Clinical trial NCT03091777
Conditions: Bacterial Vaginosis
Keywords: bacterial vaginosis vaginal infection BV
Sponsor: Balmoral Medical company
Start date: 2017-03-10; Completion date: 2018-03-27
Enrollment: 871 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This research study is being done to compare the safety and efficacy of GDC-229 (test drug) against the currently marketed reference drug (metronidazole 0.75% vaginal gel) and to establish that these two drugs work better than placebo in subjects with BV.

Detailed description:

Arms: arm 1: GDC-229 gel applied vaginally as directed. arm 2: Metronidazole Vaginal Gel, 0.75% applied vaginally as directed. arm 3: GDC-229 Vehicle
Interventions: intervention 1: GDC-229 intervention 2: Metronidazole Vaginal Gel 0.75% intervention 3: Placebo
Intervention descriptions: intervention 1: GDC-229 is a vaginal gel. intervention 2: Metronidazole Vaginal Gel 0.75% is an FDA-approved drug intervention 3: Inactive arm of the study

Protocol documents:
Prot_000.pdf: 






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PROTOCOL SYNOPSIS 
Title: 
A Multicenter, Randomized, Double-Blind, Vehicle Controlled Study 
Evaluating the Therapeutic Equivalence and Safety of GDC-229 
(Investigational Metronidazole 0.75% Vaginal Gel) and Metronidazole 
0.75% Vaginal Gel in the Treatment of Bacterial Vaginosis 
Phase of Development: 
Bioequivalence Study with Clinical Endpoint 
Sponsor: 
Gage Development Company, LLC 
Protocol Number: 
GDC-229-002 
Indication: 
Treatment of Bacterial Vaginosis (BV) 
Study Population: 
Adult females presenting with BV who meet all of the four Amsel’s 
Diagnostic Criteria (defined below in Inclusion Criteria) at the 
Screening Visit 
Objectives: 
The primary objective is to assess the therapeutic equivalence of an 
experimental formulation of a metronidazole 0.75% vaginal gel 
(GDC-229; test product) versus metronidazole 0.75% vaginal gel 
(Oceanside Pharmaceuticals) in subjects with BV.  A vehicle (placebo) 
arm is included for assay sensitivity. 
The secondary objective is to evaluate the safety and tolerability of an 
experimental formulation of a metronidazole 0.75% vaginal gel (GDC 
229; test product) versus metronidazole 0.75% vaginal gel (Oceanside 
Pharmaceuticals) and vehicle (placebo) in subjects with BV. 
Endpoints: 
Primary Endpoint: 
The proportion of subjects achieving a clinical cure at the Test of Cure 
Visit (V3) defined as follows: 
 
Return to normal physiological discharge as assessed by the 
investigator 
 
Negative 10% potassium hydroxide (KOH) whiff test 
 
Presence of clue cells at < 20% of the total epithelial cells on 
microscopic examination of the saline wet mount 
Supportive Secondary Endpoints:  
 
Nugent score of < 4 at Visit 3  
 
Responder outcome (therapeutic cure) defined as follows: 
o Clinical cure as defined in the Primary Endpoint 
o Vaginal pH < 4.7 at Visit 3 
o Nugent score of < 4 at Visit 3 (Bacteriological Cure) 
Identity of Study 
Treatment(s): 
GDC-229 (metronidazole 0.75% vaginal gel; test product) 
Marketed metronidazole 0.75% vaginal gel (Oceanside 
Pharmaceuticals); reference product 
Placebo (i.e., vehicle gel) 


