching Placebo ...............................................41 
1.4 
Potential Risks and Benefits of Participating in the Study .........................................42 
2 
OBJECTIVES .............................................................................................................43 
3 
STUDY ENDPOINTS ................................................................................................44 
4 
STUDY DESIGN .......................................................................................................45 
4.1 
Overall Study Design ..................................................................................................45 
4.2 
Treatment Arms and Duration of Study .....................................................................46 
4.3 
Number of Subjects ....................................................................................................46 
4.4 
Design Justification ....................................................................................................46 
4.4.1 
Justification for Inclusion of Adolescents in the Study ..............................................48 
5 
SELECTION OF STUDY POPULATION ................................................................50 
5.1 
Inclusion Criteria ........................................................................................................50 
5.2 
Exclusion Criteria .......................................................................................................52 
6 
INVESTIGATIONAL MEDICINAL PRODUCT .....................................................55 
6.1 
Fluconazole .................................................................................................................55 


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6.2 
Description of Investigational Medicinal Product ......................................................55 
6.2.1 
VT-1161 ......................................................................................................................55 
6.2.2 
Placebo ........................................................................................................................55 
6.3 
Investigational Medicinal Product Labeling and Packaging ......................................55 
6.4 
Investigational Medicinal Product Storage Conditions ..............................................55 
6.5 
Receipt of Supplies/Handling/Storage ........................................................................56 
6.6 
Investigational Medicinal Product Accountability .....................................................56 
6.7 
Investigational Medicinal Product Return ..................................................................56 
7 
TREATMENT OF SUBJECTS ..................................................................................57 
7.1 
Investigational Medicinal Product Administration and Dosing Schedule ..................57 
7.1.1 
Induction Phase (Screening to Day 1 Pre-Randomization) ........................................57 
7.1.2 
Maintenance Phase (Day 1 Post Randomization to Week 12) ...................................57 
7.2 
Method of Assigning Subjects to Treatment Groups .................................................58 
7.3 
Dose Interruptions and Modifications ........................................................................58 
7.4 
Prohibited and Permitted Medications/Non-Medications ..........................................58 
7.4.1 
Prohibited Medications/Non-Medications ..................................................................58 
7.4.2 
Permitted Medications/Non-Medications ...................................................................59 
7.5 
Treatment Compliance ................................................................................................59 
7.6 
Replacement of Study Subjects ..................................................................................59 
7.7 
Randomization and Blinding ......................................................................................60 
7.8 
Conditions for Breaking the Blind ..............................................................................60 
7.9 
Treatment After the End of the Study .........................................................................61 
8 
STUDY PROCEDURES ............................................................................................62 
8.1 
Assessments and Procedures ......................................................................................62 
8.1.1 
Screening Assessments and Procedures (Day -14 ±2 Days) ......................................65 
8.1.2 
Baseline (Day 1) Assessments and Procedures ..........................................................67 
8.1.3 
Day 14 (±2 Days) Assessments and Procedures .........................................................68 
8.1.4 
Week 6 (±7 Days) Assessments and Procedures ........................................................69 
8.1.5 
Week 12 (±14 Days) Assessments and Procedures ....................................................70 
8.1.6 
Week 18 (±14 Days) Assessments and Procedures ....................................................71 
8.1.7 
Week 24 (±14 Days) Assessments and Procedures ....................................................72 


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8.1.8 
Week 30 (±14 Days) Assessments and Procedures ....................................................73 
8.1.9 
Week 36 (±14 Days) Assessments and Procedures ....................................................74 
8.1.10 
Week 42 (±14 Days) Assessments and Procedures ....................................................75 
8.1.11 
Week 48 (±14 Days) Assessments and Procedures (End of Study) ...........................76 
8.1.12 
Unscheduled Visit Assessment and Procedures .........................................................77 
8.2 
Exercise .......................................................................................................................78 
9 
SAFETY ASSESSMENTS ........................................................................................79 
9.1 
Safety Tests and Assessments ....................................................................................79 
9.1.1 
Height and Weight ......................................................................................................79 
9.1.2 
Vital Signs ..................................................................................................................79 
9.1.3 
Physical Examination .................................................................................................79 
9.1.4 
Electrocardiograms .....................................................................................................79 
9.1.5 
Laboratory Determinations .........................................................................................80 
9.1.6 
KOH Wet Mount Tests or Gram Stains and Fungal Cultures ....................................81 
9.1.7 
Vulvovaginitis Clinical Assessment ...........................................................................82 
9.2 
Adverse Event Reporting ............................................................................................82 
9.2.1 
Definition of Adverse Events .....................................................................................82 
9.2.2 
Definition of a Serious Adverse Event .......................................................................83 
9.2.3 
Recording of Adverse Events .....................................................................................85 
9.2.4 
Severity of Adverse Events ........................................................................................85 
9.2.5 
Causality Assessment .................................................................................................86 
9.2.6 
Action Taken Following Adverse Events ...................................................................88 
9.2.7 
Outcome of Adverse Events .......................................................................................88 
9.2.8 
Other Reportable Events .............................................................................................89 
10 
PHARMACOKINETIC ASSESSMENTS .................................................................90 
10.1 
Sample Collection and Handling ................................................................................90 
10.2 
Analytical Procedures .................................................................................................90 
10.3 
Pharmacokinetic Parameters .......................................................................................90 
11 
STUDY TERMINATION AND SUBJECT DISCONTINUATION .........................91 
11.1 
Screening/Baseline Failures........................................................................................91 
11.2 
Subject Withdrawal or Premature Discontinuation from the Study ...........................91 


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11.3 
Subject and Study Completion ...................................................................................92 
11.4 
Premature Study Termination .....................................................................................93 
12 
STATISTICAL ANALYSIS ......................................................................................94 
12.1 
Determination of Sample Size ....................................................................................94 
12.2 
Analysis Populations ..................................................................................................95 
12.3 
Demographic and Baseline Characteristic Analyses ..................................................96 
12.4 
Efficacy Analyses .......................................................................................................96 
12.5 
Safety Analyses ..........................................................................................................97 
12.6 
Pharmacokinetic Analyses ..........................................................................................99 
12.7 
Patient Reported Outcome ..........................................................................................99 
13 
CLINICAL STUDY ADMINISTRATION/STUDY GOVERNANCE 
CONSIDERATIONS ................................................................................................100 
13.1 
Ethical Conduct of Study ..........................................................................................100 
13.2 
Informed Consent and Assent ...................................................................................100 
13.3 
Quality Control (Study Monitoring) .........................................................................100 
13.4 
Quality Assurance .....................................................................................................101 
13.5 
Compliance with Standards of Medical Research/ Deviations .................................101 
13.6 
Data Management .....................................................................................................102 
13.7 
Study and Site Closure..............................................................................................103 
13.8 
Records Retention .....................................................................................................103 
13.9 
Disclosure of Data ....................................................................................................104 
13.10 
Financial Disclosure .................................................................................................104 
13.11 
Publication Policy .....................................................................................................105 
13.12 
Confidentiality ..........................................................................................................105 
13.12.1 
Data ...........................................................................................................................105 
13.12.2 
Subject Anonymity ...................................................................................................105 
14 
REFERENCES .........................................................................................................106 


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LIST OF TABLES  
Table 1. 
Schedule of Assessments and Procedures ..................................................................15 
Table 2. 
Oral Agents Commonly Used to Treat VVC ..............................................................28 
Table 3. 
VT-1161 Antifungal MIC50 or Range (μg/mL) ..........................................................29 
 
 


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LIST OF APPENDICES 
Appendix A.   Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity Table 
(Draft November 2007) 
Appendix B.   Grading of Renal Impairment 
Appendix C.   Child-Pugh Classification of Hepatic Impairment 
Appendix D.   SF-36TM Quality of Life Questionnaire 
Appendix E.   EQ-5D-3L Health Status Questionnaire 
Appendix F.   EQ-5D-Y Health Status Questionnaire 
Appendix G.   Work Productivity and Activity Impairment: Specific Health Problems 
Questionnaire 
Appendix H   Patient Health Questionnaire- 9 
Appendix I. 
RVVC History Questionnaire (Version 01) – US Only 
Appendix J.   Extension Study – U.S. Only 
Appendix K. Protocol Amendment Summary of Changes 
 
 


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List of Abbreviations and Definition of Terms 
Abbreviation 
Definition or Term 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
CK 
creatine phosphokinase 
Cmax 
maximum plasma concentration 
CRF 
case report form 
CYP51 
lanosterol demethylase 
DDI 
drug-drug interaction 
DMID 
Division of Microbiology and Infectious Diseases 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
end of study 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
HbsAg 
hepatitis B surface antigen 
HIV 
human immunodeficiency virus 
IC50 
half maximal inhibitory concentration 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IRB 
institutional review board  
ITT 
intent-to-treat 
IWRS 
interactive web response system 
KOH 
potassium hydroxide 
MedDRA 
MCS 
Medical Dictionary for Regulatory Activities 
Mental Component Score 
MIC50 
minimum inhibitory concentration 
NOAEL 
no-observed-adverse-effect-level 
OM 
onychomycosis 
Pap 
Papanicolaou 
PK 
pharmacokinetic 
PKE 
pharmacokinetic evaluation 
PP 
per protocol 
QTc 
Fridericia correction 
RVVC 
recurrent vulvovaginal candidiasis 


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Abbreviation 
Definition or Term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
TEAE 
treatment-emergent adverse event 
Tmax 
time to reach maximum plasma concentration 
TOC 
test of cure 
ULN 
upper limit of normal 
VVC 
vulvovaginal candidiasis 
WOCBP 
women of childbearing potential 
WPAI:SHP 
Work Productivity and Activity Impairment: Specific Health Problems 
 


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1 
INTRODUCTION 
Lanosterol demethylase (CYP51), an enzyme essential for fungal growth, catalyzes an early step 
in the biosynthetic pathway of ergosterol, a sterol required for fungal cell membrane formation 
and integrity (Yoshida, 1988).  Inhibition of CYP51 results in the accumulation of 14-methylated 
sterols, some of which are toxic to the fungus.  CYP51 is the molecular target of the class of drugs 
referred to as ‘azole antifungals’.  All currently approved azole drugs contain either an imidazole 
or triazole ring system that binds tightly to the catalytic heme-iron of fungal CYP51 as well as to 
the heme-iron of many off-target mammalian cytochrome P450 enzymes.  This inherent lack of 
selectivity is responsible for many of the side effects associated with the azole antifungals.  
For example, the potent inhibition of one or more human cytochrome P450 metabolizing enzymes 
found in the liver (e.g. CYP3A4, CYP2C9, CYP2C19) or in the adrenal and sex organs 
(e.g. CYP19, CYP17, CYP21), is the basis for azole drug-drug interactions (Bates and Yu, 2003) 
and reproductive warnings (Zarn et al., 2003), respectively.  Additional azole class toxicities that 
are less well understood but may be related to off-target protein interactions include hepatic 
toxicities, skin photosensitivity, and vision impairment.  In the acute care setting, these dose-
limiting side effects prevent attainment of plasma drug levels that might reduce the longstanding 
40% mortality rate attributed to invasive fungal infections.  The safety profile of the class similarly 
limits its use for chronic treatment of non-life-threatening fungal infections, such as 
onychomycosis (OM) and recurrent vulvovaginal candidiasis (VVC).  A safer antifungal drug 
would also improve treatment options for infections seen in otherwise healthy individuals, such as 
OM and recurrent VVC, which require protracted treatment in a patient population where 
significant side-effect risks are unacceptable. 
1.1 
Background Information 
Mucosal candidiasis, also known as thrush, describes a group of yeast-like fungal infections that 
involve the mucous membranes including the mouth, urinary tract and genitals, notably the vagina 
and surrounding skin in women.  Infection is typically caused by Candida albicans, however more 
rare and difficult-to-treat Candida strains such as C. glabrata are becoming more prevalent.  
Mucosal candidiasis occurs more frequently in immunocompromised patients, but may also arise 
in immunocompetent individuals. 
1.1.1 Vulvovaginal Candidiasis 
1.1.1.1 Epidemiology 
Symptoms of vulvovaginitis (inflammation of the vagina and vulva) are common and are among 
of the most frequent reasons for women’s visits to physicians.  Vulvovaginitis is associated with 


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considerable morbidity including genital discomfort, decrease in sexual pleasure, loss of 
productivity, and psychological distress (Eschenbach, 2004).  There are several etiologies for 
vulvovaginitis; candidiasis being the second most common after bacterial vaginitis.  Vulvovaginal 
candidiasis is a common disorder, with nearly 75% of all adult women having had at least one 
“yeast infection” in their lifetime.  Approximately half of these women experience a recurrence, 
with 5 to 8% developing recurrent VVC, defined as 3 or more episodes in one year (Sobel, 2016).  
Estrogen increases the glycogen concentration of the vaginal lining; glycogen is a substrate on 
which C. albicans thrives.  As estrogen levels are significantly lower in both pre-menarcheal and 
post-menopausal females, the incidence of VVC is lower in these populations.  Vulvovaginal 
candidiasis is most common in women aged 25 to 34 years (Foxman et al., 2013). 
1.1.1.2 Pathophysiology 
Vulvovaginal candidiasis occurs when there is an overgrowth of the normal yeast in the vagina.   
Most cases (85% - 95%) are caused by C. albicans, followed by C. glabrata, and infrequently by 
C. parapsilosis, C. tropicalis, and C. krusei.  Vulvovaginitis caused by non-albicans Candida 
species, in particular C. glabrata, is clinically indistinguishable from C. albicans VVC but is more 
resistant to current treatments. 
Candida organisms gain access to the lumen and secretions of the vagina primarily from the 
adjacent perianal region.  Normal anti-candida defense mechanisms allow for long-term 
persistence of Candida as commensal organisms in the vagina without signs or symptoms of 
vaginitis.  Factors predisposing to VVC versus asymptomatic colonization include those attributed 
to the health (immunosuppression, use of antibacterial agents, pregnancy, uncontrolled diabetes 
mellitus) and behavior (frequent intercourse, orogenital sexual activity, use of oral contraceptives 
or estrogen-based hormonal replacement therapy) of the host.  Other dermatologic conditions such 
as psoriasis, lichen planus, and lichen sclerosus also predispose women to VVC (Goncalves et al., 
2016). 
1.1.1.3 Presentation and Diagnosis 
The clinical array of signs and symptoms of VVC include genital pruritus associated with edema, 
an erythematous rash and excoriation of the vulva and surrounding skin, a burning sensation in the 
vagina and vulva, and a vaginal discharge.  These symptoms may persist for days to weeks, and 
may also recur with each menstrual cycle.  Women with VVC typically most commonly present 
with acute pruritus and a vaginal discharge, though neither is specific for candidiasis.  
The discharge may range from being watery to quite thick and “cottage-cheese-like”.  
Common symptoms include vaginal soreness, irritation, vulvar burning, dyspareunia, and external 


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dysuria.  Physical examination typically reveals erythema and edema of the vulva with fissures 
and a pustulopapular rash, vaginal erythema, and a normal cervix.  Symptoms often worsen the 
week prior to menses. 
The diagnosis of VVC requires more than a history and physical examination as symptoms and 
signs, in particular pruritus, are often non-specific.  Diagnosis is made by microscopic examination 
of a 10% potassium hydroxide (KOH) wet mount showing the presence of yeast cells and mycelia 
and the absence of both clue cells (pathognomonic of bacterial infection) and trichomonads.  
The vaginal pH is normal, approximately 4.0.  A vaginal culture should also be performed, 
particularly for women with negative microscopy, as up to 50% of patients with culture-positive 
VVC will have no findings on microscopy (Sobel, 2007); additionally, a culture will precisely 
identify the organism. Papanicolaou (Pap) smears are also not reliable, typically positive in only a 
quarter of patients with VVC. 
As up to 15% of asymptomatic women are colonized with Candida species and are thus culture 
positive, the final diagnosis of VVC requires a comprehensive assessment of clinical findings, 
microscopic examination, and vaginal culture. 
1.1.1.4 Treatment and Outcome 
In general, women who are asymptomatic carriers of Candida do not require treatment.  
Acute VVC in symptomatic women requires individualized treatment, the selected agent and 
duration of therapy being based on whether the VVC is categorized as either: 
• Uncomplicated, defined as having all of the following characteristics: (mild or moderate in 
symptom severity, sporadic in frequency, C. albicans as the infecting organism, in non-
pregnant women with normal immune function), or 
• Complicated, defined as having any one or more of the following characteristics: severe in 
symptom severity, recurrent, a non-C. albicans organism as the infecting agent, abnormal 
immune function, or pregnant (Eschenbach, 2004). 
Women with uncomplicated VVC can be treated with single-dose or short-course treatments, while 
those with complicated VVC require longer-term therapy, at least 5 to 7 days and possibly 
maintenance therapy up to 6 months (Sobel et al., 2004).  Pregnant women, who are at higher risk 
of developing VVC, can only be treated with topical agents because of the potential teratogenic 
effects of azoles when administered systemically.  Topical agents are limited by local side effects, 
especially burning, and are messy to apply; therefore, most patients prefer the oral regimens.  


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However, the systemically administered azoles listed in Table 2 are characterized by systemic 
toxicities and drug-drug-interactions (DDIs) and have poor activity against C. glabrata and 
fluconazole resistant C. albicans. 
Table 2. 
Oral Agents Commonly Used to Treat VVC 
Agent 
Formulation 
Dose and Schedule 
Fluconazole (Diflucan®) 
150 mg tablet (Rx) 
Single dose 
Ketoconazole (Nizoral®) 
200 mg tablet (Rx) 
2 tablets q.d. x5d 
Itraconazole (Sporanox®) 
100 mg tablet (Rx) 
2 tablets q.d. x3d 
Abbreviations: mg = milligrams; d = day; q.d. = once daily; Rx = prescription. 
 
1.1.1.5 Recurrent, Resistant and Non-Albicans VVC 
Up to 20% of women will develop recurrent, resistant, or complicated VVC.  In a study that 
compared a 6-month maintenance weekly fluconazole regimen to placebo in patients with 
recurrent VVC, the time to recurrence increased from 4.0 to 10.2 months, and the cure rate at 
12 months doubled versus placebo from 22% to 43% (Sobel et al., 2004).  However, fewer than 
half of patients remained disease-free after discontinuation of fluconazole which highlights the 
unmet medical need for these patients. 
The prevalence of infection with non-albicans species, in particular C. glabrata, is increasing, 
especially in patients who are immunosuppressed and/or are diabetics; C. glabrata is poorly 
sensitive to current azole antifungal agents. 
1.2 
VT-1161 
VT-1161 is a novel oral antifungal agent with a lower affinity for heme-iron and a greater affinity 
for the fungal lanosterol 14 α-demethylase (CYP51) than the currently available azole drugs.  
As a result, VT-1161 more potently inhibits fungal CYP51 than current azoles and less potently 
inhibits host cytochrome P450 enzymes, resulting in greater cytochrome selectivity.  
These properties should translate to greater efficacy with an improved safety and tolerability 
profile. 
VT-1161 is being developed for the treatment of patients with mucosal or superficial fungal 
infections.  It is formulated with standard excipients known to be chemically stable when combined 
with VT-1161 into capsules for the investigational drug product. 
A detailed description of the non-clinical binding and inhibition, metabolism, microbiology, 
toxicology, safety pharmacology, Phase 1 clinical studies in which 72 subjects were exposed to 


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Product: VT-1161  
 
Protocol VMT-VT-1161-CL-011 
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29 
VT-1161 and Phase 2a proof-of-concept studies, in which 78 subjects were exposed to VT 1161 
can be found in the VT-1161 Investigational Brochure.  In the Phase 2b studies, 378 subjects were 
exposed to VT-1161.  These studies are summarized below.  The following sections provide data 
from non-clinical, Phase 1 and Phase 2 clinical trials supporting the use of VT‑1161 for patients 
with recurrent vulvovaginal candidiasis (RVVC). 
1.2.1 Non-Clinical Pharmacology 
1.2.1.1 Binding and Inhibition 
In vitro pharmacology studies demonstrated that VT-1161 is a potent inhibitor of fungal CYP51 
and binds more than 2200-fold more tightly to fungal CYP51 than to human CYP51.  VT-1161 is 
also highly selective for fungal CYP51 versus key human cytochrome P450 enzymes, non-
cytochrome metalloenzymes, and a broad panel of receptors, ion channels, and transporters. 
1.2.1.2 Metabolism 
VT-1161 was not significantly metabolized when incubated with mouse, rat, dog or human 
hepatocytes.  Only 1 possible metabolite consistent with hydroxylation and glucuronidation of 
VT-1161 was detected in dog hepatocytes.  No additional metabolites were detected in any of the 
4 species. 
1.2.1.3 Microbiology 
VT-1161 was tested against a broad range of Candida clinical isolates and showed potent activity 
(Table 3). It was also active against dermatophytes, including Trichophyton rubrum, 
T. mentagrophytes, and T. tonsurans. 
Table 3. 
VT-1161 Antifungal MIC50 or Range (μg/mL) 
Fungus (# of clinical isolates) 
VT-1161 
Comparator 
C. albicans (N=10) 
≤ 0.03 
Fluconazole 
≤ 0.125 
C. glabrata (N=10) 
0.25 
4 
C. parapsilosis (N=10) 
≤0.03 
0.125 
C. guilliermondii (N=3) 
0.125-0.25 
2-8 
T. mentagrophytes (N=12) 
0.25 
Itraconazole 
0.06 
T. rubrum (N=41) 
0.03 
≤ 0.03 
T. tonsurans (N=5) 
0.06-0.5 
≤0.03-0.06 
Abbreviations: C. = Candida; T. = Trichophyton; MIC50 = minimum inhibitory concentration for 50% of isolates;  
μg = microgram; mL = milliliter; N = number (of clinical isolates). 
 
 
In the Phase 2b RVVC study (VMT-VT-1161-CL-006), 413 clinical isolates were collected from 
subjects at screening visits until the end of the study.  The minimum inhibitory concentration 


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(MIC) ranges for VT-1161 and fluconazole for the isolates collected were; <0.0005 – >0.5 µg/ml 
and <0.06-32 µg/ml, respectively.  The MIC50 values for VT-1161 and fluconazole were 
0.004 µg/ml and 0.125 µg/ml, respectively, and the MIC90 values for VT-1161 and fluconazole 
were 0.06 µg/ml and 4 µg/ml, respectively. These data further demonstrated that VT-1161 has 
potent in vitro activity against the Candida strains obtained from clinical strains.  For all tested 
isolates, the VT-1161 demonstrated MIC50 and MIC90 that were 5 dilutions lower than those 
demonstrated by fluconazole.   
1.2.1.4 Activity in Animal Models of VVC 
VT-1161 was evaluated as an oral treatment of vaginal candidiasis (C. albicans) in a murine model 
(Garvey et al., 2012).  Three days after infection, VT-1161 was dosed orally once daily at 4, 10, 
or 25 mg/kg daily for 4 days.  Fungal burden measured in vaginal lavage fluid was highly 
significantly suppressed (p <0.0002) compared to vehicle-treated controls at all doses and when 
measured 1 or 4 days after treatment ended.  Plasma and vaginal tissue levels of the lowest dose 
of VT-1161 indicated that levels as low as 1 µg/mL resulted in this high degree of efficacy. 
1.2.1.5 Pharmacokinetics 
VT-1161 formulated as a suspension in carboxymethylcellulose was well absorbed and exhibited 
approximately dose linear pharmacokinetics (PK) and a long plasma half-life in both rats and dogs.  
There was no evidence of an effect of gender on the PK of VT-1161 in either rats or dogs.  
VT-1161 accumulated during repeat-dosing in rats and dogs as expected based on the long 
half-life.  VT-1161 was widely distributed into tissues and was mostly excreted in bile and feces 
in the rat.  In vitro plasma protein binding of VT-1161 is high with approximately 99.5% binding 
to rat, dog and human plasma and slightly lower binding in mice (97.6%).  The absolute oral 
bioavailability of the capsule formulation used in Phase 1 studies administered to dogs was 
approximately 40% in the fasted state and approximately 100% when administered in the fed state. 
1.2.1.6 General Toxicology 
Oral VT-1161 was evaluated in general Good Laboratory Practice toxicity studies of up to 
6 months and 9 months in duration in rats and dogs, respectively.  Rats were more sensitive to the 
toxicological effects of oral administration of VT-1161 than dogs.  The no observable adverse 
effect level (NOAEL) for the 6-month rat toxicity study was determined to be 0.5 mg/kg/day, 
based on an increase in incidence and severity of chronic progressive nephropathy, a rat-specific 
finding.  The NOAEL for liver findings was 1.5 mg/kg, based on adverse findings at the high dose 
of 5 mg/kg/day including a minimal increase in serum alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST) and an increase in frequency of minimal focal necrosis and 


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single cell necrosis.  Findings of liver hypertrophy, sub-capsular necrosis and multinucleated 
hepatocytes were considered rat-specific and associated with metabolic adaptation.  Focal necrosis 
may be an exaggerated response to hepatocellular hypertrophy which is known to cause 
sub-capsular and single cell necrosis.  The findings were reversible and similar to the findings 
observed in a prior 28-day study in the rat, providing support that the increased treatment duration 
in the 6-month rat study did not result in new findings of clinical concern.  At the 1.5 mg/kg dose 
at steady state on Day 182, maximum plasma concentration (Cmax) was 4,055 ng/mL and area 
under the curve (AUC0-24) was 81,900 ng·h/mL.  The NOAEL for the 9-month dog study was 
determined to be the high dose of 17 mg/kg/day (Day 273 Cmax was 74,700 ng/mL and AUC0-24 
was 1,675,000 ng·h/mL), as no adverse findings were identified.  The NOAEL in the previous 
28-day dog study was 10 mg/kg/day, based on decreased body weight and mild effects on 
lymphoid organs including increased tingible body macrophages in the mandibular and mesenteric 
lymph nodes and in the Peyer’s patches at 30 mg/kg and higher.  These findings were largely 
reversed during the recovery period. 
1.2.1.7 Genotoxicity 
VT-1161 was found to be negative for genotoxicity in the Ames bacterial reverse mutation assay, 
the chromosome aberration assay in human peripheral lymphocytes and the in vivo bone marrow 
micronucleus assay in rats. 
1.2.1.8 Reproductive Toxicology 
VT-1161 at doses resulting in maternal toxicity (clinical signs and decrease in body weights) did 
not cause alterations in uterine and ovarian parameters in embryofetal development studies in rats 
and rabbits.  Mean fetal body weights were slightly reduced in rabbits in the high dose group as a 
direct result of maternal toxicity and decreased maternal body weights.  No external, visceral and 
skeletal malformations and variations were observed at any of the dose levels evaluated. 
There were no effects on male or female fertility at clinically relevant doses.  
1.2.1.9 Safety Pharmacology 
The effects of VT-1161 on the neurological and pulmonary systems were evaluated in 
Sprague-Dawley rats.  The data demonstrated that there were no VT‑1161-related effects in either 
the neuropharmacological or pulmonary studies in rats given an oral dose of up to 1,000 mg/kg 
VT-1161, the highest dose tested.  


