Conditions: Vaginal Infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 204
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of metronidazole gel in the treatment of vaginal infections.

Detailed description:

Arms:
arm 1: One applicator full at bedtime arm 2: One applicator full at bedtime

Interventions: intervention 1: Metronidazole intervention 2: Gel vehicle
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
Cover Page created 06/18/2020 
 
Clincialtrials.gov ID: NCT02308046  
 NCT02308033 
 NCT02308007 
Protocol ID: MTC-001 (Trials 1, 2 and 3) 
Brief Title: Multi-Center Study of New Medications to Treat Vaginal Infections (SMART 
GIVES) 
 
Official Title: Solubilized Metronidazole And/oR Terconazole Gels Intra-Vaginal Efficacy 
and Safety  (SMART GIVES) 
 
Document Type: Protocol 
 
Date of Document: March 12, 2015 
 
Sponsor: Curatek Pharmaceuticals, LLC 
 


 
 
 
 
 
 
 
 
 
Protocol Number:  MTC-001 
 
 
IND # 121,229  
 
        # 124,679  
        # 124,680 
 
 
 
 
Solubilized Metronidazole And/oR Terconazole Gels Intra-Vaginal Efficacy 
and Safety 
(SMART GIVES) 
 
Phase III 
 
 
 
 
Original Protocol 
Version 1.0 12/12/14 
 
Revised Protocol 
Version 2.0 03/12/15  
 
 
Curatek Pharmaceuticals, LLC 
1965 Pratt Boulevard 
Elk Grove Village, IL  60007 
 
 
 
 
 
CONFIDENTIAL 
 
 
This confidential document is the property of Curatek Pharmaceuticals, LLC. No unpublished information 
contained herein may be disclosed without prior written approval from Curatek Pharmaceuticals, LLC. 
Access to this document must be restricted to relevant parties.




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Protocol MTC-001 
 
 
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Protocol Number:  MTC-001 
 
IND # 121,229  
        # 124,679  
        # 124,680 
 
1.2. Investigator Agreement 
Protocol Title:  Solubilized Metronidazole And/oR Terconazole Gels Intra-Vaginal Efficacy and Safety  
(SMART GIVES) 
 
I have read the above named protocol, and agree to personally conduct or supervise the trial as described.  
I verify that I am qualified by education, training, and experience to conduct the trial and will do so in 
accordance with all applicable regulatory requirements, and in accordance with Good Clinical Practice 
(GCP).  
 
I will provide copies of the protocol and all relevant study materials to study personnel who will have 
delegated responsibilities for this study and I will ensure they are all adequately trained regarding the 
protocol, investigational products (IPs)/study drugs, the conduct of the study, and their associated 
responsibilities.   
 
I agree that no subjects will be enrolled in the trial until the protocol and informed consent have been 
Institutional Review Board (IRB) approved.  All subjects will be properly consented prior to any study 
procedures being performed.   
 
I have read the Investigator’s Brochure and agree to report all adverse events that occur during the trial. 
 
My records (written and/or electronic), subject reports, and all relevant source documentation will be used 
to transcribe information onto each subject’s case report form (CRF).  By signing the CRF, I will attest to 
the authenticity of the data and the accuracy and completeness of the transcriptions.  I agree to the 
auditing and monitoring procedures described in the protocol and will provide full and unencumbered 
access to source documents and medical records to auditors, monitors, the reviewing IRB, Curatek 
representatives, and government regulatory agencies (i.e. Food and Drug Administration [FDA]), as 
applicable.   
 
I will provide Curatek/Curatek’s designee (Clinical Research Organization [CRO]) with all data generated 
during the trial and I understand that all information concerning the investigational products/study drugs 
are confidential and the exclusive property of Curatek.  I will abide by all terms outlined in the Clinical 
Trial Agreement (CTA).   
 
Investigator Signature: 
 
Date: 
 
Investigator Name (print): 
 
Name and Address of Clinical Site: 
 
 
 
 






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with parent/legal guardian available to provide written informed consent 
• 
Willing to begin treatment within 2 days of the baseline visit (Visit 1) 
• 
Currently not menstruating and not anticipating menses during treatment 
• 
Willing to abstain from sexual intercourse through Visit 2 and have their partner 
use a non-lubricated condom within the preceding 48 hours of Visit 3 if sexual 
intercourse occurs 
• 
Willing to abstain from using intravaginal/vulvovaginal products (e.g. feminine 
hygiene products such as douches and deodorants; contraceptive products such 
as diaphragms, spermicidal creams, gels, and foams; vaginal lubricants, 
moisturizers, and hormonal suppositories and creams such as Vagifem®, 
Estrace® and Premarin® cream; and tampons etc.) through Visit 2 and within 
48 hours of Visit 3. 
• 
Willing to abstain from alcohol and propylene glycol ingestion during treatment 
and for 1 day thereafter   
• 
If heterosexually active, subject must be post-menopausal for ≥ 1 year, 
surgically sterile (i.e. hysterectomy, bilateral oophorectomy, or bilateral tubal 
ligation), sexually active with a male partner who is surgically sterile (i.e. 
vasectomy), or practicing an acceptable form of birth control (i.e. oral 
contraceptives, contraceptive injections, contraceptive patch, condoms, or 
intrauterine device [IUD]) for at least 1 month before study entry and agree to 
continue the contraceptive method for the duration of the study.  If sexually 
abstinent, subjects must agree to continue abstinence or use an acceptable 
method of birth control should sexual activity commence during the study. 
• 
Willing and capable of cooperating to the extent and degree required by the 
protocol 
• 
Negative urine pregnancy test (unless subject is surgically sterile or post-
menopausal ≥ 1 year)  
Exclusion 
Criteria 
Exclusion Criteria Applicable to all Infection Studies 
• 
Other infectious causes of vulvovaginitis (e.g. Trichomonas vaginalis, 
Chlamydia trachomatis, Neisseria gonorrhoeae, active Herpes simplex virus or 
genital warts) 
• 
Subject has used systemic (oral, intravenous [IV], or intramuscular [IM]), 
intravaginal/vulvovaginal antifungal, antimicrobial, or corticosteroid therapy 
within 14 days of study enrollment 
• 
Subject is currently taking or has taken disulfiram therapy within 14 days of 
study enrollment 
• 
Subject is currently on lithium, coumarin anticoagulants (e.g. warfarin), or 
immunosuppressive therapy 
• 
Subject is expected to require the concomitant use of prohibited 
medications/products while enrolled in the study  
• 
Subject will require treatment for cervical intra-epithelial neoplasia (CIN) or 
cervical carcinoma while enrolled in the study or plans to use other 
investigational products while enrolled in the study 
• 
Nursing mother 
• 
Use of any investigational drug within 30 days of enrollment or plans to use 
other investigational products while enrolled in the study 


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• 
Known primary or secondary immunodeficiency 
• 
Presence of any condition or illness, including vulvar and vaginal conditions, 
that in the opinion of the investigator would preclude accurate evaluation of the 
subject’s condition and/or confound the interpretation of the subject’s treatment 
response 
• 
History of hypersensitivity to metronidazole or other nitroimidazoles; 
terconazole or other triazoles; parabens; or any other ingredient/component of 
the formulations  
 
Subjects who meet criteria for BV only will be entered into the BV Study and 
randomized to a BV treatment (BV Gel or Placebo Gel), subjects who meet criteria 
for VVC only will be entered into the VVC Study and randomized to a VVC 
treatment (VVC Gel or Placebo Gel) and subjects who meet criteria for both BV 
and VVC will be entered into the Mixed Infection Study and randomized to 
treatment (BV Gel, VVC Gel, or Combo Gel) for Mixed Infection.  
Study Procedures 
Screening and Enrollment/Baseline Visit (Visit 1) 
All subjects will sign an informed consent form (ICF) and inclusion/exclusion 
criteria will be evaluated to determine subject eligibility.  Evaluation of subject 
eligibility will include:  demographic information; contraceptive and obstetric 
status, medical, surgical, and gynecologic history; symptom and sign severity rating; 
a physical exam with vital signs; a pelvic exam to visually inspect for genital herpes 
and warts, assess Amsel criteria (i.e. vaginal discharge assessment, pH assessment, 
whiff test, and saline wet prep), and check for the presence or absence of motile 
trichomonads on saline wet prep and yeast on KOH wet mount; tests for  Neisseria 
gonorrhea,  Chlamydia trachomatis, Trichomonas vaginalis, and Herpes simplex (if 
suspected); culture for Candida species; a Gram stain; a pregnancy test (if 
indicated); a Pap smear if the subject is ≥ 21 years old and one was not done within 
the past 3 years; and hematology and chemistry labs for subjects enrolled in the 
Mixed Infection Study.   
 
Since some of the required tests for eligibility will not be immediately available at 
the baseline evaluation, enrollment into an infection study will be based on clinical 
criteria (i.e. Amsel criteria and/or signs and symptoms of VVC including KOH 
microscopy).  
 
Subjects will be randomized at Visit 1 based on infection diagnosis.  They will be 
dispensed study drug and applicators along with instructions for the administration 
of the drug; a listing of study instructions; condoms; packaging for return of unused 
drug; and a subject diary.  Subjects will record diary data between Visits 1-2. 
 
Subjects will be asked to return their completed diaries and their unused drug, as 
directed, at their next visit (Visit 2).     
 
Test of Cure Evaluation (Visit 2):   
Visit 2 will occur 7-14 days after randomization.  If a subject is menstruating on the 
day of this scheduled visit, she should be rescheduled to return 24 hours after 
completion of menses.   


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Visit 2 procedures will include:  symptom and sign severity rating; a pelvic exam to 
assess Amsel criteria and to check for the presence or absence of motile 
trichomonads on saline wet prep; a culture for Candida species; a Gram stain; 
hematology and chemistry labs for subjects enrolled in the Mixed Infection Study; 
and collection of unused drug.   
 
Assessment of subject compliance (i.e. with study instructions and drug 
administration) and information on time to resolution/reoccurrence of symptoms, 
concomitant medication use, and possible adverse events will be obtained by 
interviewing the subject and reviewing the subject’s diary. 
 
The investigator/clinician will be asked to document whether the subject requires 
any additional treatment for vaginal discomfort/symptoms.  Subjects who do require 
additional treatment should be treated per investigator/clinician judgment and be 
terminated from the study.  If a subject self-medicated for vaginal 
discomfort/symptoms, she should be terminated from the study.b
 
      
Subjects who do not require additional treatment and subjects who did not self-
medicate will be asked to return for a follow-up visit (Visit 3) 21-30 days after 
randomization.    
 
For those subjects continuing in the study, subject study instructions will be 
reviewed.  If unused study drug and/or the subject diary were not returned, the 
subject should be reminded to return them at the next visit.  
 
If at any time during the study the subject or investigator has concerns about 
persistent symptoms or adverse event(s), the subject may return to the office/clinic 
any time between visits to be evaluated (i.e. an unscheduled visit).  If the subject 
requires treatment for vaginal discomfort/symptoms at an unscheduled visit she 
should be terminated from the study.  If treatment is not required she may return for 
her next scheduled visit.  
 
Some Visit 1 laboratory test results used to determine whether inclusion/exclusion 
criteria have been met will not be available before subjects are randomized, but will 
become available during the course of the study.  Visit 1 test results that would 
make a subject not eligible for the study are: positive gonorrhea, chlamydia, 
trichomonas, or herpes tests; normal Nugent score < 4 (for BV and Mixed Infection 
subjects); or negative Candida culture (for VVC and Mixed Infection subjects).  
When test results that make a subject ineligible become known, subjects should be 
contacted and asked to return to the office/clinic to be terminated from the study.  
Termination procedures for these subjects are more limited and include a safety 
assessment consisting of reviewing concomitant medication use, occurrence of 
adverse events, and obtaining hematology and chemistry labs if the subject was in 
the Mixed Infection Study and labs were not already obtained at Visit 2.  Subject 
                                                 
b Self-administration of therapy includes prescription and over the counter (OTC) antimicrobial, anti-fungal, analgesics, or 
steroid treatments. 


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diaries should be reviewed, unused drug collected, and study drug 
administration/compliance ascertained if not already done.   
 
Follow-Up Evaluation (Visit 3):   
Visit 3 will occur 21-30 days after randomization.  
  
Visit 3 procedures will include:  symptom and sign severity rating; a pelvic exam to 
assess Amsel criteria and to check for the presence or absence of motile 
trichomonads on saline wet prep; a culture for Candida species; and a Gram stain.  
If any clinically significant hematology and/or chemistry lab changes were noted in 
Mixed Infection subjects at Visit 2, these labs may be repeated.  If labs for a Mixed 
Infection subject were not obtained at Visit 2, they may be obtained at Visit 3.  An 
assessment of subject compliance with study instructions, concomitant medication 
use, and possible adverse events will be obtained by interviewing the subject.  
Information on study drug administration/compliance and time to 
resolution/reoccurrence of symptoms, (if not previously ascertained or if updated 
information is available) will also be obtained by interviewing the subject. 
 
The investigator/clinician will be asked to document whether the subject requires 
any additional treatment for vaginal infection (i.e. BV, VVC, or Mixed Infection).  
Subjects who do require additional treatment should be treated per 
investigator/clinician judgment.   
 
Subjects will be asked to complete a subject satisfaction survey and will be 
terminated from the study following Visit 3.  
 
See Appendix A, Schedule of Procedures.  
Efficacy  
Endpoints and 
Safety 
Assessments  
Primary Efficacy Endpoints and End Evaluations 
1. BV Study:  BV cure rate, with cure defined as normal/physiologic dischargec
2. VVC Study:  VVC cure rate, with cure defined as resolution of all signs and 
symptoms attributable to VVC (i.e. clinical cure).  
, 
negative whiff test, and < 20% clue cells (i.e. clinical cure) 
3. Mixed Infection Study:  Mixed Infection cure rate, with cure defined as BV cure 
(i.e. BV clinical cure) AND a VVC cure (i.e.  VVC clinical cure)  
 
Primary efficacy endpoint evaluations will occur at the subject’s test-of-cure visit 
(Visit 2).  If a subject requires additional treatment (i.e. a BV subject requiring 
treatment for BV, a VVC subject requiring treatment for VVC or a Mixed Infection 
subject requiring treatment for BV and/or VVC) or self-medicatesd
 
 for vaginal 
discomfort/symptoms prior to or at Visit 2 the subject will be considered a treatment 
failure. 
                                                 
c In the event a BV subject has discharge consistent with VVC (i.e. white, creamy, and curdy [cottage cheese like] adherent to the 
epithelium), the subject will be considered a BV cure providing all other criteria for BV cure (and evaluability) are met and the 
subject has a positive yeast culture. 
d Self-administration of therapy includes prescription and over the counter (OTC) antimicrobial, anti-fungal, analgesics, or steroid 
treatments. 


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Secondary Endpoints and Evaluations 
1. BV Study:  BV clinical and Nugent score cure rates alone and combined; 
changes/improvements in Amsel criteria and Nugent scores; time to resolution 
of vaginal symptoms 
2. VVC Study:  VVC clinical (i.e. resolution of all signs and symptoms 
attributable to VVC) and mycologic cure rates (i.e. negative Candida on 
culture) alone and combined; changes/improvements in signs and symptoms 
scores; eradication (or persistence) of individual fungal species; time to 
resolution of vaginal symptoms 
3. Mixed Infection Study:  BV clinical and Nugent score cure rates alone and 
combined; changes/improvements in Amsel criteria and Nugent scores; VVC 
clinical and mycologic cure rates alone and combined; changes/improvements 
in signs and symptoms scores; eradication or persistence of individual fungal 
species; time to resolution of vaginal symptoms   
 
Secondary endpoint evaluations will occur at Visits 2 and 3 and will utilize criteria 
appropriate to the subject’s entry diagnosis (i.e. study subject was enrolled in). 
 
Safety 
Safety will be assessed by questioning subjects regarding any adverse events that 
may have occurred, concomitant medication use, review of subject diaries, and 
obtaining blood laboratory tests for Mixed Infection subjects. 
 
Safety will be assessed through summaries of adverse events (AEs) and laboratory 
evaluations. All safety analyses will be based on the safety population and will be 
summarized for each treatment group. These summaries will be presented separately 
for each infection study. Adverse events, as available, for BV Gel and VVC Gel will 
also be summarized by combining subjects who received the same treatment 
regimen across the studies. For example, those receiving BV Gel in the BV study 
will be combined with those receiving BV Gel in the Mixed Infection study. 
Randomization 
and Treatment 
An interactive voice response (IVR) system/interactive web response (IWR) system 
will randomize subjects to treatment at Visit 1 based on the infection study they are 
enrolled in.  All treatments will consist of three doses, administered by vaginal 
applicator, at bedtime for three consecutive days.  Subjects will be randomized to 
treatment as follows:    
• 
Subjects enrolled in the BV study will receive either BV Gel (0.9% 
metronidazole gel) or Placebo Gel in a 1:1 ratio  
• 
Subjects enrolled in the VVC study will receive either VVC Gel (0.8% 
terconazole gel) or Placebo Gel in a 1:1 ratio  
• 
Subjects enrolled in the Mixed Infection study will receive either Combo Gel 
(0.9% metronidazole gel and 0.8% terconazole gel), or BV Gel (0.9% 
metronidazole gel) or VVC Gel (0.8% terconazole gel) in a 1:1:1 ratio 
Dosage of Study 
Drug/Treatment 
Regimens  
• 
BV Gel:  0.9% metronidazole gel (45 mg of metronidazole/5 grams of gel);  
total metronidazole dose = 135 mg 
• 
VVC Gel:  0.8 % terconazole gel (40 mg terconazole/5 grams of gel); total 
terconazole dose = 120 mg 
• 
Combination BV & VVC Gel (Combo Gel):  0.9% metronidazole gel and 0.8% 


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terconazole gel; total metronidazole dose = 135 mg and total terconazole dose = 
120 mg 
• 
Placebo Gel:  no active ingredients 
Statistical 
Methods 
Each of the three infection studies within the trial will be analyzed separately.  The 
primary assessments of efficacy will be based on the modified intent-to-treat 
(mITT) population.  This population will include all subjects randomized to 
treatment and administered at least one dose of study drug.  In addition, subjects in 
the VVC and Mixed Infection studies must have a positive baseline vaginal fungal 
culture for Candida species.  Subjects in the BV and Mixed Infection studies must 
have a Gram stain Nugent score of ≥ 4 at the baseline visit.  
 
In addition to the mITT analyses of the data, analyses will be conducted using the 
intent-to-treat (ITT) population (all subjects randomized to treatment) as well as the 
per protocol (PP) population (subset of mITT subjects that had no major protocol 
violations and who are classified as efficacy evaluable with no missing data 
required to determine primary endpoints). 
 
Subjects will be categorized as cure or failure for the mITT and ITT analyses and as 
cure, failure, or non-evaluable for the PP analysis.  The number and percentage of 
subjects in each treatment group in each of these categories will be reported. 
 
BV Study and VVC Study:  The primary statistical objective is to demonstrate 
superiority of active treatment to placebo. This will be performed by conducting a 
continuity corrected Chi-squared test for a difference in the proportion of cure 
between active and placebo. Also, a 95% two-sided confidence interval for the 
difference in proportion of cure between the two treatments will be constructed.   
 
Mixed Infection Study:  The primary statistical objective of the Mixed Infection 
study is to demonstrate the superiority of the Combo Gel to both BV Gel and VVC 
Gel.  The assessment of superiority will be performed by conducting continuity 
corrected Chi-squared tests for a difference in the proportion of Mixed Infection 
cure between the Combo Gel and each of the two single entity treatments.  If the P-
values for both of the hypothesis tests are less than or equal to 0.05, the Combo Gel 
will be considered superior to both of the single entity gels.  Despite there being two 
comparisons made within the same study, no adjustment for multiplicity is 
necessary since both comparisons must be positive instead of “at least one,” in order 
to conclude superiority of the Combo Gel. Also, 95% two-sided confidence 
intervals for the difference in proportion of Mixed Infection cure between the 
Combo Gel and each of the two single entity treatments will be constructed. 
Sample Size 
Sample sizes were calculated for each infection study based on estimated cure rates 
for at least 90% power and 50 subjects per treatment group.  Superiority tests will 
be performed as two-sided, α = 0.05 level significance tests, and sample sizes were 
calculated using Fisher’s Exact test in case the planned Chi-squared test is not 
appropriate.    
 