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Projected Number of 
Sites: 
Approximately 40 
Countries or Regions: 
US only 
Expected Number of 
Subjects: 
738 (enrolled) 
Rationale, Background, 
Risks and Benefits: 
Bacterial vaginosis (BV) is a common vaginal infection in women. 
Untreated BV may lead to higher risk of a sexually transmitted infection 
or pregnancy problems. Symptoms of BV may include unusual vaginal 
discharge, burning when urinating, itching around the outside of the 
vagina, and vaginal irritation. Antibiotics are used to treat BV. 
Metronidazole was approved for use in the US in 1963 and is currently 
a first-line treatment for BV.  Gage Development Company, LLC is 
developing a drug product candidate that is designed to be 
therapeutically equivalent to the marketed drug metronidazole 0.75% 
vaginal gel for the treatment of BV. 
The contraindications, warnings, precautions, drug interactions, and 
adverse events (AEs) associated with the use of metronidazole are 
described in the approved product labeling for metronidazole 0.75% 
vaginal gel (Oceanside Pharmaceuticals).  
Study Design: 
This is a multicenter, randomized, double-blind, vehicle-controlled, 
bioequivalence clinical endpoint study evaluating the therapeutic 
equivalence, safety, and tolerability of GDC-229 (test product), the 
reference product metronidazole 0.75% vaginal gel (Oceanside 
Pharmaceuticals), and placebo (vehicle gel) in subjects with BV. The 
study is approximately 30 days in duration and is comprised of three 
study visits: Entry Visit (Visit 1; day of screening and randomization), 
Post-Treatment Assessment Visit (Visit 2; 7 to 14 days after 
randomization), and Test of Cure (Visit 3; 21 to 30 days after 
randomization). 
At the Entry Visit (Visit 1), the following should be collected/assessed: 
review of all inclusion and exclusion criteria, demographic information, 
gynecological history, and medical history (including concomitant 
medications used up to 30 days prior to screening), physical and pelvic 
examination, vital signs, microbiological specimen collection for 
Nugent’s score assessment and cervical infections (e.g., Chlamydia 
trachomatis, Neisseria gonorrhoeae), urine drug screening, and urine 
pregnancy test. 
Diagnosis of BV will be determined based on Amsel’s criteria, which 
requires presence of all four of the following: off-white (milky or gray), 
thin homogeneous discharge with minimal or absent pruritus and 
inflammation of the vulva and vagina; vaginal pH > 4.5; fishy odor 
upon addition of KOH to vaginal fluid (positive whiff test); and 
presence of clue cells on saline wet mount greater than or equal to 20% 
of total epithelial cells on microscopic examination of the saline wet 


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mount. If the results of the Amsel’s diagnosis exam are positive and the 
subject meets all other inclusion and exclusion criteria, the subject will 
be randomized to treatment. Note: Nugent’s result is not used for 
randomization decisions. 
Eligible women will be randomized 1:1:1 to receive GDC-229 
(investigational metronidazole 0.75% vaginal gel), marketed 
metronidazole 0.75% vaginal gel (Oceanside Pharmaceuticals) or 
placebo. Subjects will be instructed to administer treatment 
intravaginally once daily at bedtime during Days 1-5. 
At Post-Treatment Assessment (Visit 2), 7 to 14 days after 
randomization (Visit 1), the following procedures will be performed: 
pelvic examination, and collection of study medication, subject-reported 
and Investigator-assessed local site reactions, AEs, and concomitant 
medications. At this visit, subjects will be examined to assess for 
resolution of the following Amsel’s criteria: resolution of the abnormal 
vaginal discharge, negative KOH whiff test, and the presence of clue 
cells at less than 20 percent of the total epithelial cells on microscopic 
examination of the saline wet mount; in addition, the vaginal pH will be 
tested to assess if it has returned to the normal range of < 4.7. 
The Test of Cure (Visit 3) will be conducted 21 to 30 days after Visit 1 
to assess if the subject displays presence of normal vaginal discharge, 
absence of fishy odor using KOH whiff test, and less than 20% clue 
cells on microscopic examination of a wet saline wet mount; in 
addition, the vaginal pH will be tested to assess if it has returned to the 
normal range of < 4.7. At this visit, the following procedures will be 
performed: a physical examination, including a pelvic exam to assess 
for the above Amsel’s criteria and for microbiological specimen 
collection for Nugent’s score assessment; urine pregnancy test, subject-
reported and Investigator-assessed local site reactions, and assessment 
of observed or subject-reported AEs and concomitant medications. 
Inclusion Criteria: 
Subjects meeting all of the following criteria may be considered for 
study participation:  
1. Non-pregnant female aged ≥ 18 years who is in good general 
health 
2. Diagnosis of BV, defined as presence of all of the following: 
a. Clinical diagnosis of BV (e.g., off-white [milky or 
gray], thin homogeneous discharge with minimal or 
absent pruritus and inflammation of the vulva and 
vagina); AND 
b. Saline wet mount of vaginal discharge demonstrating 
the proportion of clue cells to be ≥ 20% of the total 
epithelial cells; AND 
c. Vaginal secretion pH > 4.5, using pH paper that 
measures from 4.0 to 6.0; AND 