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Evaluation of cardiovascular function in telemetered dogs revealed no treatment-related changes 
in heart rate, blood pressure, cardiac rhythm or morphology, including the QT/QTc (Fridericia 
correction) interval, at oral doses up to 300 mg/kg, the highest dose tested. 
1.2.1.10 In Vitro Cytochrome P450 Interactions 
VT-1161 
inhibited 
cytochrome 
P450 
enzymes 
with 
the 
following 
potencies:  
CYP1A2 (half maximal inhibitory concentration [IC50] ≥10 µM), CYP2B6 (IC50 = 4.0 µM), 
CYP2C8 (IC50 = 1.4 µM), CYP2C9 (IC50 ≥10 µM), CYP2C19 (IC50 = 9.7 µM), 
CYP2D6 (IC50 = 9.4 µM), and CYP3A4 (IC50 = 9.6 µM [testosterone], IC50 ≥10 µM [midazolam]).  
Based on the high plasma protein binding of VT-1161, no clinically significant drug-drug 
interactions are expected. 
1.2.1.11 Effects of VT-1161 on Cardiac Repolarization 
An in vitro human ether-à-go-go related gene study was conducted to assess the potential of 
VT-1161 to inhibit the repolarizing current of the cardiac action potential.  VT-1161 inhibited the 
human ether-à-go-go related gene potassium current by 94.7 ± 1.3% at 6 µM.  The IC50 was 
calculated to be 1.9 µM (Hill coefficient = 2).  However, a cardiovascular safety study in dogs 
showed that VT-1161 was well tolerated and did not induce any deleterious cardiovascular effects 
or affect QT intervals at test doses of up to 300 mg/kg, the highest dose tested, with exposures 
reaching 24,000 ± 6,881 ng/mL at 30 hours post-dose. 
1.2.2 Clinical Studies 
1.2.2.1 Phase 1 Studies 
VT-1161 has been evaluated in 4 Phase 1 trials, a single ascending dose trial, a multiple ascending 
dose trial, a DDI study with midazolam as a sensitive substrate, and an ethnic PK study comparing 
Japanese and Western subjects.  The primary objectives of these studies were to evaluate the safety 
and tolerability, PK and drug interaction potential of VT-1161 in healthy adult subjects.  Detailed 
descriptions of the trials can be found in the VT-1161 Investigational Brochure. 
1.2.2.1.1 Single Dose-Escalation Study (Study VMT-VT-1161-CL-001) 
Study VMT-VT-1161-CL-001 was a single-center, Phase 1, double-blind, randomized, placebo-
controlled, dose-escalating study in healthy adult subjects.  The study was designed to evaluate the 
safety, tolerability, and PK of single oral doses of VT-1161.  Sixty-four subjects (43 males and 
21 females) between 18 and 55 years of age were enrolled in 8 dose groups.  Within each dose-
group, 6 subjects received VT-1161 and 2 subjects received placebo.  In the first 7 cohorts, 
escalating single oral doses (5, 10, 20, 40, 80, 160, and 320 mg) or matching placebo were 


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administered in the fasted state.  An 8th cohort received a single 320 mg oral dose of VT-1161 or 
matching placebo after ingesting a high-fat breakfast.  Subjects in Cohorts 1 to 6 were followed 
for 14 days for safety and PK assessments.  Visits on Days 28 and 42 were added for Cohorts 7 
and 8.  Dose escalation proceeded only after safety and PK of the previous dose was determined.   
There were no deaths or serious adverse events (SAEs) reported.  There were no treatment-
emergent adverse events (TEAEs) that led to discontinuation from the study.   
Overall, mean changes from baseline in safety parameters (hematology, chemistry, urinalysis, vital 
signs, and electrocardiogram [ECG]s) were generally small and were considered not clinically 
significant.  None of the treatment-emergent physical examination abnormalities were of clinical 
significance.  The maximum tolerated dose for the study was the highest dose administered, 
320 mg, administered in the fed state. 
Following oral administration of VT‑1161 in the fasted state, median time to reach maximum 
plasma concentration (Tmax) ranged from 4 to 10 hours.  Overall, Cmax increased slightly less than 
proportional to dose. The area under the plasma concentration versus time curve from time zero to 
infinity (AUCinf) values generally increased with increase in dose, ranging from an average of 
16,145 ng•hr/mL at 20 mg to 241,971 ng•hr/mL at 320 mg.  The mean half-life ranged from 393 to 
1,467 hours.  Administration of 320 mg VT-1161 with a standard high-fat meal resulted in higher 
plasma concentrations than those observed following 320 mg in the fasted state in a separate group 
of subjects.  Average fasting Cmax was 338 ng/mL and this increased to 988 ng/mL in the fed state.  
AUCinf also increased from 241,971 ng•hr/mL when subjects were fasted to 953,119 ng•hr/mL 
with a high-fat meal. 
1.2.2.1.2 Multiple Dose-Escalation Study (Study VMT-VT-1161-CL-002) 
Study VMT-VT-1161-CL-002 was a Phase 1, single-center, randomized, double blind, placebo-
controlled, multiple dose-escalating study in healthy adult subjects.  The study was designed to 
evaluate the safety, tolerability, and PK of multiple oral doses of VT-1161.  In addition to plasma 
PK, concentrations of VT-1161 in nails and skin were assessed.  A total of 32 subjects participated 
in the study and received VT-1161 at 40, 80, 160 or 320 mg or placebo once daily for 7 days after 
ingestion of a high-fat meal.  In each cohort of 8 subjects, 6 subjects received VT-1161, and 2 
subjects received placebo.  Subjects were followed for safety and PK assessments for 42 days after 
the last dose of study drug. 
There were no deaths or SAEs reported.  Most TEAEs were mild in intensity and no severe TEAEs 
were reported. 


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Mean changes from baseline in safety parameters (hematology, chemistry, coagulation, urinalysis, 
vital signs, and ECGs) were generally small and not considered clinically significant.  There was 
no evidence of any clinically significant effect of VT-1161 on physical examinations in any dose 
group at any time point.  The maximum tolerated dose for the study was the highest dose 
administered, 320 mg, administered once daily for 7 days in the fed state. 
Following oral administration of VT-1161 in the fed state, median Tmax values ranged from 4 to 
6 hours after dosing.  The increase in mean Cmax was nearly proportional to dose over the 40 to 
320 mg dose range.  The concentrations were 3 to 4-fold higher on Day 7 than they were on Day 1, 
indicating accumulation during the 7-day dosing interval, with a mean Cmax of 3,300 ng/mL on 
Day 7 at 320 mg.  The area under the plasma concentration versus time curve over the dosing 
interval (AUCτ) values on Day 7 also increased nearly proportionally to dose over the 40 to 320 mg 
dose range.  The mean half-life ranged from 1,905 to 3,046 hours.   
1.2.2.1.3 Drug-Drug Interaction Study (Study VMT-VT-1161-CL-007) 
Study VMT-VT-1161-CL-007 was a Phase 1, single-center, open-label study in healthy adult 
subjects to evaluate the effect of single and multiple oral doses of VT‑1161 when co-administered 
with single oral doses of midazolam (DDI cohort) and to evaluate the PK of a single oral dose of 
an alternate strength of VT-1161 alone (pharmacokinetic evaluation [PKE] cohort).  All dosing 
was conducted 30 minutes after the start of a high-fat, high-calorie meal.  A total of 36 subjects 
were enrolled in the study.   
In the DDI cohort, 28 subjects were enrolled in a fixed-sequence design to receive a 2-mg oral 
dose of midazolam on Day 1, followed by 14 daily 600 mg oral doses of VT‑1161 (4 x 150 mg 
tablets) on Day 3 through Day 16 with single 2 mg oral doses of midazolam on Day 3 and Day 16.  
Subjects were followed for safety, tolerability and PK assessments through Day 17, 1 day after the 
last dose of study drug.  Twenty-four subjects in the DDI cohort completed the study and 4 subjects 
withdrew from the study prior to completion; 2 subjects voluntarily withdrew consent and 
2 subjects withdrew due to an adverse event (AE) (discussed in more detail below).   
There were no deaths reported in the study.  One SAE (acute psychosis) was reported in a subject 
in the DDI cohort on Day 11 of the study, leading to discontinuation.  The Investigator determined 
the subject likely had a pre-existing psychiatric condition based on patient report and assessed 
causality as unlikely-related to VT-1161.  One additional subject in the DDI cohort withdrew from 
the study due to an AE of abnormal ECG on Day 3 of the study.  The AE occurred prior to the first 
dose of VT-1161; the Investigator assessed causality as unrelated to study drug.  Otherwise, mean 


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changes from baseline in safety parameters (hematology, chemistry, coagulation, urinalysis, vital 
signs, and ECGs) in both the DDI and PKE cohorts were generally small and not considered 
clinically significant and there was no evidence of any clinically significant effect of VT-1161 on 
physical examinations in either cohort. 
In the DDI cohort, midazolam mean plasma Cmax increased 30% and AUCinf decreased 15% on 
Day 3 (after the first dose of VT‑1161) relative to Day 1 (midazolam alone).  Midazolam mean 
plasma Cmax decreased 3% and AUCinf decreased 37% on Day 16 (after 14 daily doses of VT‑1161) 
relative to Day 1 (midazolam alone). 
In the PKE cohort, 8 subjects were enrolled to receive a single 600 mg oral dose of VT-1161 (2 x 
300 mg tablets) on Day 1.  Subjects in the PKE cohort were followed for safety, tolerability and 
PK assessments through Day 2, 1 day after the dose of study drug.  All 8 subjects in the PKE 
cohort completed the study.  VT-1161 mean plasma Cmax and AUC0-24 values after a single oral 
administration of 600 mg VT‑1161 (2 x 300 mg) on Day 1 were 1,946 ng/mL and 
28,070 ng•hr/mL, respectively.  These values are similar to VT-1161 mean plasma Cmax and 
AUC0-24 values after a single oral administration of 600 mg VT‑1161 (4 x 150 mg) in the DDI 
cohort (1,994 ng/mL and 25,330 ng•hr/mL, respectively), indicating the comparative 
bioavailability of the 2 strengths of tablets is similar. 
1.2.2.1.4 Japanese Bridging Study (Study VMT-VT-1161-CL-008) 
Study VMT-VT-1161-CL-008 was a single-center, open-label study in healthy adult Japanese and 
Western subjects.  The objective of this ethno-bridging study was to evaluate the safety, 
tolerability, and PK of VT-1161 in these 2 ethnic populations after subjects received 14 once daily 
oral doses of VT-1161 administered in the fed state.  There was a total of 51 subjects enrolled. 
In the 300-mg dosage-group, there were 13 Japanese and 14 Western subjects.  In the 600 mg 
dosage group, there were 12 Japanese and 12 Western subjects.  The mean age of subjects was 
36.5 years, ranging from 19 to 55 years across treatment groups.  The subjects were evenly divided 
by sex across all groups and the race of the Western subjects was evenly divided by white and 
black.  
The study drug was overall well tolerated by both Western and Japanese subjects.  There were no 
significant differences between the 2 populations in any of the safety assessments.  A slight 
increase in AEs was seen in the 600 mg dosage group as compared with the 300 mg dosage group, 
but no SAEs were observed.  Only 1 subject was withdrawn from the study for an AE of rash 
(subject request), which was categorized as an unlikely-related TEAE.  There was 1 pregnancy in 


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a subject who was non-compliant with contraception requirements, which was electively 
terminated by the subject. 
Of the 51 subjects enrolled in the study, 11 Japanese subjects from both dose groups and 
12 Western subjects from both dose groups were included in the full PK analysis population. 
Trough concentrations on Days 1 through 14 rose each day; thus, steady-state conditions had not 
been met by Day 14.  Larger differences between the 2 ethnic groups were seen in Cmax and 
AUC0-72 following the 300 mg dose compared with the 600 mg dose. At the 300 mg dose, Cmax and 
AUC0-72 were approximately 40% higher in Japanese subjects compared with Western subjects. 
At the 600-mg dose, Cmax and AUC0-72 were approximately 10% higher in Japanese subjects 
compared with Western subjects. However, median Tmax was similar across doses at 4 hours for 
Japanese subjects at both the 300 mg and 600 mg dosages and 6 hours for Western subjects at both 
the 300 mg and 600 mg dosages. The terminal elimination phase was very flat and half-life 
exceeded 1800 hours. Total clearance following the 300-mg dose was 1.642 L/hr for the Japanese 
subjects compared with 2.332 L/hr for the Western subjects.  Following the 600 mg dose, clearance 
was similar for the Japanese and Western subjects (2.000 and 2.086 L/hr, respectively). 
1.2.2.2 Phase 2 Studies 
1.2.2.2.1 Dose Ranging Study in Tinea Pedis (Study VMT-VT-1161-CL-003) 
VMT-VT-1161-CL-003 was a Phase 2a, randomized, double-blind, dose-ranging study to evaluate 
the efficacy and safety of VT-1161 over-encapsulated tablets compared to placebo in the treatment 
of subjects with moderate to severe interdigital tinea pedis.  A total of 50 subjects participated in 
the study across 4 dose groups: 1) VT-1161 200 mg once daily for 4 days, followed by 50 mg once 
daily for 10 days (low dose); 2) VT-1161 600 mg once daily for 4 days, followed by 150 mg once 
daily for 10 days (mid-dose); 3) 600 mg twice daily for 4 days, followed by 300 mg once daily for 
10 days (high dose; or 4) placebo matching the VT-1161 treatment regimen.  VT-1161 plasma 
concentrations increased with dose and were as high as 6,230 ng/mL on Day 14 in the 600 mg 
twice daily/300 mg once daily dose group. Subjects were enrolled into the high-dose cohort 
following an interim analysis that included safety data generated through the test of cure (TOC) 
visit (Day 42) of the 2 lower dose groups.   
VT-1161 was safe and well tolerated at all dose levels through 6 months of follow up.  No SAEs 
were reported.  Most AEs reported were mild to moderate in severity and considered unrelated to 
study drug.  A single VT-1161 treatment related AE was reported (rash) that was considered by 
the Investigator to be “possibly related.”  The subject discontinued treatment after the first dose, 
and the rash completely resolved by the following day.  There were no clinically significant 


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treatment-emergent changes in vital signs, physical findings, ECGs, or laboratory parameters.  
One subject experienced a significant elevation of creatine kinase (CK) along with a slight increase 
in ALT and AST that was associated with a rigorous exercise program.  These changes were 
considered unrelated to treatment and all enzyme levels returned to normal at a subsequent follow-
up visit.   
At the Day 42 TOC visit, 42%, 42%, 50% and 0% of subjects receiving low dose, mid-dose or 
high dose VT-1161 or placebo were determined to have achieved effective therapeutic cure 
(defined as having a total severity score of ≤2 with no individual severity score of >1, and also, 
having negative mycology [culture and KOH]) in the intent-to-treat (ITT) population.   
1.2.2.2.2 Dose Ranging Study in Acute Vulvovaginal Candidiasis (Study VMT-VT-1161-
CL-004)  
VMT-VT-1161-CL-004 was a randomized Phase 2a, double-blind, dose ranging study to evaluate 
the efficacy and safety of VT-1161 over-encapsulated tablets compared to fluconazole in the 
treatment of 55 subjects with moderate to severe acute VVC.  A total of 55 subjects with moderate-
to-severe acute VVC (severity score ≥6 and a positive fungal KOH test) participated in the study 
across 4 dose groups: 1) VT 1161 300 mg once daily for 3 days, 2) 600 mg once daily for 3 days, 
3) 600 mg twice daily for 3 days, or 4) a single dose of fluconazole 150 mg followed by matching 
placebo.  Subjects were enrolled into the high-dose cohort following an interim analysis that 
included safety data generated through the TOC visit (Day 28) of the 2 lower dose groups.  
An additional interim analysis was conducted when the high-dose subjects had completed their 
TOC visit.   
VT-1161 was determined to be safe and well tolerated at all dose levels through Day 28.  No SAEs 
were reported and no subjects discontinued because of an AE.  Most AEs reported were considered 
unrelated to study drug and were mild in severity.  There were few treatment-related TEAEs of 
clinical concern.  Most TEAEs were reported in the low- and mid-dose cohorts and only 1 TEAE 
(insomnia) was noted in the high-dose cohort.  One subject developed urticaria that was considered 
possibly related to study drug and which resolved with prednisone.  There were no clinically 
significant treatment-emergent changes in vital signs, physical findings, ECGs or laboratory 
parameters. 
The efficacy of VT-1161 in the treatment of moderate-to-severe acute VVC was evaluated at the 
TOC visit in the ITT population (defined as all randomized subjects receiving at least 1 dose of 
study drug) and the per protocol (PP) population (defined as subjects that were compliant with all 
key aspects of the protocol).  Subjects in the ITT population were randomized into the 


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VT-1161 300 mg once daily for 3 days (n = 14), VT-1161 600 mg once daily for 3 days (n = 12), 
VT-1161 600 mg twice daily for 3 days (n = 14) or fluconazole (n = 15).  Effective clinical cure 
rate (defined as having a total severity score of 0 or 1 and a negative culture) were 29%, 83%, 86% 
and 73%, respectively.  Subjects in the PP population achieved effective therapeutic cure at a rate 
of approximately 87%, 86%, 86% and 75%, respectively, in the low-dose, mid-dose, or high-dose 
VT-1161 or fluconazole groups at the Day 28 TOC visit. 
1.2.2.2.3 Phase 2b Study in Subjects with Distal and Lateral Subungual Onychomycosis of 
the Toenail (VMT-VT-1161-CL-005) 
In this Phase 2b study, the safety, tolerability, PK and efficacy of VT-1161 in subjects with distal 
and lateral subungual onychomycosis of the toenail were evaluated.  A total of 259 subjects 
participated in the study in 5 treatment groups and were administered either: 
• 
Low dose 12-week: Loading doses of 300 mg once daily for 2 weeks, then 300 mg once weekly 
for 10 weeks, followed by placebo for 12 weeks. 
• 
Low dose 24-week: Loading doses of 300 mg once daily for 2 weeks, then 300 mg once weekly 
for 22 weeks. 
• 
High dose 12-week: Loading doses of 600 mg once daily for 2 weeks, then 600 mg once weekly 
for 10 weeks, followed by placebo for 12 weeks. 
• 
High dose 24-week: Loading doses of 600 mg once daily for 2 weeks, then 600 mg once weekly 
for 22 weeks. 
• 
Matching placebo 
Subjects in all cohorts were followed for 60 weeks.  Consenting subjects were enrolled into an 
extension study to assess the long-term safety and PK of VT-1161 through Week 96.   
The incidence of AEs was balanced across the VT-1161 treatment arms and placebo.  A total of 
148 subjects (57%) had at least 1 TEAE, and the frequency was within the range of 49% to 67% 
for all treatment groups.  The majority of TEAEs were considered by the Investigator to be mild 
or moderate and unrelated to study drug.  Most TEAEs were transient and occurred during the first 
12 weeks of treatment for all treatment groups, including placebo.  Nineteen subjects reported 
related TEAEs through Week 60.  Sixteen subjects were on VT-1161 and three subjects were on 
placebo.  The only related TEAE reported by more than 2 subjects was nausea.  Eleven subjects 
reported a total of 16 SAEs, which were considered unrelated to study drug.   


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Protocol VMT-VT-1161-CL-011 
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39 
The incidence of study drug related TEAEs was within the range of 6% to 11% for all treatment 
groups, with the highest frequency in the 600 mg 24-week group.  The most common (≥2 total 
subjects) TEAEs that were considered related to VT-1161 were nausea, dysgeusia, dizziness, 
constipation, and decreased appetite.  The most common TEAE that was considered related to 
placebo was dizziness. 
The incidence of TEAEs leading to study drug discontinuation was low, in the range of 0% to 6% 
for all treatment groups. 
There were no clinically-relevant findings noted by the Investigators with vital signs, physical 
exam findings or ECGs. 
There was no obvious clinically-relevant effect of VT-1161 on chemistry, hematology or urinalysis 
parameters.  
Overall, VT-1161 was safe and well-tolerated at all doses and treatment durations including the 
highest dose and longest duration evaluated of 600 mg 24-week treatment group.  The TEAEs 
were typical of the subject population being studied and were generally balanced across the 
VT-1161 treatment and placebo group. 
The primary efficacy endpoint was complete cure at Week 48.  The proportion of subjects in the 
ITT population with complete cure at Week 48 ranged from 32% to 42% in the VT-1161 treatment 
groups, with the lowest rate in the 300 mg 12–week treatment group and the highest rate in the 
600 mg 12–week treatment group. No subjects receiving placebo experienced complete cure at 
Week 48.  The proportion of ITT subjects with complete cure was statistically significantly higher 
for all VT-1161 treatment groups compared with placebo at Week 48 (p<0.001). 
Overall, the efficacy at Week 48 was clearly demonstrated in all the VT-1161 treatment groups, 
with little to no improvement seen in the placebo group.   
1.2.2.2.4 Phase 2b Study in Subjects with Recurrent Vulvovaginal Candidiasis 
In this Phase 2b study, the safety, tolerability, PK and efficacy of VT-1161 in subjects with 
recurrent vulvovaginal candidiasis was evaluated.  A total of 215 subjects participated in the study, 
were randomized to 5 treatment groups and were administered either: 
• 
Low dose 12-week: Loading doses of 150 mg once daily for 7 days, then 150 mg once weekly 
for 11 weeks, followed by placebo for 12 weeks. 


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• 
Low dose 24-week: Loading doses of 150 mg once daily for 7 days, then 150 mg once weekly 
for 23 weeks. 
• 
High dose 12-week: Loading doses of 300 mg once daily for 7 days, then 300 mg once weekly 
for 11 weeks, followed by placebo for 12 weeks. 
• 
High dose 24-week: Loading doses of 300 mg once daily for 7 days, then 300 mg once weekly 
for 23 weeks. 
• 
Matching placebo 
In general, the incidence of AEs was balanced across the VT-1161 treatment arms and placebo. 
Two subjects discontinued VT-1161 because of a TEAE.  Of these two, only one TEAE was 
considered related to VT-1161 by the study investigator.  Most TEAEs were considered unrelated 
to study drug and were mild or moderate in severity.  Six SAEs were reported through Week 48 
of the study, none of which were considered related to study drug by the investigator.  Interestingly, 
a higher incidence of bacterial vaginosis and urinary tract infections was reported in the placebo 
arm.   
There were no clinically-relevant findings noted by the investigators regarding vital signs, physical 
exam findings or ECGs. There was no obvious clinically-relevant effect of VT-1161 on chemistry, 
hematology or urinalysis parameters. 
The primary efficacy outcome measure was the proportion of subjects with one or more culture-
verified acute VVC episodes during the Maintenance Phase through Week 48 of the study in the 
ITT population.  Culture-verified acute VVC was defined as a positive fungal culture for Candida 
species associated with a clinical signs and symptoms score of ≥ 3.  The proportion of subjects 
with one or more culture-verified acute VVC episode through Week 48 was lower in VT-1161 
dosing regimens: 4.8% in 150 mg 12 weeks, 7.0% in 150 mg 24 weeks, 0.0% in 300 mg 12 weeks, 
and 4.9% in 300 mg 24 weeks, treatment groups compared with 52.2% in the placebo group. 
The difference was statistically significant in the VT-1161 dosing regimens compared with 
placebo (p<0.0001). 
In conclusion, VT-1161 was determined to be efficacious, safe and well tolerated at all dose levels 
through the final visit at Week 48 of the study. 


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1.3 
Study Rationale  
RVVC can be treated with topical and/or oral agents and patients may receive maintenance 
treatment for up to 6 months or longer once the acute infection has resolved.  For most patients, 
available agents do not provide the desired delay to recurrence of an acute VVC episode, 
underlining the need for more effective treatments for RVVC.  Fluconazole has been used to treat 
acute VVC episodes in patients with recurrent disease. However, fluconazole has relatively lesser 
activity against some non-albicans species that are more common in patients with complicated 
VVC. 
While oral antifungal agents offer better efficacy, they suffer from safety issues associated with 
their narrow therapeutic windows and off target toxicity.  Several properties of VT-1161 suggest 
that it has the potential to be a best-in-class oral agent for the treatment of RVVC, including its 
ability to effectively inhibit growth of causative fungal pathogens at achievable plasma levels.  
The in vitro potency against Candida species is greater than fluconazole.  Also, because it is much 
more selective for fungal CYP51 and CYP metabolizing enzymes than currently used oral agents, 
the probability of both hepatotoxicity and DDIs should be significantly reduced.  Its PK profile 
and extended half-life should also limit recurrence of VVC.  A weekly dosing regimen after the 
loading dose may improve patient compliance. 
1.3.1 Rationale for Induction Phase Treatment 
Fluconazole is an approved treatment for acute VVC and is used off-label to treat patients with 
recurrent disease.  The proposed dose regimen of 3 doses of fluconazole taken 72 hours apart 
corresponds to a regimen that is often used as the standard of care and has been regularly employed 
during the induction phase of similar clinical studies designed to study RVVC.  Treatment of the 
acute infection with fluconazole in the Induction Phase allows for a more controlled assessment of 
recurrence in the VT-1161 treatment group versus placebo. 
1.3.2 Dosing Regimen for VT-1161 and Matching Placebo 
Following cure of the acute infection by 3 doses of fluconazole every 72 hours, subjects will be 
randomly assigned to receive one of the following treatment groups:  
• VT-1161: Loading dose of 150 mg once daily for 7 days, then 150 mg once weekly for 
11 weeks. 
• Placebo: Matching VT-1161 capsules. 