BV Study:  116 per protocol, evaluable subjects 
VVC Study:  100 per protocol, evaluable subjects 




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Table of Contents 
 
 
1. Signatures .................................................................................................................................. 2 
1.1. Protocol Approval Form ............................................................................................................... 2 
1.2. Investigator Agreement................................................................................................................. 3 
2. Protocol Synopsis ...................................................................................................................... 4 
3. Background and Rationale .................................................................................................... 16 
3.1. Bacterial Vaginosis ...................................................................................................................... 16 
3.2. Vulvovaginal Candidiasis ........................................................................................................... 17 
3.3. Rationale for Metronidazole 0.9% Vaginal Gel (BV Gel) ....................................................... 17 
3.4. Rationale for Terconazole 0.8% Vaginal Gel (VVC Gel) ........................................................ 18 
3.5. Rationale for Combination Metronidazole 0.9% Gel and Terconazole 0.8% Vaginal Gel 
(Combo Gel) ........................................................................................................................................ 18 
3.6. Rationale for Comparators in Each Infection Study................................................................ 18 
4. Study Design ............................................................................................................................ 19 
5. Study Objectives and Endpoints............................................................................................ 20 
5.1. Primary Objectives ...................................................................................................................... 20 
5.2. Primary Efficacy Endpoints and Evaluations........................................................................... 21 
5.3. Secondary Endpoints and Evaluations ...................................................................................... 21 
6. Selection of Study Population ................................................................................................ 21 
6.1. Recruitment Procedures ............................................................................................................. 21 
6.2. Registration Procedures .............................................................................................................. 22 
6.2.1. Screen Failures ................................................................................................................... 22 
6.2.2. Subject Identification Log ................................................................................................. 22 
6.3. Inclusion/Exclusion Criteria ....................................................................................................... 22 
6.3.1. Inclusion Criteria ............................................................................................................... 22 
6.3.2. Exclusion Criteria Applicable to all Infection Studies.................................................... 24 
7. Study Drug ............................................................................................................................... 24 
7.1. Drug Supplies ............................................................................................................................... 24 
7.2. Randomized Treatment Regimens/Dosage and Administration ............................................. 24 
7.3. Packaging ..................................................................................................................................... 25 
7.4. Subject Numbers ......................................................................................................................... 25 
7.5. Labeling ........................................................................................................................................ 26 
7.6. Blinding ........................................................................................................................................ 26 
7.7. Drug Accountability:  Shipping, Receipt, Storage, Dispensing and Return of Study Drug . 26 
8. Prior, Concomitant, and Prohibited Medications and Treatments ................................... 27 
9. Study Procedures .................................................................................................................... 27 
9.1. Screening and Enrollment/Baseline Visit (Visit 1) ................................................................... 28 


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9.1.1. Informed Consent .............................................................................................................. 28 
9.1.2. Demographic Information, Medical & Surgical History, and Physical Exam ............. 28 
9.1.3. Subject Assessment of Symptoms ..................................................................................... 28 
9.1.4. Laboratory Tests and Specimen Collections ................................................................... 28 
9.1.5. Pelvic Examination and Specimen Collections ................................................................ 28 
9.1.6. Gram Stain Processing and Interpretation ..................................................................... 30 
9.1.7. Diagnosis for Infection Study Enrollment ....................................................................... 30 
9.1.8. Randomization and Drug Dispensing .............................................................................. 30 
9.1.9. Subject Instructions ........................................................................................................... 30 
9.2. Test of Cure Visit (Visit 2) .......................................................................................................... 31 
9.2.1. Review of Diary .................................................................................................................. 31 
9.2.2. Inquire Regarding Compliance ........................................................................................ 31 
9.2.3. Time to Symptom Resolution/Reoccurrence ................................................................... 32 
9.2.4. Subject Assessment of Symptoms ..................................................................................... 32 
9.2.5. Laboratory Tests and Specimen Collections ................................................................... 32 
9.2.6. Pelvic Examination and Specimen Collections ................................................................ 32 
9.2.7. Inquire Regarding Adverse Events .................................................................................. 33 
9.2.8. Inquire Regarding Changes in Concomitant Medication .............................................. 33 
9.2.9. Collection of Unused Study Drug ..................................................................................... 33 
9.2.10. Assessment of Clinical Status:  Need for Additional Treatment ................................. 33 
9.2.11. Determination of Cure or Failure of Subject’s Enrolled Infection ............................. 33 
9.2.12. Subject Instructions ......................................................................................................... 34 
9.3. Follow Up Visit (Visit 3) .............................................................................................................. 34 
9.3.1. Inquire Regarding Compliance ........................................................................................ 35 
9.3.2. Subject Assessment of Symptoms ..................................................................................... 35 
9.3.3. Laboratory Tests and Specimen Collections ................................................................... 35 
9.3.4. Pelvic Examination and Specimen Collections ................................................................ 35 
9.3.5. Inquire Regarding Adverse Events .................................................................................. 35 
9.3.6. Inquire Regarding Changes in Concomitant Medication .............................................. 35 
9.3.7. Assessment of Clinical Status:  Need for Additional Treatment ................................... 36 
9.3.8. Distribution of Subject Satisfaction Survey ..................................................................... 36 
9.4 Unscheduled Visits ....................................................................................................................... 36 
10. Adverse Events and Safety Reporting................................................................................. 36 
10.1. Definition of Adverse Event/Adverse Reaction/Suspected Adverse Reaction ..................... 36 
10.2. Protocol-Specific Adverse Event Considerations ................................................................... 37 
10.3. Definition of Serious Adverse Events (SAE) ........................................................................... 37 
10.4. Definition of Unexpectedness .................................................................................................... 38 
10.5. Documentation of Adverse Events ........................................................................................... 38 
10.6. Severity Criteria ........................................................................................................................ 38 
10.7. Relatedness Criteria .................................................................................................................. 38 
10.8. Serious Adverse Event Reporting ............................................................................................ 39 
10.9. Safety Reporting to Investigators, IRBs, and Regulatory Authorities by Curatek ............. 39 
11. Statistical Methods ................................................................................................................ 40 
11.1. General Methods ....................................................................................................................... 40 
11.2. Study Conduct Summaries ....................................................................................................... 41 
11.3. Analysis Populations ................................................................................................................. 41 
11.4. Determination of Sample Size .................................................................................................. 42 


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11.5. Handling of Missing Data ......................................................................................................... 43 
11.6. Efficacy Analyses ....................................................................................................................... 43 
11.6.1. Primary Efficacy Analysis ............................................................................................... 43 
11.6.2. Secondary Efficacy Analyses........................................................................................... 44 
11.7. Safety Analysis ........................................................................................................................... 44 
11.7.1. Adverse Events ................................................................................................................. 45 
11.7.2. Laboratory Assessments .................................................................................................. 45 
11.7.3. Vital Signs ......................................................................................................................... 46 
11.7.4. Physical Exams ................................................................................................................. 46 
12. Data Handling and Record Keeping ................................................................................... 46 
12.1. Source Documents ..................................................................................................................... 46 
12.2. Case Report Forms .................................................................................................................... 46 
12.3. Record Retention ....................................................................................................................... 47 
12.4. Data Management ..................................................................................................................... 47 
13. Study Management ............................................................................................................... 47 
13.1. Monitoring and Source Data .................................................................................................... 47 
13.2. Protocol Adherence ................................................................................................................... 48 
13.3. Protocol Amendments ............................................................................................................... 48 
13.4. Protocol Violations .................................................................................................................... 48 
13.5. Quality Assurance and Regulatory Agency Audits ................................................................ 48 
14. Ethical and Regulatory Considerations .............................................................................. 48 
14.1. Ethical Considerations .............................................................................................................. 49 
14.2. Institutional Review Board ....................................................................................................... 49 
14.3. Informed Consent ...................................................................................................................... 49 
14.4. Delegation Log ........................................................................................................................... 50 
14.5. Reports and Publications .......................................................................................................... 50 
14.6. Public Posting of Trial Information ......................................................................................... 50 
14.7. Subject Release from the Study ................................................................................................ 50 
14.8. Sponsor Discontinuation of Study ............................................................................................ 50 
15. References .............................................................................................................................. 51 
 
List of Appendices 
 
Appendix A:  Schedule of Procedures ..................................................................................................... 53 
Appendix B:  Instructions for Subjects ................................................................................................... 55 
Appendix C:  Instructions for Using Study Drug .................................................................................. 56 
Appendix D:  Subject Diary ..................................................................................................................... 57 
Appendix E:  Subject Satisfaction Survey .............................................................................................. 59 
 
 


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3. Background and Rationale 
 
3.1. Bacterial Vaginosis 
Bacterial vaginosis (BV) is one of the most common vaginal disorders in women of reproductive age 
affecting almost a third of United States (US) women.1  Subjects with BV often complain of unpleasant or 
malodorous vaginal discharge.  Some women experience discomfort or irritation.  Generally there is a 
lack of inflammation associated with BV.2  
 
The vaginal microbiome is complex and in healthy women various Lactobacillus species dominate the 
ecosystem.3 Originally referred to as “non-specific vaginitis,” the search for a causative organism in BV 
led the condition to be called, at various times, Haemophilus vaginalis vaginitis,4 Corynebacterium 
vaginalae vaginitis5 and Gardnerella vaginalis vaginitis.6  More recent studies have suggested that rather 
than a single causative organism, BV is characterized by a shift in the vaginal flora whereby the usual 
populations of vaginal Lactobacilli decline and are replaced by an overgrowth of facultative and 
anaerobic organisms including Gardnerella vaginalis, Atopobium, Prevotella, Bacteriodes, 
Peptostreptococcus and Mobiluncus species,7 as well as Mycoplasma hominis,8 Leptotrichia amnionii, and 
Eggerthella species.9  More recently, broad-range 165 rRNA gene PCR and pyrosequencing of vaginal 
samples from women with confirmed BV have shown that there is a large diversity of species and that no 
individual species is universally present.9   
 
The apparent lack of a single causative organism has made the diagnosis of BV somewhat more difficult 
compared to other vaginal infections.  In current medical practice, the diagnosis is generally made based 
on the following clinical signs, which are known as the “Amsel criteria”10: 
• 
Presence of a thin, homogeneous vaginal discharge 
• 
Vaginal pH > 4.5 
• 
Positive potassium hydroxide (KOH) “whiff test” indicating presence of volatile amines in the 
vaginal secretions 
• 
Presence of “clue cells” on microscopic examination of saline “wet mount” of vaginal secretions.  
Clue cells are epithelial cells whose borders are obscured by the presence of numerous bacteria 
clinging to the cell. 
 
Another method used to diagnose BV is interpretation of a vaginal Gram stain according to the “Nugent 
criteria.”11  According to this method bacteria are counted and scored based on: 
• 
Relative absence of Lactobacillus morphotypes 
• 
Presence of small Gram-variable coccobacilli and small gram-negative rods (indicative of Gardnerella 
and Prevotella/Bacteroides species) 
• 
Presence of small curved Gram-variable rods (indicative of Mobiluncus species)   
 
The scores in these three categories are added to give a composite score that categorizes flora as normal 
(score 0-3), intermediate (score 4-6) or BV (score 7-10).   
 
Current available treatments for BV in the US include oral and intravaginal forms of metronidazole and 
clindamycin12 as well as oral tinidazole.  Intravaginal preparations may have fewer adverse events 
compared to systemic medications.  Depending on the criteria used to evaluate efficacy, available 
treatments cure BV in approximately 25-55% of subjects.  The relative efficacy appears to be similar for 
all therapies.  One disadvantage of these agents is the overgrowth of yeast following therapy, which 






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time.  The subject should also be instructed that she may notify the investigator of any bothersome 
symptoms, as well as request alternative treatment, at any time. 
 
4. Study Design 
 
This is a multi-center, phase III trial, comprised of three studies, each designed to test the safety and 
efficacy of a different investigational product, for a specific vaginal infection/indication.  They are: 
1. Bacterial Vaginosis (BV) Study:  A randomized, double-blind, parallel-group, placebo-controlled 
study to test the safety and efficacy of BV Gel (0.9% metronidazole gel) for the treatment of BV 
2. Vulvovaginal Candidiasis (VVC) Study:  A randomized, double-blind, parallel-group, placebo-
controlled study to test the safety and efficacy of VVC Gel (0.8% terconazole gel) for the treatment of 
VVC 
3. Mixed Infection (Concurrent BV and VVC) Study:  A randomized, double-blind, parallel-group, 
active-controlled study to test the safety and efficacy of Combo Gel (0.9% metronidazole gel and 
0.8% terconazole gel) for the treatment of Mixed Infection 
 
All study medication is intravaginal and will be dosed as one applicatorful for three consecutive days.   
 
Subjects who sign an informed consent form (ICF), are diagnosed with BV, VVC, or Mixed Infection, 
and meet eligibility requirements will be enrolled into the appropriate infection study and subsequently 
randomized to treatment based on clinical diagnosis at the screening and enrollment/baseline visit (Visit 
1).  BV subjects will be entered into the BV Study, VVC subjects will be entered into the VVC Study, 
and concurrent BV and VVC (Mixed Infection) subjects will be entered into the Mixed Infection Study.  
 
All subjects will be asked to return for a test of cure visit (Visit 2) 7-14 days after randomization. If a 
subject is menstruating on the day of the scheduled visit, she should be rescheduled to return 24 hours 
after completion of menses.  Subjects who in the opinion of the investigator/clinician require additional 
treatment for vaginal discomfort/symptoms and subjects who self-medicated for vaginal 
discomfort/symptoms, will be terminated from the study.  All other subjects will return for a follow-up 
evaluation visit (Visit 3) 21-30 days after randomization.  
   
Study procedures will be identical in all three infection studies with the exception of safety labs (i.e. 
Hematology:  complete blood count (CBC) with differential and Chemistry:  blood urea nitrogen (BUN), 
Creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase 
(ALP), and bilirubin) which will only be obtained at Visit 1 and Visit 2 on subjects entered into the 
Mixed Infection Study.  There will be one case report form (CRF) for each subject.  The CRF will be the 
same for all three infection studies.  Analysis of safety and efficacy will be performed separately for each 
investigational product. 
 
A schematic of the study design follows. 
 




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5.2. Primary Efficacy Endpoints and Evaluations 
1.  BV Study:  BV cure rate, with cure defined as normal/physiologic discharge,e
2.  VVC Study:  VVC cure rate, with cure defined as resolution of all signs and symptoms attributable to 
VVC (i.e. clinical cure)  
 negative whiff test, and 
< 20% clue cells (i.e. clinical cure) 
3.  Mixed Infection Study:  Mixed Infection cure rate, with cure defined as BV cure (i.e. BV clinical cure) 
AND a VVC cure (i.e. VVC clinical cure)  
 
Primary efficacy endpoint evaluations will occur at the test-of-cure Visit 2.   
 
If a subject requires additional treatment for vaginal discomfort/symptoms (i.e. a BV subject requiring 
treatment for BV, a VVC subject requiring treatment for VVC or a Mixed Infection subject requiring 
treatment for BV and/or VVC) prior to or at Visit 2, the subject will be considered a treatment failure.  
These subjects will be evaluable for the intent-to-treat (ITT), modified intent-to-treat (mITT) and the per-
protocol (PP) population analyses, providing all other evaluability criteria for these population groups 
have been met.   
 
Additionally, if a subject self-medicates herself for vaginal discomfort/symptoms at any time prior to 
Visit 2 , the subject will be considered a treatment failure.f
 
  If this occurs, the subject will remain 
evaluable for the ITT and the mITT analyses, but will be non-evaluable for the PP analysis. 
5.3. Secondary Endpoints and Evaluations 
1. BV Study:  BV clinical and Nugent score cure rates alone and combined; changes/improvements in 
Amsel criteria and Nugent scores; time to resolution of vaginal symptoms 
2. VVC Study:  VVC clinical (i.e. resolution of all signs and symptoms attributable to VVC) and 
mycologic cure rates (i.e. negative Candida on culture) alone and combined; changes/improvements 
in signs and symptoms scores ; eradication (or persistence) of individual fungal species; time to 
resolution of vaginal symptoms 
3. Mixed Infection Study:  BV clinical and Nugent score cure rates alone and combined; 
changes/improvements in Amsel criteria and Nugent scores; VVC clinical and mycologic cure rates 
alone and combined; changes/improvements in signs and symptoms scores; eradication or persistence 
of individual fungal species; time to resolution of vaginal symptoms   
 
Secondary endpoint evaluations will occur at Visits 2 and 3 and will utilize criteria appropriate to the 
subject’s entry diagnosis (i.e. study subject was enrolled in). 
 
6. Selection of Study Population 
 
6.1. Recruitment Procedures 
Sites will recruit participants through various mechanisms, including but not limited to recruitment from 
an investigator’s own private/clinic patients, provider referrals, Institutional Review Board (IRB) 
                                                 
e In the event a BV subject has discharge consistent with VVC (i.e. white, creamy, and curdy [cottage cheese like] adherent to the 
epithelium), the subject will be considered a BV cure providing all other criteria for BV cure (and evaluability) are met and the 
subject has a positive yeast culture.  
f Self-administration of therapy includes prescription and over-the-counter (OTC) antimicrobial, anti-fungal, analgesics, or 
steroid treatments. 


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approved advertisements and patient registries.  The trial will be conducted at approximately 40 
investigative sites, each of which is expected to contribute an approximately equal number of subjects.  
However, differences in subject availability may result in one site enrolling more subjects than another. 
 
Subjects will be enrolled until approximately 116 evaluable BV subjects, 100 evaluable VVC subjects, 
and 189 evaluable Mixed Infection subjects, per protocol population, complete the trial. 
 
  Once the total 
number of evaluable subjects in a study is reached, that study will be closed and the remaining studies 
will continue to enroll subjects.   
 
6.2. Registration Procedures 
All subjects who sign an informed consent and are screened for enrollment into one of the three infection 
studies will be entered into the interactive voice response (IVR)/interactive web response (IWR) system. 
 
6.2.1. Screen Failures  
If a subject does not meet eligibility based on baseline clinical criteria or withdraws consent prior to 
study randomization, the subject will be considered a screen failure.  A case report form should not be 
filled out; however the reason the subject screen failed should be documented in the subject’s source 
notes.  Screen failures will be tracked in the IVR/IWR system and a screening and enrollment log will 
be maintained at each site.   
 
6.2.2. Subject Identification Log 
The investigator will maintain a subject identification log throughout the trial to allow for easy 
identification of each subject during and after the trial.  This log will be reviewed by the study 
monitor for completeness but will be treated as confidential.  As such, no copy will be made and it 
will only be filed at the investigative site. 
 
6.3. Inclusion/Exclusion Criteria 
To be enrolled into one of the three infection studies, subjects must meet all eligibility requirements as 
specified in the inclusion/exclusion criteria listed below.  Since some of the tests for determining 
eligibility will not be available at the baseline visit (i.e. tests for Trichomonas vaginalis, Chlamydia 
trachomatis, Neisseria gonorrhoeae, active Herpes simplex virus; Nugent score, and yeast culture), 
enrollment will be based on clinical criteria (i.e. Amsel criteria and/or signs and symptoms of VVC 
including wet mount microscopy).  Subjects may only be enrolled under this protocol once.   
 
6.3.1. Inclusion Criteria 
• 
Clinical diagnosis of BV based on the presence of ALL of the following:   
o Amsel criteria (all four of the following criteria must be present): 
1.  Abnormal vaginal discharge consistent with BV (i.e. off-white [milky or gray], thin, 
homogeneous discharge)g
2.  Vaginal secretion pH of > 4.5 
 
3.  A fishy odor of the vaginal discharge with the addition of a drop of 10% KOH (i.e. a 
positive “whiff test”)   
                                                 
gSubjects with Mixed Infection (i.e. concurrent BV and VVC) may have an abnormal discharge consistent with BV, consistent 
with VVC (i.e. white, creamy, and curdy [cottage cheese like] adherent to the epithelium), or an abnormal discharge of varying 
characteristics with relation to odor, color, and consistency. 
 


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4.  Presence of clue cells ≥ 20% of the total epithelial cells on microscopic examination of the 
saline wet mount 
AND 
o Nugent score of  ≥ 4 based on baseline Gram stain slide 
 
AND/OR 
 
• 
Clinical diagnosis of VVC  based on the presence of ALL of the following:   
o A composite signs and symptoms score > 2 based on rating the following six vaginal/vulvar 
signs and symptoms on a severity scale, where absent =0, mild =1, moderate =2 and severe 
=3: 
1. Itching 
2. Burning 
3. Irritation 
4. Edema 
5. Erythema  
6. Excoriation 
o Presence of yeast forms (hyphae/pseudohyphae) or budding yeasts seen on microscopic 
examination of a KOH prepared slide of vaginal secretions 
AND 
• 
Mycologic diagnosis of VVC based on positive culture for Candida species  
 
AND 
 
• 
At least 12 years of age  
• 
Capable of providing written informed consent; if a minor, capable of assent with parent/legal 
guardian available to provide written informed consent 
• 
Willing to begin treatment within 2 days of the baseline Visit (Visit 1) 
• 
Currently not menstruating and not anticipating  menses during treatment 
• 
Willing to abstain from sexual intercourse through Visit 2 and have their partner use a non-lubricated 
condom within the preceding 48 hours of Visit 3 if sexual intercourse occurs 
• 
Willing to abstain from using intravaginal/vulvovaginal products (e.g. feminine hygiene products 
such as douches and deodorants; contraceptive products such as diaphragms, spermicidal creams, 
gels, and foams; vaginal lubricants, moisturizers, and hormonal suppositories and creams such as 
Vagifem®, Estrace® and Premarin® cream; and tampons etc.) through Visit 2 and within 48 hours of 
Visit 3 
• 
Willing to abstain from alcohol and propylene glycol ingestion during treatment and for 1 day 
thereafter 
• 
If heterosexually active, subject must be post-menopausal for ≥ 1 year, surgically sterile (i.e. 
hysterectomy, bilateral oophorectomy, or bilateral tubal ligation), sexually active with a male partner 
who is surgically sterile (i.e. vasectomy), or practicing an acceptable form of birth control (i.e. oral 
contraceptives, contraceptive injections, contraceptive patch, condoms, or intrauterine device [IUD]) 
for at least one month before study entry and agree to continue the contraceptive method for the 
duration of the study.  If sexually abstinent, subjects must agree to continue abstinence or use an 
acceptable method of birth control should sexual activity commence during the study. 
• 
Willing and capable of cooperating to the extent and degree required by the protocol 
• 
Negative urine pregnancy test (unless subject is surgically sterile or post-menopausal ≥ 1 year) 


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6.3.2. Exclusion Criteria Applicable to all Infection Studies 
• 
Other infectious causes of vulvovaginitis (e.g. Trichomonas vaginalis, Chlamydia trachomatis, 
Neisseria gonorrhoeae, active Herpes simplex virus or genital warts) 
• 
Subject has used systemic (oral, intravenous [IV], or intramuscular [IM]), intravaginal/vulvovaginal 
antifungal,  antimicrobial, or corticosteroid therapy within 14 days of study enrollment 
• 
Subject is currently taking or has taken disulfiram therapy within 14 days of study enrollment 
• 
Subject is currently on lithium, coumarin anticoagulants (e.g. warfarin), or immunosuppressive 
therapy 
• 
Subject is expected to require the concomitant use of prohibited medications/products while enrolled 
in the study  
• 
Subject will require treatment for cervical intra-epithelial neoplasia (CIN) or cervical carcinoma 
while enrolled in the study 
• 
Nursing mother 
• 
Use of any investigational drug within 30 days of enrollment or plans to use other investigational 
products while enrolled in the study 
• 
Known primary or secondary immunodeficiency 
• 
Presence of any condition or illness, including vulvar and vaginal conditions, that in the opinion of 
the investigator would preclude accurate evaluation of the subject’s condition and/or confound the 
interpretation of the subject’s treatment response 
• 
History of hypersensitivity to metronidazole or other nitroimidazoles; terconazole or other triazoles; 
parabens; or any other ingredient/component of the formulations  
 
Subjects who meet criteria for BV only will be entered into the BV Study and randomized to a BV 
treatment, subjects who meet criteria for VVC only will be entered into the VVC Study and randomized 
to a VVC treatment, and subjects who meet criteria for both BV and VVC will be entered into the Mixed 
Infection Study and randomized to treatment for Mixed Infection. 
 