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d. Positive (fish odor) “whiff test” after addition of a drop 
of 10% KOH to vaginal discharge. 
3. Willing to refrain from vaginal sexual intercourse on Days 1 to 
7 (i.e., during treatment and for two post-treatment days) and 
for 48 hours prior to Visits 2 and 3.  
4. Willing to refrain from using any intravaginal product (e.g., 
spermicide, tampon, douche, feminine deodorant spray, 
diaphragm, vaginal ring birth control, or condom with 
spermicide or insertion into the vagina of any drug or non-drug 
product during treatment), other than study treatment for the 
duration of the trial.  
5. Subjects of childbearing potential who have a negative urine 
pregnancy test at the Entry Visit (Visit 1) and agree to use an 
acceptable form of birth control throughout the study. 
Acceptable forms of birth control include oral contraceptives 
(the pill), intrauterine devices (IUDs), contraceptive implants 
under the skin, patches or injections, and condoms without 
spermicide.  Oral or transdermal hormonal contraceptives must 
be in use for one full cycle (e.g., four to eight weeks) prior to 
test article application.  Injectable or implanted contraceptives 
(e.g., Depo-Provera, Nexplanon, or hormonal IUD) must be 
injected/inserted at least seven days prior to test article 
application. Subjects who are not of childbearing potential, as 
defined below, must also have a negative urine pregnancy test 
prior to randomization: 
a. Postmenopausal for at least one year prior to the Entry 
Visit (Visit 1) (defined as ≥ 50 years of age and 
amenorrheic for > one continuous year) or  
b. Surgically sterile (defined as bilateral tubal ligation, 
bilateral oophorectomy, or hysterectomy) at least 6 
months before first dose or  
c. Non-surgical permanent sterilization (e.g., 
Essure® procedure) procedure at least 3 months 
prior to first dose 
6. The subject is willing to refrain from alcohol intake on study 
Days 1 to 6 (i.e., during treatment through first post-treatment 
day). 
7. Able to understand and willing to sign the informed consent 
form (ICF) and able to comply with the requirements of the 
protocol. 
Exclusion Criteria: 
Subjects meeting any of the following criteria will be excluded: 
1. Known current or recent history (i.e., within the past two years 
prior to the Entry Visit) of alcohol or substance abuse. 