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The rationale for dose selection is provided in Section 4.4, Design Justification.     
1.4 
Potential Risks and Benefits of Participating in the Study 
The Phase 1, Phase 2a, and Phase 2b studies with VT-1161 incorporated monitoring for AEs often 
reported with other azole antifungal drugs.  No clinically significant study drug related AEs were 
observed in clinical studies with VT-1161, suggesting that it may be better tolerated than 
commonly used azole agents.  


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2 OBJECTIVES 
Primary:  
• To evaluate the efficacy of oral VT-1161 in the treatment of RVVC through Week 48. 
Secondary:  
• To evaluate the safety and tolerability of oral VT-1161 in the treatment of RVVC through 
Week 48. 
• To evaluate the impact of oral VT-1161 treatment on patient reported outcomes through Week 
48. 
 


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3 
STUDY ENDPOINTS 
The primary efficacy outcome measure is the proportion of subjects with one or more 
culture-verified acute VVC episodes during the Maintenance Phase in the ITT population. 
The Maintenance Phase is defined as post randomization through Week 48 of the study.  An acute 
VVC episode during the Maintenance Phase (considered a recurrent episode) is defined as a 
positive culture for Candida species and a clinical signs and symptoms score of ≥3.   
Secondary:  
• Time to first recurrence of a culture-verified acute VVC episode with signs and symptoms 
score ≥3 during the Maintenance Phase. 
• The proportion of subjects with at least one positive culture for Candida during the 
Maintenance Phase. 
• The proportion of subjects with at least one culture-verified acute VVC episode with signs and 
symptoms ≥3 post randomization through Week 24. 
• Change from Screening through Week 48 in the SF-36 mental component score (MCS). 
• Change from Screening through Week 48 in the SF-36 patient reported outcome survey total 
score. 


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4 
STUDY DESIGN 
4.1 
Overall Study Design 
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. 
The study is designed to evaluate the efficacy and safety of oral VT-1161 capsules in the treatment 
of subjects with RVVC.  The impact of oral VT-1161 treatment on the quality of life will also be 
evaluated using data collected from patient reported outcome assessments. 
Subjects must have a history of RVVC, defined as at least 3 episodes of acute VVC in the past 
12 months, as described below:   
• Subjects must have an acute VVC episode at the time of Screening, with a documented positive 
KOH or Gram stain performed at the investigative site 
• Subjects must also have had 2 or more additional episodes of acute VVC in the past 12 months, 
with at least 1 of the episodes documented by a positive confirmatory laboratory test (i.e., 
culture, PCR, Affirm test, KOH test, Gram stain, a documented Pap test, or other approved 
diagnostic test) 
The study consists of two Phases: 1) an open-label Induction Phase for the treatment of the acute 
VVC infection with 3 sequential 150 mg oral doses (every 72 hours) of fluconazole, and 
2) a Maintenance Phase in which subjects will be randomly assigned to receive VT-1161 or 
placebo for 7 daily doses followed by 11 weekly doses and then enter a 36-week follow-up period. 
Once subjects have provided informed consent or assent (for those ages 12 to 17), the 
investigational site will evaluate all subjects by completing a review of pertinent medical history, 
obtaining vital signs, weight and height, ECG and laboratory tests, reviewing clinical signs and 
symptoms of vulvovaginitis, performing a complete physical examination including speculum 
examination of the vagina, performing a KOH wet mount test or Gram stain from a vaginal smear 
to confirm the presence of yeast, and collecting vaginal swabs to establish a baseline culture for 
identification of fungal species. Patient reported outcome surveys (SF-36, EQ-5D-3L or EQ-5D-
Y [for ages 12 to 17], WPAI:SHP, PHQ-9) for all regions and questions regarding their RVVC 
history (US only) will also be administered. Eligible subjects will have a composite vulvovaginal 
signs and symptom score of ≥3 as outlined in Section 9.1.7, a positive local KOH or Gram stain 
that confirmed the presence of yeast, and must meet other initial entry criteria.  
Once eligibility is confirmed, subjects will enter the Induction Phase.  During the Induction Phase, 
the presenting acute VVC infection will be treated with 3 sequential 150 mg oral doses 


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(every 72 hours) of fluconazole.  Subjects will return approximately 14 days after the first dose of 
fluconazole for evaluation and, if the acute VVC infection has resolved (defined by a signs and 
symptoms score of <3), they will be randomized in a 2:1 ratio to receive either VT-1161 or a 
matching placebo regimen.  Day 1 (Baseline) is defined as the first day of investigational medicinal 
product (IMP) administration and subsequent study days are defined by the number of consecutive 
days thereafter.  If the acute VVC has not resolved (defined by a signs and symptoms score of ≥3), 
the subject will be considered a screen failure and encouraged to see their physician for further 
evaluation and follow-up care. 
4.2 
Treatment Arms and Duration of Study 
Subjects will be randomized in a 2:1 ratio to receive VT-1161 or placebo. 
The duration of individual subject participation will be approximately 50 weeks: including the 
2-week Induction Phase with fluconazole administration, followed by 12 weeks for IMP 
administration, and 36 weeks of follow-up. Assessments and procedures will be performed as 
outlined in  Table 1. Schedule of Assessments and Procedures.  Subjects who return to the clinic 
for a recurrent VVC episode should be evaluated as per the unscheduled visit noted in the Schedule 
of Assessment and Procedures. 
The planned study duration is 26 months from screening of the first subject until the last follow-up 
of the last subject. 
4.3 
Number of Subjects 
Approximately 600 screened and 300 randomized subjects are planned for this study.  Assuming 
a 20% discontinuation rate for the remainder of the study, approximately 240 subjects are expected 
to complete the study. 
Subjects will be enrolled at 60 to 80 sites in North America and Europe. 
4.4 
Design Justification 
The VT-1161 dose and duration selection in the planned Phase 3 studies is based primarily on the 
results of VMT-VT-1161-CL-006; “A Phase 2, Randomized, Double Blind, Placebo-Controlled, 
Dose Ranging Study to Evaluate the Efficacy and Safety of VT-1161 Oral Tablets in the Treatment 
of Patients with Recurrent Vulvovaginal Candidiasis.”   The study was designed to be consistent 
with the principles put forth in the ICH E4 Guideline, “Dose-Response Information to Support 
Drug Registration.”   


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Given VT-1161’s large therapeutic window and favorable safety profile as demonstrated in the 
single- and multiple-ascending dose Phase 1 studies as well as Phase 2a studies, the Phase 2b 
RVVC study was designed to demonstrate prolonged remission following short courses of 
VT-1161 dosing.    
The proportion of subjects in the ITT population with one or more culture verified acute VVC 
episodes through Week 48 was lower in the VT 1161 dose groups; 4.8% in the 150 mg/12-week, 
7.1% in the 150 mg/24-week, 0.0% in the 300 mg/12-week, and 4.9% in the 300 mg/24-week 
treatment groups, compared to 52.2% in the placebo group.  This difference was statistically 
significant in all VT-1161 groups compared to placebo (p<0.0001).  However, the study was not 
designed to demonstrate a statistical difference between the VT-1161 dosing regimens.  
In the PP population, the proportion of subjects with one or more culture-verified acute VVC 
episodes through Week 48 in VT-1161 dose groups were 3.3% in the 150 mg/12-week, 10.7% in 
the 150 mg/24-week, 0.0% in the 300 mg/12-week, and 0.0% in the 300 mg/24-week treatment 
groups, compared to 65.6% in the placebo group, indicating a numerically higher rate of recurrence 
in the lower VT-1161 dose groups.   A similar trend was observed in subjects with one or more 
positive cultures through Week 48; 13.3% in the 150 mg/12-week; 25.0% in the 150 mg/24-week; 
16.1% in the 300 mg/12-week; and 3.2% in the 300 mg/24-week treatment groups, compared to 
84% in the placebo group.  The mean plasma concentrations for the VT-1161 150 mg/12-week 
treatment group was 1.3 µg/mL at the start of weekly dosing (Day 7), 2.6 µg/mL at the end of the 
dosing phase (Week 12), and was followed by a slow decay to reach 0.75 µg/mL at Week 48. 
Based on the PP analysis, it appears that the 150 mg/12-week treatment group is at or near a 
minimally effective dose and duration of therapy. 
In the Kaplan-Meier analysis (ITT population), most recurrent episodes occurred in the early phase 
of the study.  In total, 7 subjects across all the VT-1161 dose groups exhibited a culture-verified 
recurrence while on study with 5 of 7 subjects having a recurrence in the first 5 weeks of the study.  
Notably, 3 of these 5 subjects (all in the 150 mg group) experienced a recurrence by Day 7.   
Taken together, the data suggest that these subjects in the VT-1161 low dose (150 mg) treatment 
groups may have not attained effective therapeutic drug levels early enough to prevent the early 
recurrences.  Therefore, a lower than 150 mg VT-1161 starting dose cannot be justified given the 
potential that more patients would experience recurrence, especially for less susceptible non-
albicans strains.   
The dose selection for the Phase 3 study is further supported by the safety and tolerability profile 
of VT-1161.   The frequency of AEs across all VT-1161 treatment groups in the Phase 2b study 


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was similar to the placebo group.  There were also no meaningful differences observed between 
placebo and the VT-1161 treatment groups in other safety parameters including chemistry, 
hematology and ECG analyses.  To that end, from a safety perspective any of the dosing groups 
tested in the Phase 2b study could be potentially selected for the Phase 3 studies.  This is important 
since, in addition to exhibiting excellent safety and tolerability, all VT-1161 treatment groups also 
achieved clinical outcomes that were far superior to fluconazole historic data where approximately 
60% of RVVC patients experienced one or more acute culture-verified VVC recurrences within 6 
months after the cessation of weekly prophylactic/maintenance therapy  (Sobel et al. 2004).    
The proposed dosing regimen for the Phase 3 studies, incorporates a 7-day 150 mg loading dose 
phase to minimize early breakthroughs, followed by a 150 mg once weekly maintenance dose 
phase for 11 weeks.  Based on the PK results from the Phase 2b study, the proposed dosing regimen 
of 150 mg daily for 7 days followed by a 150 mg once weekly maintenance dose is expected to 
provide a mean plasma concentration of approximately 2.5 µg/mL at the end of the dosing period 
(Week 12). 
4.4.1 Justification for Inclusion of Adolescents in the Study 
Vulvovaginal candidiasis, and especially RVVC, is rare in pre-menarcheal girls (typically pre-
adolescents less than 12 years of age) and epidemiological data is generally lacking for this 
population. 
Adolescent females (ages 12 to 17 years, inclusive) represent a menarcheal population that is 
newly influenced by reproductive hormones. The changes in reproductive hormones in adolescents 
cause vast changes in tissues and may increase the susceptibility to VVC. In this population, cases 
of VVC and RVVC exist but are substantially less common than in adult females. While 75% of 
healthy women will likely experience one episode of VVC in their lifetime, and potentially 9% 
will be characterized as having recurrent disease, the prevalence of symptomatic acute VVC in 
adolescents is less than 2% of the population and there is no published data that addresses the 
incidence of RVVC in this patient population (Fidel, 2002; Blostein, 2017; Barousse, 2004). 
Presenting symptoms of VVC in menarcheal adolescents are similar to those in the adult 
population, and treatment typically consists of topical antifungal preparations while oral antifungal 
agents are prescribed only in severe or complicated cases (Joishy, 2005). The dose and 
administration of the agents used in adolescents are the same as those used in adult females with 
VVC and RVVC. 
The United States FDA Draft Guidance Vulvovaginal Candidiasis: Developing Drugs for 
Treatment states that while uncomplicated VVC is unlikely to occur in healthy pre-menarcheal 


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girls, post-menarcheal adolescent girls with VVC should be included in Phase 3 trials. 
Accordingly, the present study will follow guidance received by the United States FDA reviewers 
and will allow enrollment of subjects 12 to 17 years of age (inclusive) to collect as much 
information as possible on the treatment of the adolescent population with RVVC. 


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5 
SELECTION OF STUDY POPULATION 
The following criteria for enrollment must be followed explicitly.  A subject will not be enrolled 
unless the following inclusion/exclusion criteria are met.  The Investigator or other study site 
personnel must record in the source documents (e.g., the site’s chart) and case report form (CRF) 
that the informed consent document (or assent for those 12-17) was signed and dated prior to any 
study procedures.  The presence of inclusion criteria and absence of exclusion criteria will be 
verified by the Investigator in the subject’s clinic chart. 
5.1 
Inclusion Criteria 
1. Subjects must be generally healthy, post-menarchal non-pregnant females 12 years of age and 
older as of Screening. 
2. Subjects must have a history of recurrent VVC as defined by three (3) or more patient reported 
and/or laboratory confirmed episodes of acute VVC in the past 12 months including the 
episode confirmed at Screening, with at least one episode (not including the current episode) 
documented by a positive culture, PCR, Affirm test, KOH test, Gram stain, or a documented 
Pap test in the prior 12 months revealing filamentous hyphae/pseudohyphae and/or budding 
yeast cells, or other approved diagnostic test. 
3. Subjects must have an acute VVC infection at Screening, defined as: 
a. a total signs and symptoms score of ≥3 and 
b. a positive KOH wet mount preparation or Gram stain from a vaginal smear revealing 
filamentous hyphae/pseudohyphae and/or budding yeast cells. 
4. Subjects must have a composite vulvovaginal signs and symptoms score of <3 at the Baseline 
(Day 1) Visit. 
5. Subjects must have a documented Pap test at Screening or within the timeline per current 
standard of care guidelines for the appropriate age requirement.  Results must be either 
“negative for intraepithelial lesion or malignancy” or “ASCUS-atypical squamous cells of 
undetermined significance” (not applicable to subjects with a history of total hysterectomy). 
6. Subjects must be suitable candidates for oral therapy and be able to swallow capsules intact.  
7. Subjects must be willing and able to provide written informed consent or assent (for those ages 
12 to 17) and authorization for use of protected health information. 
8. Subjects must be willing and able to comply with protocol requirements, instructions, and 
protocol-stated restrictions and be likely to complete the study as planned. 


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9. Subjects of non-childbearing potential must meet the requirements defined below: 
a. Pre-menopausal with documentation of surgical sterilization (i.e., hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy, or bilateral salpingectomy) at least 
3 months prior to Screening. 
b. Post-menopausal defined as amenorrhea for at least 12 months following cessation of 
all exogenous hormonal treatments at Screening. 
10. Subjects of childbearing potential (includes ages 12 to 17) must use 1 of the following methods 
of contraception during the study through Week 48: 
OPTION 1 – Highly effective methods that can be used alone: 
i. Copper intrauterine device 
ii. Levonorgestrel-releasing intrauterine system 
iii. Progestin implant 
iv. Monogamous with a vasectomized male partner 
v. Abstinencea 
OPTION 2 – Acceptable first and second barrier methods to be used in 
combination: 
FIRST (Hormonal Contraception)b 
1. Estrogen & progestin oral contraceptives, transdermal patch or 
vaginal ring. 
2. Progestin only oral contraceptives or injection 
SECOND (Barrier Method) 
1. Diaphragm (with spermicide) 
2. Cervical cap (with spermicide) 
3. Male condom (with or without spermicide) 
In addition to OPTIONS 1 and 2, subjects of childbearing potential (includes ages 12-17) may 
also use 1 of the following methods of contraception after completing the Induction Phase on 
Study Day 1 through Week 48: 
OPTION 3 (Day 1 – Week 48)c – Acceptable first and second barrier methods to 
be used in combination: 
FIRST (Barrier Method) 
1. Diaphragm (with spermicide) 


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2. Cervical cap (with spermicide) 
SECOND (Barrier Method) 
1. Male condom (with or without spermicide) 
 
a Sexual abstinence is defined as refraining from heterosexual intercourse during the entire study 
period and where this is the usual life style of the subject. Periodic abstinence (calendar, 
symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhoea method are not considered to be acceptable methods of contraception. 
b Subjects who started taking a hormonal contraceptive less than 3 months prior to the first dose of 
fluconazole must agree to use a double-barrier method (i.e. diaphragm plus spermicide or condom) 
through 3 months after starting the hormonal contraceptive.   
c Because of the teratogenic risk associated with repeat dosing of fluconazole, OPTION 3 
contraceptive methods cannot be used during Screening and the Induction Phase of the study [from 
Screening until Baseline (Day 1) of the study].   
5.2 Exclusion Criteria 
1. Subjects must not have the presence of concomitant vulvovaginitis caused by other pathogens 
(e.g., bacterial vaginosis, Trichomonas vaginalis, Chlamydia trachomatis, or Neisseria 
gonorrhoeae) at Screening visit and at the Day 1 visit if an infection is suspected. 
2. Subjects must not have an active HPV infection as evidenced by visible condylomas on 
vulvovaginal examination at Screening and Day 1 visits. 
3. Subjects must not have the presence or a history of another vaginal or vulvar condition(s) that 
in the Investigator’s opinion would confound the interpretation of clinical response. 
4. Subjects must not have a history of cervical cancer. 
5. Subjects must not use any systemic (e.g., oral or injectable) corticosteroid therapy during the 
study or within 30 days prior to Screening, nor use of topical vulvar or vaginal steroids during 
the study or within 7 days prior to Screening. However, use of topical (no vulvar or vaginal 
steroids), inhaled, ophthalmic, collunarium/nasal, intraarticular and intralesional steroids is 
permitted.  
6. Subjects must not use any systemic (e.g., oral or injectable) or topical (applied to the vulva or 
vaginal area) antifungal, antibacterial, or antitrichomonal drugs or vaginal douches during the 
study (unless prescribed by the Investigator) or within 7 days prior to Screening. 


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7. Subjects must not be using drugs with a narrow therapeutic index that are metabolized by 
CYP3A4 and sensitive to induction of CYP3A4 during the study (i.e. cyclosporine, fentanyl, 
quinidine, sirolimus and tacrolimus). 
8. Subjects must not use any vaginal estrogen replacement therapy, ospemifene, Vitamin E gel 
capsules (vaginally) or lubricants within 7 days prior to Screening. 
9. Subjects must not have a condition that would require treatment during the study with 
concomitant topical (applied to vulva and vagina) or systemic antimicrobial therapy for any 
reason. 
10. Subjects must not have received an immunosuppressive medication (carbamazepine, 
cyclosporine, tacrolimus, methotrexate, 6 mercaptopurine, mycophenolate, etc.), or radiation 
therapy within 3 months prior to Screening or have a medical condition where it would be 
likely that the subject may need to use these therapies during the study. 
11. Subjects must not have evidence of any clinically significant major organ disease or current 
clinically significant infection or any other conditions (with the exception of acute VVC) that 
may affect the clinical assessment of RVVC per Investigator judgment. 
12. Subjects must not have any comorbid condition that in the opinion of the Investigator would 
preclude the safe participation of the subject in the study or would prevent the subject from 
meeting the study requirements. 
13. Subjects must not have any condition that in the opinion of the Investigator could impact drug 
absorption (e.g. gastrectomy, Roux-en-Y gastric bypass surgery, gastric bands or staples, etc.), 
distribution, or elimination. 
14. Subjects must not have poorly controlled diabetes mellitus (HbA1c ≥8.5% at Screening). 
15. Subjects must not have moderate or severe hepatic and/or renal disease (defined in Appendix B 
and Appendix C). 
16. Subjects must not have a laboratory abnormality that in the opinion of the Investigator is likely 
to introduce additional risk to the subject or might interfere with data interpretation. 
The specific findings listed below are excluded at Screening (a single repeat laboratory 
evaluation is allowed for eligibility determination, except for HIV, HbsAg and antibodies to 
hepatitis C virus): 


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a. Serum ALT ≥2.0x the upper limit of normal (ULN) of the reference range. 
b. Serum AST ≥2.0x the ULN of the reference range.  
c. Serum total bilirubin ≥1.5x the ULN of the reference range, unless the elevation is 
consistent with Gilbert’s Syndrome.  
d. Electrocardiographic QTc interval >470 msec as corrected by the Fridericia formula, 
or any clinically significant electrocardiographic abnormality. 
e. Positive test for antibodies to human immunodeficiency virus (HIV), hepatitis B 
surface antigen (HbsAg), or antibodies to hepatitis C virus. 
17. Subjects of childbearing potential must not be pregnant (positive pregnancy test at Screening), 
lactating, or planning to become pregnant during the study period. 
18. Subjects must not have planned surgery or other medical procedures that in the Investigator’s 
opinion would impact compliance with the protocol. 
19. Subjects must not have active substance abuse (e.g., drugs of any kind, including alcohol) or 
any other medical, psychiatric or social condition that in the Investigator’s opinion would 
preclude compliance with the protocol.   
20. Subjects must not have received VT-1161 study medication in a previous study. 
21. Subjects must not have received any IMP in a clinical trial within 5 half-lives of that IMP prior 
to Screening (if unknown, 60 days prior to Screening). 
22. Subjects must not have a known history of intolerance or hypersensitivity to azole antifungal 
drugs (e.g., fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole), or any 
excipients of the capsule formulation. 
 


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Product: VT-1161  
 
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55 
6 INVESTIGATIONAL MEDICINAL PRODUCT 
All protocol-specific criteria for administration of study treatments must be met and documented 
prior to IMP administration. Study treatments will be administered only to eligible subjects under 
the supervision of the Investigator. 
6.1 Fluconazole 
Fluconazole tablets or capsules containing 150 mg of active pharmaceutical ingredient for the 
Induction Phase of the study will be provided by Mycovia Pharmaceuticals (or its designee) or by 
the Investigator for use in the Induction Phase and for treatment of acute VVC episodes during the 
Maintenance Phase (as described in Section 7.4.2). 
6.2 Description of Investigational Medicinal Product 
6.2.1 VT-1161 
Active IMP will be supplied by Mycovia Pharmaceuticals (or its designee) as capsules containing 
150 mg of VT-1161. 
6.2.2 Placebo 
Placebo will be supplied by Mycovia Pharmaceuticals (or its designee) as capsules matching the 
appearance of VT-1161 capsules. 
6.3 Investigational Medicinal Product Labeling and Packaging 
Mycovia Pharmaceuticals (or its designee) will package the VT-1161 and placebo capsules.  
IMP will be supplied according to applicable regulatory requirements.  Information pertaining to 
labeling and a description of the specific packaging and storage conditions will be supplied to the 
Investigator or designee.   
VT-1161 and placebo will be provided in bottles for daily dosing on Days 1-7 and weekly dosing 
through Week 12 of the study. 
6.4 Investigational Medicinal Product Storage Conditions 
IMP will be stored in a secure location at a controlled room temperature of 15°C to 25°C (59°F to 
77°F) and protected from light and moisture.  The storage of IMP will be locked with limited 
access, available to appropriate study personnel only. 


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6.5 Receipt of Supplies/Handling/Storage 
Only subjects enrolled in the study may receive study treatment, and only authorized site staff may 
supply or administer study treatment. All study treatments must be stored in a secure 
environmentally controlled and monitored area in accordance with the labelled storage conditions 
with access limited to the Investigator and authorized staff. 
Further guidance and information for final disposition of unused study treatments are provided in 
the Study Procedures Manual. 
6.6 Investigational Medicinal Product Accountability 
Mycovia Pharmaceuticals will provide the Investigator with sufficient amounts of IMP.  It is the 
responsibility of the Investigator to ensure that a current record of inventory/IMP accountability is 
maintained. 
6.7 Investigational Medicinal Product Return 
Upon the completion or termination of the study, and with supporting documentation from 
Mycovia Pharmaceuticals (or designee), all unused and/or partially used IMP should be returned 
to Sponsor or its designee or destroyed at the investigational site per the site’s standard operating 
procedure (SOP) for IMP destruction.  Prior to destruction of any used or unused IMP at a site, 
Mycovia Pharmaceuticals (or designee) must review and provide written documentation that: 
1. The site SOP for IMP destruction is acceptable.  
2. The clinical site monitor has conducted and documented full accountability of the IMP.  