7. Study Drug 
 
7.1. Drug Supplies 
Curatek Pharmaceuticals, LLC, Elk Grove Village, IL will supply BV Gel (0.9% metronidazole), VVC 
Gel (0.8% terconazole), Combo Gel (0.9% metronidazole and 0.8% terconazole), and Placebo Gel for this 
study.  All of these gels will be manufactured at 
and packaged in 
identical 30 gram tubes.   
 
7.2. Randomized Treatment Regimens/Dosage and Administration 
Randomization, determined by a computer generated randomization scheme, will be used to avoid bias in 
the assignment of subjects to treatment and to enhance the validity of statistical comparisons between 
treatments. 
 
All eligible subjects will be randomized at the baseline visit (Visit 1) utilizing an interactive voice 
response (IVR)/interactive web response (IWR) system.  Subjects in the BV or VVC study will be 
randomly assigned to one of two treatment groups in a 1:1 ratio while subjects in the Mixed Infection 
study will be randomized to one of three treatment groups in a 1:1:1 ratio.  All treatments, regardless of 
study, consist of three doses, to be administered by vaginal applicator at bedtime for three consecutive 
days.   


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Subjects will be randomized to treatment as follows: 
• 
Subjects diagnosed with BV will be randomized to receive treatment with either BV Gel (0.9% 
metronidazole gel) or Placebo Gel.  Each 5-gram dose of BV Gel contains 45 mg of metronidazole 
for a total dose of 135 mg of metronidazole.                                                                                                                        
• 
Subjects diagnosed with VVC will be randomized to receive treatment with either VVC Gel (0.8% 
terconazole) or Placebo Gel.  Each 5-gram dose of VVC Gel contains 40 mg of terconazole for a total 
dose of 120 mg of terconazole.   
• 
Subjects diagnosed with Mixed Infection will be randomized to receive treatment with BV Gel, VVC 
Gel, or Combo Gel (0.9% metronidazole and 0.8% terconazole).  Each 5-gram dose of the Combo 
Gel contains 45 mg of metronidazole and 40 mg of terconazole for a total dose of 135 mg of 
metronidazole and 120 mg of terconazole. 
 
7.3. Packaging  
BV Gel, VVC Gel, Combo Gel, and Placebo Gel will have identical primary, secondary, and tertiary 
packaging.  Each tube of study drug will be placed in a box (secondary packaging) with three disposable 
applicators.  Each box will then be placed inside another larger box (tertiary packaging), containing study 
instructions (Appendix B), instructions for the use of study drug (Appendix C), condoms, a subject diary 
(Appendix D), and return packaging to be utilized when drug is returned (i.e. the drug tube with any 
remaining unused drug inside).  The outer box will be sealed and labeled with a two-part label, as 
described in Section 7.5.  The entire contents of the boxes will comprise a study Drug Kit. 
 
Each Drug Kit will be labeled (as described in Section 7.5, Labeling) with a unique Drug Kit number, 
previously determined by a computer generated randomization scheme (as described in Section 7.2, 
Randomized Treatment Regimens/Dosage and Administration), that dictates the treatment assignment for 
each subject.  Both subject numbers and corresponding Drug Kit numbers will be assigned at Visit 1 via 
the IVR/IWR system at the time of randomization.                                                                                                                    
 
Drug Kit demonstration boxes will be provided to each site for subject instructions and education.  The 
investigator/clinician will use the demonstration kit to show each subject how to puncture the seal on the 
drug tube, fill the applicators and administer the gel.  Subjects will be instructed to use one applicatorful 
of study drug at bedtime for three consecutive days. All subjects should place their  drug tube in the return 
packaging provided, seal the packaging and return it to the study staff at the next scheduled visit (as 
described in Section 7.6, Blinding). 
 
Instructions for completing the diary will be reviewed with the subject.  The diary will track study drug 
dosing, study compliance, symptom resolution/reoccurrence, and adverse events.  Subjects will be 
instructed to return the completed diary at their next scheduled visit (Visit 2).   
 
7.4. Subject Numbers 
Subject numbers will have a two-digit prefix representing the unique site number followed by another 
three digit number.  Subject numbers will be assigned at the baseline visit via the interactive voice 
response (IVR)/interactive web response (IWR) system to all subjects who sign an informed consent.  
Subjects who meet enrollment criteria and are entered into an infection study will maintain the same 
subject number throughout enrollment.   
 


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7.5. Labeling 
All study drug tubes will have the lot number printed on them.  The lot numbers will be covered by 
opaque labels containing the following information:   
• 
Protocol number  
• 
Unique Drug Kit number 
• 
Instructions: “Insert one applicatorful of drug in the vagina at bedtime for 3 consecutive days.” 
• 
Caution statement – “Caution:  New Drug-Limited by Federal (United States) law to investigational 
use.” 
• 
Storage statement: “Store at 20°-25° C (68°-77° F); excursions permitted to 15°-30° C (59°-86° F).” 
• 
Sponsor identification: Curatek Pharmaceuticals, LLC  Elk Grove Village, IL 60007 
 
A two-part tear-off label will be attached to the sealed outer box of the Drug Kits.  Both parts of this label 
will have matching information:  the protocol number, the unique Drug Kit number, a storage statement, 
sponsor identification, and a place to enter the subject’s initials and subject number at the time of Drug 
Kit dispensation.   
 
7.6. Blinding 
The investigator/study staff will be blinded to the therapy each subject receives.  Blinding will be 
achieved by identical primary, secondary, and tertiary packaging of study drugs (i.e. Drug Kits) for all 
treatment arms in all infection studies.  All infection studies will be double-blind.  
 
To maintain investigator/study staff blinding upon return of study drug, subjects will be instructed to 
place their unused drug inside the opaque packaging provided and return it sealed at their next scheduled 
visit.  
  
Investigators will not receive randomization codes.  The codes will be maintained within the IVR/IWR 
system which investigators will have the capability of breaking for an individual subject if necessary.  
The blind should only be broken if a specific emergency treatment would be dictated by knowing the 
treatment assignment of the subject.  In such instances, the investigator must first notify Curatek.  If 
Curatek is unable to be contacted, the investigator may telephone the IVR/IWR system to identify the 
subject’s treatment assignment.  In this instance, Curatek must be notified as soon as possible.  Details 
regarding the un-blinding including the date, time, and reason for un-blinding must be documented in the 
subject’s source notes and the CRF. 
 
7.7. Drug Accountability:  Shipping, Receipt, Storage, Dispensing and Return of Study Drug 
Curatek/Curatek’s designee is responsible for shipping and supplying each investigator with study drug 
(i.e. Drug Kits) and study supplies.  No drug will be shipped until all required regulatory documentation 
has been obtained (i.e. IRB approval of the protocol and informed consent, Form FDA 1572, investigator 
curriculum vitae (CV)(s) and financial disclosure(s) etc.).  All shipments of drug will contain a packing 
slip/shipping invoice which must be used to inventory the shipment and maintained in the regulatory 
binder.  Confirmation of receipt of the shipment must be made via the IVR/IWR system.   
 
The investigator/designee is responsible for ensuring that the study drug is stored in a secure, limited 
access area at controlled and monitored room temperature (20°-25° C [68°-77° F]; excursions permitted 
to 15°-30° C [59°-86° F] see USP controlled room temperature).  A temperature log must be maintained 
and will be reviewed by the monitor during monitoring visits.  
 


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The investigator/designee will be responsible for accountability of study drug.  Documentation of drug 
accountability must be maintained and kept current throughout the study and includes the receipt, subject 
dispensation, subject return of unused drug, and the return of unused and never dispensed drug to 
Curatek/Curatek’s designee.  During the study, drug accountability records will be reviewed by the 
monitor and at the end of the study the completed records will be maintained in the trial master file 
(TMF).   
  
Subjects will be instructed to return their unused drug as described in Section 7.6 above to the study site 
at Visit 2.  The return of unused drug is required to complete drug accountability and for subsequent 
return, weighing, and destruction of study drug by Curatek/Curatek’s designee. Subjects will also be 
asked to return their completed diaries at Visit 2 so that study drug administration/compliance can be 
confirmed.   
 
8. Prior, Concomitant, and Prohibited Medications and Treatments 
 
Subjects receiving drug therapy for conditions other than BV and/or VVC may continue those 
medications during the study, provided they are not exclusionary or prohibited medications.  New 
medications for the treatment of conditions other than BV and/or VVC may be initiated during the study, 
provided they are not prohibited medications and would not interfere with the evaluation of the study 
assessments. All concomitant medication use will be documented in the subject’s source documents.   
 
Prohibited medications during the entire study include: 
• 
systemic, intravaginal/vulvovaginal antifungal, antimicrobial (i.e. other than study drug), and 
corticosteroid drugs  
(Note:  Inhaled, intranasal, intra-articular, and/or topical steroids [provided they are not 
intravaginal/vulvovaginal] are not prohibited.)   
• 
immunosuppressive therapy 
 
Prohibited medications during treatment and for two days thereafter: 
• 
disulfiram, lithium, and coumarin anticoagulants (e.g. warfarin) 
 
Prohibited products through Visit 2 and within 48 hours of Visit 3 include: 
• 
Intravaginal/vulvovaginal product use (e.g. feminine hygiene products such as douches and 
deodorants; contraceptive products such as diaphragms, spermicidal creams, gels, and foams; 
vaginal lubricants, moisturizers, and hormonal suppositories and creams such as Vagifem®, 
Estrace® and Premarin® cream; and tampons)  
• 
Following Visit 2 and for the remainder of study enrollment, subjects will be encouraged to 
refrain from the use of intravaginal/vulvovaginal products. 
 
Additional restrictions: 
• 
Alcoholic beverages and propylene glycol ingestion are prohibited during treatment and for 1 day 
thereafter.   
 
9. Study Procedures 
 
The following sections describe the procedures to be completed at each visit.  Whenever possible, 
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Information obtained should be recorded in source documents and subsequently transcribed onto the 
CRF.  A schedule of procedures is provided in Appendix A.   
 
9.1. Screening and Enrollment/Baseline Visit (Visit 1)  
Inclusion/exclusion criteria will be reviewed and the following procedures will be performed during the 
baseline visit to determine subject eligibility for infection study enrollment and to establish baseline 
parameters.   
 
9.1.1. Informed Consent 
All subjects must give written informed consent prior to performing any study-related activities.  
Assent for subjects between 12 and 18 years will be obtained per IRB requirements.  Refer to Section 
14.3. Informed Consent.  
 
9.1.2. Demographic Information, Medical & Surgical History, and Physical Exam  
Demographic information, a medical and surgical history, and physical examination inclusive of vital 
signs will be performed on each subject.  The subject’s contraceptive, obstetric, and gynecological 
history will be obtained.  Concomitant medication usage (i.e. current and within 30 days of 
enrollment) as well as treatments for BV and/or VVC infections within the past year will be obtained. 
 
9.1.3. Subject Assessment of Symptoms   
Subjects will be asked to rate their current vulvovaginal symptoms of itching, burning, and irritation 
as absent=0, mild=1, moderate=2 or severe=3.  The sum of the symptom score will be added to the 
vulvovaginal signs score obtained during the pelvic examination to determine a combined symptom 
and sign severity score.  This combined score must be ≥ 2 in order to meet entry criteria for 
enrollment into the VVC or Mixed Infection Study. 
 
9.1.4. Laboratory Tests and Specimen Collections 
The lab tests listed below will be obtained at the baseline visit (Visit 1).  
• 
Urine pregnancy test for all women of child bearing potential 
• 
Papanicolaou smear (if subject is ≥ 21 years old and a Pap smear was not done within the past 3 
years)  
• 
Tests for Neisseria gonorrhoeae,  Chlamydia trachomatis, and Trichomonas vaginalis  
• 
Culture for Herpes simplex (only if suspected) 
• 
Vaginal culture for Candida species 
• 
Vaginal Gram stain 
• 
CBC with differential and blood chemistries (i.e. BUN, Creatinine, ALT, AST, ALP, and 
bilirubin) for subjects enrolled in the Mixed Infection Study 
 
9.1.5. Pelvic Examination and Specimen Collections 
A non-lubricated speculum (tap water rinse acceptable) should be used during the pelvic examination.  
Components of the pelvic examination should include the following: 
• 
Visual inspection:  rule out lesions caused by Herpes simplex virus or human papilloma virus (i.e. 
genital warts) 
• 
Vulvovaginal signs rating:  rate the degree of vulvovaginal edema, erythema, and excoriation as 
absent = 0, mild = 1, moderate = 2 or severe = 3.  The sum of these ratings will be added to the 
vulvovaginal symptoms score given by the subject to determine a combined symptom and sign 


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severity score.  This total score must be > 2 in order to meet entry criteria for enrollment into the 
VVC or Mixed Infection study. 
• 
Vaginal discharge characterization:  By visual examination, characterize vaginal discharge in 
accordance with the descriptions below.   
o Normal/physiologic:  normal discharge may vary in appearance and consistency depending 
on the menstrual cycle;  
o Abnormal:  consistent with BV (i.e. off-white [milky or gray], thin, homogeneous discharge);   
o Abnormal:  consistent with VVC (i.e. white, creamy, and curdy [cottage cheese like] adherent 
to the epithelium);  
o Abnormal:  consistent with Mixed Infection (i.e. discharge of varying characteristics with 
relation to odor, color, and consistency)  
• 
pH measurement:  Obtain a vaginal pH measurement with the pH indicator strips provided.  Take 
care to avoid contacting cervical mucus with the sample. 
• 
Whiff test and KOH and saline wet mounts 
o Swab lateral vaginal walls with a cotton-tipped applicator and place a liberal amount of 
discharge on each of 2 glass slides.   
o Mix 2 drops of 10% KOH with the discharge on one slide and immediately determine if a 
fishy, amine-like odor is present. 
o Mix 2 drops of 0.9% saline with the discharge on the other slide and place cover slips over 
both slides. 
o Examine both slides under a light microscope at both 100 X and 400 X magnifications. 
o On the KOH slide note presence or absence of yeast organisms (hyphae, pseudohyphae, 
and/or budding yeast).  The presence of yeast is required to meet entry criteria for the VVC or 
Mixed Infection Study.  Several fields should be examined.  
o On the saline slide note presence or absence of clue cell and motile trichomonads.  Multiple 
representative fields should be examined and the ratio of clue cells to epithelial cells 
determined.  Clue cells will be identified as epithelial cells with such a heavy coating of 
bacteria that their peripheral borders are obscured.  Clue cells must be > 20% of vaginal 
epithelial cells in order to meet entry criteria for the BV or Mixed Infection study. 
• 
Vaginal Candida culture:  Obtain a Candida culture as specified in the central laboratory manual 
utilizing the collection and shipment supplies provided. Cultures should be shipped on the day of 
collection; unless otherwise specified for weekends and holidays. 
• 
Vaginal Gram stain:  Obtain and prepare a slide for the central lab to Gram stain as specified 
below. 
o Swab lateral vaginal walls with a cotton-tipped applicator.  Place a moderate amount of 
discharge on a glass slide and roll the applicator back and forth across the slide as evenly as 
possible. 
o Allow the slide to air dry.  Do not fix or stain the slide.   
o Label the slide with subject’s initials and unique subject number, visit number, and date.  
o Place the slide in a microscope slide holder.  Label the holder with the subject’s initials and 
unique subject number, visit number, and the date. 
o Gram stains should be shipped the day of collection; unless otherwise specified for weekends 
and holidays. 
• 
Papanicolaou smear:  Obtain a Pap smear if subject is ≥ 21 years old and has not had one within 
the past 3 years.  Pap smears may be sent to a local lab.   


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• 
Test for Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis as specified 
in the central laboratory manual utilizing the collection and shipment supplies provided. Cultures 
should be shipped on the day of collection; unless otherwise specified for weekends and holidays.   
• 
Culture for Herpes simplex (only if suspected) as specified in the central laboratory manual 
utilizing the collection and shipment supplies provided.  Cultures should be shipped on the day of 
collection; unless otherwise specified for weekends and holidays. 
 
9.1.6. Gram Stain Processing and Interpretation 
Gram stains will be obtained, processed, and shipped by individual study sites as described above 
(Section 9.1.5.).  They will then be stained and interpreted by a blinded microbiologist at a central 
laboratory.  The method of interpretation is according to the Nugent scoring system.11  
 
For secondary endpoint evaluations, Gram stain scores will be categorized as:  0-3 = normal; 4-6 = 
intermediate, and 7-10 = BV.   
 
9.1.7. Diagnosis for Infection Study Enrollment   
Following baseline assessment, the examining clinician/investigator will determine if the subject 
meets the criteria for a diagnosis of BV, VVC, or Mixed Infection.  The clinical diagnosis (i.e. all 4 
Amsel criteria for BV diagnosis; combined symptom and sign severity score ≥ 2 and yeast on KOH 
wet mount for VVC diagnosis; and all 4 Amsel criteria, a combined symptom and sign severity score 
≥ 2, and yeast on KOH microscopy for Mixed Infection diagnosis) will determine if a subject 
qualifies for enrollment.   
 
9.1.8. Randomization and Drug Dispensing 
After determining that a subject meets all entry criteria, the investigator/designee will obtain a subject 
and a Drug Kit number via the IVR/IWR system.  The Drug Kit corresponding to the assigned subject 
number will be dispensed to the subject.   
 
At the time of dispensing, the subject’s initials and number will be entered on both parts of the two-
part tear-off label attached to the Drug Kit.  The tear-off portion of the label will then be affixed to the 
appropriate page of the subject’s CRF.  (The other portion will remain on the Drug Kit box being 
dispensed.)  This will allow Curatek to verify that the correct Drug Kit was dispensed to the correct 
subject by matching the Drug Kit number on the label in the subject’s CRF to the Drug Kit number 
assigned to the subject via the IVR/IWR system.  A hard copy of the IVR/IWR system’s confirmation 
of the Drug Kit number assigned to the subject should be maintained with the subject’s source 
documents. 
 
9.1.9. Subject Instructions 
At randomization, subjects will be dispensed their assigned Drug Kit which contains study drug along 
with instructions for the administration/use of the drug, study instructions, and a subject diary to track 
drug dosing and study compliance, symptom resolution/reoccurrence, and adverse events, should any 
occur.  Subjects will record diary data between Visits 1 and 2.   
 
The following study instructions will be reviewed with all subjects at Visit 1.  
• 
Instruct the subject on proper dosing of study drug. 
• 
Demonstrate how to open the drug tube, fill the applicator, and administer the drug.  Sample 
tubes and applicators will be available for this purpose. 


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• 
Remind the subject to begin study drug within 2 days of the baseline visit (Visit 1).  
• 
Counsel the subjects of child bearing potential on the requirement to continue an acceptable 
method of birth control while in the study. 
• 
Counsel the subject not to engage in sexual intercourse through Visit 2 and to use provided non-
lubricated condoms within the preceding 48 hours of Visit 3 if sexual intercourse occurs.  
• 
Remind the subject not to use intravaginal/vulvovaginal products (e.g. feminine hygiene products 
such as douches and deodorants; contraceptive products such as diaphragms, spermicidal creams, 
gels, and foams; vaginal lubricant, moisturizers and hormonal suppositories and creams such as 
Vagifem®, Estrace® and Premarin® cream; and tampons) through Visit 2 and within 48 hours of 
Visit 3.  Subjects should also be encouraged not to use these products at any time during study 
enrollment. 
• 
Instruct the subject to abstain from alcohol and propylene glycol ingestion during study treatment 
and for 1 day thereafter.  
• 
Review prohibited medications with subject:  systemic and intravaginal/vulvovaginal antifungal, 
antimicrobial (other than study drug), and corticosteroid drugs (inhaled, intranasal, intra-articular, 
and/or topical steroids [provided they are not intravaginal/vulvovaginal] are not prohibited); and 
immunosuppressants. 
• 
Counsel the subject to inform the investigator/study staff if there are any changes to concomitant 
medications or if new medications are taken.   
• 
Show example subject diary and explain how to complete it properly.  Instruct the subject to 
return it at the next visit.  
• 
Remind the subject that unused drug must be placed inside the return packaging provided, sealed, 
and returned at the next visit.   
• 
Instruct the subject to contact the office/clinic if she is concerned about any adverse events during 
treatment or if her symptoms remain bothersome.   
 
A date and time should be scheduled for Visits 2 and 3.   
 
9.2. Test of Cure Visit (Visit 2) 
The procedures listed below will be performed 7-14 days after randomization for the purpose of 
determining subject compliance/evaluability with drug administration and study instructions, evaluating 
the subject’s response to therapy and whether or not additional treatment is needed (i.e. cure or failure), 
and obtaining information on concomitant medication use and possible adverse events.  If the subject is 
menstruating on the day of this scheduled follow-up visit, she should be rescheduled to return 24 hours 
after completion of menses. 
 
9.2.1. Review of Diary  
The diary should be reviewed with the subject and any discrepancies noted between the diary and 
subject report during the visit should be addressed.  Reconciliation of discrepant information should 
be made and documented in the subject’s source notes.  If the subject diary is not returned at Visit 2, 
the subject should be reminded to return it at the next visit.  Reasonable attempts to retrieve a diary if 
it is not returned at scheduled visits should be made and documented in the subject’s source notes. 
 
9.2.2. Inquire Regarding Compliance 
Subjects should be asked the questions listed below to determine compliance with study drug 
administration and study instructions. 
1. Did you start your study medicine more than two days after your office/clinic visit? 


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2. Were there any problems with taking your study medicine as prescribed; that is one applicatorful 
of medicine at bedtime for three days in a row? 
3. On which days did you take your study medicine? 
4. Did you have menstrual bleeding during treatment? 
5. Have you taken/received any systemic (oral, IM, or IV) or intravaginal/vulvovaginal antifungal, 
antimicrobial (other than study drug), corticosteroid, or immunosuppressant drugs since starting 
the study?   
6. Have you used any intravaginal/vulvovaginal products (other than study drug) since starting the 
study? 
7. Did you have sexual intercourse since starting the study?  
  
If the subject answers “Yes” to questions 1, 2, 4, 5, 6, or 7 or if the subject’s response to question 3 
does not indicate that study drug was taken for three consecutive days, a protocol violation occurred.  
Protocol violations should be documented in subject’s source documents, the CRF, and reported to 
Curatek and to the IRB as per reporting guidelines.   
 