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2. Experienced a clinically significant medical event within 90 
days prior to the Entry Visit (e.g., stroke, myocardial infarction, 
surgery). 
3. Abnormal pap or high risk human papillomavirus (HPV) within 
the last three months requiring colposcopic evaluation or 
treatment (e.g., cryotherapy, loop electrosurgical excision 
procedure [LEEP], or conization of the cervix). 
4. History or presence of clinically significant central nervous 
system (CNS), cardiovascular, pulmonary, hepatic, renal, 
hematologic, gastrointestinal, endocrine, immunologic, 
gynecologic, dermatologic, neurologic, oncologic, or 
psychiatric disease, or any other condition that, in the opinion 
of the Investigator, would jeopardize the safety of the subject or 
the validity of the study results. 
5. Pregnant, lactating, or planning to become pregnant or 
breastfeed during the study period. 
6. Menstruating when diagnosis of BV is determined at the Entry 
Visit (Visit 1). 
7. Primary or secondary immunodeficiency. 
8. History of severe liver disease. 
9. History of CNS-related disorders. 
10. Evidence of any vulvovaginitis at screening other than BV 
(e.g., vulvovaginal candidiasis, Trichomonas vaginalis, 
Chlamydia trachomatis, Neisseria gonorrhoeae, active herpes 
simplex, or active HPV). 
11. At the Entry Visit, the subject is receiving any antibacterial 
therapy unrelated to BV. 
12. Subject has received vaginal therapy within two weeks prior to 
the Entry Visit, or plans to receive vaginal therapy for the 
duration of the trial. 
13. Subject is or will be undergoing treatment for cervical 
intraepithelial neoplasia (CIN) or cervical carcinoma. 
14. History of hypersensitivity or allergy to metronidazole, 
parabens, other nitroimidazole derivatives, or other ingredients 
of the GDC-229 (metronidazole 0.75% vaginal gel), 
metronidazole 0.75% vaginal gel (Oceanside Pharmaceuticals), 
or vehicle gel. 
15. Use within 2 weeks prior to the Entry Visit of 1) disulfiram, 
2) lithium, 3) topical or systemic antibiotics, or 4) topical or 
systemic antifungals. 
16. Use of spermicides, tampons, douches, diaphragms, condoms or 
other intravaginal product within 48 hours prior to dosing on 
study Day 1. 
17. Current use of anticoagulation therapy or cimetidine. 
18. Participating in a clinical trial involving an investigational 
product within the 30 days prior to the Entry Visit (Visit 1) or is 
planning to participate in another clinical trial during this study. 
Safety Parameters: 
The following safety parameters will be collected: 


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 
Urine pregnancy test at every site visit 
 
Urine drug screen (Visit 1) 
 
Medical and gynecological history (Visit 1) 
 
Physical exam (Visits 1 and 3) and pelvic examinations (Visits 
1, 2, and 3) 
 
Vital sign assessments including oral temperature, sitting blood 
pressure, heart rate, and respiratory rate (Visits 1, 2, and 3) as 
well as weight (Visits 1 and 3) 
 
AE and concomitant medications reporting (Visits 1, 2, and 3) 
 
Local site reaction assessments (subject-reported and 
Investigator-assessed at Visits 2 and 3) 
 
Screening for Chlamydia trachomatis, Neisseria gonorrhoeae 
(Visit 1) 
Efficacy Evaluations: 
Primary:  Clinical cure defined as return to normal physiological 
discharge, negative whiff test, and the presence of clue cells at <20% of 
the total epithelial cells on microscopic examination of the saline wet 
mount at Test of Cure (Visit 3; Day 21-30). 
Secondary: Bacteriological Cure defined as: Nugent’s score <4 at Visit 
3 (Day 21-30).  Therapeutic cure defined as: having achieved clinical 
cure, vaginal pH of <4.7, and bacteriological cure. 
Other Assessments: 
Demographic characteristics will be collected. 
Statistical Considerations: 
The following assumptions were considered for the power and sample 
size assessment: 
 
the proportion of participants in the test and reference arms 
achieving a clinical cure is at least 36% and within 4% of each 
other,  
 
the proportion subjects receiving placebo that achieves clinical 
cure is 20% and  
 
12.4% of randomized subjects do not qualify for the modified 
Intent-to-Treat (mITT) population,  
Based on the above assumptions 603 subjects will be required.  
However, the previous studies that were used to estimate effect size had 
significant differences in study design and definition of primary 
endpoint.  Taking these differences into consideration, 738 subjects will 
be randomized to achieve at least 90% power for superiority and 
bioequivalence. 
 
Analysis Datasets 
Intent-to-Treat (ITT) Population:  All randomized subjects. 