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7 TREATMENT OF SUBJECTS 
7.1 Investigational Medicinal Product Administration and Dosing Schedule  
7.1.1 Induction Phase (Screening to Day 1 Pre-Randomization) 
All subjects will receive 3 sequential 150 mg doses of fluconazole that are administered 72 hours 
apart. 
Regarding the dosing of fluconazole in adolescent subjects (12 to 17 years of age, inclusive), 
fluconazole exposure at the planned dose is anticipated to be similar to that in adults and 
proportional to weight. AEs associated with fluconazole would also be expected to be similar in 
adolescents as in adults. There are currently no United States FDA- or European-approved doses 
or regimens of fluconazole for treatment of VVC or RVVC in adolescents. While the United States 
FDA-approved labeling for fluconazole (Diflucan, Pfizer 2017) is silent on treatment of 
adolescents with VVC, the European prescribing information for fluconazole (Diflucan® Summary 
of Product Characteristics [2017]) provides the following guidance; “If treatment is imperative in 
adolescents (from 12 to 17 years old), the posology should be the same as in the adult population.”  
Therefore, adolescent subjects (ages 12 to 17 years) enrolled in the study will receive the same 
150 mg doses of fluconazole as adult subjects.  
7.1.2 Maintenance Phase (Day 1 Post Randomization to Week 12) 
Subjects will receive either: 
• 150 mg once daily dose of VT-1161 for 7 days followed by a 150-mg once weekly dose of 
VT-1161 for 11 weeks, or  
• a matching placebo regimen for 12 weeks.   
All subjects will take 1 capsule once daily on Days 1 to 7 and 1 capsule once weekly starting at 
Week 2 (7 days after the completion of daily dosing) through Week 12 of the study.   
Subjects will be instructed to take the doses of VT-1161 within 30 minutes after ingestion of the 
subject’s main meal (as determined by the subject), at approximately the same time of the day 
consistently throughout the study.  Subjects should consume approximately 240 mL 
(approximately 8 oz.) of water with each dose of IMP. 
Using similar rationale as above for fluconazole, the exposure after dosing of VT-1161 at 150 mg 
doses is anticipated to be similar in adolescents as in adults and proportional to weight. Therefore, 
adolescents (ages 12 to 17 years) enrolled into the study will receive the same dosing regimen as 


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58 
adult subjects. It should also be noted that the United States FDA has reviewed this protocol and 
accepted the planned dosing regimen for fluconazole and VT-1161 in adolescent subjects. 
7.2 Method of Assigning Subjects to Treatment Groups 
Each subject who completes the study Screening assessments, meets all eligibility criteria, and is 
accepted for the study will be assigned a unique sequential identification number and will receive 
the corresponding treatment according to the randomization scheme described in the Statistical 
Analysis Plan (SAP).  For more information on subject randomization, see Section 7.7. 
7.3 Dose Interruptions and Modifications 
If any subject experiences a Grade 3 AE that is considered possibly related, or related to IMP, 
dosing will be discontinued in that subject and the AE will be followed until resolution (refer to 
Section 9.2 for AE reporting).  Dosing of IMP will not be re-initiated in any subject who 
experiences a possibly related or related Grade 3 AE.  Although these subjects should stop the 
study drug, they are encouraged to return for their remaining study visits.  Elevation in laboratory 
values that do not require medical or surgical treatment or discontinuation from the study will not 
be considered AEs (Section 9.2.1). 
If any subject experiences a Grade 4 AE that is considered possibly related or related to IMP, the 
subject may be unblinded at the discretion of the Investigator and dosing of IMP will be 
discontinued and the AE will be followed until resolution.  Dosing of IMP will not be re-initiated 
in any subject who experiences a possibly related or related Grade 4 AE. 
7.4 Prohibited and Permitted Medications/Non-Medications 
All medications taken 30 days prior to the Screening visit including all prescription and non-
prescription medications (e.g., herbal and/or vitamin supplements), through the End of Study 
(EOS) visit will be recorded for each subject.  
All concomitant therapies and procedures (including any surgical and diagnostic procedures) that 
were performed 72 hours prior to Screening through the EOS visit will be recorded for each 
subject. 
7.4.1 Prohibited Medications/Non-Medications 
The following prescription and over-the-counter drug products are prohibited during the study and 
will be considered a protocol deviation: 


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1. Topical or oral antifungal drugs (with the exception of fluconazole when prescribed by the 
Investigator to treat a subject with a recurrent VVC episode; refer to Section 8.1.12 on 
treatment options if fluconazole is ineffective).  
2. Topical products applied to the vulva or vagina (e.g. antibiotic, antitrichomonal, 
corticosteroids, or anti-inflammatory agents). 
3. Oral antibacterial or antitrichomonal agents for the treatment of bacterial vaginosis, 
trichomonas, or other concomitant (urogenital) infection unless prescribed by the Investigator.  
4. Oral or injectable corticosteroid or immunosuppressive drugs for the duration of the study. Use 
of topical (no vulvar or vaginal steroids), inhaled, ophthalmic, collunarium/nasal, or 
intraarticular and intralesional steroids is permitted. 
5. Drugs with a narrow therapeutic index that are metabolized by CYP3A4 and sensitive to the 
induction of CYP3A4 (carbamazepine, cyclosporine, fentanyl, quinidine, sirolimus and 
tacrolimus). 
6. Vaginal douches or benzalkonium chloride disinfectant during the study. 
7.4.2 Permitted Medications/Non-Medications  
The Investigator may prescribe a single dose of fluconazole to treat an acute VVC recurrence 
during the Maintenance Phase, when confirmed by a positive local KOH or Gram stain showing 
presence of yeast and clinical signs and symptoms score of ≥3. 
Medications to treat any AEs the subject experiences during the study are permitted.  If a subject 
is unable to comply with the excluded medications criteria (Section 7.4.1), the subject’s continued 
participation in the study will be re-evaluated by the Investigator, in consultation with Mycovia 
Pharmaceuticals’ Medical Monitor. 
7.5 Treatment Compliance 
IMP will be administered or dispensed only to eligible subjects under the supervision of the 
Investigator. 
7.6 Replacement of Study Subjects  
Any subject who receives ≥1 dose of study drug will be considered evaluable and will not be 
replaced. 


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7.7 Randomization and Blinding 
A randomized design through an interactive web response system (IWRS) will be used to assign 
subjects in a 2:1 ratio to the dose regimen of VT-1161 or placebo.  Day 1 (Baseline) is defined as 
the first day of VT-1161/Placebo administration and subsequent study days are defined by the 
number of consecutive days thereafter. 
The subjects, study Investigators and their staff, all clinical staff members within Mycovia 
Pharmaceuticals, the clinical study monitor, the study project team, and the study Medical 
Monitor(s) will remain blinded to individual treatment assignments until the completion of the 
study.  The Unblinded Statistician responsible for creating the final randomization list and the 
IWRS personnel responsible for loading the final randomization list into the IWRS will be 
unblinded to the treatments.  The bioanalytical personnel responsible for assay of VT-1161 in 
plasma samples will also be unblinded to subject treatments. 
7.8 Conditions for Breaking the Blind 
In the event the breaking of the blind is required, the following will apply: 
• The Investigator may unblind a subject’s treatment assignment only in the case of an 
emergency (i.e., a Grade 4 AE) OR in the event of a serious medical condition when knowledge 
of the study treatment is essential for the appropriate clinical management or welfare of the 
subject as judged by the Investigator. If the SAE requires that an expedited regulatory report 
be sent to 1 or more regulatory agencies, a copy of the report, identifying the subject’s 
treatment assignment, may be sent to Investigators in accordance with local regulations.  
• The Investigator must contact the Medical Monitor or appropriate Mycovia Pharmaceuticals 
study personnel to communicate the reasons for unblinding the subject’s treatment assignment 
immediately after the unblinding occurred. 
• If unblinding is required, the Mycovia Pharmaceuticals’ Medical Monitor and Investigator will 
be provided with the treatment assigned to the subject. The Investigator must NOT disclose 
the treatment assignment to the subject and/or other study personnel including other site 
personnel, monitors, or the Sponsor’s project team; nor should there be any written or verbal 
disclosure of the code in any of the corresponding subject documents.  The treatment 
assignment of the subject is to be revealed only if that information is important to the safety of 
subjects currently in the study. 
• The date and reason for unblinding must be fully documented in the eCRF. 


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7.9 Treatment After the End of the Study 
After the completion of the study, 
Mycovia 
Pharmaceuticals 
will follow local 
regulatory/International Conference on Harmonisation (ICH) guidelines for any follow-up 
treatment provided to subjects. The Investigator is responsible for ensuring that consideration has 
been given to the post-study care of a subject’s medical condition. 


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8 STUDY PROCEDURES  
8.1 Assessments and Procedures 
The study subjects should be seen within the timeframes noted in the Table 1. Schedule of 
Assessments and Procedures. All study visits should be scheduled within the visit windows and 
projected from the Baseline (Day 1) visit.




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Abbreviations noted above – AEs: adverse events; CBC, complete blood count; ECG: electrocardiogram; EOS: End of Study; HbsAg: Hepatitis B surface antigen; HCV: Hepatitis 
C virus; HIV: human immunodeficiency virus; IMP, investigational medicinal product; KOH: potassium hydroxide prep; PK: pharmacokinetic; WOCBP: women of childbearing 
potential. 
a. 
All medication taken 30 days prior to Screening and all non-pharmacologic treatments received 72 hours prior to Screening will be recorded through the EOS visit. 
b. SF-36, EQ-5D-3L or EQ-5D-Y (for ages 12 to 17), WPAI:SHP, and PHQ-9 patient reported outcome surveys. 
c. 
Weight only 
d. Vital signs include sitting heart rate, blood pressure, temperature, and respiratory rate.  
e. 
Limited Physical Examination, i.e. vaginal speculum examination plus a symptom directed physical examination 
f. 
PK Samples should be collected before the weekly dosing of study drug (placebo/VT-1161). 
g. Serum chemistry (creatinine, BUN, AST, ALT, alkaline phosphatase, total bilirubin, conjugated bilirubin, albumin, total protein, total carbon dioxide, glucose, sodium, 
potassium, chloride, calcium, and phosphorus, creatine phosphokinase [CK], cholesterol, and triglycerides). Testing for HbA1c is performed at Screening. Cultures to test for 
Chlamydia trachomatis and Neisseria gonorrhoeae will be taken at Screening and sent to the central lab. Testing for Bacterial vaginosis will be done locally at Screening.  An 
OSOM® Rapid test or similar test will be performed for Trichomonas vaginalis locally at Screening. 
h. For WOCBP, a local lab urine pregnancy test will be performed at every study visit. A central lab serum pregnancy test will also be performed at Screening, Baseline, and Weeks 
12, 24, and 48. 
i. 
IMP is to be administered within 30 minutes after the subject’s main meal of the day (as determined by the subject) at approximately the same time of the day consistently 
throughout the study. Approximately 240 mL (approx. 8 oz.) of water is to be consumed with each dose of IMP.  Remind subject to bring IMP to each visit to ensure compliance.  
j. 
All procedures listed are to be completed only for unscheduled visits where a recurrent VVC episode is suspected. If the unscheduled visit is for repeat procedures (i.e., ECG, 
safety labs, etc.), only those specific procedures need to be performed, along with collection of any changes in medical treatments or medications and collection of any AEs. 


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8.1.1 Screening Assessments and Procedures (Day -14 ±2 Days) 
Subjects will be screened 14 days prior to randomization.  The subject will start open-label 
fluconazole treatment at Screening if the subject has met all preliminary enrollment criteria, 
(central lab results are not required to initiate fluconazole treatment).  Proper written informed 
consent (or assent for those ages 12 to 17) must be obtained from all subjects prior to any study 
procedures, see Section 13.2 for more information.  Once the subject has signed the 
Institutional Review Board (IRB) / Independent Ethic Committee (IEC) approved informed 
consent document or assent the following evaluations will be performed to assess subject 
eligibility: 
1. Review Inclusion and Exclusion criteria. 
2. Document subject demographics, including date of birth, race, and ethnic origin.  
3. Document and review medical/medication and surgical history, including all current, 
pertinent and major past illnesses and surgical procedures. All concomitant therapies or 
procedures (including any surgical or diagnostic procedures) that were performed 72 hours 
prior to the Screening will be recorded. 
4. Review alcohol and tobacco history (previous 12 months). 
5. Record all medications, including prescription and non-prescription medications, herbal 
products, and vitamin/mineral supplements taken within 30 days prior to Screening.       
6. Administer the SF-36, EQ-5D-3L or EQ-5D-Y (for ages 12 to 17), WPAI:SHP, and PHQ-
9 Patient Reported Outcomes Surveys for all regions and RVVC History Questionnaire 
(US only). 
7. Assess height and weight to determine the body mass index. 
8. Obtain vital signs in the sitting position (blood pressure, heart rate, respiratory rate, and 
temperature). 
9. Conduct a comprehensive physical examination, including vaginal exam, as described in 
Section 9.1.3. For proper assessment, it is best the subject is not menstruating at time of 
the visit. 


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10. Recording of clinical signs and symptoms of vulvovaginitis, as outlined in Section 9.1.7. 
Subjects must be cautioned to not use any treatment (topical or systemic) for their infection 
during the Screening period. 
11. KOH wet mount test or Gram stain, performed locally (Section 9.1.6). 
12. Vaginal swab for culture will be obtained and sent to the central mycology laboratory 
(Section 9.1.6). 
13. Standard 12-lead ECG will be obtained in the supine position (Section 9.1.4).    
14. Clinical chemistries, hematology, and urinalysis for study eligibility as outlined in Section 
9 and the Schedule of Assessments and Procedures.  Cultures for testing of Chlamydia 
trachomatis and Neisseria gonorrhoeae will also be taken. Vaginal pH will be determined. 
Local testing will be done for Bacterial vaginosis and an OSOM® Rapid test or similar test 
will be performed locally for Trichomonas vaginalis.   
15. Testing for HbsAg, HCV, and HIV as outlined in Section 9.1.5.2 and the Schedule of 
Assessments and Procedures. (Results for these tests are not required for the start of 
Induction Phase- treatment with fluconazole). 
16. A urine pregnancy test will be performed locally and a serum pregnancy test will be 
obtained and sent to the central laboratory for all women of childbearing potential 
(WOCBP). 
17. Provide subject with 3 doses of fluconazole.  The subject should be advised to take one 
fluconazole tablet or capsule on the day of the visit (day 1) and on days 4 and 7 at home, 
at approximately the same time of the day. 
18. Remind subject to return for Day 1 visit. 
Central laboratory results are not required prior to start of treatment with fluconazole.  
Subjects may be eligible for re-screening, one time.  The investigative site is to refer to the 
Study Procedures Manual and contact the study clinical monitor for guidance. 
 
 


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8.1.2 Baseline (Day 1) Assessments and Procedures 
The subjects will return to the investigative site for the following evaluations: 
1. Confirm all Inclusion and Exclusion criteria have been met 
2. Record all medications taken since the previous visit, including all prescription and non-
prescription medications, herbal products, and vitamin/mineral supplements. All 
concomitant therapies or procedures (including any surgical or diagnostic procedures) that 
were performed since the last visit will be recorded. 
3. Review and record any AEs.  
4. Obtain vital signs in the sitting position, (blood pressure, heart rate, respiratory rate, and 
temperature). 
5. Limited physical examination, includes vaginal exam (as described in Section 9.1.3).  For 
proper assessment, it is best the subject is not menstruating at time of the visit. 
6. Recording of clinical signs and symptoms of vulvovaginitis, as outlined in Section 9.1.7. 
Subjects must be cautioned to not use any treatment (topical or systemic) for vulvovaginitis 
except study drug. 
7. Vaginal swab for culture will be obtained and sent to the central mycology laboratory 
(Section 9.1.6). 
8. Standard 12-lead ECG will be obtained in the supine position (Section 9.1.4).  
9. Obtain PK plasma specimen prior to the first dose of study drug (placebo/VT-1161). 
10. Obtain clinical chemistries, hematology, and urinalysis as outlined in Section 9 and the 
Schedule of Assessments and Procedures.  
11. A urine pregnancy test will be performed locally and a serum pregnancy test will be 
obtained and sent to the central laboratory for all WOCBP. 
12. IWRS randomization of the subject to a treatment arm. 
13. Provide bottle for IMP daily dosing to subject along with instructions. 
14. Remind subject to return for Day 14 (±2 days) visit. 


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8.1.3 Day 14 (±2 Days) Assessments and Procedures 
Subjects will return to the investigative site for follow-up evaluation as follows: 
1. Record all medications taken since the previous visit, including all prescription and non-
prescription medications, herbal products, and vitamin/mineral supplements. All 
concomitant therapies or procedures (including any surgical or diagnostic procedures) that 
were performed since the previous visit. 
2. Review and record any AEs.  
3. Obtain vital signs in the sitting position, (blood pressure, heart rate, respiratory rate, and 
temperature). 
4. Limited physical examination, includes vaginal exam (as described in Section 9.1.3).  For 
proper assessment, it is best the subject is not menstruating at time of the visit. 
5. Recording of clinical signs and symptoms of vulvovaginitis, as outlined in Section 9.1.7. 
Subjects must be cautioned to not use any treatment (topical or systemic) for vulvovaginitis 
except study drug. 
6. Vaginal swab for culture will be obtained and sent to the central mycology laboratory 
(Section 9.1.6). 
7. Standard 12-lead ECG will be obtained in the supine position (Section 9.1.4).  
8. Obtain PK plasma specimen. 
9. Obtain clinical chemistries, hematology, and urinalysis as outlined in Section 9 and the 
Schedule of Assessments and Procedures.  
10. A urine pregnancy test will be performed locally for all WOCBP. 
11. Collect and review accountability of IMP daily dose bottle with the subject for compliance.  
12. Dispense bottle for IMP weekly dosing to the subject along with instructions 
13. Remind subject to return for Week 6 (±7 days) visit. 
 


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8.1.4 Week 6 (±7 Days) Assessments and Procedures 
Subjects will return to the investigative site for follow-up evaluation as follows: 
1. Record all medications taken since the previous visit, including all prescription and non-
prescription medications, herbal products, and vitamin/mineral supplements. All 
concomitant therapies or procedures (including any surgical or diagnostic procedures) that 
were performed since the previous visit.     
2. Review and record any AEs.  
3. Obtain vital signs in the sitting position, (blood pressure, heart rate, respiratory rate, and 
temperature). 
4. Limited physical examination, includes vaginal exam (as described in Section 9.1.3).  For 
proper assessment, it is best the subject is not menstruating at time of the visit. 
5. Recording of clinical signs and symptoms of vulvovaginitis, as outlined in Section 9.1.7. 
Subjects must be cautioned to not use any treatment (topical or systemic) for vulvovaginitis 
except study drug. 
6. Vaginal swab for culture will be obtained and sent to the central mycology laboratory 
(Section 9.1.6). 
7. Obtain clinical chemistries, as outlined in Section 9.1.5.3. 
8. A urine pregnancy test will be performed locally for all WOCBP. 
9. Review accountability of IMP weekly dose bottle with the subject for compliance.   
10. Remind subject to return for Week 12 (±14 days) visit. 
 
 


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8.1.5 Week 12 (±14 Days) Assessments and Procedures 
The subjects will return to the investigative site for the following evaluations: 
1. Record all medications taken since the previous visit, including all prescription and non-
prescription medications, herbal products, and vitamin/mineral supplements. All 
concomitant therapies or procedures (including any surgical or diagnostic procedures) that 
were performed since the previous visit.     
2. Review and record any AEs.  
3. Obtain body weight. 
4. Obtain vital signs in the sitting position, (blood pressure, heart rate, respiratory rate, and 
temperature). 
5. Limited physical examination, includes vaginal exam (as described in Section 9.1.3).  For 
proper assessment, it is best the subject is not menstruating at time of the visit. 
6. Recording of clinical signs and symptoms of vulvovaginitis, as outlined in Section 9.1.7. 
Subjects must be cautioned to not use any treatment (topical or systemic) for vulvovaginitis 
except study drug. 
7. Vaginal swab for culture will be obtained and sent to the central mycology laboratory 
(Section 9.1.6). 
8. Standard 12-lead ECG will be obtained in the supine position (Section 9.1.4).  
9. Obtain PK plasma specimen. 
10. Obtain clinical chemistries, hematology, and urinalysis as outlined in Section 9 and the 
Schedule of Assessments and Procedures.  
11. A urine pregnancy test will be performed locally and a serum pregnancy test will be 
obtained and sent to the central laboratory for all WOCBP. 
12. Collect and conduct final review accountability of IMP weekly dose bottle with the subject 
for compliance.  
13. Remind subject to return for Week 18 (±14 days) visit. 


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8.1.6 Week 18 (±14 Days) Assessments and Procedures 
The subjects will return to the investigative site for the following evaluations: 
1. Record all medications taken since the previous visit, including all prescription and non-
prescription medications, herbal products, and vitamin/mineral supplements. All 
concomitant therapies or procedures (including any surgical or diagnostic procedures) that 
were performed since the previous visit.     
2. Review and record any AEs.  
3. Obtain vital signs in the sitting position, (blood pressure, heart rate, respiratory rate, and 
temperature). 
4. Limited physical examination, includes vaginal exam (as described in Section 9.1.3).  For 
proper assessment, it is best the subject is not menstruating at time of the visit. 
5. Recording of clinical signs and symptoms of vulvovaginitis, as outlined in Section 9.1.7. 
Subjects must be cautioned to not use any treatment (topical or systemic) for vulvovaginitis 
except study drug. 
6. Vaginal swab for culture will be obtained and sent to the central mycology laboratory 
(Section 9.1.6). 
7. Obtain clinical chemistries, as outlined in Section 9.1.5.3. 
8. A urine pregnancy test will be performed locally for all WOCBP. 
9. Remind subject to return for Week 24 (±14 days) visit. 
 
 


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8.1.7 Week 24 (±14 Days) Assessments and Procedures 
Subjects will return to the investigative site for follow-up evaluations as follows: 
1. Record all medications taken since the previous visit, including all prescription and non-
prescription medications, herbal products, and vitamin/mineral supplements. All 
concomitant therapies or procedures (including any surgical or diagnostic procedures) that 
were performed since the previous visit.     
2. Review and record any AEs.  
3. Administer the SF-36, EQ-5D-3L or EQ-5D-Y (for ages 12 to 17), WPAI:SHP, and PHQ-
9 Patient Reported Outcomes Surveys. 
4. Obtain body weight. 
5. Obtain vital signs in the sitting position, (blood pressure, heart rate, respiratory rate, and 
temperature). 
6. Limited physical examination, includes vaginal exam (as described in Section 9.1.3).  For 
proper assessment, it is best the subject is not menstruating at time of the visit. 
7. Recording of clinical signs and symptoms of vulvovaginitis, as outlined in Section 9.1.7. 
Subjects must be cautioned to not use any treatment (topical or systemic) for vulvovaginitis 
except study drug. 
8. Vaginal swab for culture will be obtained and sent to the central mycology laboratory 
(Section 9.1.6). 
9. Standard 12-lead ECG will be obtained in the supine position (Section 9.1.4).  
10. Obtain PK plasma specimen. 
11. Obtain clinical chemistries, hematology, and urinalysis as outlined in Section 9 and the 
Schedule of Assessments and Procedures.  
12. A urine pregnancy test will be performed locally and a serum pregnancy test will be 
obtained and sent to the central laboratory for all WOCBP. 
13. Remind subject to return for Week 30 (±14 days) visit. 


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8.1.8 Week 30 (±14 Days) Assessments and Procedures 
Subjects will return to the investigative site for follow-up evaluations as follows: 
1. Record all medications taken since the previous visit, including all prescription and non-
prescription medications, herbal products, and vitamin/mineral supplements. All 
concomitant therapies or procedures (including any surgical or diagnostic procedures) that 
were performed since the previous visit.     
2. Review and record any AEs.  
3. Obtain vital signs in the sitting position, (blood pressure, heart rate, respiratory rate, and 
temperature). 
4. Limited physical examination, includes vaginal exam (as described in Section 9.1.3).  For 
proper assessment, it is best the subject is not menstruating at time of the visit. 
5. Recording of clinical signs and symptoms of vulvovaginitis, as outlined in Section 9.1.7. 
Subjects must be cautioned to not use any treatment (topical or systemic) for vulvovaginitis 
except study drug. 
6. Vaginal swab for culture will be obtained and sent to the central mycology laboratory 
(Section 9.1.6). 
7. Obtain clinical chemistries, as outlined in Section 9.1.5.3. 
8. A urine pregnancy test will be performed locally for all WOCBP. 
9. Remind subject to return for Week 36 (±14 days) visit. 
 
 


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8.1.9 Week 36 (±14 Days) Assessments and Procedures 
Subjects will return to the investigative site for follow-up evaluations as follows: 
1. Record all medications taken since the previous visit, including all prescription and non-
prescription medications, herbal products, and vitamin/mineral supplements. All 
concomitant therapies or procedures (including any surgical or diagnostic procedures) that 
were performed since the previous visit.     
2. Review and record any AEs.  
3. Obtain vital signs in the sitting position, (blood pressure, heart rate, respiratory rate, and 
temperature). 
4. Limited physical examination, includes vaginal exam (as described in Section 9.1.3).  For 
proper assessment, it is best the subject is not menstruating at time of the visit. 
5. Recording of clinical signs and symptoms of vulvovaginitis, as outlined in Section 9.1.7. 
Subjects must be cautioned to not use any treatment (topical or systemic) for vulvovaginitis 
except study drug. 
6. Vaginal swab for culture will be obtained and sent to the central mycology laboratory 
(Section 9.1.6). 
7. Obtain PK plasma specimen. 
8. Obtain clinical chemistries, hematology, and urinalysis as outlined in Section 9 and the 
Schedule of Assessments and Procedures.  
9. A urine pregnancy test will be performed locally for all WOCBP. 
10. Remind subject to return for Week 42 (±14 days) visit. 
 
 


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8.1.10 Week 42 (±14 Days) Assessments and Procedures 
Subjects will return to the investigative site for follow-up evaluations as follows: 
1. Record all medications taken since the previous visit, including all prescription and non-
prescription 
medications, 
herbal 
products, 
and 
vitamin/mineral 
supplements. 
All concomitant therapies or procedures (including any surgical or diagnostic procedures) 
that were performed since the previous visit.     
2. Review and record any AEs.  
3. Obtain vital signs in the sitting position, (blood pressure, heart rate, respiratory rate, and 
temperature). 
4. Limited physical examination, includes vaginal exam (as described in Section 9.1.3).  For 
proper assessment, it is best the subject is not menstruating at time of the visit. 
5. Recording of clinical signs and symptoms of vulvovaginitis, as outlined in Section 9.1.7. 
Subjects must be cautioned to not use any treatment (topical or systemic) for vulvovaginitis 
except study drug. 
6. Vaginal swab for culture will be obtained and sent to the central mycology laboratory 
(Section 9.1.6). 
7. Obtain clinical chemistries, as outlined in Section 9.1.5.3. 
8. A urine pregnancy test will be performed locally for all WOCBP. 
9. Remind subject to return for Week 48 (±14 days) visit. 
 
 


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8.1.11 Week 48 (±14 Days) Assessments and Procedures (End of Study) 
Subjects will return to the investigative site for follow-up evaluations as follows: 
1. Record all medications taken since the previous visit, including all prescription and non-
prescription medications, herbal products, and vitamin/mineral supplements. All 
concomitant therapies or procedures (including any surgical or diagnostic procedures) that 
were performed since the previous visit.     
2. Review and record any AEs.  
3. Administer the SF-36, EQ-5D-3L or EQ-5D-Y (for ages 12 to 17), WPAI:SHP, and PHQ-
9 Patient Reported Outcomes Surveys. 
4. Obtain body weight. 
5. Obtain vital signs in the sitting position, (blood pressure, heart rate, respiratory rate, and 
temperature). 
6. Limited physical examination, includes vaginal exam (as described in Section 9.1.3).  For 
proper assessment, it is best the subject is not menstruating at time of the visit. 
7. Recording of clinical signs and symptoms of vulvovaginitis, as outlined in Section 9.1.7. 
Subjects must be cautioned to not use any treatment (topical or systemic) for vulvovaginitis 
except study drug. 
8. Vaginal swab for culture will be obtained and sent to the central mycology laboratory 
(Section 9.1.6). 
9. Standard 12-lead ECG will be obtained in the supine position (Section 9.1.4).  
10. Obtain PK plasma specimen. 
11. Obtain clinical chemistries, hematology, and urinalysis as outlined in Section 9 and the 
Schedule of Assessments and Procedures.  
12. A urine pregnancy test will be performed locally and a serum pregnancy test will be 
obtained and sent to the central laboratory for all WOCBP. 