Subjects with the above protocol violations may remain in the study and be evaluated at Visit 3 and 
have all per protocol procedures performed.  One exception is subjects who used prohibited systemic, 
intravaginal/vulvovaginal antifungal, antimicrobial, and/or corticosteroids for the treatment of vaginal 
discomfort/symptoms.  These subjects should be terminated from the study at Visit 2.  
 
9.2.3. Time to Symptom Resolution/Reoccurrence 
Symptom resolution and reoccurrence will be assessed by review of the subject’s diary and subject 
interview.  Dates of symptom resolution and/or symptom recurrence should be documented.   
 
9.2.4. Subject Assessment of Symptoms 
Subjects will be asked to rate their current vulvovaginal symptoms of itching, burning, and irritation 
as absent=0, mild=1, moderate=2, or severe=3.  The sum of this symptom score will be added to the 
vulvovaginal signs score obtained during the pelvic examination to determine a combined symptom 
and sign severity score. 
 
9.2.5. Laboratory Tests and Specimen Collections  
The lab tests listed below will be obtained at Visit 2.  
• 
CBC with differential and blood chemistries (i.e. BUN, Creatinine, ALT, AST, ALP, and 
bilirubin) only for subjects enrolled in the Mixed Infection Study  
• 
Vaginal culture for Candida species 
• 
Vaginal Gram stain 
 
9.2.6. Pelvic Examination and Specimen Collections 
A non-lubricated speculum (tap water rinse acceptable) should be used during the pelvic examination.  
Components of the pelvic examination should be performed as described above in Section 9.1.5 
(Pelvic Examination and Specimen Collections) and include the following:  
• 
Vulvovaginal signs rating  
• 
Vaginal discharge characterization 
• 
Vaginal pH measurement   


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• 
Whiff test and saline wet mountsh
• 
Vaginal Candida culture 
 
• 
Vaginal Gram stain 
   
9.2.7. Inquire Regarding Adverse Events 
Subjects should be asked whether or not they experienced any adverse events since starting study 
drug.  If so, information regarding the adverse event(s) should be obtained.  
 
9.2.8. Inquire Regarding Changes in Concomitant Medication 
Subjects should be asked if there have been any changes to medications that were being taken at the 
start of the study and/or new medications taken since the start of the study.  
 
9.2.9. Collection of Unused Study Drug 
Study staff should collect unused study drug from subjects for subsequent return to Curatek/designee.   
 
9.2.10. Assessment of Clinical Status:  Need for Additional Treatment 
Following subject evaluation, the investigator/clinician will be asked to document whether the subject 
requires any additional treatment for vaginal discomfort/symptoms.  Subjects who do require 
additional treatment should be treated per investigator/clinician judgment and terminated from the 
study.  These subjects should have all visit 2 procedures completed (see Appendix A, Schedule of 
Procedures).  Subjects who do not require treatment (and subjects who did not self-medicate) may 
remain in the study and return for their regularly scheduled follow up visit (Visit 3). 
 
9.2.11. Determination of Cure or Failure of Subject’s Enrolled Infection 
BV subjects will be evaluated for BV cure.  All three of the clinical criteria listed below must be 
satisfied in order to be considered a BV cure (i.e. clinical cure).   
• 
Discharge has returned to normal/physiologici
• 
The whiff test is negative for any amine “fishy” odor. 
 
• 
The saline wet mount is < 20% clue cells. 
 
If in the investigator/clinician’s opinion the subject requires additional treatment for BV or if the 
subject self-administered drug therapy for vaginal discomfort/symptoms after completing therapy, the 
subject will be considered a BV failure.j
 
 
VVC subjects will be evaluated for VVC cure.  In order to be considered a VVC cure, all signs and 
symptoms attributable to VVC must be resolved (i.e. clinical cure).  
 
If in the investigator/clinician’s opinion the subject requires additional treatment for VVC or if the 
subject self-administered drug therapy for vaginal discomfort/symptoms after completing therapy, the 
subject will be considered a VVC failure.j 
                                                 
h Subjects found to have motile trichomonads on saline wet mount at Visit 2 should be treated per investigator judgment and 
terminated from the study.  These subjects should have all visit 2 procedures completed, per protocol.  They will not be evaluable 
for the PP analysis.   
i In the event a subject treated for BV gets a secondary yeast infection following treatment and discharge is consistent with VVC 
(i.e. white, creamy, and curdy [cottage cheese like] adherent to the epithelium), the subject will be considered a clinical cure 
providing all other clinical criteria for BV cure are met and the subject has a positive yeast culture. 
j Self-administration of therapy includes prescription and OTC antimicrobial, anti-fungal, analgesics, or steroid treatments. 


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Mixed Infection subjects will be evaluated for Mixed Infection cure.   
• 
A Mixed Infection cure is a subject who meets the definition of a BV cure AND a VVC cure. 
 
If in the investigator/clinician’s opinion the subject requires additional treatment for either BV, VVC, 
or Mixed Infection or if the subject self-administered drug therapy for vaginal discomfort/symptoms 
after completing therapy, the subject will be considered a Mixed Infection failure.k
 
 
9.2.12. Subject Instructions 
The instructions listed below should be reviewed with all subjects continuing in the study:  
• 
Counsel the subject on the requirement to continue an acceptable method of birth control while in 
the study (i.e. if of child bearing potential and sexually active with men who have not been 
sterilized). 
• 
Remind the subject to have their partner use a non-lubricated condom if sexual intercourse occurs 
within the preceding 48 hours of Visit 3.  
• 
Remind the subject not to use any intravaginal/vulvovaginal products within 48 hours of Visit 3.  
Subjects should also be encouraged not to use these products at any time during study enrollment. 
• 
Review prohibited medications with subject:  systemic and intravaginal/vulvovaginal antifungal, 
antimicrobial (other than study drug), and corticosteroid drugs (inhaled, intranasal, intra-articular, 
and/or topical steroids [provided they are not intravaginal/vulvovaginal] are not prohibited); and 
immunosuppressants. 
• 
Counsel the subject to inform the investigator/study staff if there are any changes to concomitant 
medications or if new medications are taken.   
• 
Instruct the subject to contact the office/clinic if she is concerned about any adverse events during 
treatment or if her symptoms remain bothersome.   
 
Remind the subject of the date and time of her Visit 3 appointment.  If an appointment has not been set, 
schedule one (i.e. 21-30 days after randomization).   
 
If the subject did not return her diary or unused medication at Visit 2 remind her to bring the missing 
items to Visit 3. 
 
9.3. Follow Up Visit (Visit 3) 
The following procedures will be performed 21-30 days after randomization for the purpose of 
determining subject compliance; determining either presence or absence of the subject’s baseline 
infection and whether or not additional treatment is needed; and obtaining information on concomitant 
medication use and possible adverse events.   
 
If a subject was unable to return for Visit 2 but returns for Visit 3, available information that was to be 
obtained at Visit 2 regarding study drug administration/compliance and time to resolution/reoccurrence of 
symptoms may be obtained at Visit 3.  The subject’s diary should be reviewed and unused drug collected.  
Subjects in the Mixed Infection Study who missed Visit 2 should have hematology and chemistry labs 
obtained.   
 
                                                 
k Self-administration of therapy includes prescription and OTC antimicrobial, anti-fungal, analgesics, or steroid treatments. 


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9.3.1. Inquire Regarding Compliance 
Subjects should be asked the following questions to determine protocol compliance. 
1. Have you taken/received any systemic (oral, IM, or IV) or intravaginal/vulvovaginal antifungal, 
antimicrobial (other than study drug), corticosteroid, or immunosuppressant drugs since starting 
the study?    
2. Have you used any intravaginal/vulvovaginal products (other than study drug) prior to Visit 2 or 
within 48 hours of Visit 3?  
3. Have you had sexual intercourse prior to Visit 2 or sexual intercourse without using a non-
lubricated condom within 48 hours of Visit 3? 
 
If the subject answers “Yes” to questions 1, 2, or 3 above, a protocol violation occurred.  Protocol 
violations should be documented in subject’s source notes, the CRF, and reported to Curatek and to 
the IRB as per reporting guidelines.  All Visit 3 procedures should be performed on these subjects.  
 
9.3.2. Subject Assessment of Symptoms 
Subjects will be asked to rate their current vulvovaginal symptoms of itching, burning, and irritation 
as absent=0, mild=1, moderate=2, or severe=3.  The sum of this symptom score will be added to the 
vulvovaginal signs score obtained during the pelvic examination to determine a combined symptom 
and sign severity score. 
 
9.3.3. Laboratory Tests and Specimen Collections 
The lab tests listed below will be obtained at Visit 3. 
• 
Vaginal culture for Candida species 
• 
Vaginal Gram stain 
 
9.3.4. Pelvic Examination and Specimen Collections 
A non-lubricated speculum (tap water rinse acceptable) should be used during the pelvic examination.  
Components of the pelvic examination should be performed as described above in Section 9.1.5 
above (Pelvic Examination and Specimen Collections) and include the following: 
• 
Vulvovaginal signs rating  
• 
Vaginal discharge characterization 
• 
Vaginal pH measurement   
• 
Whiff test and saline wet mountsl
• 
Vaginal Candida culture 
 
• 
Vaginal Gram stain 
 
9.3.5. Inquire Regarding Adverse Events 
Subjects should be asked whether or not they experienced any adverse events since starting study 
drug.  If so, information regarding the adverse event(s) should be obtained. 
 
9.3.6. Inquire Regarding Changes in Concomitant Medication 
Subjects should be asked if there have been any changes to medications that were being taken at the 
start of the study and/or new medications taken since the start of the study.   
                                                 
l Subjects found to have motile trichomonads on saline wet mount at Visit 3 should have all Visit 3 procedures completed.  
Subjects should be treated per investigator/clinician judgment.  They will not be evaluable for the PP analysis.  
 


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9.3.7. Assessment of Clinical Status:  Need for Additional Treatment 
Following subject evaluation, the investigator/clinician will be asked to document whether the subject 
requires any additional treatment for vaginal infection.  Subjects who do require additional treatment 
should be treated per investigator/clinician judgment.  
 
9.3.8. Distribution of Subject Satisfaction Survey 
Subjects should be given the Subject Satisfaction Survey and asked to complete the form before 
leaving the clinic (Appendix E).  Completion of the survey is voluntary and does not affect 
participation in the study in any way. 
 
9.4 Unscheduled Visits  
 
Unscheduled visits are visits that occur less than 7 days after randomization or between Visit 2 and Visit 
3.  If the subject or investigator has concerns about persistent symptoms or adverse events that require an 
unscheduled visit, the subject may return to the office/clinic to be evaluated.  If the subject needs 
additional treatment for vaginal discomfort/symptoms (either based on investigator judgment or as a 
result of the subject self-medicating) before Visit 2, then Visit 2 procedures should be completed.  If such 
an unscheduled visit occurs between Visit 2 and Visit 3 then Visit 3 procedures should be completed. If 
the subject does not need to be treated, and is willing, she may remain in the study and return for her next 
scheduled visit.  
 
In instances where Visit 1 lab results make a subject ineligible for the study (i.e. subject randomized but 
did not meet inclusion/exclusion criteria), subjects should be terminated when exclusionary lab results 
become known.  Procedures for these subjects are more limited but require a safety assessment including 
collection of adverse events, concomitant medications, and safety blood labs if the subject was enrolled in 
the Mixed Infection Study and safety labs were not already obtained at Visit 2.  Subject diaries should be 
reviewed and unused drug tubes collected.  Drug administration/compliance should be ascertained if not 
already done.  Lab results that would make a subject ineligible are:  positive gonorrhea, chlamydia, 
trichomonas, or herpes tests; normal Nugent score < 4 (for BV and Mixed Infection subjects); or negative 
Candida culture (for VVC and Mixed Infection subjects).  See Appendix A, Schedule of Procedures. 
 
Other reasons for an unscheduled visit include withdrawal by subject or investigator decision, or 
pregnancy (see Section 10.1).   
 
10. Adverse Events and Safety Reporting 
 
All adverse events occurring during the course of the clinical study, regardless of relation to study drug, 
will be recorded in source documentation and on the appropriate page(s) of the CRF.  The investigator 
will assess subjects for the occurrence of adverse events at both follow-up visits.  Subject diaries will also 
be reviewed for the occurrence of adverse events.  Spontaneously reported adverse events by subjects at 
any time during the study will also be recorded.   
 
10.1. Definition of Adverse Event/Adverse Reaction/Suspected Adverse Reaction 
An adverse event (AE) is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use 


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of a drug, without any judgment about causality.  An adverse reaction means any adverse event caused by 
a drug.  Adverse reactions are a subset of all suspected adverse reactions for which there is reason to 
conclude that the drug caused the event.  A suspected adverse reaction implies a lesser degree of certainty 
about causality than an adverse reaction.  
 
Pre-existing conditions are not considered adverse events unless there is an unexpected change in the 
frequency, intensity, or nature of the condition.  Pre-planned hospitalizations, diagnostic or elective 
procedures/surgeries for pre-existing conditions, where there is no change in the subject’s condition, will 
not be considered adverse events.   
 
A newly diagnosed pregnancy during study enrollment will also not be considered an adverse event.  If a 
pregnancy occurs during the dosing phase of the study, the subject will be asked to discontinue study drug 
and be terminated from the study.  Curatek/Curatek’s designee should be notified via phone, fax, or e-
mail/scan within 24 hours of the site learning of the pregnancy.  A pregnancy notification form must be 
completed and sent to Curatek/Curatek’s designee.  Subjects should be asked to provide consent on an 
authorization for disclosure of medical information form so that follow-up information regarding the 
pregnancy outcome could subsequently be obtained.  If a pregnancy results in an abnormal outcome (i.e. a 
congenital anomaly/birth defect, neonatal death, stillbirth, spontaneous abortion etc.) a serious adverse 
event must be reported.   
 
10.2. Protocol-Specific Adverse Event Considerations 
For purposes of this study, spontaneous reports of vaginal discharge and/or vulvovaginal signs and 
symptoms (e.g. itching, burning, irritation, erythema etc.) associated with the application of study drug 
should be reported as adverse events.  However, changes in clinical criteria (i.e. Amsel criteria and/or 
vulvovaginal signs and symptoms) from baseline that are associated with one of the vaginal infections 
under study (i.e. BV, VVC, or Mixed Infection) will be captured on the corresponding CRF page and 
should not be recorded as adverse events with the following exceptions: 
• 
If in the investigator/clinician’s opinion a subject treated for BV gets a secondary yeast infection, the 
yeast infection should be captured as an adverse event. 
• 
If in the investigator/clinician’s opinion a subject treated for VVC gets BV, the BV should be 
captured as an adverse event. 
 
10.3. Definition of Serious Adverse Events (SAE) 
Each adverse event or suspected adverse reaction must be assessed for its seriousness.  The term “serious” 
is not synonymous with “severe” that may be used to describe the intensity of an event or reaction.  An 
AE or suspected adverse reaction is considered serious if in the view of either the investigator or sponsor: 
• 
Results in death 
• 
Is life threatening  
The term “life threatening” refers to an adverse event or suspected adverse reaction in which either 
the investigator or the sponsor believe the subject was at risk of death at the time of the event or 
reaction; it does not refer to an event that hypothetically might have caused death if it were more 
severe.   
• 
Requires inpatient hospitalization or prolongs an existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
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Important medical events are those that may not be immediately life threatening, but are of major 
clinical significance and may require intervention to prevent one of the other serious outcomes listed 
above.  Examples include a seizure that did not require in-subject hospitalization or allergic 
bronchospasm that necessitated emergency treatment. 
 
All adverse events or suspected adverse reactions that do not meet the criteria for serious will be regarded 
as non-serious. 
 
10.4. Definition of Unexpectedness 
An adverse event or suspected adverse reaction is considered unexpected if the nature/specificity or 
severity of the event or reaction is not consistent with applicable product information (e.g. Investigator’s 
Brochure for an unapproved investigational product or a package insert/summary of an approved 
product). 
 
The current Investigator’s Brochure lists the adverse events or suspected adverse reactions known to be 
associated with metronidazole and terconazole.   
 
10.5. Documentation of Adverse Events  
All adverse events (i.e. serious and non-serious) that occur from the time informed consent is signed 
through Visit 3 must be reported and recorded in source documentation and on the appropriate page(s) of 
the CRF.  Information to be documented for each adverse event includes the following:  adverse event 
term, severity of the event (i.e. mild, moderate or severe), start and stop date (if applicable) of the event, 
time of event if event occurred on the first day of study drug administration, relationship to study drug 
(i.e. none, possible, probable, definite), action taken with the study drug (i.e. none, study drug interrupted, 
study drug discontinued), action taken for the adverse event (i.e. none, new medication/treatment, 
terminated, hospitalized, or other), outcome of the event (resolved, resolved with sequelae, ongoing,  
death, or unknown) and whether or not the event meets serious criteria. 
 
If adverse event signs and symptoms are the result of a specific diagnosis, the diagnosis only (and not the 
cluster of signs and symptoms that make up the diagnosis) should be reported on the CRF. 
 
10.6. Severity Criteria  
Severity criteria for adverse events will be defined as follows:   
• 
Mild:  awareness of signs/symptoms that are easily tolerated causing minimal discomfort and not 
interfering with normal daily activities 
• 
Moderate:  Sufficient discomfort is present and may interfere with normal daily activities 
• 
Severe:  Extreme distress is present causing significant impairment of functioning or incapacitation 
preventing normal daily activities 
 
The investigator should use clinical judgment in assessing the intensity of adverse events not directly 
experienced by the subject (e.g. lab abnormalities). 
 
10.7. Relatedness Criteria 
An adverse event is considered associated with the use of the drug if the attribution is possible, probable, 
or definite.  Attribution definitions for the relatedness of adverse events will be defined as follows: 
• 
None:  An adverse event that is not related to the use of study drug 


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• 
Possible:  An adverse event that might be due to the use of the drug; an alternative explanation (e.g. a 
concomitant drug or illness) is inconclusive.  The relationship to time is reasonable. 
• 
Probable:  An adverse event that might be due to the use of the drug; an alternate explanation (e.g. a 
concomitant drug or illness) is less likely.  The relationship in time is suggestive. 
• 
Definite:  An adverse event that cannot be reasonably explained with an alternate explanation (e.g. a 
concomitant drug or illness).  The relationship in time is very suggestive.  A direct cause and effect 
relationship between the study drug and the adverse event exists. 
 
10.8. Serious Adverse Event Reporting 
All serious adverse events (SAE) that occur during the trial regardless of their relationship to study drug 
must be reported to Curatek/Curatek’s designee as soon as possible but no later than 24 hours after 
learning of the event.  Initial notification may be made via phone, fax, or e-mail/scan.   
 
 
Additionally, a Serious Adverse Event (SAE) Report form must be filled out and sent via fax or e-
mail/scan to Curatek/Curatek’s designee as soon as possible.  Information included with initial 
notification should include as much of the information requested on the form as possible.  The SAE 
Report form should not be held up if all the information regarding the SAE is not yet available.  The 
Concomitant Medications and the Adverse Events CRF pages should also be faxed or e-mailed/scanned 
with the SAE Report form.   
 
When additional/new information regarding the SAE becomes available, an updated SAE Report form, 
Concomitant Medications, and Adverse Events CRF pages should be promptly submitted to 
Curatek/Curatek’s designee.  Copies of any relevant data from hospital notes (e.g. laboratory tests, 
discharge summary, ECGs, ER records etc.) should also be submitted when they become available.   
 
Specific contact information for the reporting of SAEs and submission of the SAE Report form and 
accompanying documents will be available on the Serious Adverse Event (SAE) Report form and on the 
contact list for the study.  
 
All serious adverse events should be followed and treated appropriately until there is satisfactory 
resolution of the adverse event, the adverse event becomes stable or can be explained by other causes, 
clinical judgment indicates further evaluation is not needed, or it appears unlikely that additional 
information can be obtained given due diligence has been done. 
 
Investigators must comply with all applicable regulatory requirements related to the reporting of serious 
adverse events (i.e. regulatory authorities, IRB, institution reporting requirements etc.).   
 
10.9. Safety Reporting to Investigators, IRBs, and Regulatory Authorities by Curatek 
Curatek/Curatek designee will be responsible for reporting to the regulatory authorities (i.e. FDA) and all 
participating investigators any adverse event associated with the use of study drug (i.e. suspected adverse 
reaction) that is both serious and unexpected; or any findings from clinical, epidemiological, or pooled 
analysis from multiple studies or any findings from animal or in vitro testing that suggest a significant 
risk in humans exposed to the drug in an IND safety report.  IND safety reports will be sent as soon as 
possible but in no event later than 15 calendar days after Curatek/Curatek’s designee’s initial receipt of 
the information. 
 


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Curatek/Curatek’s designee will also notify the FDA by telephone or fax of any unexpected fatal or life-
threatening  experience associated with the use of the study drug (i.e. suspected adverse reactions) as soon 
as possible but in no event later than 7 calendar days after Curatek/Curatek’s designee’s initial receipt of 
the information.   
 
Follow-up information to a safety report (if applicable) will be submitted as soon as relevant information 
is available. 
 
Study sites utilizing a local IRB must report IND safety reports to their reviewing IRB and institution in 
accordance with IRB regulations and institutional policies.  Curatek/Curatek’s designee will report IND 
safety reports to the reviewing central IRB on behalf of those sites utilizing a central IRB.   
 
Curatek/Curatek’s designee will be responsible for safety oversight, which includes the review of all 
adverse events.  If there are concerns on the part of any investigator or Curatek that would prevent the 
study from continuing, the study will be terminated at that time and no more subjects will be enrolled. 
 
11. Statistical Methods  
 
Summary statistics of all important demographic, study conduct, efficacy, and safety data will be 
provided in tables.  Case report form, clinical laboratory, and efficacy evaluation data will be provided in 
listings.  
 
11.1. General Methods 
Data from this study will be summarized with descriptive statistics.  Descriptive summaries of baseline 
and demographic data will include frequency and percent relative frequency for categorical data; 
frequency and median for ordinal data; and frequency, mean, standard deviation, and minimum and 
maximum for quantitative data.  In addition, 95% confidence intervals will be calculated, as appropriate.   
 