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Safety Population:  All randomized subjects who receive at least 1 dose 
of study drug. 
Modified Intent-to-Treat (mITT) Population:  All randomized subjects 
excluding those who subsequently demonstrate a positive test result for 
other concomitant vaginal or cervical infections at baseline 
(e.g. C. trachomatis, N. gonorrhoeae) which may interfere with the 
efficacy assessment for BV or who have a baseline Nugent score<4, 
received study treatment, and returned for at least one post-baseline 
visit. 
Per Protocol (PP) Population:  Includes all subjects who qualify for the 
mITT population and who follow important components of the trial 
(including subjects who adhere to treatment and follow-up for efficacy 
within the prescribed timeframe). 
Subjects in the mITT population who discontinue early from the study 
and do not have an assessment of clinical cure and bacteriological cure 
will be included in the mITT population analyses as treatment failures. 
These subjects without outcomes, but are classified as treatment failures 
will not be included in the PP analyses. 
To establish bioequivalence, the 90% confidence interval for the 
primary endpoint (the difference [test-reference] in proportion of 
subjects achieving a clinical cure) must be within [-0.20, +0.20], using 
the PP population. 
As a parameter for determining adequate study sensitivity, the test 
product and the reference drug should both be statistically superior to 
placebo (p<0.05, two-sided) for the primary endpoint, using the mITT 
study population. 
Duration of Treatment: 
Subjects will be treated on Days 1 to 5 with Visit 2 to occur between 
Days 7 and 14 (inclusive). 
Test of Cure (Visit 3) will occur between Days 21 and 30 (inclusive) 
after randomization to assess the primary and secondary endpoints. 
Study Duration: 
Approximately eight months for recruitment and completion of study 
subject participation. 
Compliance: 
The trial will be carried out in accordance with Good Clinical Practice 
(GCP) as required by the following: United States (US) Code of Federal 
Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 
CFR Parts 50, 54, 56, 312, and320), ICH E6, and the 2013 revision of 
the Declaration of Helsinki. 


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TABLE OF CONTENTS 
1 
INTRODUCTION AND BACKGROUND ...............................................................14 
2 
STUDY OBJECTIVES ..............................................................................................15 
3 
INVESTIGATIONAL PLAN .....................................................................................16 
3.1 
Description of Overall Study Design and Plan ...........................................................16 
3.2 
Study Design Rationale ..............................................................................................16 
3.3 
Selection of Subjects ...................................................................................................16 
3.3.1 
Inclusion Criteria ........................................................................................................17 
3.3.2 
Exclusion Criteria .......................................................................................................18 
3.4 
Withdrawal of Subjects ...............................................................................................19 
3.5 
Study Treatments ........................................................................................................19 
3.5.1 
Method of Assigning Subjects to Treatments .............................................................19 
3.5.2 
Identity of Study Drug and Treatments Administered ...............................................19 
3.5.3 
Contraindications, Warnings, and Precautions ...........................................................20 
3.5.4 
Drug Packaging and Labeling ....................................................................................24 
3.5.5 
Drug Storage ...............................................................................................................24 
3.5.6 
Drug Disposal/Return .................................................................................................24 
3.5.7 
Retention Samples ......................................................................................................24 
3.5.8 
Blinding and Unblinding ............................................................................................25 
3.5.9 
Treatment Compliance ................................................................................................25 
3.5.10 
Prior and Concomitant Medications ...........................................................................25 
4 
STUDY PROCEDURES ............................................................................................27 
4.1 
Informed Consent .......................................................................................................27 
4.2 
Subject Demographics, Height, and Weight ...............................................................27 
4.3 
Medical and Gynecological History ...........................................................................27 
4.4 
Physical and Pelvic Examination................................................................................27 
4.5 
Vital Signs ..................................................................................................................27 
4.6 
Concomitant Medications and Procedures .................................................................27 
4.7 
Adverse Events (AEs) .................................................................................................27 
4.8 
Clinical Laboratory Evaluations .................................................................................28 
4.8.1 
Urine Drug Screening .................................................................................................28 