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If the Investigator suspects the subject is experiencing a recurrent episode at a regular study 
visit, a local KOH wet mount test or Gram stain is to be performed to confirm whether 
filamentous hyphae/pseudohyphae and/or budding yeast cells are present. 
8.1.12 Unscheduled Visit Assessment and Procedures 
Subjects should be encouraged to return for an unscheduled visit if they experience a 
recurrence of VVC anytime during the study.  The following evaluations are to be performed: 
1. Record all medications taken since the previous visit, including all prescription and non-
prescription medications, herbal products, and vitamin/mineral supplements. All 
concomitant therapies or procedures (including any surgical or diagnostic procedures) that 
were performed since the previous visit.     
2. Review and record any AEs.  
3. Administer the SF-36, EQ-5D-3L or EQ-5D-Y (for ages 12 to 17), WPAI:SHP, and PHQ-
9 Patient Reported Outcomes Surveys. 
4. Obtain vital signs in the sitting position, (blood pressure, heart rate, respiratory rate, and 
temperature). 
5. Limited physical examination, includes vaginal exam (as described in Section 9.1.3).  For 
proper assessment, it is best the subject is not menstruating at time of the visit. 
6. Recording of clinical signs and symptoms of vulvovaginitis, as outlined in Section 9.1.7. 
Subjects must be cautioned to not use any treatment (topical or systemic) for vulvovaginitis 
except study drug. 
7.  KOH wet mount test or Gram stain, performed locally (Section 9.1.6). 
8. Vaginal swab for culture will be obtained and sent to the central mycology laboratory 
(Section 9.1.6). 
9. Obtain PK plasma specimen. 
10. A urine pregnancy test will be performed locally for all WOCBP. 
11. Obtain clinical chemistries, as outlined in Section 9.1.5.3. 


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If a subject has a recurrent acute VVC episode prior to the end of treatment at Week 12, the 
subject will continue her assigned treatment through Week 12 and will receive one dose of 
fluconazole to treat her acute VVC infection.  Throughout the Maintenance Phase, the 
Investigator is to prescribe one dose of fluconazole to treat the acute VVC episode, once 
confirmed by a positive KOH or Gram stain to show presence of yeast and if the clinical signs 
and symptoms score is ≥3.  If a subject fails to respond to fluconazole treatment, the 
Investigator may employ treatment options corresponding to the site’s standard of care 
treatment upon consult with the Medical Monitor. 
If a subject comes in for an unscheduled visit to repeat a procedure (i.e., ECG, safety labs, 
etc.), only those specific procedures need to be performed, along with collection of any changes 
in medical treatments, medications and collection of any AEs. 
If subjects experience any AEs other than a potential recurrent VVC episode they may be 
evaluated at the site at the Investigators discretion. 
8.2 Exercise 
Subjects will be encouraged, if possible, to avoid engaging in strenuous activity within 
48 hours prior to study visits.  Walking at a normal pace during these periods is acceptable. 


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9 SAFETY ASSESSMENTS 
9.1 Safety Tests and Assessments 
Safety assessments will include attention to relevant changes in the following parameters, 
which are identified as occurring after the start of IMP, regardless of whether the change is in 
an examination finding, test result, or symptom(s) reported by a subject, and regardless of 
presumed relationship to IMP (VT-1161 or placebo). The Investigator will follow all clinically 
significant abnormal findings after IMP treatment until resolution, return to baseline, or 
permanent documented change in medical history. 
9.1.1 Height and Weight 
Height and body weight will be collected at times specified in the Table 1. Schedule of 
Assessments and Procedures. 
9.1.2 Vital Signs 
Vital signs to include body temperature, heart rate (pulse), breathing rate, and blood pressure 
will be obtained in a sitting position at times specified in the Table 1. Schedule of Assessments 
and Procedures. 
9.1.3 Physical Examination 
Comprehensive Physical Examination: general appearance; head, eyes, ears, nose, and throat; 
thyroid/neck (endocrine); chest and lungs; cardiovascular system, abdomen, pelvic exam, 
musculoskeletal system, lymph nodes, extremities/skin, and neurological system will be 
performed at Screening.  Special attention should be given during the vulvovaginal 
examination to erythema, edema, and excoriation.  For proper assessment, it is best the subject 
is not menstruating at time of the study visits.   
Symptom Directed Physical Examination: A symptom directed physical exam consists of a 
very brief history of present illness. Investigators should use the symptom directed exam for 
all study visits after the Screening visit. If the subject has no present illness this should be 
documented by the Investigator or qualified designee.   
9.1.4 Electrocardiograms 
Standard 12-lead ECGs to assess heart rate, rhythm, and interval information such as PR, QRS, 
QT, and QTc will be obtained in the supine position at times specified in the Table 1. Schedule 
of Assessments and Procedures. 


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9.1.5 Laboratory Determinations 
After the Baseline (Day 1) visit, laboratory test values that fall outside the reference range on 
the laboratory reports and are deemed clinically significant by the Investigator may be repeated 
at the discretion of the Investigator.  Those values deemed clinically significant should be 
followed until resolution or permanent documented change in medical history.    
The following laboratory samples will be obtained at times specified in the Schedule of 
Assessments and Procedures and analyzed by the central laboratory: 
9.1.5.1 Pregnancy Testing 
All WOCBP must undergo urine and serum pregnancy testing at Screening and Baseline to 
assess protocol eligibility. Urine pregnancy testing will be performed at every study visit. 
Serum pregnancy tests will be performed periodically throughout the study as specified in the 
Schedule of Assessments and Procedures. 
9.1.5.2 Immunology 
HIV antibody, HbsAg, anti-HCV at Screening.  Laboratory results are not required prior to 
start of treatment with fluconazole.  Investigators are to follow local and/or state laws in regards 
to parental disclosure of any positive pregnancy tests or reportable and treatable serologies or 
STDs in adolescents. 
9.1.5.3 Clinical Chemistry Panel 
Creatinine, blood urea nitrogen, AST, ALT, alkaline phosphatase, total bilirubin, conjugated 
bilirubin, albumin, total protein, total carbon dioxide, glucose, sodium, potassium, chloride, 
calcium, phosphorus, CK, cholesterol, and triglycerides. Testing for HbA1c should be 
performed for all subjects at Screening. Central laboratory results are not required prior to start 
of treatment with fluconazole. 
After the Baseline (Day 1) visit, subjects may be re-tested for ALT, AST and total bilirubin to 
confirm any abnormal values and to determine if they are increasing or decreasing.  
The Investigator will also assess the subject for any associated emergent symptoms. 
9.1.5.4 Hematology 
A complete blood count with differential to include red blood cell count, total and differential 
white blood cell counts, hemoglobin, hematocrit, RBC, MCV, MCH, MCHC, RDW and 
platelet count will be performed at times specified in the Table 1. Schedule of Assessments 


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and Procedures.  Central laboratory results are not required prior to start of treatment with 
fluconazole. 
9.1.5.5 Urinalysis 
Testing for glucose, ketones, leukocyte esterase, nitrite, blood, pH, protein, and specific gravity 
will be performed at times specified in the Schedule of Assessments and Procedures.  Central 
laboratory results are not required prior to start of treatment with fluconazole. 
9.1.5.6 Chlamydia Trachomatis and Neisseria Gonorrhoeae 
Cultures to test for Chlamydia trachomatis and Neisseria gonorrhoeae will be taken at 
Screening and sent to the central laboratory.   
9.1.5.7 Trichomonas Vaginalis 
An OSOM® Rapid test or similar test will be performed for Trichomonas vaginalis locally at 
Screening.  Instructions for collecting, processing, storing, and shipping samples to the central 
laboratory are outlined in the laboratory manual. 
9.1.5.8 Bacterial Vaginosis 
Testing for Bacterial vaginosis will be done locally. 
9.1.6 KOH Wet Mount Tests or Gram Stains and Fungal Cultures 
A local KOH wet mount test or Gram stain will be performed locally at the Screening visit and 
at unscheduled visits where a recurrent VVC episode is suspected.  The investigative site is to 
use the same local mycology test (KOH wet mount or Gram stain) consistently for all subjects 
throughout the study.   
A vaginal fungal culture will be obtained at Screening and all subsequent visits and sent to the 
central mycology laboratory for fungal identification and susceptibility testing according to 
approved Clinical Laboratory Standards Institute methods.  Subjects should not be 
menstruating at time of the study visits to ensure proper sample collection of the vaginal fluid.  
Details as to the collection of samples, shipping, testing methods and analysis will be 
delineated in a laboratory manual.  Mycology samples may be retained for future analysis for 
a period of up to 15 years, after which time the samples will be destroyed. 
 
 


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9.1.7 Vulvovaginitis Clinical Assessment 
Vulvovaginal signs and symptoms will be evaluated at the Screening and each subsequent 
study visit.  Each of the following vulvovaginal signs and symptoms will be scored and the 
individual scores combined for a maximum score of 18, using the following scale: 
a. Signs: erythema, edema, and excoriation 
b. Symptoms: itching, burning, and irritation 
 
Scoring Scale: Each score should be objectively defined on a scale of 0 to 3 as follows: 
0 = none (complete absence of any signs or symptoms) 
1 = mild (slight) 
2 = moderate (definitely present) 
3 = severe (marked, intense) 
9.2 Adverse Event Reporting 
9.2.1 Definition of Adverse Events 
Monitoring of all AEs will be conducted throughout the study as specified in the Schedule of 
Assessments and Procedures. 
An AE is any untoward, undesired, unplanned clinical event in the form of signs, symptoms, 
disease, or laboratory or physiological observations occurring in a human participating in a 
clinical study with a Mycovia Pharmaceuticals product, regardless of causal relationship. 
A “pre-existing” condition is one that is present prior to the start of IMP administration and is 
reported as part of the subject’s medical history.  Pre-existing conditions should be reported as 
Aes only if the frequency, intensity, or character of the pre-existing condition worsens during 
the study. 
Any abnormal safety assessments, such as ECGs, radiological scans, vital sign measurements, 
that are judged by the Investigator to be clinically significant should be recorded as an AE or 
SAE provided it meets one of those definitions.  Laboratory abnormalities generally are not 
considered AEs unless they are associated with clinical signs or symptoms or require medical 
intervention.  A laboratory abnormality (e.g., a clinically significant change detected on 
clinical chemistry, hematology) that is independent from a known underlying medical 
condition and that requires medical or surgical intervention, or leads to IMP interruption or 
discontinuation, should be considered an AE. 


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Clinically significant abnormal laboratory findings or other abnormal assessments that are 
associated with the disease being studied are not considered AEs unless their severity is greater 
than expected in the judgement of the Investigator.  
In addition, the following apply: 
• All AEs, including clinically significant laboratory abnormalities, will be documented as 
an AE and followed until resolution. 
• All AEs and SAEs will be collected from the start of taking the first dose of fluconazole 
until the last follow-up visit of the study, at the time points specified in the Schedule of 
Assessments and Procedures. 
• Medical occurrences that begin prior to the start of fluconazole but after obtaining informed 
consent should be recorded in the medical history section of the eCRF. 
• Investigators are not obligated to actively seek AEs or SAEs in former study subjects. 
However, if the Investigator learns of an SAE, including a death, at any time after a subject 
has been discharged from the study, and he/she considers the event reasonably related to 
the study treatment or study participation, the Investigator must promptly notify Mycovia 
Pharmaceuticals. 
9.2.2 Definition of a Serious Adverse Event 
An SAE is any AE occurring after the first administration of fluconazole that results in any of 
the following outcomes: 
• Deatha 
• Is a life-threatening experienceb 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in a persistent or significant disability/incapacityc 
• Results in a congenital anomaly/birth defect 
• Additionally, important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical intervention to 


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prevent 1 of the outcomes listed above.  Example: allergic bronchospasm requiring 
intensive treatment in an emergency room or at home. 
NOTES: 
a. “Death” is an outcome and is NOT the AE.  In the event of death, the cause of death should 
be recorded as the SAE.  The only exception is “sudden death” when the cause is unknown. 
b. Life-threatening SAEs include any adverse drug experience, which, in the view of the 
Investigator, places the subject at immediate risk of death from the reaction as it occurs. It 
does not include a reaction that, had it occurred in a more serious form, might have caused 
death. 
c. Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions. 
All SAEs, regardless of causal relationship, must be reported to Mycovia Pharmaceuticals 
(or designee) within 24 hours of the site’s knowledge of the event.  The initial report must be 
captured in the electronic SAE CRFs within 1 business day. 
The SAE report should provide as much of the required information as is available at the time. 
The following minimum information is required for reporting an SAE: subject identification 
number, reporting source, and an event outcome.  Supplemental information may be entered 
into the electronic SAE CRFs and should not delay the initial report.  Mycovia Pharmaceuticals 
(or designee) may contact the investigational site to solicit additional information or to follow-
up on the event. 
If there is any doubt whether the information constitutes an SAE, the information will be 
treated as an SAE for the purposes of this protocol. 
All SAEs will be followed until resolution, return to baseline (when worsening of a pre-existing 
condition is reported), or permanent documented change in medical history. 
All relevant documentation pertaining to the SAE (additional laboratory tests, consultation 
reports, discharge summaries, post-mortem reports, etc.) will be provided by the Investigator 
to Mycovia Pharmaceuticals (or designee) in a timely manner. 


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9.2.3 Recording of Adverse Events  
Subjects should be instructed to report all AEs to the Investigator.  In addition, the Investigator 
should seek to elicit any clinical or objective reactions by open-ended questioning (“How have 
you been feeling?”) and, as appropriate, by examination.  All AE information obtained during 
the subject questioning should be documented in the subjects’ clinical records and entered into 
the CRF.  All clearly related signs, symptoms, and results of diagnostic procedures performed 
because of an AE should be grouped together and recorded as a single diagnosis.  The 
component parts of the diagnosis may be listed for verification.  If the AE is a laboratory 
abnormality that is part of a clinical condition or syndrome, it should be recorded as the 
syndrome or diagnosis rather than the individual laboratory abnormality.  It should also be 
documented, verbatim, directly on the laboratory report. 
To avoid vague, ambiguous, or colloquial expressions, all AEs should be recorded in standard 
medical terminology on the CRF and on the medical record rather than in the subject’s own 
words.  Each AE will also be described in terms of duration (start and stop date), severity, 
association with the IMP, action(s) taken, and outcome. 
9.2.4 Severity of Adverse Events 
All AEs and SAEs will be assessed by the Investigator or MD designee for severity, according 
to the Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity Table, (Draft, 
November 2007) Appendix A.  For AEs involving a body system or laboratory value which is 
not addressed in the DMID Adult Toxicity Table, the most recent version of the Common 
Terminology Criteria for Adverse Events, version 4.0 published by the National Cancer 
Institute will be used. 
Where discrepancies in the ULN and lower limit of normal (LLN) laboratory ranges occur 
between those included in the DMID and those of the central laboratory that performs the 
assays, the values provided by the central laboratory will be used for assignment of severity 
grade. 
For AEs involving a body system or laboratory value not addressed in the DMID Adult 
Toxicity Table, the following general scale may be used with Investigator discretion to assign 
severity: 
• GRADE 1 Mild: An event easily tolerated by the subject; transient or mild discomfort 
(usually < 48 hours); no medical intervention/therapy required. 


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• GRADE 2 Moderate: An event that may interfere with normal, everyday activities; some 
assistance may be needed; no or minimal medical intervention/therapy required. 
• GRADE 3 Severe: An event that prevented the subject from performing their normal, 
everyday activities; some assistance usually required; medical intervention/therapy 
required; hospitalizations possible. 
• GRADE 4 Life-threatening: At the time of the event the subject was at risk of death or 
the event resulted in a persistent or significant disability or incapacity. 
• GRADE 5 Death: An event that resulted in death. 
When changes in the severity of an AE occur more frequently than once a day, the maximum 
severity for the experience that day should be noted. If the severity category changes over 
several days, then those changes should be recorded separately (with distinct onset dates). 
NOTE: An AE that is assessed as severe should not be confused with an SAE.  Severity is a 
category utilized for rating the intensity of an event (such as mild, moderate, or severe 
myocardial infarction).  However, the event itself may be of relatively minor medical 
significance, (such as a severe headache), and both AE(s) and SAE(s) can be assessed as 
severe.  An event is defined as ‘serious’ when it meets one of the pre-defined outcomes as 
described in Section 9.2.2. 
Where discrepancies in the ULN and lower limit of normal of laboratory ranges occur between 
those included in the DMID tables and those of the central laboratory that performs the assays, 
the values provided by the central laboratory will be used for assignment of severity grade. 
9.2.5 Causality Assessment 
The Investigator is obligated to assess the relationship between the IMP and the occurrence of 
each AE or SAE by using his or her best clinical judgment.  It should be clearly documented 
in the medical notes that he/she has reviewed the AE/SAE and that they are the ones providing 
the assessment of causality. Other elements to be considered, such as the history of the 
underlying disease, concomitant therapy, other risk factors, and the temporal relationship of 
the event to the IMP will be considered and investigated.  The Investigator will also consult 
the VT-1161 Investigational Brochure and the study Medical Monitor in estimating the 
relationship. 


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An SAE may be recorded when the Investigator has minimal information to include in the 
initial report. However, the Investigator must always make an assessment of causality for every 
event prior to reporting the SAE report. The Investigator may change his or her opinion of the 
causality upon evaluation of follow-up information or discussions with the study Medical 
Monitor with subsequent amendment of the SAE report. Causality assessment is one of the 
criteria used to determine regulatory reporting requirements and should not be left blank. 
For each reported adverse reaction, the Investigator must assess the relationship of the event 
to the IMP using the following scale: 
Unrelated: 
• Does not follow a known response pattern to the suspect IMP (if response pattern is 
previously known). 
• Can clearly be explained by the known characteristics of the subject’s clinical state or other 
modes of therapy administered to the subject. 
Unlikely Related: 
• The temporal sequence from administration of the IMP suggests that a relationship is 
unlikely. 
• Follows a response pattern that is unlike that of the suspect IMP (if response pattern is 
previously known). 
• Could be reasonably explained by the subject’s clinical state or other modes of therapy 
administered to the subject. 
Possibly Related: 
• Follows a reasonable temporal sequence from administration of the IMP. 
• May follow a known response pattern to the suspect IMP (if response pattern is previously 
known). 
• Could also be reasonably explained by the subject’s clinical state or other modes of therapy 
administered to the subject. 
 


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Related: 
• Follows a reasonable temporal sequence from administration of the IMP. 
• Could not be reasonably explained by the known characteristics of the subject’s clinical 
state or any other modes of therapy administered to the subject. 
• Is confirmed by improvement on stopping or slowing administration of the IMP, if 
applicable. 
If an assessment is not provided, the event will be treated as Possibly Related for purposes of 
regulatory reporting. 
9.2.6 Action Taken Following Adverse Events 
For each reported AE and SAE, the Investigator must document the action taken according to 
the following criteria: 
• No action taken 
• Non-pharmacologic treatment added 
• New drug therapy added 
• IMP interrupted 
• Discontinued from study 
• New or prolonged hospitalization 
9.2.7 Outcome of Adverse Events 
For each reported AE and SAE, the Investigator must document the outcome according to the 
following criteria: 
• Resolved 
• Ongoing 
• Unknown 
• Death 


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The appropriate AE or SAE report page will be updated once the outcome is determined. 
The Investigator will also ensure that additional follow-up information includes any 
supplemental data that may explain causality of the event(s). 
For SAEs, new or updated information will be recorded on the originally completed SAE 
report, with all changes signed and dated by the Investigator or designee.  The updated SAE 
report will then be signed by the Investigator and resubmitted to Mycovia Pharmaceuticals (or 
designee). 
9.2.8 Other Reportable Events 
Reports of overdose (with or without an AE), abuse, dependency, inadvertent or accidental 
exposure, pregnancy and unexpected therapeutic benefit should be forwarded to Mycovia 
Pharmaceuticals (or designee) in the same time frame as an SAE. 
Overdose occurs when a subject is administered or has taken a dose substantially greater than 
the intended or scheduled dose specified by the protocol. 
All pregnancies occurring from the time the subject takes their first dose of IMP through the 
last study visit (Week 48) must be followed for information regarding the course of pregnancy, 
delivery, and condition of the newborn.  Follow-up should be provided by the Investigator to 
Mycovia Pharmaceuticals in a timely manner. 
 


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10 PHARMACOKINETIC ASSESSMENTS  
10.1 Sample Collection and Handling 
Blood samples for determination of VT-1161 plasma concentrations will be collected at visits 
specified in Schedule of Assessments and Procedures.  Timing of samples will be with respect 
to the day and time study drug is administered.  The initial PK sample must be drawn prior to 
the first dose of study drug (placebo/VT-1161). The date and time of each PK sample will be 
recorded in the CRF.  PK samples should be stored frozen at -20°C or colder.  Detailed shipping 
instructions will be provided in the lab manual. 
10.2 Analytical Procedures 
Plasma samples will be analyzed to determine concentrations of VT-1161 using a validated, 
specific and sensitive liquid chromatography/tandem mass spectrometry method at a 
bioanalytical laboratory designated by Mycovia Pharmaceuticals.  Pharmacokinetic samples 
may be retained for future analysis of the metabolite profile for a period of up to 15 years, after 
which time the samples will be destroyed. 
10.3 Pharmacokinetic Parameters 
For subjects in the VT-1161 treatment arm, VT-1161 concentrations will be presented by visit 
with descriptive statistics.  The PK data may be used in a cross-population PK analysis that 
may be presented in a separate report.   


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11 STUDY TERMINATION AND SUBJECT DISCONTINUATION 
11.1 Screening/Baseline Failures 
Subjects who sign and date the informed consent form or assent (for those ages 12 to 17) but 
fail to be randomized are defined as screen failures.  Site personnel should maintain 
documentation for all subjects who sign an informed consent or assent. 
11.2 Subject Withdrawal or Premature Discontinuation from the Study 
The following actions must be taken in relation to a subject who fails to attend the clinic for a 
required study visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible. 
• The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in the 
study. 
• In cases where the subject is deemed ‘lost to follow-up’, the Investigator or designee must 
make every effort to regain contact with the subject (e.g., multiple telephone calls on 
various dates/time, a certified letter to the subject’s last known mailing address, or 
equivalent methods). These contact attempts should be documented in the subject’s source 
documents. 
• Should the subject continue to be unreachable, only then will they be considered to have 
withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from the study at any time at his/her own request or may be withdrawn 
at any time at the discretion of the Investigator for safety, behavioral, or administrative reasons.  
If a subject withdraws from the study, he/she may request destruction of any laboratory 
samples taken, and the Investigator must document this in the site study records and 
communicate this request to Mycovia Pharmaceuticals. 
A subject may be withdrawn due to lack of tolerability or safety concerns, including study 
drug-related AEs or development of clinically-significant study drug-related laboratory 
abnormalities.  If a subject is withdrawn from treatment, the subject must be followed clinically 
until the event is resolved or deemed stable. A subject must be discontinued from the study 


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drug if ALT or/and AST is > 5 × the upper limit of normal (ULN) or ALT or/and AST is > 3 
× ULN and serum total bilirubin is > 2.0 ULN. 
Subject who want to discontinue from the study should be encouraged to remain in the study 
for all remaining visits through Week 48 for safety and efficacy assessments.  All subjects who 
do discontinue early from the study should have all EOS procedures performed on the day of 
discontinuation.  
If a subject is prematurely discontinued from study treatment for any reason other than 
withdrawal of consent, the Investigator (or designee) should request that the subject continues 
to participate in the study, attending all remaining visits in accordance with the Schedule of 
Assessments and Procedures.  If the subject does not agree to remain in the study, the 
Investigator (or designee) must make every effort to perform the early withdrawal visit/EOS 
visit procedures.  Subjects who prematurely discontinue study medication, but remain in the 
study, may be treated according to the standard local practice.   
11.3 Subject and Study Completion 
A completed subject is one who has completed all visits, Screening through Week 48 (EOS), 
as defined in the Schedule of Assessments and Procedures. Study completion is defined as 
when the last subject has completed their last study visit. 


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11.4 Premature Study Termination 
Reasons for discontinuation of the study at the investigative site may include, but are not 
limited to, the following: 
• The incidence or severity of AEs in the study indicates a potential health hazard to subjects. 
• Subject wishes to withdraw consent for reasons other than an AE. 
• Subject non-compliance or unwillingness to comply with the procedures required by the 
protocol. 
• Investigator request to withdraw from participation. 
• Sponsor decision. 
• Serious and/or persistent non-compliance by the Investigator with the protocol, the clinical 
research agreement, the Form Food and Drug Administration 1572, or applicable 
regulatory guidelines in conducting the study. 
• Decision by the IRB/IEC to terminate or suspend approval for the investigation or the 
Investigator. 
• Investigator fraud (altered data, omitted data, or manufactured data). 
 