For scheduled measurements which are repeated out of schedule, such as repeat laboratory tests, the last 
measurement within a scheduled time interval will be used for data summaries.  All results, whether 
scheduled or repeat, will be listed. 
  
Each of the three infection studies within the trial will be analyzed separately.   
 
The primary statistical objective of each infection study is listed below: 
1. BV Study:  Demonstrate the superiority of BV Gel (0.9% metronidazole gel) to Placebo Gel in the 
treatment of bacterial vaginosis (BV). 
2. VVC Study: Demonstrate the superiority of VVC Gel (0.8% terconazole gel) to Placebo Gel in the 
treatment of vulvovaginal candidiasis (VVC). 
3. Mixed Infection Study:  Demonstrate the superiority of Combo Gel (0.9% metronidazole gel and 0.8% 
terconazole gel) to both single entity gels (BV Gel alone and VVC Gel alone).   
 
The primary and secondary endpoints are reflective of each of the infection studies within the protocol 
include: 
   
• 
Primary Endpoints  


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o BV Study:  BV cure rate defined as normal/physiologic dischargem
o VVC Study:  VVC cure rate defined as resolution of all signs and symptoms attributable to VVC 
(i.e. clinical cure)  
, negative whiff test, and 
< 20% clue cells (i.e. clinical cure) 
o Mixed Infection Study:  Mixed Infection cure rate defined as BV cure (i.e. BV clinical cure) 
AND a VVC cure (i.e.  VVC clinical cure)  
 
• 
Secondary Endpoints   
o BV Study:  BV clinical and Gram stain Nugent score cure rates alone and combined; 
changes/improvements in Amsel criteria and Nugent scores; time to resolution of symptoms 
o VVC Study:  VVC clinical (i.e. resolution of all signs and symptoms attributable to VVC) and 
mycologic cure rates (i.e. negative Candida on culture) alone and combined; 
changes/improvements in signs and symptoms scores; eradication (or persistence) of individual 
fungal species; time to resolution of symptoms 
o Mixed Infection Study:  BV clinical and Gram stain Nugent score cure rates alone and combined; 
changes/improvements in Amsel criteria and Nugent scores; VVC clinical and mycologic cure 
rates alone and combined; changes/improvements in signs and symptoms scores; eradication or 
persistence of individual fungal species; time to resolution of symptoms   
 
A Statistical Analysis Plan (SAP) will be prepared, with comprehensive details for all statistics to be 
presented for both primary and secondary endpoints of each study.  
 
11.2. Study Conduct Summaries 
The number of subjects who were enrolled, treated with at least one dose of study drug, who completed 
the study, as well as the reasons for withdrawal, will be summarized with counts and percentages by 
treatment group within each infection study and for the trial overall.  This table will also include number 
of screening failures and reasons for screening failures.  Protocol violations, inclusion/exclusion criteria, 
and study drug administration data will also be summarized. 
 
11.3. Analysis Populations 
The primary assessments of efficacy will be based on the modified intent-to-treat (mITT) population.  In 
addition to the mITT analyses of the data, analyses will be conducted using the intent-to-treat (ITT) 
population as well as the per protocol (PP) population.  The data analysis populations are defined as: 
• 
ITT:  The intent-to-treat analysis will include all subjects randomized to treatment.  
• 
mITT:  The modified intent-to-treat population will include all subjects randomized to treatment and 
administered at least one dose of study drug.  In addition, subjects in the VVC and Mixed Infection 
studies must have a positive baseline vaginal fungal culture for Candida species.  Subjects in the BV 
and Mixed Infection studies must have a Gram stain Nugent score of ≥ 4 at the baseline visit.  
• 
PP:  The per protocol analysis will include the subset of mITT subjects that had no major protocol 
violations and who are classified as efficacy evaluable with no missing data required to determine 
primary endpoints.  Major protocol violations likely to bias assessment of the primary endpoint for 
the per protocol population will be determined prior to unblinding the data. 
                                                 
m In the event a BV subject has discharge consistent with VVC (i.e. white, creamy, and curdy [cottage cheese like] adherent to 
the epithelium), the subject will be considered a BV cure providing all other criteria for BV cure (and evaluability) are met and 
the subject has a positive yeast culture.  


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• 
Safety:  The safety population will include all subjects randomized to treatment and administered at 
least one dose of study drug. 
 
11.4. Determination of Sample Size 
Approved labeling, clinical data included in New Drug Applications and approval packages, and sponsor 
experience with the compounds in this study and similar therapies provide the following estimates and 
ranges of the cure rates (as proportions) for the treatments within each infection study.  
 
1. BV Subjects  
a. BV Gel (0.9% metronidazole gel): .50 (.35-.45)  
b. Placebo Gel:  .20 (.10-.20) 
2. VVC Subjects  
a. VVC Gel (0.8% terconazole gel): .70 (.65-.75)  
b. Placebo Gel: .20 (.15-.25) 
3. Mixed Infection Subjects 
a. Combo Gel (0.9% metronidazole gel and 0.8% terconazole gel): .35 (.25-.35) 
b. VVC Gel (0.8% terconazole gel): .10 (.05-.15)  
c. BV Gel (0.9% metronidazole gel): .10 (.05-.15) 
 
Under the assumption that the above estimated cure rates will be observed in this study, sample sizes were 
calculated for each infection study based on these estimates for at least 90% power and at least 50 
subjects per treatment group.  Superiority tests will be performed as two-sided, α = 0.05 level significance 
tests, and sample sizes were calculated using Fisher’s Exact test in case the planned Chi-squared test is 
not appropriate.   
 
The following table provides the sample size required for each treatment group within each infection 
study.  The total sample size is given, and represents the number of evaluable subjects required (Per 
Protocol population).  Entry in each infection study of the trial will be stopped when this number of 
evaluable subjects is reached, since evaluable/not-evaluable can be determined from the completed case 
report form prior to unblinding. 
 
Required Number of Evaluable Subjects, by Infection Study and Treatment Group 
Study: 
BV Only Subjects 
VVC Only Subjects 
Mixed Infection Only Subjects 
Treatment 
Arm: 
BV Gel 
Placebo Gel 
VVC 
Gel 
Placebo Gel 
BV Gel 
VVC 
Gel 
Combo 
Gel 
Expected 
Cure Rate 
50% 
20% 
70% 
20% 
10% 
10% 
35% 
n for at 
least 80% 
Power, and 
at least 50 
per group 
58 
58 
50 
50 
63 
63 
63 
Actual 
Power 
90.0%  
>99.9%  
90%  
Total N  
405 
 




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VVC Study:  The primary statistical objective of the VVC infection study is to demonstrate the 
superiority of VVC Gel to Placebo Gel.  The assessment of superiority will be performed by 
conducting a continuity corrected Chi-squared test for a difference in the proportion of VVC cure 
between the two treatments.  Also, a 95% two-sided confidence interval for the difference in 
proportion of VVC cure between the two treatments will be constructed.   
 
Mixed Infection Study: The primary statistical objective of the Mixed Infection Study is to 
demonstrate the superiority of the Combo Gel to both BV Gel and VVC Gel.  The assessment of 
superiority will be performed by conducting a continuity corrected Chi-squared tests for a difference 
in the proportion of Mixed Infection cure between the Combo Gel and each of the two single entity 
treatments.  If the P-values for both of the hypothesis tests are less than or equal to 0.05, the Combo 
Gel will be considered superior to both of the single entity gels.  Despite there being two comparisons 
made within the same study, no adjustment for multiplicity is necessary since both comparisons must 
be positive instead of “at least one,” in order to conclude superiority of the Combo Gel.  Also, 95% 
two-sided confidence intervals for the difference in proportion of Mixed Infection cure between the 
Combo Gel and each of the two single entity treatments will be constructed. 
 
11.6.2. Secondary Efficacy Analyses  
Secondary efficacy endpoints are listed in Section 5.3.  These endpoints include variables that are 
categorical (including binary variables), ordinal (such as rating scores), or time to event variables 
(such as time to resolution of symptoms). The analysis of the secondary endpoints will be performed 
using the mITT population with worst case scenario imputation for missing data, with supportive 
analyses conducted using the PP population. 
 
For the secondary endpoints which are categorical or ordinal with four or fewer levels (including 
binary outcome variables), the analysis will include the proportion of subjects with each criteria or 
each score, at baseline and endstudy.  The comparison of treatment groups will be performed using 
Chi-squared tests if all expected cell counts are at least 5, and Fisher’s Exact test otherwise.  For 
binary outcomes, (clinical outcome, mycological outcome, and eradication [or persistence] of 
individual fungal species) 95% two-sided confidence intervals for the difference in proportions will 
also be constructed.  
 
Secondary endpoints which are ordinal data with more than four levels, such as Nugent score, the 
median score at baseline, endstudy, and the change from baseline will be computed, in addition to the 
proportion of subjects at each level.  Treatment comparisons will be performed using the Wilcoxon 
Rank Sum test. 
 
The secondary endpoint of time to resolution of symptoms will be analyzed in each infection study 
using log-rank tests and Kaplan-Meier plots.  Kaplan-Meier estimates of the quartiles for time to 
resolution will be computed, along with 95% confidence intervals. 
 
The analysis of eradication (persistence) of individual fungal species will be conducted in subgroups 
of subjects defined by fungal species present at baseline (for the VVC and Mixed Infection studies).   
 
11.7. Safety Analysis 
Safety will be assessed through summaries of adverse events (AEs) and laboratory evaluations.  All safety 
analyses will be based on the safety population, as defined in Section 10.3 and will be summarized for 


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each treatment group.  These summaries will be presented separately for each infection study.  In 
addition, adverse events, as available, for BV Gel and VVC Gel will also be summarized by combining 
subjects who received the same treatment regimen across the studies.  For example, those receiving BV 
Gel in the BV study will be combined with those receiving BV Gel in the Mixed Infection Study. 
 
11.7.1. Adverse Events 
Adverse events will be coded by system organ class and preferred term using a current version of 
Medical Dictionary for Regulatory Activities (MedDRA). Each verbatim adverse event will be 
translated to a preferred term, a higher-level included term, and finally a system organ class.  Adverse 
events will be summarized at each level of the hierarchy, counting proportions of the subjects who 
experienced at least one such adverse event.  Frequencies of subjects with treatment-emergent 
adverse events (TEAEs), sorted by system organ class, will be summarized by treatment group. 
TEAEs are defined as those AEs that develop or worsen after the first dose of study drug and up to 
the date of the final visit.  Any adverse events that are not considered treatment emergent will be 
provided in listings.   
 
A secondary analysis of TEAEs judged by the investigator to be related to study drug will be 
performed. This analysis will be summarized identically to the above analysis. Additional 
breakdowns of serious adverse events (SAEs) and treatment-related SAEs will be summarized and 
described in a similar fashion.  
 
Summaries of AE durations, severity, relatedness to study drug, countermeasures taken, outcome, and 
seriousness will also be produced as warranted.  At the least, incidence of study drug discontinuation 
and death will be summarized. 
 
11.7.2. Laboratory Assessments 
CBC with differential and blood chemistry data will be tabulated and compared to baseline for the 
Mixed Infection study population.  Laboratory endpoints will be summarized for baseline, endstudy, 
and for change from baseline to endstudy using descriptive statistics (mean, median, standard error, 
minimum, and maximum).  In addition, summarization of laboratory values that deviate substantially 
from the normal reference range will be provided.  The reference ranges for normal laboratory values 
will be provided by the central laboratory.   
 
Shift tables will be provided, which tabulate the proportion of subjects in each treatment group who 
change from low abnormal (< LLN), normal, or high abnormal (> ULN) at baseline to low abnormal, 
normal, or high abnormal at Visit 2, as shown in the following table. 
  
 
 
Visit 2/EndStudy  
 
Baseline Lab Value: 
< LLN 
Normal 
> ULN 
Active Medication 
< LLN 
x (x.x%) 
x (x.x%) 
x (x.x%) 
 
Normal 
x (x.x%) 
x (x.x%) 
x (x.x%) 
 
> ULN 
x (x.x%) 
x (x.x%) 
x (x.x%) 
 
 
 
 
 
Placebo 
< LLN 
x (x.x%) 
x (x.x%) 
x (x.x%) 
 
Normal 
x (x.x%) 
x (x.x%) 
x (x.x%) 
 
> ULN 
x (x.x%) 
x (x.x%) 
x (x.x%) 
 


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All laboratory data will be provided in listings.  Abnormal laboratory values, defined as observations 
outside the normal range, will be flagged in the listing. 
 
11.7.3. Vital Signs 
Vital signs are only collected before administration of study drug, and will be summarized within 
each infection study pooling treatment groups.  Vital sign data will also be presented in listings. 
 
11.7.4. Physical Exams 
All physical exam data will be presented in listings.   
 
12. Data Handling and Record Keeping 
 
12.1. Source Documents   
Source data is all information in a clinical trial that would allow for the reconstruction and evaluation of 
the trial.  Source data are contained in source documents.  Source documents are original documents and 
include:  clinic, office, and hospital records (i.e. paper or electronic); source document worksheets that 
will be provided by Curatek to assist sites in capturing protocol required data; laboratory results;  subject 
diaries; drug accountability records, etc.  The nature and location of all source documents should be 
known to Curatek/Curatek’s designee (and the study staff) so that original subject data recorded can be 
verified against data entered on the CRF.  All source notes should be signed and dated by the 
investigator/study staff so that the author of the note/entry (and the date) can be identified.   
  
12.2. Case Report Forms 
Paper case reports forms (CRF) will be provided by Curatek Pharmaceuticals, LLC.  Curatek/Curatek’s 
designee will train appropriate study staff on the use of the CRFs.  CRFs will be printed in triplicate on 
non-carbon required (NCR) paper.  The original and one copy of each page of the CRF will be collected 
by Curatek/Curatek’s designee during routine monitoring visits.   
 
Case report forms should be completed in accordance with CRF completion guidelines provided by 
Curatek.  All CRF entries and corrections must be made by the investigator or designee listed on a 
delegation of responsibility log. Corrections of data entered on the CRF must be made in the following 
manner: 
• 
If the original CRF page is still at the study site, the incorrect entry will be crossed out (on the 
original page) with a single line so as to remain legible.  No correction fluid or erasers are permitted.  
The correct data will then be entered in ink next to the crossed-out entry.  Each correction, change, or 
addition of new data must be initialed and dated by the individual making the correction, change, or 
addition. 
• 
If the original page has already been sent to Curatek/data management and a data error is noted by the 
site or the site monitor, a site initiated data clarification form (SIDCF) should be generated by the site 
or the site monitor and submitted to data management to request a data change.  If data management 
believes a data point needs to be corrected/clarified, a data clarification form (DCF) will be generated 
by data management (either manually or automated) and sent to the site.  In either instance, the 
original SIDCF or DCF will be retained by the site and a copy scanned to data management.    
 
The investigator must initial or sign and date where indicated on the CRF page(s), indicating that all data 
entries are accurate and complete. The investigator must retain full responsibility for the accuracy and 
authenticity of all data entered on the CRFs from his/her site.  


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CRFs should be completed promptly after a subject visit unless data is pending regarding a lab or culture 
result or adverse event follow-up information.  Data reported in the CRFs should be recorded/transcribed 
from source documents.  Diaries filled out by subjects will be recognized as source documents. 
 
The clinical monitor will review the CRF against appropriate source documents and evaluate all data 
entries for accuracy and completeness.  If data is missing or errors are noted, the investigator/designee 
should correct the CRF as above. 
 
12.3. Record Retention 
U.S. FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP require that records and 
documents pertaining to the conduct of this study and the distribution of investigational drug, including 
CRFs, consent forms, laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 2 years after the last marketing application approval 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. All state 
and local laws for retention of records also apply.  
 
These documents should be retained for a longer period of time if required by applicable regulatory 
requirements or by an agreement with Curatek.  No documents should be destroyed unless written 
approval to do so has been received by Curatek. Written notification should be provided to Curatek for 
transfer of any records to another party or moving them to another location. 
 
12.4. Data Management 
The data management center will be determined by Curatek prior to the start of the study.  Data will 
arrive by paper case report forms, except laboratory data which will arrive electronically from the central 
lab.  
 
The data management center will use validated software to process both the paper case report forms and 
electronic laboratory data.  An electronic audit trail will be maintained to document all changes to the 
database after double data entry or receipt of electronic data.  Prior to processing data, a data management 
plan will be written by the data management center detailing the process steps involved and quality 
checks incorporated into the study.  This document will be reviewed and approved by the sponsor, and 
updated during the study as needed. 
 
13. Study Management 
 
13.1. Monitoring and Source Data 
Clinical monitors/representatives of Curatek Pharmaceuticals, LLC will perform on-site monitoring visits 
as often as necessary to ensure that all aspects of the protocol are followed.  Monitors will record their 
visits on a site visit log that will be kept at the site.  A site initiation visit (SIV) for the purpose of training 
the investigator(s) and study staff on the protocol, CRFs, and all related study activities will be conducted 
at each site prior to subject screening.  The first post-initiation visit will take place shortly after subject 
enrollment begins at each site and a close out visit will occur after the last subject completes the study.  
 
During monitoring visits, source documentation will be reviewed for verification of data entered on the 
CRF.  Source documents include but are not limited to clinic and office charts (i.e. paper and/or 


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electronic), laboratory and vaginal culture results, Gram stain results, and subject diaries.  In collaboration 
with Curatek, the study monitor will assist in assessing whether electronic records generated from 
computerized medical record systems used at investigational sites can serve as source documents for the 
purposes of this protocol. If a site’s computerized medical record system is not adequately validated for 
the purposes of clinical research (as opposed to general clinical practice), applicable hardcopy source 
documents must be maintained to ensure that critical protocol data entered into the CRFs can be verified.   
 
The review of regulatory documents, informed consents, and drug storage and accountability records will 
also be done during monitoring visits.  Monitors will meet with the principal investigator periodically 
throughout the study to provide feedback on the study and the site’s performance.  Monitors will also 
provide feedback to Curatek regarding site visits on a regular basis.   
 
Direct access to source documentation (i.e. paper and/or electronic), and to the drug storage and 
dispensing area must be allowed during monitoring visits.  It is also expected that investigator/study staff 
will be available to assist the monitor in his/her activities, CRFs will be completed, and ICFs, drug 
accountability and regulatory records will be available for review.  A suitable area should be provided for 
the monitor to work during monitoring visits. 
 
13.2. Protocol Adherence 
The investigator must read this protocol thoroughly and not deviate from it, unless a protocol waiver is 
received or it is necessary to eliminate an immediate hazard to study subjects.  Should this occur the 
investigator should notify Curatek/Curatek’s designee immediately and the reviewing IRB.   
 
13.3. Protocol Amendments 
Changes in any portion of this protocol after signatures of agreement are obtained must be presented in 
the form of an amendment, signed by Curatek and the principal investigator, and approved by the 
reviewing IRB prior to the amendment being implemented.  The only time a protocol amendment may be 
initiated without IRB approval is when the change is necessary to eliminate apparent immediate hazard(s) 
to the subject(s).  In such an event Curatek will forward the protocol amendment to the FDA and the 
investigator will forward it to the reviewing IRB.  Minor study management issues, administrative 
changes, and typographical errors do not require protocol amendments.  
 
13.4. Protocol Violations   
All protocol violations should be documented in subject’s source notes and on the appropriate CRF page.  
Protocol violations should be reported to Curatek and the reviewing IRB, as per their requirements.  
  
13.5. Quality Assurance and Regulatory Agency Audits   
The study site may be audited by the IRB, Curatek/Curatek designees, independent auditors, or regulatory 
agencies (i.e. FDA).  If the site is contacted by a regulatory agency for an inspection, Curatek should be 
notified immediately.   
 
In accordance with ICH guidelines, the investigator/institution must allow direct access to all trial related 
records for the reviewing IRB, Curatek/Curatek designees, auditors, and regulatory agencies (i.e. FDA).   
 
14. Ethical and Regulatory Considerations 
 


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14.1. Ethical Considerations 
All aspects of this study will be conducted in compliance with the protocol and in accordance with all 
applicable regulatory requirements, and in accordance with Good Clinical Practice (GCP). Investigators 
must also conduct the study in accordance with all of the above and any local/regional regulatory 
requirements.  Many of the investigator responsibilities for this study are contained within the Form FDA 
1572-Statement of Investigator which must be completed and signed before the investigator may 
participate in the study. 
 
14.2. Institutional Review Board 
This protocol (and any subsequent amendments) must be reviewed and approved by an appropriate 
Institutional Review Board (IRB) that complies with federal regulations 21CFR, Part 56 prior to initiation 
of the study.  Curatek will supply all documents required for submission to the IRB for review and 
approval.  These documents include the protocol, investigator’s brochure, informed consent template, 
subject recruitment/advertising materials, written information that will be provided to subjects (i.e. 
instructions for subjects, instructions for using study drug, subject diary, and subject satisfaction survey) 
and any other documents that the IRB needs to fulfill its responsibilities.  Formal written notification of 
the protocol and informed consent approval is required by Curatek prior to the study commencing and 
drug being shipped to the investigator.  Approval letters must be dated and clearly identify the documents 
approved.   
 
Investigative sites must adhere to all requirements stipulated by their reviewing IRB.  These include 
notification to the IRB regarding protocol amendments, updates/changes to informed consents, protocol 
violations, recruitment/advertising materials, safety reporting requirements, ongoing review of the study 
at specified intervals, and submission of a final report.  A copy of IRB approvals and relevant 
correspondence/documentation between the investigative site and the IRB must be maintained and 
provided to Curatek/Curatek’s designee as requested.  
 
Payment to subjects must be approved by the IRB and should not be so large as to present problems of 
coercion or exert undue influence for study participation.  
 
14.3. Informed Consent 
The investigator/designee will be responsible for obtaining written informed consent from each subject 
prior to performing any study-related procedures.  (Assent for children between 12 and 18 years will be 
obtained per IRB requirements.)  The consent form should be reviewed by Curatek/Curatek’s designee 
(i.e. if changes were made from the informed consent template provided by Curatek) and must be 
approved by the reviewing IRB.  The consent form should be in accordance with all applicable regulatory 
requirements, and in accordance with Good Clinical Practice (GCP).  
 
Subjects should be given ample time to review the consent and ask any questions they may have.  Once 
they decide to participate in the study, the informed consent must be signed and dated by the subject and 
by the person who conducted the informed consent discussion.  The investigator/designee must document 
the informed consent process in the subject’s source document.  A copy of the signed informed consent 
should be given to the subject. 
 
A written subject authorization (i.e. HIPAA authorization) either provided as a separate document or 
contained within the informed consent that explains to the subject the permissible uses and disclosures of 


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the subject’s personal health information (PHI) must also be obtained.  Stand-alone authorizations do not 
require review or approval from an IRB; however core elements and statements must be included in them. 
 
If there are any revisions to the informed consent or to written materials given to the subjects, they should 
be IRB approved prior to their use.  Subjects should be informed in a timely manner of any new 
information that becomes available during the course of the study that may be relevant to the subject’s 
participation in the study.  All revised informed consent forms must be reviewed and signed by the 
subject in the same manner as the original informed consent.  The subject should receive a copy of the 
signed, revised consent and the date of re-consenting should be documented in the subject’s source 
document.  
 
All original signed and dated consent forms will be kept by the investigator. 
 
14.4. Delegation Log 
The investigator will maintain a delegation log throughout the study.  The delegation log will comprise a 
listing of appropriately qualified persons to whom the investigator has delegated significant trial-related 
activities/tasks.  The investigator should initial and date the delegation log at the beginning of the trial 
when activities/tasks are delegated and when changes occur.  The investigator should also sign the 
delegation log at the end of the study; the completed log will be maintained in the trial master file (TMF).   
 
14.5. Reports and Publications 
Publication of study results should be followed as presented in the Clinical Trial Agreement (CTA). 
 
14.6. Public Posting of Trial Information  
Curatek will register this trial as required by the Food and Drug Administration Modernization Act 
(FDAMA) Section 113 and the Food and Drug Administration Amendments Act (FDAAA) Section 801. 
Information posted may include participating investigators’ names and contact information.   
 
14.7. Subject Release from the Study 
All subjects are free to withdraw from participation in the study at any time, and for whatever reason, 
specified or unspecified, and without prejudice.  The reason for the discontinuation will be entered onto 
the study termination page of the CRF. 
 
No constraints will be placed on ordinary subject management, and subjects may be placed on other 
conventional therapy upon request or whenever clinically necessary. 
 
14.8. Sponsor Discontinuation of Study 
Premature termination of this study may occur as a result of a regulatory (i.e. FDA) or IRB decision, a 
drug safety issue, or at the discretion of Curatek.  Curatek retains the right to discontinue development of 
BV, VVC, Combo, and Placebo Gels at any time.   
 
If the study is prematurely terminated, Curatek will promptly notify all investigators.  Investigators must 
then promptly contact all enrolled subjects, as applicable.  Final subject evaluations and the collection of 
study materials as directed by Curatek should be done to the greatest extent possible. 


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15. References 
 
1. Allsworth JE, Peipert JF. Prevalence of bacterial vaginosis: 2001-2004 National Health and Nutrition 
Examination Survey data. Obstetrics and Gynecology 2007;109(1):114-20. 
2. Spiegel CA. Vaginitis/vaginosis. Clinics in Laboratory Medicine 1989;9:525-533. 
3. Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SS, McCulle SL, Karlebach S, Gorle R, Russell 
J, Tacket CO, Brotman RM, Davis CC, Ault K, Peralta L, Forney LJ. Vaginal microbiome of 
reproductive-age women. Proceedings of the National Academy of Science. 2011;108 Suppl 1:4680-
7. 
4. Gardner HL, Dukes CD. Haemophilus vaginalis vaginitis. American Journal of Obstetrics and 
Gynecology 1955;69:962. 
5. Zinneman K, Turner GC. The taxonomic position of Haemophilus vaginalis (Corynebacterium 
vaginale). Journal of Pathology and Bacteriology 1963;85:213-219. 
6. Greenwood JR, Pickett MJ. Transfer of Haemophilus vaginalis Gardner and Dukes to a new genus 
Gardnerella: G. vaginalis (Gardner and Dukes) comb. nov. International Journal of Systematic 
Bacteriology 1980;30:170-178. 
7. Spiegel CA, Amsel R, Eschenbach DA, Schoenkneckt R, Holmes KK. Anaerobic bacteria in non-
specific vaginitis. New England Journal of Medicine 1980;303:601-606. 
8. Paavonen J, Miettinen A, Stevens C, Chen KCS, Holmes KK. Mycoplasma hominis in non-specific 
vaginitis. Sexually Transmitted Diseases 1983;10:271-275. 
9. Srinivasan S, Hoffman NG, Morgan MT, Matsen FA, Fiedler TL, Hall RW, Ross FJ, McCoy 
CO, Bumgarner R, Marrazzo JM, Fredricks DN. Bacterial communities in women with 
bacterial vaginosis: high resolution phylogenetic analyses reveal relationships of microbiota to 
clinical criteria. PLoS One. 2012;7(6):e37818.  
10. Amsel R, Totten PA, Spiegel CA, Chen KCS, Eschenbach DA, Holmes KK. Nonspecific vaginitis: 
diagnostic criteria and microbial and epidemiological associations. American Journal of Medicine 
1983;74;14-22. 
11. Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a 
standardized method of Gram stain interpretation. Journal of Clinical Microbiology 1991;29:297-301 
12. Centers for Disease Control. Sexually transmitted disease treatment guidelines 2002. Morbidity and 
Mortality Weekly Report 2002;51(RR-6):1-78. 
13. Package inserts for MetroGel-Vaginal and Cleocin Vaginal Cream.  Physician’s Desk Reference 
2013.  
14. Sobel JD. Vaginal infections in adult women. Sexually Transmitted Diseases 1990;74:1573-1602. 
15. Hurley R, DeLouvois. Candida vaginitis. Postgraduate Medical Journal 1979;55:645-647. 
16. Ringdahl E. Treatment of recurrent vulvovaginal candidiasis. American Family Physician 
2000;11:3306-3312. 
17. Schaff VM, Perez-Stable EJ, Borchart K. The limited value of symptoms and signs in the diagnosis of 
vaginal infections. Archive of Internal Medicine 1990;150:1929-1933. 
18. Landers DV, Wiesenfeld HC, Heine P, Krohn MJ, Hillier SL. Predictive value of the clinical 
diagnosis of lower genital tract infection in women. American Journal of Obstetrics and Gynecology 
2004;190:1004-1010. 
19. Hoffstetter SE, Barr S, LeFevre C, Leong FC, Leet T. Self-reported yeast symptoms compared with 
clinical wet mount analysis and vaginal yeast culture in a specialty clinic setting. Journal of 
Reproductive Medicine 2008;53(6):402-6. 


Curatek Pharmaceuticals, LLC 
Protocol MTC-001 
 
 
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20. Ferris DG, Hendrich J, Payne PM, Getts A, Rassekh R, Mathis D, Litaker MS. Office based diagnosis 
of vaginitis. Clinician-performed tests compared with a rapid nucleic acid hybridization test. The 
Journal of Family Practice 1995;41(6):575-581. 
21. Petersen CS, Danielsen AG, Renneberg J. Direct or referral microscopy of vaginal wet smear for 
bacterial vaginosis: experience from and STD clinic. Acta Dermatologica Vererologica 1999;79:473-
474. 
22. Ferris DG, Nyirjesy P, Sobel JD, Soper D, Pavletic A, Litaker MS. Over-the-counter antifungal drug 
misuse associated with patient-diagnosed vulvovaginal candidiasis. Obstetrics and Gynecology 
2002;99:419-425. 
23. Redondo-Lopez V, Meriwether C, Schmitt C, Opitz M, Cook R, Sobel JD. Vulvovaginal candidiasis 
complicating recurrent bacterial vaginosis. Sexually Transmitted Diseases 1990;17:51-53. 
24. Sanchez S, Garcia PJ, Thomas KK, Catlin M, Holmes KK. Intravaginal metronidazole gel versus 
metronidazole plus nystatin ovules for bacterial vaginosis: a randomized controlled trial. American 
Journal of Obstetrics and Gynecology 2004;191:1898-1906. 
25. Jones BM, Geary I, Lee ME, Duerden BI. Comparison of the in vitro activities of fenticonazole, other 
imidazoles, metronidazole, and tetracycline against organisms associated with bacterial vaginosis and 
skin infections. Antimicrobial Agents and Chemotherapy 1989;33(6):970-972. 


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Appendix A:  Schedule of Procedures 
 
 
Procedure 
Baseline 
Visit 
Test of Cure Visit 
Follow Up Visit 
Visit 1 
Visit 2 
Visit 3 
 
(7-14 days after  
randomization) 
(21-30 days after 
randomization) 
Informed consent signed 
X 
 
 
Demographic information 
X 
 
 
Contraceptive, obstetric, & gynecologic history  
X 
 
 
Medical & surgical history 
X 
 
 
Physical exam and vital signs 
X 
 
 
Pelvic Examination 
 
 
 
• 
Symptom and Sign Severity Score 
o 
Evaluate symptoms:  itching, burning, and irritation 
o 
Evaluate signs:  edema, erythema, & excoriation 
X 
X 
X 
• 
Visual inspection for genital herpes and warts 
X 
 
 
• 
Characterization of vaginal discharge  
X 
X 
X 
• 
Vaginal pH  
X 
X 
X 
• 
KOH “whiff test” 
X 
X 
X 
• 
KOH wet mount—examine for yeast forms 
X 
 
 
• 
Saline wet mount— examine for clue cells  
X 
X 
X 
• 
Saline wet mount— examine for motile trichomonads  
X 
X 
X 
Tests/Cultures 
 
 
 
• 
Vaginal Gram stain  
X 
X 
X 
• 
Vaginal Yeast culture  
X 
X 
X 
• 
Tests for N. gonorrhoeae, Chlamydia trachomatis, and 
Trichomonas vaginalis 
X 
 
 
• 
Culture for herpes (if suspected) 
X 
 
 
• 
Pap smear (if ≥ 21 yrs and not done within past 3 years) 
X 
 
 
• 
Pregnancy testa  
X 
 
 
• 
CBC and blood chemistryb, d 
X 
X 
Xc    
Inclusion/exclusion criteria 
X 
 
 
Diagnosis for infection study enrollment 
X 
 
 
Randomization and dispensation of study drug  
X 
 
 
Study drug administration and dosing instructions 
X 
 
 


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Procedure 
Baseline 
Visit 
Test of Cure Visit 
Follow Up Visit 
Visit 1 
Visit 2 
Visit 3 
 
(7-14 days after  
randomization) 
(21-30 days after 
randomization) 
Subject instructions/reinforcement of instructions 
X 
X 
 
Schedule/confirm next visits 
X 
X 
 
Subject Compliance 
 
 
 
• 
Study instructions 
 
X 
X 
• 
Study drug administration/complianced 
 
X 
 Xc 
Time to symptom resolution/reoccurrence (subject assessment) 
 
X 
 Xc 
Prior/concomitant medication assessmentd 
X 
X 
X 
Adverse event assessmentd 
 
X 
X 
Assessment of Clinical Status:  Need for additional treatment for 
vaginal discomfort/symptoms  
 
X 
 
Assessment of Clinical Status:  Need for additional treatment for 
vaginal infection 
 
 
X 
Collect returned, unused study drugd  
 
X 
 Xc 
Collect and review diaryd 
 
X 
 Xc 
Subject satisfaction survey 
 
 
X 
Study Termination 
 
 
X 
a. Pregnancy test is required if subject is not post-menopausal ≥ 1 year or is not surgically sterile (i.e. hysterectomy bilateral oophorectomy, or bilateral tubal ligation).   
b. CBC and blood chemistries to be obtained only for subjects randomized to the Mixed Infection Study.  
c. If previously not done at Visit 2; or updated information regarding time to resolution/reoccurrence of symptoms is available.  
d. Limited procedures for subjects terminated (at any visit) for the following reason:  randomized and later found not to meet eligibility criteria (i.e. positive baseline 
culture for gonorrhea, chlamydia, trichomoniasis or herpes; Nugent score < 4 for subjects enrolled in the BV or Mixed Infection Study; negative fungal culture for 
Candida for subjects enrolled in the VVC or Mixed Infection Study).  


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Appendix B:  Instructions for Subjects 
 
 
• 
You should begin the study drug as soon as possible but not later than two days after your 
office/clinic visit.  
• 
Insert one applicator of the study drug into your vagina at bedtime for three days in a row.  (See 
the Instructions for Using Study Drug that you have been given.)  Do not take any extra drug 
even there is some left in the tube.   
• 
Do not have sexual intercourse during treatment or before you return for your next visit (Visit 2). 
• 
You should not become pregnant while you are in the study, and if you are heterosexually active 
you must be on an acceptable method of birth control throughout the study. 
• 
Do not use any intravaginal/vulvovaginal products (except your study drug) during treatment or 
before you return for your next visit (Visit 2).  You should also not use any 
intravaginal/vulvovaginal products within 48 hour of your final visit (Visit 3).  Examples of 
products you should not use include feminine deodorants and douches; spermicidal creams, gels, 
and foams; vaginal lubricants, moisturizers, and hormonal suppositories and creams such as 
Vagifem®, Estrace® and Premarin® cream; and tampons.  You should try not to use any of these 
products during the entire time you are in the study. 
• 
Do not take any systemic (i.e. oral, IV, or IM) or intravaginal/vulvovaginal antifungal (yeast), 
antimicrobial (antibiotics), corticosteroid, or immunosuppressant medicine while you are in the 
study.   
• 
Do not ingest alcohol or propylene glycol during treatment and for 1 day thereafter.  
• 
If you start or stop any medicines different than what you were taking when you started the study, 
let the study doctor or study staff know.  
• 
If you have sexual intercourse within 48 hours of your last scheduled visit, have your partner use 
a non-lubricated condom.   
• 
Complete the diary that was given to you and return it at your next visit (Visit 2).  
• 
After you finish taking your study drug, place the drug tube (and any remaining drug) inside the 
packaging given to you.  Seal the package and return it at your next visit (Visit 2).  Do not return 
the applicators.  
• 
If you are concerned about any possible side effects or if your symptoms continue to bother you, 
you may call the office/clinic to be evaluated.  


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Appendix C:  Instructions for Using Study Drug 
 
Instructions for Using Your Study Drug  
 
Insert one applicatorful of the study drug you received into your vagina at bedtime for 3 days in a row.   
 
Filling the Applicator 
 
1. 
Remove the cap from the tube and puncture the seal on the drug tube (if necessary) with the pointed 
tip of the cap (Figure 1). 
2. 
Screw the applicator onto the tube (Figure 2). 
3. 
Slowly squeeze the tube from the bottom until the applicator is full.  The plunger will stop when the 
applicator is full (Figure 3). 
4. 
Unscrew the applicator and replace the cap on the drug tube. 
 
 
 
Inserting the Applicator 
 
1. Lie on your back with your knees drawn up (or any position that is comfortable for you).  Hold the 
filled applicator by the barrel and gently insert it into your vagina as far as it will comfortably go 
(Figure 4) 
2. 
Slowly press the plunger until it stops to deposit all of the study drug in the applicator into the vagina.  
3. 
Withdrawal the applicator.  Discard the applicator after each use.   
 
 
.  


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Appendix D:  Subject Diary 
 
 
Subject Diary   
 
Please complete this diary and bring it with you at your final study visit.  
 
1. Enter the date you took each dose of study drug. 
 
Dose 1:  _____/_____/_____      Dose 2:  _____/_____/_____      Dose 3:  _____/_____/_____ 
             month      date       year                            month     date      year                            month     date      year  
 
Time of first dose:  _________ AM  
                                                     PM  
2. Place a mark in the box that best describes your symptoms for each time-point listed. 
 
No 
Symptoms 
Much 
Better 
A Little 
Better 
No 
Change 
A Little 
Worse 
Much 
Worse 
Half hour after my first 
dose of study drug 
 
 
 
 
 
 
Just before taking my 
second dose of study drug 
 
 
 
 
 
 
Just before taking my 
third dose of study drug 
 
 
 
 
 
 
Next day after my last 
dose of study drug 
 
 
 
 
 
 
 
3. Did your vaginal symptoms ever get completely better?  Circle your 
answer.  
      Yes  or  No 
• 
If Yes, enter the date your vaginal symptoms were completely gone.   _____/_____/_____ 
 month     date      year 
• 
If your vaginal symptoms later returned, enter the date they 
returned, or NA (not applicable) if they never returned. 
_____/_____/_____    or   NA 
 month    date      year   
 
 
4. Did you use any intravaginal/vulvovaginal products (besides your study drug) at any time while you were 
in the study?  Circle your answer.  Yes     or     No   
(Examples of these products include feminine deodorants like FDS; douches like Summer’s Eve; contraceptive products like 
spermicidal creams, gels or foams such as Gynol II; vaginal lubricants and moisturizers like KY® Jelly or Replens®; hormonal 
suppositories and creams like Vagifem®, Estrace® and Premarin®; and yeast medicines.) 
• 
If No, go to question 5. 
• 
If Yes, enter on the lines below any product used and the date it was started and stopped.  
  
Name of Product 
Date Started 
Date Stopped 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5. Did you experience any side effects while you were in the study?  Side effects may be local in the vaginal 
area or they may be in other places of your body.  Circle your answer.  Yes    or    No 
• 
If No, you are finished filling out this diary.  
• 
If Yes, enter on the lines below what side effects you experienced, when they started and stopped, and how 
severe they were.   
 
Side Effect 
Date Started 
Date Stopped 
Severity 
1=Mild 
2=Moderate 
3=Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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Appendix E:  Subject Satisfaction Survey 
 
 
Subject Satisfaction Survey 
(To be completed by subject at final visit) 
 
This questionnaire asks about your experience with the study medicine.  It will help Curatek 
Pharmaceuticals, LLC know what you thought about the medicine you took.  Please circle your answer to 
each question.  When you are finished, please initial the bottom of the page.  
 
1. Have you ever used intravaginal medicine(s) before (for example over the counter yeast 
medicines like Monistat or Gyne-Lotrimin, etc.)? 
YES 
NO  
• 
If yes, go to question 2.   
• 
If no, skip to question 3.  
 
2. How would you rate the medicine you used in this study compared to vaginal medicine(s) you 
used in the past? 
 
 
BETTER 
 
WORSE 
 
SAME 
 
3. On a scale of 1 to 5, how would you rate your satisfaction with the study drug?  (The lower the 
number, the less satisfied you were; the higher the number the more satisfied you were.) 
 
1 
2 
3 
4 
5 
Very  
Dissatisfied 
Somewhat 
Dissatisfied 
Neither Satisfied 
Nor Dissatisfied 
Satisfied 
Very  
Satisfied 
 
Did any of the following things bother you?   
 
• 
Leaking study drug?   
 
 
 
YES 
NO 
• 
Greasy feeling?   
 
 
 
YES 
NO 
• 
Stains in underwear? 
 
 
 
YES 
NO 
 
 
4. If you had the same infection again, would you like to be treated with this drug again?   
YES    NO                           
 
 
 
 
 

SAP_001.pdf: 
Cover Page created 06/18/2020 
 
Identifiers:  NCT02308046 
NCT02308033 
NCT02308007 
Protocol ID: MTC-001 (Trials 1, 2 and 3) 
Brief Title: Multi-Center Study of New Medications to Treat Vaginal Infections 
 
Official Title: Solubilized Metronidazole And/oR Terconazole Gels Intra-Vaginal Efficacy 
and Safety  (SMART GIVES) 
 
Document: Statistical Analysis Plan  
 
Date of Document: May 1, 2018 
 
Sponsor: Curatek Pharmaceuticals, LLC 
 






Curatek Pharmaceuticals, LLC. Protocol MTC-001 
Statistical Analysis Plan. May 1, 2018 
 
 
 
 
 
 
 
 
 
 
       
Page 3 of 21 
 
Table of Contents 
 
1. INTRODUCTION ................................................................................................................................ 5 
1.1 
Study Objectives ............................................................................................................................... 5 
1.2 
Study Design ..................................................................................................................................... 5 
2. CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES ........................ 7 
2.1 
Changes in the Conduct of the Study ................................................................................................ 7 
2.2 
Changes from the Analyses Planned in the Protocol ........................................................................ 7 
3. STUDY OBSERVATIONS .................................................................................................................. 7 
3.1 
Screening/Baseline Evaluations ........................................................................................................ 7 
3.2 
Test of Cure Visit (Visit 2) Evaluations ............................................................................................ 8 
3.3 
Follow Up Visit (Visit 3) Evaluations .............................................................................................. 9 
3.4 
Limited Termination Visit .............................................................................................................. 10 
4. STATISTICAL METHODS .............................................................................................................. 10 
4.1 
General Methods ............................................................................................................................. 11 
4.2  
Analysis Populations ....................................................................................................................... 11 
4.3  
Efficacy Endpoints and Evaluations ............................................................................................... 12 
4.4  
Study Conduct Summaries .............................................................................................................. 13 
4.5  
Determination of Sample Size ........................................................................................................ 13 
4.6  
Handling of Missing Data ............................................................................................................... 14 
4.7 
Efficacy Analyses ........................................................................................................................... 14 
4.7.1  
Primary Efficacy Analysis .......................................................................................................... 14 
4.7.2  
Secondary Efficacy Analyses ...................................................................................................... 15 
4.7 
Safety Analysis ............................................................................................................................... 16 
4.8.1  
Adverse Events ........................................................................................................................... 16 
4.8.2  
Laboratory Assessments ............................................................................................................. 17 
4.8.3  
Vital Signs ................................................................................................................................... 17 
4.8.4  
Physical Exams ........................................................................................................................... 17 
5. REFERENCES ................................................................................................................................... 18 
14. LIST OF TABLES, FIGURES, AND LISTINGS ........................................................................... 19 
LIST OF TABLES AND FIGURES ........................................................................................................... 19 
14.1  Demographic and Study Conduct Summaries ................................................................................... 19 
14.2  Efficacy Summaries ........................................................................................................................... 19 
14.3  Safety Summaries .............................................................................................................................. 20 
LIST OF LISTINGS ................................................................................................................................... 20 
16.1  Demographic and Study Conduct Listings ........................................................................................ 20 


Curatek Pharmaceuticals, LLC. Protocol MTC-001 
Statistical Analysis Plan. May 1, 2018 
 
 
 
 
 
 
 
 
 
 
       
Page 4 of 21 
 
16.2  Efficacy Listings ................................................................................................................................ 21 
16.3  Safety Listings ................................................................................................................................... 21 
 


Curatek Pharmaceuticals, LLC. Protocol MTC-001 
Statistical Analysis Plan. May 1, 2018 
 
 
 
 
 
 
 
 
 
 
       
Page 5 of 21 
 
1. INTRODUCTION 
 
Name of Sponsor   
Curatek Pharmaceuticals, LLC 
 
Active Ingredient(s) and Dose of Investigational Products 
 
BV Gel:  0.9% metronidazole gel (45 mg of metronidazole/5 grams of gel) 
 
VVC Gel:  0.8% terconazole gel (40 mg of terconazole/5 grams of gel) 
 
Combination Gel:  0.9% metronidazole gel and 0.8% terconazole gel (45 mg metronidazole and 40 
mg of terconazole/5 grams of gel) 
 
Protocol Number 
MTC-001 
 
This analysis plan describes the statistical techniques that will be used to assess the efficacy, safety, and 
tolerability of BV Gel, VVC Gel, and Combo Gel, in subjects diagnosed with bacterial vaginosis (BV), 
vulvovaginal candidiasis (VVC), or concurrent BV and VVC (Mixed Infection). The formats for the 
tables, listings, and figures described in this SAP are provided in a companion document.  
 