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12 STATISTICAL ANALYSIS  
The SAP will provide a detailed description of the proposed data analysis methods and 
procedures.  The SAP was drafted and submitted to regulatory bodies prior to the start of the 
study and will be finalized before 50% of subjects are enrolled.  The SAP contains all the 
details for the analysis of the primary and secondary endpoints as well as the sensitivity 
analyses planned for all endpoints.  The additions to the SAP since that initial submission 
include additional sensitivity analyses, 
 
 
 
. The handling of missing data is explained 
in detail in the SAP including the descriptions of the sensitivity analyses that will be performed 
for each endpoint in order to assess the impact of the handling of the missing data on the results. 
Any deviation from the analyses outlined in the protocol will be described in the SAP. 
The primary statistical objective of this study is to determine if there are differences in the 
proportions of subjects with one or more culture-verified acute VVC episodes with signs and 
symptoms of ≥3 during the Maintenance (post randomization through Week 48) in those 
receiving VT-1161 compared to those receiving placebo during the Maintenance Phase. 
12.1 Determination of Sample Size 
For the primary efficacy endpoint determination, a sample size of 68 active subjects and 
34 placebo subjects provides at least 95% power to detect a treatment difference of 
35% between the VT-1161 treatment group and the placebo treatment group in percentage of 
subjects with one or more culture-verified acute VVC episodes during the Maintenance Phase 
(post randomization through Week 48). (PASS 2008: Fisher’s exact test, two-sided alpha = 
0.05, and assuming 50% of placebo subjects have recurrence).   Based on an estimated 20% 
discontinuation rate, approximately 128 total subjects (85 active, 43 placebo) will be necessary 
for randomization to arrive at approximately 102 evaluable subjects. 
The placebo rate was based on the data generated in Phase 2b RVVC study; the primary 
efficacy outcome measure in this study was the proportion of subjects with one or more culture-
verified acute VVC episodes during the Maintenance Phase through Week 48 of the study in 
the ITT population (all randomized subjects).  Culture-verified acute VVC was defined as a 
positive fungal culture for Candida species associated with a total signs and symptoms score 
of ≥ 3.  The proportion of subjects with one or more culture-verified acute VVC episodes 
through Week 48 was lower in the VT-1161 dosing regimens (0-7%) compared with the 
placebo group (52.2%).  This difference was statistically significant in all VT-1161 treatment 
groups compared with placebo (p<0.0001).  When powering the VMT-VT-1161-CL-011 


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study, it was determined that a separation of at least 35% between the treatment groups would 
be a clinically meaningful separation.  Thus, the sample size was powered to pick up at least a 
35% separation between the treatment groups.   
While 102 total subjects will provide more than 90% power to detect reasonable differences 
between treatment groups in most of the pre-specified key secondary endpoints a sample size 
of 160 active subjects and 80 placebo subjects is needed to provide 80% power to detect a 
treatment difference of 3.9 between the VT-1161 treatment group and the placebo group in the 
change from screening through Week 48 in the SF-36 MCS with a standard deviation of 10 
points. (PASS 2008: two-sample t-test, alpha = 0.05).  Therefore, with the expected 
discontinuation rate, approximately 300 subjects will be necessary for randomization to arrive 
at approximately 240 evaluable subjects.  Approximately 600 subjects will be screened to 
randomize approximately 300 subjects that would meet the inclusion/ exclusion criteria.  
12.2 Analysis Populations 
ITT Population: All randomized subjects. 
Safety Population: All randomized subjects who received at least 1 dose of IMP.  
PP Population: All randomized subjects who had the following:  
• Had no deviations to inclusion/exclusion criteria that could impact treatment outcome. 
• Were compliant with the assigned study treatment, defined as ≥80% compliance during the 
daily dosing phase and ≥50% compliance during the weekly dosing phase. 
• Had the Week 48 visit completed within the acceptable time window (±14 days). 
• Had no major protocol violations that would impact treatment outcome. 
Modified ITT: All randomized subjects who had the following: 
• Positive KOH or Gram stain at Screening. 
• Positive culture at Screening. 
• Negative culture at Baseline. 
All statistical populations will be defined in the SAP. 


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12.3 Demographic and Baseline Characteristic Analyses 
Subject disposition, demographics, baseline characteristics and study drug exposure will be 
summarized by treatment group. 
12.4 Efficacy Analyses  
Clinical and mycological assessments will be conducted as outlined in the Schedule of 
Assessments and Procedures. 
The primary efficacy outcome measure is the proportion of subjects with one or more culture-
verified acute VVC episodes during the Maintenance Phase (post randomization through Week 
48 of the study) in the ITT population.  An acute VVC episode in the Maintenance Phase 
(considered a recurrent episode) is defined as a positive culture for Candida species and a 
clinical signs and symptoms score of ≥3. 
The primary method of analysis is a Chi-square test for active treatment versus placebo based 
on the ITT population.  
 
 
 
The number and percentage of subjects with one or more culture-verified acute VVC episodes 
with signs and symptoms of ≥3 post randomization through Week 48 will be summarized 
across treatment groups including a 95% exact confidence interval and odds ratio.  
The percentages will also be plotted by treatment group. 
The key secondary efficacy outcome measures include the following: 
• Time to first recurrence of a culture-verified acute VVC episode with signs and symptoms 
score ≥3 during the Maintenance Phase. 
• The proportion of subjects with at least one positive culture for Candida species during the 
Maintenance Phase. 
• The proportion of subjects with at least one culture-verified acute VVC episode with signs 
and symptoms ≥3 post randomization through Week 24. 
• Change from Screening through Week 48 in the SF-36 patient mental component score 
(MCS). 
• Change from Screening through Week 48 in the SF-36 patient reported outcome survey 
total score. 
 


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Subject who want to discontinue from the study should be encouraged to remain in the study 
for all remaining visits through Week 48 for safety and efficacy assessments.  Subjects who do 
discontinue early from the study should have all Week 48/EOS assessments performed on the 
day of discontinuation.  
Every effort will be made to obtain required data at each scheduled evaluation from all subjects 
who have been randomized, including those who discontinue the study prior to the EOS Week 
48 visit.      
For scheduled visits where the investigator’s assessment of clinical signs and symptoms or the 
culture result is missing, missing values will be imputed using the method of multiple 
imputation.  For subjects who discontinue the study early and have missing assessments for all 
visits after discontinuation, the missing values for the expected scheduled visits will be 
imputed using the method of multiple imputation.  The missing values will be imputed using 
the following auxiliary information: region, treatment, baseline BMI, baseline age, ethnicity, 
and visit.  The procedure PROC MI in SAS will be used to generate 10 possible imputed 
datasets.  Using these multiple imputation datasets, determination of meeting the primary 
endpoint of a culture-verified acute VVC episode during the Maintenance Phase will be 
derived.  Subjects with a culture-verified acute VVC episode at any point from post 
randomization through Week 48 (including unscheduled visits) will be counted as having an 
episode when calculating the primary endpoint.  The multiple datasets containing the primary 
endpoint will be analyzed using a Chi-square test and the results will be combined using PROC 
MIANALYZE to obtain an inferential result.  Sensitivity analyses will be performed for the 
primary endpoint to assess the impact of missing/censored data on the results using different 
time to event and censoring calculations.  Further details on the steps of these analyses are 
presented in the VMT-VT-1161-CL-011 SAP. 
12.5 Safety Analyses  
To meet the safety dataset requirement, approximately 600 subjects will be screened to 
randomize approximately 300 subjects that would meet the inclusion/ exclusion criteria. 
Assuming a 20% discontinuation rate, it is expected that approximately 240 subjects will 
complete the study. 
All subjects who receive at least one dose of IMP will be included in the safety analyses. 
Subjects will be analyzed as per the treatment they receive.  The number and percentage of 
subjects having TEAEs will be tabulated by system organ class and preferred term with a 


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breakdown by treatment group.  Mean changes from pre-treatment in vital signs, ECGs, and 
clinical laboratory variables will be summarized by treatment group.  
AEs will be collected from the date of the first dose of fluconazole through Week 48 (EOS).   
Physical examination findings, vital signs, ECGs and safety laboratory tests (hematology and 
chemistry) will be obtained throughout the study as outlined in the Schedule of Assessments 
and Procedures.  All concomitant medications taken during the period from 30 days prior to 
Screening through the Week 48 (EOS) visit will be recorded in the CRF.  Pertinent and all 
major medical conditions will be recorded on the Medical History CRF.   
For subjects discontinuing early from the study, every effort will be made for all EOS 
procedures to be performed as outlined in the Schedule of Assessments and Procedures.  
AEs will be coded with the Medical Dictionary for Regulatory Activities (MedDRA®) version 
21 dictionary, or higher.  The number and percentage of subjects having treatment-emergent 
AEs will be tabulated by system organ class and MedDRA® preferred term with a breakdown 
by treatment group.  Mean changes from pre-treatment in vital signs, ECG, and clinical 
laboratory variables will be summarized by treatment group.  The AE profile will be 
characterized with severity and relationship to IMP.  SAEs and AEs resulting in 
discontinuation of IMP will be identified. 
Treatment-emergent abnormal laboratory test results will be identified.  Treatment-emergent 
abnormal laboratory tests results are those in which the baseline value is within normal 
laboratory limits and at least 1 post-baseline value is outside normal laboratory limits.  Baseline 
will be defined as the last clinical laboratory result obtained before the first dose of IMP.  
Per protocol, the baseline for laboratory values should be obtained at the Day 1 (Baseline) visit.   
Change from baseline to the minimum, maximum, and final vital sign value after first dosing 
will be summarized descriptively.   
ECG measurements will include heart rate, QT interval, QTc interval, PR interval, and QRS 
interval.  Baseline for ECG measurements is defined per protocol as the value pre-dosing at 
the Day 1 (Baseline) visit.  Change from baseline will be summarized descriptively at each 
scheduled evaluation.  Subjects with clinically significant changes in ECG rhythm or 
waveform will be identified.  Subjects who meet each of the following criteria from ICH 
Guideline E14 “Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic 
Potential for Non-Antiarrhythmic Drugs” (October 2005) for QT and corrected QT intervals 
will be identified. 


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• 
QT or Fridericia-corrected QT >450 msec 
• 
QT or Fridericia-corrected QT >480 msec 
• 
QT or Fridericia-corrected QT >500 msec 
• 
QT or Fridericia-corrected QT increases from baseline by at least 30 msec  
• 
QT or Fridericia-corrected QT increases from baseline by at least 60 msec 
12.6 Pharmacokinetic Analyses  
For subjects in the VT-1161 treatment arms, VT-1161 concentrations will be presented by visit 
with descriptive statistics.  The PK data may be used in a cross-population PK analysis that 
may be presented in a separate report. 
12.7 Patient Reported Outcome 
Validated Patient Reported Outcomes, SF-36™, EQ-5D-3L or EQ-5D-Y (for ages 12 to 17), 
WPAI:SHP, and PHQ-9 Health Surveys, will be administered for all regions participating in 
this study (see Appendices D, E, F, G, and H, respectively).  Data will be reviewed for overall 
quality of life changes from the Screening visit to the Week 48 visit.  For US only, questions 
regarding RVVC history will be administered at Screening using the RVVC History 
Questionnaire (see Appendix I) to collect information on the disease, diagnosis, and treatment 
profile for the subjects enrolled in the study. 


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13 CLINICAL STUDY ADMINISTRATION/STUDY GOVERNANCE 
CONSIDERATIONS 
13.1 Ethical Conduct of Study 
The study will be conducted in accordance with ICH Good Clinical Practice (GCP), all 
applicable subject privacy requirements, the guiding principles of the current version of the 
Declaration of Helsinki, and applicable country-specific regulatory requirements. This 
includes, but is not limited to, the following: 
• IRB/IEC review and favorable opinion/approval of the study protocol and amendments, as 
applicable, informed consent and assent (for those ages 12 to 17) documents, and 
investigational brochure. 
• Signed informed consent form or assent (for those ages 12 to 17) to be obtained for each 
subject before participation in the study (and for amendments as applicable). 
• Investigator 
reporting 
requirements 
(e.g., 
continuing 
reviews, 
reporting 
of 
AEs/SAEs/protocol deviations to the IRB/IEC). 
• If any documents are translated, an official certificate of translation must be maintained. 
13.2 Informed Consent and Assent 
Written informed consent or assent (for ages 12 to17) must be obtained from all subjects. 
The informed consent or assent document must be signed and dated prior to the initiation of 
study-related tests and prior to administration of fluconazole.  The original signed informed 
consent or assent for each participating subject shall be filed with records kept by the 
Investigator(s).  A copy of the informed consent or assent document must be provided to the 
subject.  If applicable, it will be provided in a certified translation of the local language. 
13.3 Quality Control (Study Monitoring) 
In accordance with applicable regulations, including GCP, the representative(s) or the 
designated clinical study monitor of Mycovia Pharmaceuticals will contact the site staff prior 
to the start of the study to review the protocol, study requirements, and their responsibilities to 
satisfy regulatory, ethical, and Mycovia Pharmaceuticals’ requirements. When reviewing the 
data collection procedures, the discussion will also include identification, agreement, and 
documentation of data items that will serve as the source document. 


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Mycovia Pharmaceuticals representative(s) or the designated clinical study monitor will 
monitor the study and site activity at regular intervals throughout the study to verify the 
following:  
• Data are authentic, accurate, and complete. 
• Safety and rights of subjects are being protected. 
• Study is conducted in accordance with the currently approved protocol and any other study 
agreements, GCP, and all applicable regulatory requirements. 
The Investigator and the head of the medical institution (where applicable) agrees to allow the 
clinical study monitor direct access to all relevant documents. 
Relevant documents or source documents are defined as the results of original observations 
and activities of a clinical investigation.  Source documents may include, but are not limited 
to, study progress notes, e-mail correspondences, computer printouts, laboratory data, and drug 
accountability records.   
13.4 Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, Mycovia 
Pharmaceuticals may conduct a quality assurance assessment and/or audit of the site records, 
and the regulatory agencies may conduct a regulatory inspection at any time during or after the 
completion of the study. In the event of an assessment, audit or inspection, the Investigator 
(and institution) must agree to grant the advisor(s), auditor(s), and inspector(s) direct access to 
all relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues, and to implement any corrective and/or 
preventative actions to address any findings/issues identified. 
13.5 Compliance with Standards of Medical Research/ Deviations 
This protocol will be conducted in accordance with the applicable ICH guidelines and GCP. 
Any instance of non-compliance with the protocol will result in a documented deviation. If a 
change is deemed necessary to protect the safety, rights or welfare of a subject, Mycovia 
Pharmaceuticals and IRB/IEC should be notified as soon as possible and preferably prior to 
introducing the deviation. Major deviations are defined as, but not limited to, the following: 
• Subjects who did not meet entry criteria. 


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• Subjects who developed withdrawal criteria during the study but were not withdrawn. 
• Subjects who received the wrong treatment or incorrect dose. 
• Subjects who were <80% IMP compliant in the Induction Phase or <50% IMP compliant 
in the Maintenance Phase. 
• Subjects who received an excluded concomitant medication or treatment. 
13.6 Data Management 
Electronic case report forms (eCRFs) will be used to capture study results and data.  The study 
coordinator or other authorized site study personnel will transcribe data from source documents 
into the eCRFs.  All eCRFs will be reviewed and source verified by the clinical study monitor 
during periodic site visits, and the clinical study monitor will ensure that all data in the eCRF 
are correct and complete.  Prior to or between visits, the Medical Monitor or clinical study 
monitor may request copies of the eCRFs for preliminary medical review. Once the eCRFs are 
complete and source verified, the Investigator must sign and date all required pages, verifying 
the accuracy of all data contained within the eCRF. 
Training will be provided for the Electronic Data Capture (EDC) system.  All personnel using 
the EDC system must have the appropriate education, training, and experience, or any 
combination thereof. The Investigator will be provided with SOPs (contained in the 
Study Procedures Manual or a vendor-specific SOP) on the use of the EDC system. 
Documentation for employee education, training, and previous experience that pertains to the 
EDC system must be present in the Investigator files. 
If electronic data systems other than those provided and maintained by Mycovia 
Pharmaceuticals are used for documentation and data capture, the Investigator must ensure that 
the systems are validated and ensure regular data back-up. 
The eCRF will be signed by the Principal Investigator listed on the Food and Drug 
Administration (FDA) 1572 form.  It is the responsibility of the Principal Investigator to ensure 
the eCRFs are completed and submitted to Mycovia Pharmaceuticals (or designee) in an 
accurate and timely manner.  The processing of eCRFs will include an audit trail (to include 
changes made, reason for change, date of change, and person making change). At the 
completion of the study, the Investigator will be provided with a final copy of the eCRFs for 
their subjects.  Mycovia Pharmaceuticals will be provided with a final copy of all subject eCRF 
data for the study. 


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Management of clinical data will be performed in accordance with applicable Mycovia 
Pharmaceuticals standards and data cleaning procedures to ensure the integrity of the data (e.g., 
removing errors and inconsistencies in the data).  AEs and concomitant medications will be 
coded using MedDRA®.  Electronic CRFs (including queries and audit trails) will be retained 
by the Mycovia Pharmaceuticals and copies will be sent to the Investigator to maintain as the 
Investigator copy. 
13.7 Study and Site Closure 
Upon completion or premature discontinuation of the study, the representative (or designated 
clinical study monitor) of Mycovia Pharmaceuticals will conduct site closure activities with 
the Investigator or site staff, as appropriate, in accordance with applicable regulations 
including GCP.  Mycovia Pharmaceuticals reserves the right to temporarily suspend or 
prematurely discontinue this study at any time for reasons including, but not limited to, safety 
or ethical issues or severe non-compliance. For multicenter studies, this can occur at 1 or more 
or at all sites.  If the Sponsor determines such action is needed, Mycovia Pharmaceuticals will 
discuss the reasons for taking such action with the Investigator or head of the medical 
institution (where applicable).  When feasible, Mycovia Pharmaceuticals will provide advance 
notification to the Investigator or head of the medical institution (where applicable) of the 
impending action.  If the study is suspended or prematurely discontinued for safety reasons, 
Mycovia Pharmaceuticals will promptly inform all Investigators, heads of medical institutions 
(where applicable), and/or institutions conducting the study.  Mycovia Pharmaceuticals will 
also promptly inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  If required by applicable 
regulations, the Investigator must inform the IRB/IEC promptly and provide the reason(s) for 
the suspension or premature discontinuation. 
13.8 Records Retention 
Following closure of the study, the Investigator must maintain all site study records (except 
for those required by local regulations to be maintained elsewhere), in a safe and secure 
location.  The records must be maintained to allow easy and timely retrieval when needed (e.g., 
for a Mycovia Pharmaceuticals audit or regulatory inspection) and must be available for review 
in conjunction with the assessment of the facility, supporting systems, and relevant site staff. 
When permitted by local laws/regulations or institutional policy, some or all of the records can 
be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); 
however, caution needs to be exercised before such action is taken.  The Investigator must 
ensure that all reproductions are legible and are a true and accurate copy of the original and 


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meet accessibility and retrieval standards, including regenerating a hard copy, if required. 
Furthermore, the Investigator must ensure there is an acceptable back-up of these reproductions 
and that an acceptable quality control process exists for making these reproductions.   
Investigators are required to retain essential documents pertaining to the conduct of this study 
for at least 2 years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region or at least 
2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product, per ICH guidelines.  The minimum retention time will meet the 
strictest standard applicable to that site for the study, as dictated by any institutional 
requirements, local laws or regulations, or Mycovia Pharmaceuticals’ standards/procedures. 
The Investigator must notify Mycovia Pharmaceuticals of any changes to the archival 
arrangements, including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the Investigator is no longer associated with the site. 
13.9 Disclosure of Data 
The Investigator agrees by his/her participation that the results of this study may be used for 
submission to national and/or international registration and supervising authorities.  If required, 
these authorities will be provided with the names of Investigators, their addresses, 
qualifications, and extent of involvement.  It is understood that the Investigator is required to 
provide Mycovia Pharmaceuticals with all study data, complete reports, and access to all study 
records. 
Data generated by this study must be available for inspection by the United States FDA and 
other regulatory authorities, by Mycovia Pharmaceuticals, and the IRB/IEC as appropriate.  
At a subject’s request, medical information may be given to his or her personal physician or 
other appropriate medical personnel responsible for his or her welfare. Subject medical 
information obtained during this study is confidential and disclosure to third parties other than 
those noted above is prohibited. 
13.10 Financial Disclosure 
The United States FDA Financial Disclosure by Clinical Investigators (21 Code of Federal 
Regulations 54) regulations require Sponsors to obtain certain financial information from 
Investigators participating in covered clinical studies; each Principal Investigator and 
Sub-Investigator is required to provide the required financial information and to promptly 
update Mycovia Pharmaceuticals with any relevant changes to their financial information 
throughout the course of the clinical study and for up to 1 year after its completion.  This rule 


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applies to all Investigators and Sub-Investigators participating in covered clinical studies to be 
submitted to the FDA in support of an application for market approval. 
13.11 Publication Policy 
The publication policy is outlined in the Clinical Trial Agreement. 
13.12 Confidentiality 
Confidentiality is outlined in the Clinical Trial Agreement. 
13.12.1 
Data 
All information about the nature of the proposed investigation provided by Mycovia 
Pharmaceuticals or the designated clinical study monitor to the Investigator (with the exception 
of information required by law or regulations to be disclosed to the IRB/IEC, the subject, or 
the appropriate regulatory authority) must be kept in confidence by the Investigator. 
13.12.2 
Subject Anonymity 
The anonymity of participating subjects must be maintained. Subjects will be identified by an 
assigned subject number on CRFs and other documents retrieved from the site or sent to the 
designated 
clinical 
study 
monitor, 
Sponsor, 
regulatory 
agencies, 
or 
central 
laboratories/reviewers.  Documents that identify the subject (e.g., the signed informed consent 
document, subject identification record) must be maintained in strict confidence by the 
Investigator, except to the extent necessary to allow auditing by the appropriate regulatory 
authority, the clinical study monitor, or Mycovia Pharmaceuticals representatives. 


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14 REFERENCES 
Barousse, M., et al. Vaginal yeast 106icromole106a106, prevalence of vaginitis, and associated local 
immunity in adolescents. Sexually Transmitted Infections, 2004;80(1):48-53. 
Bates DW and Yu DT. Clinical impact of drug-drug interactions with systemic azole antifungals.  Drugs 
Today 2003; 39: 801-813. 
Blostein, F., et al. Recurrent vulvovaginal candidiasis. Annals of Epidemiology, 2017: In press. 
Diflucan® 150 Capsules [Summary of Product Characteristics]. Pfizer Limited. Sandwich, UK.  
Accessed through http://www.medicines.org.uk/emc/medicine/1458/spc.  Last updated 19-May-2017.   
Eschenbach DA. Chronic Vulvovaginal Candidiasis. New Engl J Med 2004; 351: 851-852. 
Fidel, P., Jr. and J. Sobel. Host defense against vaginal candidiasis. Candida and candidiasis, ed. R. 
Calderone. Washington, D.C.: ASM Press. 2002, 193-209. 
Foxman B, Muraglia R, Dietz JP, et al. Prevelence of recurrent Vulvovaginal Candidiasis in 5 European 
countries and the United States:  results from an internet panel survey.  Am Soc of Colposcopy and 
Cervical Path 2013; 17(3): 340-345. 
Garvey EP, Fidel PL, Lilly EA, et al. The clinical antifungal agent VT-1161 is orally efficacious in a 
murine model of C. albicans vaginitis.  Presented at the 11th American Society for Microbiology 
Conference on Candida and Candidiasis, San Francisco, CA. Abstract #33C (2012). 
Goncalves B, Ferreira C, Alves CT, et al. Vulvovaginal candidiasis: epidemiology, microbiology and 
risk factors.  Crit Rev Microbiol 2016; 42(2): 905-927. 
Joishy, M., et al., Do we need to treat vulvovaginitis in prepubertal girls? British Medical Journal, 
2005;330(7484):186-188. 
Pfizer, 
I. 
Diflucan®, 
fluconazole 
tablet, 
<https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f694c617-3383-416c-91b6-
b94fda371204> (2017). 
Sobel JD. Recurrent vulvovaginal candidiasis. Am J Obstet Gynecol. 2016 (1):6. 
Sobel JD, Wiesenfeld HC, Martens M, et al. Maintenance fluconazole therapy for recurrent 
Vulvovaginal Candidiasis. New Engl J Med 2004; 351:876-883. 
Sobel JD. Vulvovaginal Candidosis.  Lancet 2007; 369:1961-1971. 
VT-1161 Investigational Brochure, v005. Durham, NC.  Mycovia Pharmaceuticals Inc. (2017). 
Yoshida Y. Cytochrome P450 of fungi: primary target for azole antifungal agents.  Curr Top Med 
Mycol 1988; 2: 388-418. 
Zarn JA, Bruschweiler BJ, Schlatter JR. Azole fungicides affect mammalian steroidogenesis by 
inhibiting sterol 14α-demethylase and aromatase.  Env Health Pers 2003; 111: 255-261. 
 
 


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APPENDICES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix A. Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity 
Table (Draft November 2007) Modified for Use in VMT-VT-1161-CL-012 
Study 
*This toxicity table is applicable for subjects ages 12-17 years of age. 
 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal          LLN = Lower Limit of Normal 
Rx = Therapy                                      Req = Required 
Mod = Moderate                                 IV = Intravenous 
ADL = Activities of Daily Living       Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
 
GRADE 1 
Mild: 
Transient 
or 
mild 
discomfort 
(<48 
hours); 
no 
medical 
intervention/therapy required 
GRADE 2 
Moderate: Mild to moderate limitation in activity – some assistance may be 
needed; no or minimal medical intervention/therapy required 
GRADE 3 
Severe: Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalizations possible. 
GRADE 4 
Life-threatening:  
Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice care 
probable 
 
SERIOUS OR LIFE-THREATENING AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a Grade 4 event.   
 
LABORATORY RANGES 
Where discrepancies in the ULN and LLN of laboratory ranges occur between those included 
in this document and those of the laboratory that performs the assays, the values provided by 
the laboratory will be used for assignment of severity grade. 














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Fever: oral 
37.7 – 38.5 C or 
100.0 – 101.5 F 
38.6 – 39.5 C or 
101.6 – 102.9 F 
39.6 – 40.5 C or 
103 – 105 F 
> 40 C or > 105 F 
Fatigue 
normal activity 
reduced < 48 hours 
 normal activity 
decreased 25- 50% 
> 48 hours 
normal activity 
decreased > 50% 
cannot work 
unable to care for 
self 
Appendix B:  Grading of Renal Impairment 
 
GFR categories in CKD 
Category 
GFR 
ml/min/1.73 m2 
Terms 
G1 
     ≥90 
Normal or high 
G2 
60 – 89 
Mildly decreased* 
G3a 
45 – 59 
Mildly to moderately decreased 
G3b 
30 – 44 
Moderately to severely decreased 
G4 
15 – 29 
Severely decreased 
G5 
     <15 
Kidney failure 
Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate. 
*Relative to young adult level. 
In the absence of evidence of kidney damage, neither GFR category G1 nor G2 fulfill the criteria for CKD. 
 