The study has been conducted as Protocol MTC-001, finalized December 12, 2014 and amended on 
March 12, 2015. No subjects were enrolled under the protocol finalized on December 12, 2014 and there 
have been no previous statistical analysis plans. 
 
 
1.1 Study Objectives 
 
There are three primary objectives of the trial; one for each product/indication. They are to:    
1. BV Study: Evaluate the safety and efficacy of BV Gel in the treatment of bacterial vaginosis (BV) 
2. VVC Study: Evaluate the safety and efficacy of VVC Gel in the treatment of vulvovaginal candidiasis 
(VVC) 
3. Mixed Infection Study: Evaluate the safety and efficacy of Combo Gel in the treatment of concurrent 
BV and VVC (mixed infections) 
 
 
1.2 Study Design 
 
This is a multi-center, phase III trial, comprised of three studies, each designed to test the safety and 
efficacy of a different investigational product, for a specific vaginal infection/indication. They are:  
1. Bacterial Vaginosis (BV) Study: A randomized, double-blind, parallel-group, placebo-controlled 
study to test the safety and efficacy of BV Gel (0.9% metronidazole gel) for the treatment of BV  
2. Vulvovaginal Candidiasis (VVC) Study: A randomized, double-blind, parallel-group, placebo-
controlled study to test the safety and efficacy of VVC Gel (0.8% terconazole gel) for the treatment of 
VVC  
3. Mixed Infection (Concurrent BV and VVC) Study: A randomized, double-blind, parallel-group, 
active-controlled study to test the safety and efficacy of Combo Gel (0.9% metronidazole gel and 
0.8% terconazole gel) for the treatment of Mixed Infection  
 
All study medication is intravaginal and will be dosed as one applicator for three consecutive days.  
Subjects who sign an informed consent form (ICF), are diagnosed with BV, VVC, or Mixed Infection, 
and meet eligibility requirements will be enrolled into the appropriate infection study and subsequently 


Curatek Pharmaceuticals, LLC. Protocol MTC-001 
Statistical Analysis Plan. May 1, 2018 
 
 
 
 
 
 
 
 
 
 
       
Page 6 of 21 
 
randomized to treatment based on clinical diagnosis at the screening and enrollment/baseline visit 
(Visit 1). BV subjects will be entered into the BV Study, VVC subjects will be entered into the VVC 
Study, and concurrent BV and VVC (Mixed Infection) subjects will be entered into the Mixed Infection 
Study.  
 
All subjects will be asked to return for a test of cure visit (Visit 2) 7-14 days after randomization. If a 
subject is menstruating on the day of the scheduled visit, she should be rescheduled to return 24 hours 
after completion of menses. Subjects who in the opinion of the investigator/clinician require additional 
treatment for vaginal discomfort/symptoms and subjects who self-medicated for vaginal 
discomfort/symptoms, will be terminated from the study. All other subjects will return for a follow-up 
evaluation visit (Visit 3) 21-30 days after randomization.  
 
Study procedures will be identical in all three infection studies with the exception of safety labs (i.e. 
Hematology: complete blood count (CBC) with differential and Chemistry: blood urea nitrogen (BUN), 
Creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase 
(ALP), and bilirubin), which will only be obtained at Visit 1 and Visit 2 on subjects entered into the 
Mixed Infection Study. There will be one case report form (CRF) for each subject. The CRF will be the 
same for all three infection studies. Analysis of safety and efficacy will be performed separately for each 
investigational product. 
 
All eligible subjects will be randomized at the baseline visit (Visit 1) utilizing an interactive voice 
response (IVR)/interactive web response (IWR) system. Subjects in the BV or VVC study will be 
randomly assigned to one of two treatment groups in a 1:1 ratio while subjects in the Mixed Infection 
study will be randomized to one of three treatment groups in a 1:1:1 ratio. All treatments, regardless of 
study, consist of three doses, to be administered by vaginal applicator at bedtime for three consecutive 
days. 
 
Subjects will be randomized to treatment as follows:  
 
Subjects diagnosed with BV will be randomized to receive treatment with either BV Gel (0.9% 
metronidazole gel) or Placebo Gel. Each 5-gram dose of BV Gel contains 45 mg of metronidazole for 
a total dose of 135 mg of metronidazole.  
 
Subjects diagnosed with VVC will be randomized to receive treatment with either VVC Gel (0.8% 
terconazole) or Placebo Gel. Each 5-gram dose of VVC Gel contains 40 mg of terconazole for a total 
dose of 120 mg of terconazole.  
 
Subjects diagnosed with Mixed Infection will be randomized to receive treatment with BV Gel, VVC 
Gel, or Combo Gel (0.9% metronidazole and 0.8% terconazole). Each 5-gram dose of the Combo Gel 
contains 45 mg of metronidazole and 40 mg of terconazole for a total dose of 135 mg of 
metronidazole and 120 mg of terconazole.  
 
The study consists of three visits:  a Screening and Enrollment/Baseline visit (visit 1), a Test of Cure visit 
(visit 2) and one follow-up clinic visit (visit 3). Visit 2 will occur 7-14 days after randomization for the 
purpose of determining subject compliance/evaluability with drug administration and study instructions, 
evaluating the subject’s response to therapy and whether or not additional treatment is needed (i.e. cure or 
failure), and obtaining information on concomitant medication use and possible adverse events. Visit 3 
will occur 21-30 days after randomization for the purpose of determining subject compliance; 
determining either presence or absence of the subject’s baseline infection and whether or not additional 
treatment is needed; and obtaining information on concomitant medication use and possible adverse 
events.  
 


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Statistical Analysis Plan. May 1, 2018 
 
 
 
 
 
 
 
 
 
 
       
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If a subject was unable to return for Visit 2 but returns for Visit 3, available information that was to be 
obtained at Visit 2 regarding study drug administration/compliance and time to resolution/reoccurrence of 
symptoms may be obtained at Visit 3. The subject’s diary should be reviewed and unused drug collected. 
Subjects in the Mixed Infection Study who missed Visit 2 should have hematology and chemistry labs 
obtained at Visit 3.  
 
2. CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES 
 
2.1 Changes in the Conduct of the Study 
 
The original protocol was version 1.0 and dated December 12, 2014. There has been one revision to the 
protocol, numbered version 2.0 and dated March 12, 2015, as of the development of this Statistical 
Analysis Plan (SAP). Changes per the revision are incorporated in this SAP. 
 
2.2 Changes from the Analyses Planned in the Protocol 
 
This analysis plan details analyses to be conducted for the study. Some of the analyses detailed here may 
be more explicit or in some aspects different than those stated in the protocol. In case of differences, this 
SAP supersedes the statistical sections in the protocol. 
 
3. STUDY OBSERVATIONS 
 
The evaluation of subject eligibility will occur at the Baseline visit (visit 1). Eligible subjects will receive 
a maximum duration of treatment of three days and a maximum trial duration of 30 days from the time of 
randomization. The test of cure visit (visit 2) will occur 7-14 days after randomization. If the subject did 
not need additional treatment for vaginal discomfort/symptoms (and the subject did not self-medicate), 
the subject will be asked to return 21-30 days after randomization (visit 3).  
 
3.1 Screening/Baseline Evaluations  
 
Baseline (visit 1) medical evaluations will include: 
o Medical and surgical history 
o Contraceptive/obstetric status and gynecologic history 
o Use of concomitant medications (i.e. current and within 30 days of enrollment) as well as treatments 
for BV and/or VVC infections within the past year 
o Subject Assessment of Symptoms: Subjects will be asked to rate their current vulvovaginal symptoms 
of itching, burning, and irritation as absent=0, mild=1, moderate=2 or severe=3. The sum of the 
symptom score will be added to the vulvovaginal signs score obtained during the pelvic examination 
to determine a combined symptom and sign severity score. 
o General physical examination and vital signs 
o Laboratory tests  
• Urine pregnancy test for all women of child bearing potential  
• Papanicolaou smear (if subject is ≥ 21 years old and a Pap smear was not done within the past 3 
years)  
• Tests for Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis  
• Culture for Herpes simplex (only if suspected)  
• Vaginal culture for Candida species  
• Vaginal Gram stain  


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• CBC with differential and blood chemistries (i.e. BUN, Creatinine, ALT, AST, ALP, and 
bilirubin) for subjects enrolled in the Mixed Infection Study  
 
Baseline (visit 1) pelvic examination and specimen collections will include:
o Visual inspection: rule out lesions caused by Herpes simplex virus or human papilloma virus (i.e. 
genital warts)  
o Vulvovaginal signs rating: rate the degree of vulvovaginal edema, erythema, and excoriation as 
absent = 0, mild = 1, moderate = 2 or severe = 3. The sum of these ratings will be added to the 
vulvovaginal symptoms score given by the subject to determine a combined symptom and sign 
severity score. This total score must be > 2 in order to meet entry criteria for enrollment into the VVC 
or Mixed Infection study.  
o Vaginal discharge characterization: By visual examination, characterize vaginal discharge in 
accordance with the descriptions below.  
• Normal/physiologic: normal discharge may vary in appearance and consistency depending on the 
menstrual cycle;  
• Abnormal: consistent with BV (i.e. off-white [milky or gray], thin, homogeneous discharge);  
• Abnormal: consistent with VVC (i.e. white, creamy, and curdy [cottage cheese like] adherent to 
the epithelium);  
• Abnormal: consistent with Mixed Infection (i.e. discharge of varying characteristics with relation 
to odor, color, and consistency)  
o pH measurement: Obtain a vaginal pH measurement with the pH indicator strips provided.  
o KOH Whiff Test 
o KOH and saline wet mounts  
o Vaginal Candida culture: Obtain a Candida culture as specified in the central laboratory manual 
utilizing the collection and shipment supplies provided.  
o Vaginal Gram Stain: Obtain a Gram Stain as specified in the central laboratory manual utilizing the 
collection and shipment supplies provided. 
o Papanicolaou smear: Obtain a Pap smear if subject is ≥ 21 years old and has not had one within the 
past 3 years.  
o Test for Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis as specified in 
the central laboratory manual utilizing the collection and shipment supplies provided.  
o Culture for Herpes simplex (only if suspected).  
 
3.2 Test of Cure Visit (Visit 2) Evaluations 
 
The procedures listed below will be performed 7-14 days after randomization for the purpose of 
determining subject compliance/evaluability with drug administration and study instructions, evaluating 
the subject’s response to therapy and whether or not additional treatment is needed (i.e. cure or failure), 
and obtaining information on concomitant medication use and possible adverse events.  
o Review of Diary  
o Assessment of Compliance: Subjects are queried to determine compliance with study drug 
administration and study instructions.  
o Time to Symptom Resolution/Reoccurrence:  Symptom resolution and reoccurrence will be assessed 
by review of the subject’s diary and subject interview. Dates of symptom resolution and/or symptom 
recurrence should be documented. 
o Subject Assessment of Symptoms: Subjects will be asked to rate their current vulvovaginal symptoms 
of itching, burning, and irritation as absent=0, mild=1, moderate=2, or severe=3. The sum of this 
symptom score will be added to the vulvovaginal signs score obtained during the pelvic examination 
to determine a combined symptom and sign severity score. 
o Laboratory Tests and Specimen Collections: The lab tests listed below will be obtained at Visit 2. 


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• CBC with differential and blood chemistries (i.e. BUN, Creatinine, ALT, AST, ALP, and 
bilirubin) only for subjects enrolled in the Mixed Infection Study  
• Vaginal culture for Candida species  
• Vaginal Gram stain  
o Pelvic Examination and Specimen Collections 
• Vulvovaginal signs rating  
• Vaginal discharge characterization  
• Vaginal pH measurement  
• KOH Whiff Test  
• Saline wet mount 
• Vaginal Candida culture  
• Vaginal Gram stain  
o Assessment of Clinical Status, Need for Additional Treatment:  Following subject evaluation, the 
investigator/clinician will be asked to document whether the subject requires any additional treatment 
for vaginal discomfort/symptoms. Subjects who do require additional treatment should be treated per 
investigator/clinician judgment and terminated from the study. Subjects who do not require treatment 
(and subjects who did not self-medicate) may remain in the study and return for their regularly 
scheduled follow up visit (Visit 3).    
o Determination of Cure or Failure of Subject’s Enrolled Infection:   
• BV subjects must satisfy all three of the clinical criteria listed below in order to be considered a 
BV cure (i.e. clinical cure).  
 
Discharge has returned to normal/physiologic1 
 
The whiff test is negative for any amine “fishy” odor.  
 
The saline wet mount is < 20% clue cells.  
If in the investigator/clinician’s opinion the subject requires additional treatment for BV or if the 
subject self-administered drug therapy for vaginal discomfort/symptoms after completing therapy, 
the subject will be considered a BV failure2. 
 
• VVC subjects must have all signs and symptoms attributable to VVC resolved (i.e. clinical cure), 
in order to be considered a VVC cure. If in the investigator/clinician’s opinion the subject requires 
additional treatment for VVC or if the subject self-administered drug therapy for vaginal 
discomfort/symptoms after completing therapy, the subject will be considered a VVC failure2. 
• A Mixed Infection cure is a subject who meets the definition of a BV cure AND a VVC cure. If in 
the investigator/clinician’s opinion the subject requires additional treatment for either BV, VVC, 
or Mixed Infection or if the subject self-administered drug therapy for vaginal 
discomfort/symptoms after completing therapy, the subject will be considered a Mixed Infection 
failure. 
 
1. In the event a subject treated for BV gets a secondary yeast infection following treatment and discharge is consistent with VVC 
(i.e. white, creamy, and curdy [cottage cheese like] adherent to the epithelium), the subject will be considered a clinical cure 
providing all other clinical criteria for BV cure are met and the subject has a positive yeast culture. 
2. Self-administration of therapy includes prescription and OTC antimicrobial, anti-fungal, analgesics, or steroid treatments. 
 
3.3 Follow Up Visit (Visit 3) Evaluations 
 
The following procedures will be performed 21-30 days after randomization for the purpose of 
determining subject compliance; determining either presence or absence of the subject’s baseline 
infection and whether or not additional treatment is needed; and obtaining information on concomitant 
medication use and possible adverse events.  
 


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Statistical Analysis Plan. May 1, 2018 
 
 
 
 
 
 
 
 
 
 
       
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If a subject was unable to return for Visit 2 but returns for Visit 3, available information that was to be 
obtained at Visit 2 regarding study drug administration/compliance and time to resolution/reoccurrence of 
symptoms may be obtained at Visit 3. The subject’s diary should be reviewed and unused drug collected. 
Subjects in the Mixed Infection Study who missed Visit 2 should have hematology and chemistry labs 
obtained. 
o Assessment of Compliance: Subjects are queried to determine compliance with study drug 
administration and study instructions.  
o Subject Assessment of Symptoms: Subjects will be asked to rate their current vulvovaginal symptoms 
of itching, burning, and irritation as absent=0, mild=1, moderate=2, or severe=3. The sum of this 
symptom score will be added to the vulvovaginal signs score obtained during the pelvic examination 
to determine a combined symptom and sign severity score. 
o Laboratory Tests and Specimen Collections: The lab tests listed below will be obtained at Visit 3. 
• Vaginal culture for Candida species  
• Vaginal Gram stain  
o Pelvic Examination and Specimen Collections 
• Vulvovaginal signs rating  
• Vaginal discharge characterization  
• Vaginal pH measurement  
• KOH Whiff Test  
• Saline wet mount 
• Vaginal Candida culture  
• Vaginal Gram stain  
o Assessment of Clinical Status, Need for Additional Treatment:  Following subject evaluation, the 
investigator/clinician will be asked to document whether the subject requires any additional treatment 
for vaginal infection. Subjects who do require additional treatment should be treated per 
investigator/clinician judgment.     
o Subject Satisfaction Survey:  Subjects should be given the Subject Satisfaction Survey and asked to 
complete the form before leaving the clinic. Completion of the survey is voluntary and does not affect 
participation in the study in any way. 
 
3.4 Limited Termination Visit 
 
In instances where Visit 1 lab results make a subject ineligible for the study (i.e. subject randomized but 
did not meet inclusion/exclusion criteria), subjects should be terminated when exclusionary lab results 
become known. Procedures for these subjects are more limited but require a safety assessment including 
collection of adverse events, concomitant medications, and safety blood labs if the subject was enrolled in 
the Mixed Infection Study and safety labs were not already obtained at Visit 2. Subject diaries should be 
reviewed and unused drug tubes collected. Drug administration/compliance should be ascertained if not 
already done. Lab results that would make a subject ineligible are: positive gonorrhea, chlamydia, 
trichomonas, or herpes tests; normal Nugent score < 4 (for BV and Mixed Infection subjects); or negative 
Candida culture (for VVC and Mixed Infection subjects).  
 
4. STATISTICAL METHODS 
 
The following is a detailed proposal of the statistical summaries planned for subject data collected during 
the trial. Summary statistics of all important demographic, study conduct, efficacy, and safety data will be 
provided in tables. Case report form, clinical laboratory, and efficacy evaluation data will be provided in 
listings. 
 


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Statistical Analysis Plan. May 1, 2018 
 
 
 
 
 
 
 
 
 
 
       
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4.1 General Methods 
 
Data from this study will be summarized with descriptive statistics. Descriptive summaries of baseline 
and demographic data will include frequency and percent relative frequency for categorical data; 
frequency and median for ordinal data; and frequency, mean, standard deviation, and minimum and 
maximum for quantitative data. In addition, 95% confidence intervals will be calculated, as appropriate.  
For scheduled measurements that are repeated out of schedule, such as repeat laboratory tests, the last 
measurement within a scheduled time interval (i.e. days 7 – 14 for Visit 2 and days 21 – 30 for Visit 3) 
will be used for data summaries. All results, whether scheduled or repeat, will be listed.  
 
Each of the three infection studies within the trial will be analyzed separately.  
 
The primary statistical objective of each infection study is listed below:  
1. BV Study: Demonstrate the superiority of BV Gel (0.9% metronidazole gel) to Placebo Gel in the 
treatment of bacterial vaginosis (BV).  
2. VVC Study: Demonstrate the superiority of VVC Gel (0.8% terconazole gel) to Placebo Gel in the 
treatment of vulvovaginal candidiasis (VVC).  
5. Mixed Infection Study: Demonstrate the superiority of Combo Gel (0.9% metronidazole gel and 0.8% 
terconazole gel) to both single entity gels (BV Gel alone and VVC Gel alone).  
 
4.2  Analysis Populations 
 
The primary assessments of efficacy will be based on the modified intent-to-treat (mITT) population. In 
addition to the mITT analyses of the data, analyses will also be conducted on the per protocol (PP) 
population. The data analysis populations are defined as: 
 
ITT: The intent-to-treat population will include all subjects randomized to treatment.  
 
mITT: The modified intent-to-treat population will include all subjects randomized to treatment and 
administered at least one dose of study drug. Subjects who are Lost to Follow-up and for whom there 
is no documentation to ascertain whether or not they were administered treatment will be excluded 
from the mITT population.  
o In addition, to be included in the mITT population subjects in the VVC and Mixed Infection 
studies must have a positive baseline vaginal fungal culture for Candida species. Subjects in 
the BV and Mixed Infection studies must have a Gram stain Nugent score of ≥ 4 at the 
baseline visit.  
o Subjects randomized to treatment but whose baseline laboratory tests subsequently reveal 
positive results for Trichomonas vaginalis, Chlamydia trachomatis, and/or Neisseria 
gonorrhoeae will be excluded from the mITT population. 
 
PP: The per protocol population will include the subset of mITT subjects that had no major protocol 
violations and who are classified as efficacy evaluable with no missing data required to determine 
primary endpoints. Major protocol violations likely to bias assessment of the primary endpoint for the 
per protocol population will be determined prior to unblinding the data.  
 
Safety: The safety population will include all subjects randomized to treatment and administered at 
least one dose of study drug.   


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Statistical Analysis Plan. May 1, 2018 
 
 
 
 
 
 
 
 
 
 
       
Page 12 of 21 
 
Major protocol deviations (i.e. deviations likely to bias assessment of the primary efficacy measure) that 
will be used to assess inclusion in the PP population will be determined and reviewed by the Sponsor prior 
to unblinding the data. 
4.3  Efficacy Endpoints and Evaluations 
 
The primary and secondary endpoints are reflective of each of the infection studies within the protocol. 
These include: 
 
Primary Endpoints  
 
 
BV Study: BV cure rate, with cure defined as normal/physiologic discharge, negative whiff test, and 
< 20% clue cells (i.e. clinical cure)  
 
VVC Study: VVC cure rate, with cure defined as resolution of all signs and symptoms attributable to 
VVC (i.e. clinical cure)  
 
Mixed Infection Study: Mixed Infection cure rate, with cure defined as BV cure (i.e. BV clinical cure) 
AND a VVC cure (i.e. VVC clinical cure)  
 
Primary efficacy endpoint evaluations will occur at the test-of-cure Visit 2.  
 
If a subject requires additional treatment for vaginal discomfort/symptoms (i.e. a BV subject requiring 
treatment for BV, a VVC subject requiring treatment for VVC or a Mixed Infection subject requiring 
treatment for BV and/or VVC) prior to or at Visit 2, the subject will be considered a treatment failure. 
These subjects will be evaluable for the modified intent-to-treat (mITT) and the per-protocol (PP) 
population analyses, providing all other evaluability criteria for these population groups have been met.  
 
Additionally, if a subject self-medicates herself for vaginal discomfort/symptoms at any time prior to 
Visit 2, the subject will be considered a treatment failure. If this occurs, the subject will remain evaluable 
for the mITT analyses but will be non-evaluable for the PP analysis. 
 
 
Secondary Endpoints   
 
Note, for BV a Gram stain Nugent score cure will be defined as a score of < 4, i.e. 0 – 3.   
 
 
BV Study: BV clinical and Gram stain Nugent score combined cure rate, and Gram stain Nugent 
score cure rate alone; changes/improvements in Amsel criteria and Nugent scores; time to resolution 
of symptoms  
o In addition, cure rates over time will be explored 
 
VVC Study: VVC clinical and mycologic cure rates combined and mycologic cure alone; 
changes/improvements in signs and symptoms scores; eradication (or persistence) of individual 
fungal species; time to resolution of symptoms  
 
Mixed Infection Study: BV clinical and Gram stain Nugent score cure rates alone and combined; 
changes/improvements in Amsel criteria and Nugent scores; VVC clinical and mycologic cure rates 
alone and combined; changes/improvements in signs and symptoms scores; eradication or persistence 
of individual fungal species; time to resolution of symptoms  


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Statistical Analysis Plan. May 1, 2018 
 
 
 
 
 
 
 
 
 
 
       
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4.4  Study Conduct Summaries 
 
The number of subjects who were enrolled, treated with at least one dose of study drug, who completed 
the study, as well as the reasons for withdrawal, will be summarized with counts and percentages by 
treatment group within each infection study. This table will also include number of screening failures and 
reasons for screening failures. Protocol violations, inclusion/exclusion criteria, and study drug 
administration data will also be summarized.  
 
4.5  Determination of Sample Size 
 
Approved labeling, clinical data included in New Drug Applications and approval packages, and sponsor 
experience with the compounds in this study and similar therapies provide the following estimates and 
ranges of the cure rates (as proportions) for the treatments within each infection study.  
 
1. BV Subjects  
a. BV Gel (0.9% metronidazole gel): .50 (.45-.55) 
b. Placebo Gel: .20 (.15-.25) 
2. VVC Subjects  
a. VVC Gel (0.8% terconazole gel): .70 (.65-.75)  
b. Placebo Gel: .20 (.15-.25)  
3. Mixed Infection Subjects  
a. Combo Gel (0.9% metronidazole gel and 0.8% terconazole gel): .35 (.30-.40) 
b. VVC Gel (0.8% terconazole gel): .10 (.05-.15)  
c. BV Gel (0.9% metronidazole gel): .10 (.05-.15)  
 
Under the assumption that the above estimated cure rates are true for the population, sample sizes were 
calculated for each infection study based on these estimates for at least 90% power and at least 50 
subjects per treatment group. Superiority tests will be performed as two-sided, α = 0.05 level significance 
tests, and sample sizes were calculated using Fisher’s Exact test in case the planned Chi-squared test is 
not appropriate.  
 
The following table provides the sample size required for each treatment group within each infection 
study. The total sample size is given, and represents the number of evaluable subjects required (Per 
Protocol population). Entry in each infection study of the trial will be stopped when this number of 
evaluable subjects is reached, since evaluable/not-evaluable can be determined from the completed case 
report form prior to unblinding. 
 
Required Number of Evaluable Patients, by Infection Study and Treatment Group 
Study: 
BV Only Patients 
VVC Only Patients 
Mixed Infection Only Subjects 
Treatment Arm: 
BV  
Gel 
Placebo 
Gel 
VVC 
Gel 
Placebo 
Gel 
BV 
Gel 
VVC 
Gel 
Combo 
Gel 
Expected Cure Rate  
50%  
20% 
70% 
20% 
10% 
10% 
35% 
n for at least 80% Power,  
and at least 50 per group  
58  
58 
50 
50 
63 
63 
63 
Actual Power 
90.0% 
> 99.9% 
90% 
Total N 
405 
 
Thus, subjects will be enrolled until approximately 405 evaluable subjects, as indicated above, for all 
three infection studies, have completed the trial. 
 




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Page 15 of 21 
 
accurate. Therefore, if all expected cell counts are not at least 5, Fisher’s Exact test and confidence 
intervals using the method of Chan and Zhang (1999) will be used.  
 
The primary efficacy analysis for each of the three infection studies will be performed using the mITT 
population with worst case scenario imputation for missing data. Supportive analyses will also be 
conducted using the PP population.  
 
Efficacy analysis will not be done for the ITT population, as subjects in the BV and Mixed studies who 
do not have a gram stain > 4, or subjects in the VVC and Mixed studies who do not have a positive yeast 
culture, are not evaluated for efficacy. These subjects do not return for Visit 2; rather, they have the 
Limited Termination visit for safety evaluations only. 
 
BV Study: The primary statistical objective of the BV infection study is to demonstrate the superiority of 
BV Gel to Placebo Gel in the treatment of BV. The assessment of superiority will be performed by 
conducting a continuity corrected Chi-squared test for a difference in the proportion of BV cure between 
the two treatments. Also, a 95% two-sided confidence interval for the difference in proportion of BV cure 
between the two treatments will be constructed. 
 
VVC Study: The primary statistical objective of the VVC infection study is to demonstrate the 
superiority of VVC Gel to Placebo Gel. The assessment of superiority will be performed by conducting a 
continuity corrected Chi-squared test for a difference in the proportion of VVC cure between the two 
treatments. Also, a 95% two-sided confidence interval for the difference in proportion of VVC cure 
between the two treatments will be constructed.  
 
Mixed Infection Study: The primary statistical objective of the Mixed Infection Study is to demonstrate 
the superiority of the Combo Gel to both BV Gel and VVC Gel. The assessment of superiority will be 
performed by conducting a continuity corrected Chi-squared tests for a difference in the proportion of 
Mixed Infection cure between the Combo Gel and each of the two single entity treatments. If the P-values 
for both of the hypothesis tests are less than or equal to 0.05, the Combo Gel will be considered superior 
to both of the single entity gels. Despite there being two comparisons made within the same study, no 
adjustment for multiplicity is necessary since both comparisons must be positive instead of “at least one,” 
in order to conclude superiority of the Combo Gel. Also, 95% two-sided confidence intervals for the 
difference in proportion of Mixed Infection cure between the Combo Gel and each of the two single entity 
treatments will be constructed. 
 
4.7.2  
Secondary Efficacy Analyses 
 
Secondary efficacy endpoints are listed in Section 4.3. These endpoints include variables that are 
categorical (including binary variables), ordinal (such as rating scores), or time to event variables (such as 
time to resolution of symptoms). The analysis of the secondary endpoints will be performed using the 
mITT population with worst case scenario imputation for missing data, with supportive analyses 
conducted using the PP population.  
 
For the secondary endpoints that are categorical or ordinal with four or fewer levels (including binary 
outcome variables), the analysis will include the proportion of subjects with each criteria or each score, at 
baseline and endstudy. The comparison of treatment groups will be performed using Chi-squared tests if 
all expected cell counts are at least 5, and Fisher’s Exact test otherwise. For binary outcomes, (clinical 
outcome, mycological outcome, and eradication [or persistence] of individual fungal species) 95% two-
sided confidence intervals for the difference in proportions will also be constructed using the continuity 
corrected Wald intervals when Chi-square tests are appropriate, or the method of Chan and Zhang (1999) 
otherwise.  


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Statistical Analysis Plan. May 1, 2018 
 
 
 
 
 
 
 
 
 
 
       
Page 16 of 21 
 
 
Secondary endpoints that are ordinal data with more than four levels, such as Nugent score, the median 
score at baseline, endstudy, and the change from baseline will be computed, in addition to the proportion 
of subjects at each level. Treatment comparisons will be performed using the Wilcoxon Rank Sum test.  
 
The secondary endpoint of time to resolution of symptoms will be analyzed in each infection study by 
arm using log-rank tests to compare arms within each study and Kaplan-Meier plots. Kaplan-Meier 
estimates of the quartiles for time to resolution will be computed, along with 95% confidence intervals. 
Censoring times for the Kaplan-Meier estimates will be based on the date of last contact or visit 3 
(whichever is earliest) if symptoms never resolved or the patient was an early withdrawal and status is 
unknown. 
 
The analysis of eradication (persistence) of individual fungal species will be conducted in subgroups of 
subjects defined by fungal species present at baseline (for the VVC and Mixed Infection studies).  
 
In addition, for each study a summary will be made of subjects classified as: 
 
Persistent Infection – no cure at Visit 2 or Visit 3 
 
Persistent Cure – cure at Visit 2 and Visit 3 
 
Late Cure – no cure at Visit 2 but cure at Visit 3 
 
Recurrence – cure at Visit 2 but no cure at Visit 3 
 
A descriptive analysis of the primary endpoint (cure rate) for BV subjects will be performed to assess the 
impact of loss of potency of the BV gel over time.  The proportion of patients achieving a cure will be 
computed among cohorts of patients completing Visit 2 during each month the study was underway.  
These proportions will be tabulated by month for the BV Gel arms of the BV study and the mixed 
infection study.  In addition, a plot of the proportions by month will be presented.   
 
4.7 Safety Analysis 
 
Safety will be assessed through summaries of adverse events (AEs) and laboratory evaluations. All safety 
analyses will be based on the safety population, as defined in Section 4.2, and will be summarized for 
each treatment group. These summaries will be presented separately for each infection study. In addition, 
adverse events and laboratory evaluations, as available, for BV Gel and VVC Gel will also be 
summarized by combining subjects who received the same treatment regimen across the studies. For 
example, those receiving BV Gel in the BV study will be combined with those receiving BV Gel in the 
Mixed Infection Study. 
 
4.8.1  
Adverse Events 
 
Adverse events will be coded by system organ class and preferred term using the current version of 
Medical Dictionary for Regulatory Activities (MedDRA). Each verbatim adverse event will be translated 
to a preferred term, a higher-level included term, and finally a system-organ class. Adverse events will be 
summarized by system organ class and preferred term, counting proportions of the patients who 
experienced at least one such adverse event. Frequencies of patients with treatment-emergent adverse 
events (TEAEs), sorted by system organ class, will be summarized by treatment group. TEAEs are 
defined as those AEs that develop or worsen after the first dose of study medication. 
 
A secondary analysis of TEAEs judged by the Investigator to be related to study drug will be performed. 
This analysis will be summarized identically to the above analysis. Additional breakdowns of serious 
adverse events (SAEs) and treatment related SAEs will be summarized and described in a similar fashion.  


Curatek Pharmaceuticals, LLC. Protocol MTC-001 
Statistical Analysis Plan. May 1, 2018 
 
 
 
 
 
 
 
 
 
 
       
Page 17 of 21 
 
 
Summaries of AE durations, severity, relatedness to study drug, counter measures taken, and outcome 
will also be produced as warranted. At the least, incidence of drug discontinuation and death will be 
summarized. 
 
4.8.2  
Laboratory Assessments 
 
CBC with differential and blood chemistry data will be collected in the Mixed Infection study only.  
Values will be tabulated and compared to baseline for the Mixed Infection study population. Laboratory 
endpoints will be summarized for baseline, endstudy, and for change from baseline to endstudy using 
descriptive statistics (mean, median, standard error, minimum, and maximum). In addition, 
summarization of laboratory values that deviate substantially from the normal reference range will be 
provided. The reference ranges for normal laboratory values will be provided by the central laboratory.  
 
A shift table will be provided, which will tabulate the proportion of subjects in each treatment group who 
change from low abnormal (< LLN), normal, or high abnormal (> ULN) at baseline to low abnormal, 
normal, or high abnormal at Visit 2, as shown in the following table.  
Mixed Infection Study 
Endpoint 
Treatment 
Baseline 
Visit 2/EndStudy 
Low (L) 
Normal (N) 
High (H) 
BUN 
BV Gel 
Low (L) 
xx 
xx 
xx 
Normal (N) 
xx 
xx 
xx 
High (H) 
xx 
xx 
xx 
n 
xxx 
VVC Gel 
 
 
 
 
 
Low (L) 
Normal (N) 
High (H) 
Low (L) 
xx 
xx 
xx 
Normal (N) 
xx 
xx 
xx 
High (H) 
xx 
xx 
xx 
n 
xxx 
Combo Gel 
 
 
 
 
 
Low (L) 
Normal (N) 
High (H) 
Low (L) 
xx 
xx 
xx 
Normal (N) 
xx 
xx 
xx 
High (H) 
xx 
xx 
xx 
etc 
n 
xxx 
 
All laboratory data will be provided in listings. Abnormal laboratory values, defined as observations 
outside the normal range, will be flagged in the listing. 
 
4.8.3  
Vital Signs 
  
Vital signs are only collected before administration of study drug and will be summarized within each 
infection study pooling treatment groups. Vital sign data will also be presented in listings. 
 
4.8.4  
Physical Exams 
  
All physical exam data will be presented in listings. 
 


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Statistical Analysis Plan. May 1, 2018 
 
 
 
 
 
 
 
 
 
 
       
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5. REFERENCES 
 
Chan, I.S.F., Zhang, Z., (1999). "Test-Based Exact Confidence Intervals for the 
Difference of Two Binomial Proportions." Biometrics 55: 1202-1209. 
 
 
 


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Statistical Analysis Plan. May 1, 2018 
 
 
 
 
 
 
 
 
 
 
       
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14. 
LIST OF TABLES, FIGURES, AND LISTINGS 
 
LIST OF TABLES AND FIGURES  
14.1  Demographic and Study Conduct Summaries 
Table 14.1.1   
Summary of Subject Disposition, All Randomized Subjects 
  
Table 14.1.2   
Summary of Subject Accounting, All Randomized Subjects 
  
Table 14.1.3   
Summary of Major Protocol Violations, All Randomized Subjects 
  
Table 14.1.4   
Summary of Inclusion/Exclusion Criteria Not Met, All Randomized Subjects 
  
Table 14.1.5   
Summary of Demographic and Baseline Characteristics, mITT Population 
  
Table 14.1.6   
Summary of Contraceptive and Obstetric Status, mITT Population 
  
Table 14.1.7   
Summary of History of Gynecologic Infection, mITT Population 
  
Table 14.1.8   
Summary of Infection Medications, mITT Population   
Table 14.1.9   
Summary of Past Medical and Surgical History, mITT Population 
  
Table 14.1.10  
Summary of Current Medical and Surgical History, mITT Population 
  
Table 14.1.11   Summary of Baseline Vital Signs, mITT Population 
  
Table 14.1.12   Summary of Baseline Physical Exam, mITT Population   
Table 14.1.13   Summary of Baseline Symptom and Sign Severity Score, mITT Population 
  
Table 14.1.14   Summary of Baseline Pelvic Exam, mITT Population 
  
 
14.2  Efficacy Summaries 
Table 14.2.1.1   Summary of Primary Endpoint for BV Study – Test-of-Cure, mITT Population  
Table 14.2.1.2   Summary of Primary Endpoint for BV Study – Test-of-Cure, PP Population 
 
Table 14.2.2.1   Summary of Primary Endpoint for VVC Study – Test-of-Cure, mITT Population 
Table 14.2.2.2  Summary of Primary Endpoint for VVC Study – Test-of-Cure, PP Population 
 
Table 14.2.3.1   Summary of Primary Endpoint for Mixed Infection Study – Test-of-Cure, mITT 
Population 
 
Table 14.2.3.2   Summary of Primary Endpoint for Mixed Infection Study – Test-of-Cure, PP Population  
Table 14.2.4  
Exploratory Analysis of Primary Endpoint by Month of Study, For Patients Receiving 
BV Gel – Test-of-Cure, mITT Population 
 
Figure 14.2.5   
Time Plot of Primary Endpoint by Month of Study, For Patients Receiving BV Gel – 
Test-of-Cure, mITT Population 
Table 14.2.6  
Summary of Visit 2 Symptom and Sign Severity Score, mITT Population 
 
Table 14.2.7   
Summary of Visit 2 Pelvic Exam, mITT Population 
 
Table 14.2.8   
Summary of Visit 2 Compliance Assessment, mITT Population  
Table 14.2.9   
Summary of Visit 2 Need for Additional Treatment, mITT Population  
Table 14.2.10.1   Summary of Visit 2 BV Clinical Cure, mITT Population 
 
Table 14.2.10.2   Summary of Visit 2 BV Clinical Cure, PP Population 
 
Table 14.2.11.1   Summary of Visit 2 VVC Clinical Cure, mITT Population 
 
Table 14.2.11.2   Summary of Visit 2 VVC Clinical Cure, PP Population  
Table 14.2.12.1   Summary of Visit 2 Gram Stain Cure, mITT Population  
Table 14.2.12.2   Summary of Visit 2 Gram Stain Cure, PP Population 
 
Table 14.2.13.1   Summary of Visit 2 Candida Culture Cure, mITT Population 
 
Table 14.2.13.2   Summary of Visit 2 Candida Culture Cure, PP Population 
 
Table 14.2.14.1   Summary of Visit 2 Combined BV Clinical and Gram Stain Cure, mITT Population 
 
Table 14.2.14.2   Summary of Visit 2 Combined BV Clinical and Gram Stain Cure, PP Population 
Table 14.2.15.1   Summary of Visit 2 VVC Clinical and Candida Culture Cure, mITT Population  
Table 14.2.15.2   Summary of Visit 2 VVC Clinical and Candida Culture Cure, PP Population 
 


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Statistical Analysis Plan. May 1, 2018 
 
 
 
 
 
 
 
 
 
 
       
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Table 14.2.16   Summary of Visit 2 Change in Pelvic Exam Results, mITT Population  
Table 14.2.17   Summary of Visit 2 Change in Signs and Symptoms, mITT Population  
Table 14.2.18   Summary of Visit 2 Eradication/Persistence of Candida Species, mITT Population 
 
Table 14.2.19   Summary of Time to Resolution of Symptoms, mITT Population 
 
Figure 14.2.20   Kaplan-Meier Curve of Time to Resolution of Symptoms 
 
Table 14.2.21.1   Summary of Shifts in Cure Status From Visit 2 to Visit 3, mITT Population 
 
Table 14.2.21.2   Summary of Shifts in Cure Status From Visit 2 to Visit 3, PP Population 
 
14.3  Safety Summaries 
Table 14.3.1   
Summary of Study Drug Exposure, Safety Population  
Table 14.3.2   
Summary of Study Drug Compliance, Safety Population 
 
Table 14.3.3   
Summary of Treatment Emergent Adverse Events, Safety Population 
 
Table 14.3.4   
Summary of Treatment-Related Treatment Emergent Adverse Events, Safety Population  
Table 14.3.5   
Summary of Serious Treatment Emergent Adverse Events, Safety Population 
 
Table 14.3.6   
Summary of Serious Treatment-Related Treatment Emergent Adverse Events, Safety 
Population 
 
Table 14.3.7   
Summary of Treatment Emergent Adverse Events by Severity, Safety Population 
 
Table 14.3.8   
Summary of Lab Values, Safety Population 
 
Table 14.3.9   
Summary of Abnormal Lab Values, Safety Population  
Table 14.3.10   Summary of Lab Shifts from Baseline, Safety Population 
 
Table 14.3.11  
 Summary of Study Drug Exposure in Combined Studies, Safety Population 
 
Table 14.3.12   Summary of Treatment Emergent Adverse Events in Combined Studies, Safety 
Population 
 
Table 14.3.13   Summary of Treatment-Related Treatment Emergent Adverse Events in Combined 
Studies, Safety Population 
 
Table 14.3.14   Summary of Serious Treatment Emergent Adverse Events in Combined Studies, Safety 
Population 
 
Table 14.3.15   Summary of Serious Treatment-Related Treatment Emergent Adverse Events in 
Combined Studies, Safety Population  
Table 14.3.16   Summary of Treatment Emergent Adverse Events by Severity in Combined Studies, 
Safety Population 
 
 
 
LIST OF LISTINGS  
 
16.1  Demographic and Study Conduct Listings 
Listing 16.1.1 
End of Study Record  
Listing 16.1.2  
Demographics  
Listing 16.1.3  
Contraceptive and Obstetric Status 
 
Listing 16.1.4 
History of Gynecologic Infections 
 
Listing 16.1.5 
Demographic and Baseline Characteristics 
 
Listing 16.1.6  Contraceptive and Obstetric Status 
 
Listing 16.1.7 
History of Gynecologic Infection 
 
Listing 16.1.8 
BV, VVC and /or Mixed Infection Medications in Past Year 
 
Listing 16.1.9 
Medical and Surgical History  
Listing 16.1.10  Baseline Vital Signs 
 


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Statistical Analysis Plan. May 1, 2018 
 
 
 
 
 
 
 
 
 
 
       
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Listing 16.1.11 Baseline Physical Exam 
 
Listing 16.1.12 Diagnosis 
 
Listing 16.1.13  Inclusion/Exclusion Criteria Waivers  
Listing 16.1.14  Investigator Comments/Protocol Violations 
 
Listing 16.1.15  Randomization and Kit Number 
 
Listing 16.1.16  Concomitant Medications 
 
 
16.2  Efficacy Listings 
 
Listing 16.2.1 
 Compliance Assessment 
 
Listing 16.2.2 
 Tests/Cultures Taken  
Listing 16.2.3 
 Symptom and Sign Severity Score 
 
Listing 16.2.4 
 Pelvic Exam  
Listing 16.2.5 
 Need for Additional Treatment 
Listing 16.2.6 
 Test-of-Cure  
Listing 16.2.7 
 Symptom Resolution/Recurrence 
 
 
 
16.3  Safety Listings 
 
Listing 16.3.1 
 Study Drug Administration 
 
Listing 16.3.2 
 Study Drug Compliance 
 
Listing 16.3.3 
 Adverse Events 
 
Listing 16.3.4 
 Adverse Events Resulting in Early Termination from the Study  
Listing 16.3.5 
 Adverse Events Resulting in Death 
 
Listing 16.3.6 
 Lab Values