Albuminuria categories in CKD 
Category 
ACR (mg/g) 
Terms 
A1 
      <30 
Normal to mildly increased 
A2 
30 – 300 
Moderately increased* 
A3 
     >300 
Severely increased** 
Abbreviations: ACR, albumin-to-creatinine ratio; CKD, chronic kidney disease. 
*Relative to young adult level. 
**Including nephrotic syndrome (albumin excretion ACR >2220 mg/g) 
Reference:  https://www.kidney.org/professionals/explore-your-knowledge/how-to-classify-ckd 
 
 


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Appendix C: Child-Pugh Classification of Hepatic Impairment 
 
The Child- Pugh classification is a means of assessing the severity of liver cirrhosis. 
Score 
1 
2 
3 
bilirubin (micromol/l) 
<34 
34 – 50 
>50 
albumin (g/l) 
>35 
28 – 35 
<28 
PT (s prolonged) 
<4 
4 – 6 
>6 
encephalopathy 
none 
mild 
marked 
ascites 
none 
mild 
marked 
If there is primary biliary cirrhosis or sclerosing cholangitis then bilirubin is classified as <68 =1; 6 
– 170 = 2; >170 = 3. 
The individual scores are summed and then grouped as: 
• 
<7 = A (Mild impairment) 
• 
7 – 9 = B (Moderate impairment) 
• 
>9 = C (Severe impairment) 
A C classification forecasts a survival of less than 12 months. 
From: Pugh RNH, Murray-Lyon IM, Dawson JL et al. Transection of the oesophagus for bleeding 
oesophageal varices. Br J Surg 1973;60:649-9.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix D. SF-36TM Quality of Life Questionnaire 
 
 


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Appendix E. EQ-5D-3L Health Status Questionnaire 
 
 


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Figure 1:  EQ-5D-3L (UK English sample version) 
 
By placing a tick in one box in each group below, please indicate which 
statements best describe your own health state today. 
 
Mobility 
I have no problems in walking about                                                                       ❑ 
I have some problems in walking about                                                                   ❑ 
I am confined to bed                                                                                                ❑ 
 
Self-Care 
I have no problems with self-care                                                                            ❑ 
I have some problems washing or dressing myself                                                 ❑ 
I am unable to wash or dress myself                                                                       ❑ 
 
Usual Activities (e.g. work, study, 
housework, family or leisure activities) 
I have no problems with performing my usual activities                                          ❑ 
 
I have some problems with performing my usual activities                                      ❑ 
I am unable to perform my usual activities                                                              ❑ 
 
Pain/Discomfort 
I have no pain or discomfort                                                                                    ❑ 
I have moderate pain or discomfort                                                                         ❑ 
I have extreme pain or discomfort                                                                           ❑ 
 
Anxiety/Depression 
I am not anxious or depressed                                                                                ❑ 
I am moderately anxious or depressed                                                                    ❑ 
I am extremely anxious or depressed                                                                      ❑ 
 


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Appendix F. EQ-5D-Y Health Status Questionnaire 
 
 
 


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Appendix G.   Work Productivity and Activity Impairment: Specific Health Problems 
Questionnaire 
 
 


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Work Productivity and Activity Impairment Questionnaire: 
Specific Health Problem V2.0 (WPAI:SHP) 
 
 
The following questions ask about the effect of vaginal yeast infections on your ability to work and perform 
regular activities. Please fill in the blanks or circle a number, as indicated. 
 
 
1. Are you currently employed (working for pay)?              NO        YES 
If NO, check “NO” and skip to question 6. 
 
The next questions are about the past seven days, not including today. 
 
2. During the past seven days, how many hours did you miss from work because of problems 
associated with a vaginal yeast infection? Include hours you missed on sick days, times you went in 
late, left early, etc., because of a vaginal yeast infection. Do not include time you missed to participate 
in this study. 
 
           HOURS 
 
 
3.  During the past seven days, how many hours did you miss from work because of any other 
reason, such as vacation, holidays, time off to participate in this study? 
 
          HOURS 
 
 
4.  During the past seven days, how many hours did you actually work? 
 
          HOURS (If “0”, skip to question 6.) 


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5.  During the past seven days, how much did a vaginal yeast infection affect your 
productivity while you were working? 
Think about days you were limited in the amount or kind of work you could do, days you 
accomplished less than you would like, or days you could not do your work as carefully as usual. 
If a vaginal yeast infection affected your work only a little, choose a low number. Choose a high 
number if a vaginal yeast infection affected your work a great deal. 
 
Consider only how much the vaginal yeast infection affected 
productivity while you were working. 
 
Vaginal yeast 
Vaginal yeast 
infection had no 
effect on my 
0 
1 
2    3 
4 
5 
6 
7 
8 
9 
10 
infection 
completely 
work 
prevented me 
from working 
CIRCLE A NUMBER 
 
 
6.  During the past seven days, how much did a vaginal yeast infection affect your ability to 
do your regular daily activities, other than work at a job? 
 
By regular activities, we mean the usual activities you do, such as work around the house, 
shopping, childcare, exercising, studying, etc. Think about times you were limited in the amount or 
kind of activities you could do and times you accomplished less than you would like. If a vaginal 
yeast infection affected your activities only a little, choose a low number. Choose a high number if 
a vaginal yeast infection affected your activities a great deal. 
 
Consider only how much the vaginal yeast infection affected your ability to do your 
regular daily activities, other than work at a job. 
 
 
 
Vaginal yeast 
infection had 
Vaginal yeast 
infection 
no effect on my 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
completely 
daily activities 
prevented me 
from doing my 
daily activities 
CIRCLE A NUMBER 
 
 
 
WPAI:SHP V2.0 (US English) 
Reilly MC, Zbrozek AS, Dukes E: The validity and reproducibility of a work productivity and activity impairment measure.                                 
PharmacoEconomics 1993; 4(5):353-365. 
 
 


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Appendix H. Patient Health Questionnaire – 9  
 
 


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Appendix I. RVVC History Questionnaire (Version 01) – US Only 
 
 


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RVVC History Questionnaire (Version 01) 
 
1. How many vaginal yeast infections have you had in the last 12 months? 
___________ 
2. Of the ____ vaginal yeast infections you have had in the last 12 months, how many 
did you receive a diagnosis from a health care provider (physician, nurse, 
physician’s assistant, etc.)?  ___________ 
3. Of the ____ vaginal yeast infections you have had in the last 12 months that were 
diagnosed by a healthcare professional, for how many did you receive a pelvic 
exam? ___________ 
4. Of the ____ vaginal yeast infections you have had in the last 12 months for which 
you received a pelvic exam, how many did a healthcare professional take a vaginal 
swab and run a test to confirm the diagnosis (either during your appointment or 
with a follow-up call)?  
5. How many years in a row have you experienced at least 3 vaginal yeast infections 
per year?  
a) Only the last year 
b) More than 1 year but not more than 2 years 
c) More than 2 years but not more than 5 years 
d) More than 5 years 
6. Please estimate the total number of vaginal yeast infections you have had in your 
lifetime: _____ 
7. Since you began experiencing recurrent vaginal yeast infections, have you ever 
taken a prescription pill once a week for a number of weeks in order to prevent 
recurrence of vaginal yeast infections? ___________ 
8. Prior to enrolling in this study, what treatment or treatments do you typically use to 
treat a vaginal yeast infection? Select up to 3  
a) One to three pills of fluconazole/Diflucan by prescription 
b) One to three pills of fluconazole/Diflucan over-the-counter (i.e., without a 
prescription – only available in some countries) 
c) Fluconazole/Diflucan taken every week, by prescription 
d) Fluconazole/Diflucan taken every week, over-the-counter (i.e., without a 
prescription – only available in some countries) 
e) Prescription topical cream, ointment, or suppository  
f) Over-the-counter topical cream, ointment, or suppository  
g) Homeopathic Remedies (such as probiotics, tea tree oil, coconut oil, garlic, 
yogurt, etc.) 
h) Dietary or lifestyle change 
i) I don’t know, it depends on what my doctor says 
j) I don’t know, it depends on what my pharmacist says 
k) Other (please specify): ___________________ 


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9. When you’ve used the treatment or treatments you previously specified, for how 
many days do your vaginal yeast infection symptoms typically last (from beginning 
of symptoms until symptoms are gone)? ___________ 
10. Please estimate how much it personally cost you to diagnose, treat and prevent your 
last vaginal yeast infection (the one prior to this one), in each of the following 
categories of costs. Please enter “0” for any categories in which you had no out-of-
pocket costs (do not leave blanks)  
a) Over-the counter medications: ___________ 
b) Prescription payments: _____________ 
c) Physician visit payments: ___________ 
d) Payments for diagnostic tests: ___________ 
e) Other (e.g. probiotics, homeopathic remedies, pain/itch relievers, etc.): 
___________ 
11. Please estimate how much it has personally cost you in total to diagnose and treat 
all your recurrent vaginal yeast infections over the last 12 months, in each of the 
following categories of costs. Please enter “0” for any categories in which you had 
no out-of-pocket costs (do not leave blanks).  
a) Over-the counter medications: ___________ 
b) Prescription payments: _____________ 
c) Physician visit payments: ___________ 
d) Payments for diagnostic tests: ___________ 
e) Other (e.g. probiotics, homeopathic remedies, pain/itch relievers, etc.): 
___________ 
12. How many days of work would you estimate you have missed over the past 12 
months, specifically due to having or wanting to prevent a vaginal yeast 
infection?  
 


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Appendix J.   Extension Study – U.S. Only 
 
 
 
 


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APPENDIX J.  
OBSERVATIONAL EXTENSION STUDY: VMT-VT-1161-CL-011 
1.0 BACKGROUND INFORMATION AND RATIONALE 
Several properties of VT-1161 suggest that it has the potential to be a best-in-class oral agent for 
the treatment of recurrent vulvovaginal candidiasis (RVVC), to effectively inhibit growth of 
causative fungal pathogens at achievable plasma levels.  Its pharmacokinetic profile and extended 
half-life should limit recurrence of VVC. The purpose of this twelve-month Observational 
Extension Study is to gain additional insight into the ability of VT-1161 to prevent VVC beyond 
Week 48 in RVVC subjects yet to experience a recurring episode on completion of study VMT-
VT-1161-CL-011. This is an observational study; there will be no active treatment.  The Sponsor 
may choose, prior to the end of study, to extend this Extension Study for an additional period for 
subjects willing to continue.   
2.0 STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective is to evaluate changes in culture-verified acute VVC episode recurrence 
rates through Week 96 in subjects free of a recurring VVC episode upon completion of their Week 
48 visit in study VMT-VT-1161-CL-011 and who have qualified for the Extension, in an 
observational study. 
3.0 STUDY DESIGN 
Approximately 100 subjects in the United States who completed their Week 48 (EOS) visit and 
did not have a RVVC episode during the Maintenance Phase (post-randomization through Week 
48 for study VMT-VT-1161-CL-011) will be offered the opportunity to enroll in an observational 
Extension Study. The Extension Study will monitor for recurring episodes of VVC for an 
additional 48 Weeks, for a total study participation of 96 weeks.  
Subjects must sign the Extension Study informed consent form (ICF), or assent, at the Week 48 
(EOS) visit prior to any Extension Study procedures. Subjects will be contacted approximately 
every 6 weeks to monitor for recurrence of VVC. Subjects experiencing a suspected recurrent 
episode of VVC will return to the investigational site for evaluation at an unscheduled visit.  


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3.1 Extension Duration of the Study  
The observational Extension Study duration is expected to be approximately 23 months from 
consenting of the first subject until last visit of the last subject. The maximum Extension Study 
duration of individual subject participation will be 48 weeks.   
3.2 Number of Study Sites/Total enrollment  
Approximately 70 investigative sites in the United States will participate in the Extension Study.  
The study will seek to enroll approximately 100 subjects. Assuming a 20% discontinuation rate 
for the duration of the study, approximately 80 subjects are expected to complete the study.  
4.0 STUDY POPULATION 
The Investigator or other study site personnel must record in the source documents (e.g., the site’s 
chart) and case report form (CRF) that the ICF document was signed and dated and all entry criteria 
were met prior to conducting any Extension Study procedures.  The following criteria for 
enrollment must be followed explicitly; any violations of these criteria must be reported in 
accordance with Institutional Review Board (IRB) Policies and Procedures.  
4.1 Inclusion Criteria 
1. Subjects must have participated in the VMT-VT-1161-CL-011 study and completed the Week 
48 visit. 
2. Subjects must be willing and able to provide written informed consent (or assent, if applicable) 
and provide authorization for use of protected health information (HIPAA). 
3. Subjects must be willing and able to comply with protocol requirements, instructions, and 
protocol-stated restrictions and be likely to complete the study as planned. 
4.2 Exclusion Criteria 
1. Subjects who, in the opinion of the Investigator, were non-compliant in the main study and / 
or may become non-compliant with study schedules or procedures. 
2. Subjects who had a positive KOH and clinical signs and symptoms score of ≥3 during the 
Maintenance Phase (post-randomization through Week 48) of study VMT-VT-1161-CL-011.  
3. Subjects must not plan to participate in another clinical trial.   
4. Subjects must not be taking any prohibited medications. 


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5.0 
PROHIBITED MEDICATIONS 
The following prescription and over-the-counter drug products are prohibited during the study and 
will be considered a protocol deviation: 
1. Topical or oral antifungal drugs, except when prescribed by the Investigator to treat a subject 
with a recurrent VVC episode.  
2. Topical products applied to the vulva or vagina (e.g. antibiotic, antiviral, antitrichomonal, 
corticosteroids, or anti-inflammatory agents). 
3. Oral antibacterial, antiviral, or antitrichomonal agents for the treatment of bacterial vaginosis, 
trichomonas, or other concomitant (urogenital) infection unless prescribed by the Investigator.  
4. Vaginal douches, boric acid, or benzalkonium chloride disinfectant during the study. 
6.0 STUDY ASSESSMENTS AND PROCEDURES 
6.1 Assessments 
The study subjects should be contacted within the timeframes noted in (Table 1) the Schedule of 
Assessments and Procedures.  
 
 




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6.1.1 Week 48 – Clinic Visit 
Once the subject has signed the IRB / Independent Ethic Committee (IEC) approved informed 
consent (or assent, if applicable) document, the following procedures will be performed: 
• Review Inclusion and Exclusion criteria to assess the subject’s eligibility.   
• Remind the subject that they will be contacted approximately every 6 weeks beginning at 
Week 54. 
• Remind the subject not to self treat or seek care from another healthcare professional for 
any suspected RVVC episode but instead return to the study site for evaluation (and 
treatment, if needed) anytime during the study. 
6.1.2 Every 6 Weeks (±14 Days) – Subject Contact  
The subjects will be contacted by investigative site personnel, every 6 weeks (±14 Days) at 
approximately Weeks 54, 60, 66, 72, 78, 84, 90, and 96 for the following evaluations: 
• Review and record any excluded medications taken since the previous visit. 
• Remind the subject not to self treat or seek care from another healthcare professional for 
any suspected RVVC episode but instead return to the study site for evaluation (and 
treatment, if needed) during the Extension Study. 
• If applicable, review and record if the subject has become pregnant or pregnancy status if 
previously recorded. 
• Remind subject that they will be contacted every 6 weeks and that the site will keep 
contacting the subject until they are available to discuss their status. 
6.1.3 Week 96 (±14 Days) – Subject Contact  
The subjects will be contacted at Week 96 for their final contact to close their participation in the 
study. The items below should be discussed: 
• Review and record all excluded medications taken since the previous visit. 
• If applicable, review and record if the subject has become pregnant or pregnancy status if 
previously recorded. 
• Complete the “Subject Contact” and “Termination Extension” eCRF pages. 


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• Thank the subject for their participation and let them know this is the last study contact. 
6.1.4 Unscheduled Visit - Clinic Visit  
Unscheduled visits are to be used if the subject suspects an RVVC episode.  The following 
evaluations are to be performed: 
• Record all excluded medications taken since the previous visit. 
• Perform a vaginal exam including an assessment of clinical signs and symptoms of 
vulvovaginitis, as outlined in 6.2.3.   
• Perform KOH wet mount test, performed locally (Error! Reference source not found.). 
• Obtain vaginal swab for culture to send to the central mycology laboratory (7.1.3.1). 
• Obtain PK plasma specimen. 
• Remind the subject not to self treat or seek care from another healthcare professional for 
any suspected RVVC episode but instead return to the study site for evaluation (and 
treatment, if needed) during the Extension Study. 
• If applicable, review and record if the subject has become pregnant or pregnancy status if 
previously recorded. 
• Remind subject that they will be contacted every 6 weeks and that the site will keep 
contacting the subject until they are available to discuss their status. 
6.2 Study Procedures 
6.2.1 
Pregnancies 
Subjects may become pregnant during the Extension Study. For any subject that became pregnant 
during the main study protocol or becomes pregnant during the Extension Study, the outcome of 
their pregnancy (birth or termination) must be documented in the subject’s medical record.  
6.2.2 
KOH Wet Mount and Fungal Cultures 
A vaginal fungal culture will be obtained at the unscheduled clinic visit and sent to the central 
mycology laboratory for fungal identification and susceptibility testing according to approved 
Clinical Laboratory Standards Institute methods. Details as to the collection of samples, shipping, 
testing methods and analysis will be delineated in a laboratory manual.  Mycology samples may 


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be retained for future analysis for a period of up to 15 years, after which time the samples will be 
destroyed. 
A local KOH wet mount test will be performed at the unscheduled clinic visit where a recurrent 
VVC episode is suspected.  (If the Investigator site used the Gram stain test instead of the KOH 
test in the main study, they may continue to use it in the Extension Study). 
Subjects should not be menstruating at time of the study visits to ensure proper sample collection 
of the vaginal fluid.   
6.2.3 
Vulvovaginal Exam and Clinical Assessment 
A vulvovaginal exam and clinical assessment of signs and symptoms will be evaluated at the 
unscheduled clinic visit.  Each of the following vulvovaginal signs and symptoms will be scored 
and the individual scores combined for a maximum score of 18, using the following scale: 
a. Signs: erythema, edema, and excoriation 
b. Symptoms: itching, burning, and irritation 
 
Scoring Scale: Each score should be objectively defined on a scale of 0 to 3 as follows: 
0 = none (complete absence of any signs or symptoms) 
1 = mild (slight) 
2 = moderate (definitely present) 
3 = severe (marked, intense) 
7.0 PHARMACOKINETIC ASSESSMENTS 
Assays to measure VT-1161 concentrations in plasma PK samples will be performed using a 
validated bioanalytical assay at a laboratory designated by Mycovia Pharmaceuticals.   
The PK data may be used in a cross-population PK analysis that may be presented in a separate 
report. Pharmacokinetic samples may be retained for future analysis of the metabolite profile for 
a period of up to 15 years, after which time the samples will be destroyed. 


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8.0 STUDY TERMINATION AND SUBJECT DISCONTINUATION  
8.1 Extension Study Screen Failures 
Subjects who sign and date the Extension Study consent (or assent, if applicable) but fail to 
meet the inclusion and exclusion criteria are defined as entry failures.  Site personnel need to 
maintain a screening log to document all subjects who sign a consent (or assent). A copy of 
the log should be retained in the Investigator’s study files. Additionally, site personnel must 
complete the eCRF “Termination Extension” page. 
8.2 Early Termination Conditions 
If the Investigator suspects the subject is experiencing a recurrent episode, at any time during 
the Extension Study, the subject should be examined. The suspected RVVC episode will be 
documented on an ‘unscheduled visit’ eCRF and considered the subject’s End of Extension 
Study (EOES) visit ONLY if the signs and symptoms score is ≥3 and the KOH is positive. 
The Investigator is to perform all unscheduled visit procedures, including submission of 
vaginal mycology swab to central lab for culture analysis. Upon diagnosis of a recurrent 
episode, the Investigator should:  
a. offer the subject standard of care treatment options.  
b. Complete the “unscheduled visit” and “Termination Extension” eCRF pages. 
An unconfirmed RVVC episode is one where the subject self-treats or sees a (non-Investigator 
Site) health care professional and does not have documentation of the visit including the 
required study signs and symptoms and a positive KOH. 
8.3 Subject Withdrawal and Premature Discontinuation from the Extension 
Study  
Appropriate actions should be taken to ensure subjects complete each study visit within the 
protocol specified window and do not become lost to follow-up.  
A subject may withdraw from the study at any time at her own request or may be withdrawn at 
any time at the discretion of the Investigator for safety, behavioral, or administrative reasons.  If a 
subject withdraws her consent from the study participation, she may request destruction of any 
laboratory samples taken, and the Investigator must document this in the site study records and 
communicate this request to Mycovia Pharmaceuticals. 


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Reasons for subject discontinuation of the Extension Study at the investigative site may include, 
but are not limited to, the following: 
• Safety reasons that are study related or serious adverse events (SAEs) that may affect the 
subjects’ ability to continue with the required study procedures and assessments.  The subject 
must be followed clinically until the event is resolved or deemed stable. 
• Subject wishes to withdraw consent for any reason. The reason for withdrawing consent should 
be captured if the subject is willing to share. 
• Subject non-compliance or unwillingness to comply with the procedures required by the 
protocol. 
• Investigator discretion. 
• Due to low enrollment/ continuation in the study, the Sponsor decides to stop the study. 
8.4 Study Termination 
Reasons for discontinuation of the Extension Study at the investigative site may include, but are 
not limited to, the following: 
• Subject enrollment is unsatisfactory. 
• Investigator request to withdraw from participation. 
• Sponsor decision. 
• Serious and/or persistent non-compliance by the Investigator with the protocol, the clinical 
research agreement, the Form (FDA) 1572 or applicable regulatory guidelines in conducting 
the study. 
• Decision by the IRB/IEC to terminate or suspend approval for the investigation or the 
Investigator. 
• Investigator fraud (altered data, omitted data, or manufactured data). 
8.5 Subject and Study Extension Completion  
A completed subject is one who has completed all Extension Study visits: Weeks 48 through Week 
96 or was determined to have a positive KOH with signs and symptoms score of  ≥3 at an 
unscheduled clinic visit.  


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9.0    STATISTICAL ANALYSIS 
9.1 Statistical Methods and Planned Analysis 
Descriptive statistical methods will be used to summarize the data from this Extension Study. 
There will be no hypothesis testing.  Unless otherwise stated, the term “descriptive statistics” refers 
to number of subjects, mean, median, standard deviation, minimum, and maximum for continuous 
data, confidence intervals and frequencies and percentages for categorical data.  
9.2 Demographic and Baseline Characteristic Analyses 
Subject disposition, demographics, and baseline characteristics will be summarized by treatment 
group. 
9.3 Efficacy Analysis 
Clinical and mycological assessments will be conducted as outlined in Table 1 of the Extension 
Study. 
Subjects will be required to return to the study site if they suspect a recurring episode of VVC 
during the Extension Study. The primary objective is to measure the proportion of subjects with 
one or more culture-verified acute VVC episodes during the Maintenance Phase (post-
randomization through Week 96) in the ITT population. An acute VVC episode during the 
Extension (considered a recurrent episode) is defined as a positive culture for Candida species and 
a clinical signs and symptoms score of ≥3.  
9.4 Pharmacokinetic Analysis 
PK samples will be collected at the unscheduled clinic visit to determine VT-1161 concentrations. 
Data will be presented by visit with descriptive statistics.   
10.0 CLINICAL STUDY ADMINISTRATION/STUDY GOVERNANCE 
CONSIDERATIONS 
10.1 Ethical Conduct of Study 
The study will be conducted in accordance with ICH Good Clinical Practice (GCP), all applicable 
subject privacy requirements, the guiding principles of the current version of the Declaration of 
Helsinki, and applicable country-specific regulatory requirements. This includes, but is not limited 
to, the following: 


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• IRB/IEC review and favorable opinion/approval of the study protocol and amendments, as 
applicable, informed consent and assent (for those ages 12 to 17) documents, and 
investigational brochure. 
• Signed informed consent form or assent (for those ages 12 to 17) to be obtained for each subject 
before participation in the study (and for amendments as applicable). 
• Investigator reporting requirements (e.g., continuing reviews, reporting of AEs/SAEs/protocol 
deviations to the IRB/IEC). 
If any documents are translated, an official certificate of translation must be maintained. 
10.2 Informed Consent  
Written informed consent must be signed and dated by the subject prior to their initiation of study-
related procedures or tests.  The original signed informed consent for each participating subject 
shall be filed with records kept by the Investigator(s).  A copy of the informed consent document 
must be provided to the subject.  If applicable, it will be provided in a certified translation of the 
local language. 
10.3 Quality Control (Study Monitoring) 
In accordance with applicable regulations, including GCP, the representative(s) or the designated 
clinical study monitor of Mycovia Pharmaceuticals will contact the site staff prior to the start of 
the study to review the protocol, study requirements, and their responsibilities to satisfy regulatory, 
ethical, and Mycovia Pharmaceuticals’ requirements. When reviewing the data collection 
procedures, the discussion will also include identification, agreement, and documentation of data 
items that will serve as the source document. 
Mycovia Pharmaceuticals representative(s) or the designated clinical study monitor will review 
the study data remotely at regular intervals throughout the study and may perform on-site visits to 
verify the following:  
• Data are Attributable, Legible, Contemporaneous, Original, Accurate and Complete 
(ALCOAC). 
• Safety and rights of subjects are being protected. 


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• Study is conducted in accordance with the currently approved protocol and any other study 
agreements, GCP/ICH E6(R2), and all applicable regulatory requirements. 
The Investigator and the head of the medical institution (where applicable) agrees to allow the 
clinical study monitor, direct access to all relevant documents. 
Relevant documents or source documents are defined as the results of original observations and 
activities of a clinical investigation.  Source documents may include, but are not limited to, study 
progress notes, e-mail correspondences, computer printouts, laboratory data, and drug 
accountability records. 
10.4 Quality Assurance 
To ensure compliance with GCP/ICH E6(R2) and all applicable regulatory requirements, Mycovia 
Pharmaceuticals may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or after the 
completion of the study. In the event of an assessment, audit or inspection, the Investigator (and 
institution) must agree to grant the advisor(s), auditor(s), and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss the conduct of 
the study, any findings/relevant issues, and to implement any corrective and/or preventative 
actions to address any findings/issues identified. 
10.5 Compliance with Standards of Medical Research/ Deviations 
This protocol will be conducted in accordance with the applicable ICH E6(R2) guidelines and 
GCP. Any instance of non-compliance with the protocol will result in a documented deviation. If 
a change is deemed necessary to protect the safety, rights or welfare of a subject, Mycovia 
Pharmaceuticals and IRB/IEC should be notified as soon as possible and preferably prior to 
introducing the deviation. Major deviations are defined as, but not limited to, the following: 
• Subjects who did not meet entry criteria. 
• Subjects who developed withdrawal criteria during the study but were not withdrawn. 
10.6 Data Management 
Electronic case report forms (eCRFs) will be used to capture study results and data.  The study 
coordinator or other authorized site study personnel will transcribe data from source documents 
into the eCRFs.  The Extension eCRFs may be reviewed and source verified by the clinical study 
monitor to ensure data in the eCRF are correct and complete.  The Medical Monitor or clinical 


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study monitor may request redacted copies of source documents for medical review. Once the 
Extension Study is complete, the Investigator must sign and date all required pages, verifying the 
accuracy of all data contained within the eCRF. 
Training will be provided for the Electronic Data Capture (EDC) system.  All personnel using the 
EDC system must have the appropriate education, training, and experience, or any combination 
thereof. The Investigator will be provided with SOPs (contained in the Study Procedures Manual 
or a vendor-specific SOP) on the use of the EDC system. Documentation for employee education, 
training, and previous experience that pertains to the EDC system must be present in the 
Investigator files. 
If electronic data systems other than those provided and maintained by Mycovia Pharmaceuticals 
are used for documentation and data capture, the Investigator must ensure that the systems are 
validated and ensure regular data back-up. 
The eCRF will be signed by the Principal Investigator listed on the Food and Drug Administration 
(FDA) 1572 form.  It is the responsibility of the Principal Investigator to ensure the eCRFs are 
completed and submitted to Mycovia Pharmaceuticals (or designee) in an accurate and timely 
manner.  The processing of eCRFs will include an audit trail (to include changes made, reason for 
change, date of change, and person making change). At the completion of the Extension study, 
eCRFs (including queries and audit trails) will be retained by the Mycovia Pharmaceuticals and 
copies will be sent to the Investigator to maintain as the Investigator copy. 
Management of clinical data will be performed in accordance with applicable Mycovia 
Pharmaceuticals standards and data cleaning procedures to ensure the integrity of the data (e.g., 
removing errors and inconsistencies in the data).  Concomitant medications will be coded using 
WHO-DD.   
10.7 Study and Site Closure 
Upon completion or premature discontinuation of the study, the representative (or designated 
clinical study monitor) of Mycovia Pharmaceuticals will conduct site closure activities with the 
Investigator or site staff, as appropriate, in accordance with applicable regulations including GCP.  
Mycovia Pharmaceuticals reserves the right to suspend or prematurely discontinue this study at 
any time for reasons including, but not limited to, safety or ethical issues or severe non-compliance. 
For multicenter studies, this can occur at 1 or more or at all sites.  If the Sponsor determines such 
action is needed, Mycovia Pharmaceuticals will discuss the reasons for taking such action with the 
Investigator or head of the medical institution (where applicable).  When feasible, Mycovia 


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Pharmaceuticals will provide advance notification to the Investigator or head of the medical 
institution (where applicable) of the impending action.  If the study is suspended or prematurely 
discontinued for safety reasons, Mycovia Pharmaceuticals will promptly inform all Investigators, 
heads of medical institutions (where applicable), and/or institutions conducting the study.  
Mycovia Pharmaceuticals will also promptly inform the relevant regulatory authorities of the 
suspension or premature discontinuation of the study and the reason(s) for the action.  If required 
by applicable regulations, the Investigator must inform the IRB/IEC promptly and provide the 
reason(s) for the suspension or premature discontinuation. 
Mycovia Pharmaceuticals requires the following data and materials before a study can be 
considered complete or terminated: 
1. Clinical data and all test results from Extension Study Week 48 through Week 96. 
2. Electronic CRFs properly completed by appropriate study personnel and signed and dated by 
the Investigator. 
3. All outstanding queries and site issues resolved. 
4. Copies of protocol amendments and IRB approval/notification if appropriate. 
5. A close-out summary for the site, prepared by the Principal Investigator (an IRB summary 
letter is acceptable). 
 
10.8 Record Retention 
Following closure of the study, the Investigator must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and secure location.  
The records must be maintained to allow easy and timely retrieval when needed (e.g., for a 
Mycovia Pharmaceuticals audit or regulatory inspection) and must be available for review in 
conjunction with the assessment of the facility, supporting systems, and relevant site staff. When 
permitted by local laws/regulations or institutional policy, some or all records can be maintained 
in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to 
be exercised before such action is taken.  The Investigator must ensure that all reproductions are 
legible and are a true and accurate copy of the original and meet accessibility and retrieval 
standards, including regenerating a hard copy, if required. Furthermore, the Investigator must 
ensure there is an acceptable back-up of these reproductions and that an acceptable quality control 
process exists for making these reproductions.   
Investigators are required to retain essential documents pertaining to the conduct of this study for 
at least 2 years after the last approval of a marketing application in an ICH region and until there 


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are no pending or contemplated marketing applications in an ICH region or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational product, 
per ICH guidelines.  The minimum retention time will meet the strictest standard applicable to that 
site for the study, as dictated by any institutional requirements, local laws or regulations, or 
Mycovia Pharmaceuticals’ standards/procedures. The Investigator must notify Mycovia 
Pharmaceuticals of any changes to the archival arrangements, including, but not limited to, 
archival at an off-site facility or transfer of ownership of the records in the event the Investigator 
is no longer associated with the site. 
10.9 Disclosure of Data 
The Investigator agrees by his/her participation that the results of this study may be used for 
submission to national and/or international registration and supervising authorities.  If required, 
these authorities will be provided with the names of Investigators, their addresses, qualifications, 
and extent of involvement.  It is understood that the Investigator is required to provide Mycovia 
Pharmaceuticals with all study data, complete reports, and access to all study records. 
Data generated by this study must be available for inspection by the United States FDA and other 
regulatory authorities, by Mycovia Pharmaceuticals, and the IRB/IEC as appropriate.  At a 
subject’s request, medical information may be given to his or her personal physician or other 
appropriate medical personnel responsible for his or her welfare. Subject medical information 
obtained during this study is confidential and disclosure to third parties other than those noted 
above is prohibited. 
10.10 Financial Disclosure 
The United States FDA Financial Disclosure by Clinical Investigators (21 Code of Federal 
Regulations 54) regulations require Sponsors to obtain certain financial information from 
Investigators participating in covered clinical studies; each Principal Investigator and 
Sub-Investigator is required to provide the required financial information and to promptly update 
Mycovia Pharmaceuticals with any relevant changes to their financial information throughout the 
course of the clinical study and for up to 1 year after its completion.  This rule applies to all 
Investigators and Sub-Investigators participating in covered clinical studies to be submitted to the 
FDA in support of an application for market approval. 
10.11 Publication Policy 
The publication policy is outlined in the Clinical Trial Agreement. 


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10.12 Confidentiality 
Confidentiality is outlined in the Clinical Trial Agreement. 
10.12.1 
Data 
All information about the nature of the proposed investigation provided by Mycovia 
Pharmaceuticals or the designated clinical study monitor to the Investigator (except for 
information required by law or regulations to be disclosed to the IRB/IEC, the subject, or the 
appropriate regulatory authority) must be kept in confidence by the Investigator. 
10.12.2 
Subject Anonymity 
The anonymity of participating subjects must be maintained. Subjects will be identified by an 
assigned subject number on CRFs and other documents retrieved from the site or sent to the 
designated clinical study monitor, Sponsor, regulatory agencies, or central laboratories/reviewers.  
Documents that identify the subject (e.g., the signed informed consent document, subject 
identification record) must be maintained in strict confidence by the Investigator, except to the 
extent necessary to allow auditing by the appropriate regulatory authority, the clinical study 
monitor, or Mycovia Pharmaceuticals representatives. 
 
 
 


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Appendix K. Protocol Amendment Summary of Changes 
 
 


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Protocol Version 5 (Amendment 4): 01 October 2019 
Country-Specific Amendment: U.S. Only 
Section 
Change 
Reason 
Impact on 
Human 
Subject 
(risk/benefit) 
Version 4/ 
Amendment 
3 
The Version 4/ Amendment 3 Extension Study Protocol was 
not implemented and should not be released or filed at the 
Investigator Site. 
Redesign of the 
Extension Study 
Protocol on 01 
October 2019. 
Benefit 
 
 
 
 
Protocol Version 4 (Amendment 3): 18 June 2019 
Country-Specific Amendment: U.S. Only 
Section 
Change 
Reason 
Impact on 
Human 
Subject 
(risk/benefit) 
Synopsis 
Page 15 
& 16, 
Table 1 
Added “The initial PK sample must be drawn prior to the first 
dose of study drug (placebo/VT-1161).” 
To clarify timing 
of initial PK 
sample 
Benefit 
8.1  
Table 1 
Added “The initial PK sample must be drawn prior to the first 
dose of study drug (placebo/VT-1161).” 
To clarify timing 
of initial PK 
sample 
Benefit 
 
 


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Protocol Version 4 (Amendment 3): 18 June 2019 
Country-Specific Amendment: U.S. Only 
Section 
Change 
Reason 
Impact on 
Human 
Subject 
(risk/benefit) 
Synopsis 
Page 15 
& 16, 
Table 1 
Added “The initial PK sample must be drawn prior to the first 
dose of study drug (placebo/VT-1161).” 
To clarify timing 
of initial PK 
sample 
Benefit 
8.1  
Table 1 
Added “The initial PK sample must be drawn prior to the first 
dose of study drug (placebo/VT-1161).” 
To clarify timing 
of initial PK 
sample 
Benefit 
8.1.2 #9 
Added “The initial PK sample must be drawn prior to the first 
dose of study drug (placebo/VT-1161).” 
To clarify timing 
of initial PK 
sample 
Benefit 
10.1 
Added “The initial PK sample must be drawn prior to the first 
dose of study drug (placebo/VT-1161).” 
To clarify timing 
of initial PK 
sample 
Benefit 
Appendix 
J 
Added Appendix J: Study Extension. 
Implementing an 
Extension Study 
for U.S. only, to 
track long-term 
efficacy and safety 
Benefit 
 
 
 


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Protocol Version 3 (Amendment 2): 25 February 2019 
Section 
Change 
Reason 
Impact on 
Human 
Subject 
(risk/benefit) 
Page 3 
Clarified ICH E6’(R2)’ would be followed for study 
performance.   
Added ‘Regulatory authorities, if required by national law, 
must give a favorable opinion/approval of the study 
protocol and amendments, informed consent and assent 
(for those ages 12 to 17) documents, and investigational 
brochure.’ 
Updated GCP 
reference to reflect 
current version; 
additional 
information regarding 
potential regulatory 
authorities’ 
requirements. 
Benefit 
Page 3 
Changed Medical Responsible information from J. Gordon 
Still to Claude Hughes 
Individual serving as 
Medical Responsible 
for the study changed. 
Not 
applicable 
Synopsis 
4.1 
Clarified Maintenance Phase dosing for VT-1161 or 
placebo, ‘7 daily doses followed by 11 weekly doses.’ 
Expanded description 
to prevent confusion 
of dosing regimen. 
Benefit 
Synopsis 
Table 1 
4.1 
8.1.1 
12.7 
Append I 
Added ‘for all regions and questions regarding their 
RVVC history (US only)’. 
Added ‘for all regions. At Screening, subjects will also be 
required to answer questions regarding their RVVC history 
(US only).’ 
Added ‘for all regions and RVVC History Questionnaire 
(US Only)’. 
Added ‘all regions participating in’ and ‘For US only, 
questions regarding RVVC history will be administered at 
Screening using the RVVC History Questionnaire (see 
Appendix I) to collect information on the disease, 
diagnosis, and treatment profile for the subjects enrolled in 
the study.’ 
Added Appendix I RVVC History Questionnaire. 
To collect 
information on 
subjects’ historical 
experience and 
impact of RVVC in 
the United States. 
Not 
applicable 
Synopsis 
Incl #1 
5.1 
 
Added ‘post-menarchal’. 
To clarify patient 
population eligible 
for enrollment (post-
menarchal was 
previously assumed). 
Benefit 
Synopsis 
Incl #2 
5.1 
Added ‘, or other approved diagnostic tests.’ 
To allow 
establishment of 
RVVC history based 
on locally-approved 
testing as outlined in 
the study design 
(missing from 
inclusion criterion 
language). 
Benefit 
Synopsis 
Incl #5 
5.1 
Added ‘timeline per’ and minor grammatical changes. 
Improved clarity on 
timelines for Pap test 
requirement. 
Benefit 


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Product: VT-1161  
 
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Synopsis 
Incl #9 
5.1 
 
Changed ‘study entry’ to ‘Screening’ and added ‘at 
Screening’. 
Clarified 
requirements for non-
childbearing potential 
as they relate to time 
from Screening 
Benefit 
Synopsis 
Incl #10 
5.1 
Changed ‘study medication’ to ‘fluconazole’ for footnote 
b. 
Clarified that footnote 
is applicable to start 
of fluconazole 
treatment during 
Induction Phase. 
Benefit 
Synopsis 
7.4.1 
8.1.12 
Added ‘; refer to Section 8.1.12 on treatment options if 
fluconazole is ineffective)’ 
Added ‘If a subject fails to respond to fluconazole 
treatment, the Investigator may employ treatment options 
corresponding to the site’s standard of care treatment upon 
consult with the Medical Monitor.’ 
Clarified instructions 
for the Investigator 
should a subject not 
respond to 
fluconazole treatment 
for an acute VVC 
episode during the 
study. 
Benefit 
Synopsis 
7.4.1 
Added ‘(urogenital)’. 
Clarity on assumed 
type of other 
concomitant 
infections. 
Benefit 
Synopsis 
Excl #5 
5.2 
7.4.1 
Added ‘collunarium/nasal’ to list of concomitant steroids 
permitted and to Exclusion Criterion #5. 
Clarity on 
collunarium/nasal 
steroid use was 
missing. 
Benefit 
Synopsis 
Excl #5 
5.2 
Added ‘nor use of topical vulvar or vaginal steroids during 
the study or within 7 days prior to Screening’. 
Reduce potential 
confounding factors 
for efficacy 
assessments. 
Benefit 
Synopsis 
Excl #6 
5.2 
7.4.1 
Added subjects must not use any ‘vaginal douches or 
benzalkonium chloride disinfectant during the study.’ 
Added ‘or vaginal douches’ to Exclusion Criterion #6. 
Reduce potential 
confounding factors 
for efficacy 
assessments. 
Benefit 
Synopsis 
Excl #7 
5.2 
7.4.1 
Added ‘carbamazepine’ to list of drugs with narrow 
therapeutic index that are metabolized by and sensitive to 
induction of CYP3A4. 
Clarified complete 
list of narrow 
therapeutic index 
drugs metabolized by 
or sensitive to 
CYP3A4. 
Benefit 
Synopsis 
Excl #14 
Table 1 
5.2 
9.1.5.3 
Removed ‘performed only on known diabetics or subjects 
suspected to have diabetes by the investigative site’. 
Added ‘for all subjects’ in Section 9.1.5.3.  
HbA1c testing will be 
performed on all 
subjects at Screening. 
Benefit 
Table 1 
Separated central serum pregnancy test from local urine 
pregnancy test 
Improved clarity for 
which testing is used 
at each visit 
Benefit 
Table 1 
8.1.1 
Added ‘±2 days’ to Screening (Day -14) Visit 
Allow flexibility for 
scheduling Screening 
visit with respect to 
Day 1 without impact 
to assessments  
Benefit 


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Product: VT-1161  
 
Protocol VMT-VT-1161-CL-011 
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160 
Table 1 
9.1.5.3 
Added cholesterol and triglycerides testing. 
Implement testing 
requested by PMDA 
globally to evaluate 
across all subject 
populations. 
Benefit 
1.1.1.3 
Remove ‘%’ 
Corrected erroneous 
unit given to pH 
value. 
Not 
applicable 
1.2 
Replaced ‘tablets’ with ‘capsules’. 
VT-1161 is a capsule 
formulation for this 
study. 
Not 
applicable 
5 
Added ‘(or assent for those 12-17)’. 
Clarified informed 
consent document 
includes assent for 
subjects 12-17. 
Not 
applicable 
8.1.1 
9.1.5.6 
9.1.5.7 
9.1.5.8 
Clarified Bacterial vaginosis testing will be done locally 
and Chlamydia trachomatis and Neisseria gonnorrhoeae 
testing will be done by central laboratory. 
Added Section 9.1.5.8 Bacterial Vaginosis, moved 
‘Testing for Bacterial vaginosis will be done locally.’ 
From Section 9.1.5.7. 
Prevent confusion on 
which testing is being 
performed locally and 
centrally. 
Benefit 
8.1.1 
9.1.5.3 
9.1.5.4 
9.1.5.5 
Added ‘Central’. 
Clarified central 
laboratory results are 
not required prior to 
start of fluconazole 
treatment. 
Benefit 
8.1.1 
Added ‘one time’. 
Clarified subjects can 
be eligible for re-
screening one time. 
Benefit 
11.2 
Added ‘A subject may be withdrawn due to lack of 
tolerability or safety concerns, including study drug-related 
AEs or development of clinically-significant study drug-
related laboratory abnormalities.  If a subject is withdrawn 
from treatment, the subject must be followed clinically 
until the event is resolved or deemed stable. A subject 
must be discontinued from the study drug if ALT or/and 
AST is > 5 × the upper limit of normal (ULN) or ALT 
or/and AST is > 3 × ULN and serum total bilirubin is > 2.0 
ULN.’ 
 
Added ‘Subjects who prematurely discontinue study 
medication, but remain in the study, may be treated 
according to the standard local practice.’ 
Additional 
discontinuation 
criteria. 
Benefit 
11.3 
Added ‘Study completion is defined as when the last 
subject has completed their last study visit.’ 
To define study 
completion. 
Benefit 
12 
Expanded language to ‘The SAP will provide a detailed 
description of the proposed data analysis methods and 
procedures.  The SAP was drafted and submitted to 
regulatory bodies prior to the start of the study and will be 
finalized before 50% of subjects are enrolled.  The SAP 
contains all the details for the analysis of the primary and 
secondary endpoints as well as the sensitivity analyses 
planned for all endpoints.  The additions to the SAP since 
that initial submission include additional sensitivity 
Provided additional 
information on plans 
for primary and 
secondary analyses 
and handling of 
missing data. 
Not 
applicable 


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Product: VT-1161  
 
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161 
analyses
 
 
 
 
. The handling of missing data is explained in 
detail in the SAP including the descriptions of the 
sensitivity analyses that will be performed for each 
endpoint in order to assess the impact of the handling of 
the missing data on the results.’ 
Originally read ‘A formal SAP will be finalized prior to 
enrollment of the first subject. The SAP will provide a 
more technical and detailed description of the proposed 
data analysis methods and procedures.’ 
12.1 
Added ‘The placebo rate was based on the data generated 
in Phase 2b RVVC study; the primary efficacy outcome 
measure in this study was the proportion of subjects with 
one or more culture-verified acute VVC episodes during 
the Maintenance Phase through Week 48 of the study in 
the ITT population (all randomized subjects).  Culture-
verified acute VVC was defined as a positive fungal 
culture for Candida species associated with a total signs 
and symptoms score of ≥ 3.  The proportion of subjects 
with one or more culture-verified acute VVC episodes 
through Week 48 was lower in the VT-1161 dosing 
regimens (0-7%) compared with the placebo group 
(52.2%).  This difference was statistically significant in all 
VT-1161 treatment groups compared with placebo 
(p<0.0001).  When powering the VMT-VT-1161-CL-011 
study, it was determined that a separation of at least 35% 
between the treatment groups would be a clinically 
meaningful separation.  Thus, the sample size was 
powered to pick up at least a 35% separation between the 
treatment groups.’   
Provided explanation 
for how sample size 
was determined. 
Not 
applicable 
12.4 
Added ‘The primary method of analysis is a Chi-square 
test for active treatment versus placebo based on the ITT 
population.  
 
. 
 
 
The number and percentage of subjects with one or more 
culture-verified acute VVC episodes with signs and 
symptoms of ≥3 post randomization through Week 48 will 
be summarized across treatment groups including a 95% 
exact confidence interval and odds ratio.  The percentages 
will also be plotted by treatment group.’ 
Added ‘Every effort will be made to obtain required data at 
each scheduled evaluation from all subjects who have been 
randomized, including those who discontinue the study 
prior to the EOS Week 48 visit.      
For scheduled visits where the investigator’s assessment of 
clinical signs and symptoms or the culture result is 
missing, missing values will be imputed using the method 
of multiple imputation.  For subjects who discontinue the 
study early and have missing assessments for all visits 
after discontinuation, the missing values for the expected 
scheduled visits will be imputed using the method of 
Provided additional 
information on the 
analysis and how 
missing data for the 
handled for the 
primary endpoint. 
Not 
applicable 


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Product: VT-1161  
 
Protocol VMT-VT-1161-CL-011 
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multiple imputation.  The missing values will be imputed 
using the following auxiliary information: region, 
treatment, baseline BMI, baseline age, ethnicity, and visit.  
The procedure PROC MI in SAS will be used to generate 
10 possible imputed datasets.  Using these multiple 
imputation datasets, determination of meeting the primary 
endpoint of a culture-verified acute VVC episode during 
the Maintenance Phase will be derived.  Subjects with a 
culture-verified acute VVC episode at any point from post 
randomization through Week 48 (including unscheduled 
visits) will be counted as having an episode when 
calculating the primary endpoint.  The multiple datasets 
containing the primary endpoint will be analyzed using a 
Chi-square test and the results will be combined using 
PROC MIANALYZE to obtain an inferential result.  
Sensitivity analyses will be performed for the primary 
endpoint to assess the impact of missing/censored data on 
the results using different time to event and censoring 
calculations.  Further details on the steps of these analyses 
are presented in the VMT VT-1161-CL-011 SAP.’ 
12.5 
Changed ‘14’ to ‘21’. 
The MedDRA® 
dictionary used for 
coding AEs will be 
version 21 for this 
study 
Not 
applicable 
13.5 
Changed ‘Subjects who were <80% or >120% compliant 
of all doses of IMP’ to ‘Subjects who were <80% IMP 
compliant in the Induction Phase or <50% IMP compliant 
in the Maintenance Phase.’ 
Modified protocol 
deviation criterion for 
consistency with 
statistical analysis 
population 
definitions. 
Benefit 
Multiple, 
see below 
Changes made for Protocol Version 2 (Amendment 1 – 
Region/Country Specific Amendment) 
Implementing 
changes made during 
UK-MHRA review as 
were beneficial to 
subject safety and 
data quality from a 
global perspective. 
Benefit 


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Product: VT-1161  
 
Protocol VMT-VT-1161-CL-011 
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163 
Protocol Version 2 (Amendment 1): 12 September 2018  
Region/Country Specific Amendment: EU/UK, Poland, and Bulgaria 
Section 
Change 
Reason 
Impact on 
Human 
Subject 
(risk/benefit) 
Synopsis, 
Table 1, 
8.1.2 – 
8.1.12, 
9.1.5.1 
Added local urine pregnancy testing for all visits for WOCBP. 
Monitor more 
frequently for 
pregnancies 
throughout the 
study for all 
WOCBP. 
Benefit 
Synopsis, 
Inclus 
#10, 
5.1 
For OPTION 3 contraceptive methods, added ‘In addition to 
OPTIONS 1 and 2, subjects of childbearing potential (includes 
ages 12-17) may also use 1 of the following methods of 
contraception after completing the Induction Phase on Study 
Day 1 through Week 48.’   
Added footnotes for: ‘Sexual abstinence is defined as refraining 
from heterosexual intercourse during the entire study period and 
where this is the usual life style of the subject. Periodic 
abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhoea method are not considered to be 
acceptable methods of contraception;’ ‘ Subjects who started 
taking a hormonal contraceptive less than 3 months prior to the 
first dose of study medication must agree to use a double-barrier 
method (i.e. diaphragm plus spermicide or condom) through 3 
months after starting the hormonal contraceptive;’ and ‘ 
Because of the teratogenic risk associated with repeat dosing of 
fluconazole, OPTION 3 contraceptive methods cannot be used 
during Screening and the Induction Phase of the study (from 
Screening until Baseline (Day 1) of the study).’  
Provide 
clarification for 
definition of 
abstinence and 
restrict 
contraceptive 
methods during 
repeat dosing of 
fluconazole to only 
highly effective 
methods. 
Benefit 
7.3 
Removed ‘Medical Monitor and’ from unblinding procedures 
if Grade 4 AE considered related to IMP. 
Clarified 
guidelines for 
consistency with 
unblinding 
guidelines outlined 
in Section 7.8. 
Benefit 
7.8 
Removed ‘The Investigator must contact the Medical Monitor 
or appropriate Mycovia Pharmaceuticals study personnel to 
discuss options regarding unblinding the subject’s treatment 
assignment.’ 
Removed ‘Mycovia Pharmaceuticals’ Medical Monitor’ and 
changed to ‘The Investigator” for who may unblind a subject’s 
treatment assignment only in the case of an emergency (i.e., a 
Grade 4 AE) OR in the event of a serious medical condition 
when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the subject as 
judged by the Investigator.   
Guidelines to 
allow the 
Investigator the 
ability to unblind a 
subject’s treatment 
assignment in an 
emergency to 
facilitate 
fulfillment of 
Investigator 
responsibilities 
Benefit 


CONFIDENTIAL 
 
Mycovia Pharmaceuticals, Inc. 
 
Product: VT-1161  
 
Protocol VMT-VT-1161-CL-011 
IND 111675 
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164 
 
 
Added ‘The Investigator must contact the Medical Monitor or 
appropriate Mycovia Pharmaceuticals study personnel to 
communicate the reasons for unblinding the subject’s 
treatment assignment immediately after the unblinding 
occurred (ICH GCP 4.7).’ 
according to ICH 
GCP 4.3.1 and 4.7. 

SAP_001.pdf: 
PRS COVER PAGE for STATISTICAL ANALYSIS PLAN 
 
TITLE: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of VT-1161 Oral Capsules in the 
Treatment of Subjects with Recurrent Vulvovaginal Candidiasis (VMT-VT-
1161-CL-011) 
 
DATE: 25 July 2020 
 
CLINICALTRIALS.GOV ID: NCT03562156