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4.8.2 
Pregnancy Testing ......................................................................................................28 
4.8.3 
Screening for Sexually Transmitted Infections ..........................................................28 
4.8.4 
Microbiological Sample ..............................................................................................28 
5 
SCHEDULE OF ASSESSMENTS AND STUDY VISIT PROCEDURES ..............29 
5.1 
Entry Visit (Visit 1) ....................................................................................................29 
5.2 
Post-Treatment Assessment (Visit 2) .........................................................................30 
5.3 
Test of Cure Visit (Visit 3) .........................................................................................31 
5.4 
Early Discontinuation Visit ........................................................................................31 
5.5 
Unscheduled Visit .......................................................................................................32 
5.6 
Schedule of Assessments ............................................................................................32 
6 
END OF STUDY CRITERIA ....................................................................................34 
6.1 
Completion of the Study .............................................................................................34 
6.2 
Subject Discontinuation ..............................................................................................34 
6.3 
Study Termination ......................................................................................................35 
7 
EVALUATIONS ........................................................................................................36 
7.1 
Efficacy Parameters ....................................................................................................36 
7.2 
Safety Evaluation ........................................................................................................36 
7.3 
Appropriateness of Measurements .............................................................................36 
8 
SAFETY .....................................................................................................................37 
8.1 
Adverse Events and Serious Adverse Events .............................................................37 
8.1.1 
Definitions and Criteria ..............................................................................................37 
8.1.2 
Assessing Intensity and Relationship of Adverse Events ...........................................39 
8.1.3 
Reporting Procedures and Requirements for Adverse Events ....................................40 
8.1.4 
Laboratory Test Abnormalities ...................................................................................43 
8.1.5 
Pregnancy ...................................................................................................................43 
8.2 
Other Safety Concerns ................................................................................................44 
9 
STATISTICAL AND ANALYTICAL METHODS ..................................................45 
9.1 
Sample Size ................................................................................................................45 
9.2 
Analysis Populations ..................................................................................................45 
9.3 
Disposition of Subjects ...............................................................................................46 
9.4 
Demographic and Other Subject Characteristics ........................................................46 


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9.5 
Extent of Exposure .....................................................................................................46 
9.6 
Efficacy Analyses .......................................................................................................46 
9.6.1 
Primary Endpoints ......................................................................................................46 
9.6.2 
Secondary Endpoints ..................................................................................................46 
9.7 
Safety Parameters .......................................................................................................46 
9.7.1 
Adverse Events ...........................................................................................................47 
9.7.2 
Incidence of Adverse Events ......................................................................................47 
9.7.3 
Discontinuation Due to Adverse Events .....................................................................47 
9.7.4 
Serious Adverse Events (SAEs) .................................................................................47 
9.7.5 
Deaths .........................................................................................................................47 
10 
MEDICAL MONITOR ..............................................................................................48 
11 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................49 
11.1 
Compliance with Good Clinical Practice ...................................................................49 
11.2 
Interactions with Institutional Review Boards (IRBs) ................................................49 
11.3 
Informed Consent .......................................................................................................49 
11.4 
Confidentiality ............................................................................................................50 
12 
STUDY MONITORING AND DOCUMENTATION ..............................................51 
12.1 
Clinical Monitoring, Quality Control, and Quality Assurance ...................................51 
12.2 
Administrative and Record Management ...................................................................51 
12.3 
Study Documentation .................................................................................................51 
12.4 
Electronic Data Capture (EDC) System/Data Transmission ......................................51 
12.5 
Data Handling and Processing ....................................................................................52 
12.6 
Confidentiality and Reporting of Results ...................................................................52 
12.7 
Retention of Data ........................................................................................................52 
12.8 
Publication Policy .......................................................................................................53 
12.9 
Reimbursement, Indemnity, and Insurance ................................................................53 
12.10 
Adherence to the Protocol ..........................................................................................53 
13 
INVESTIGATOR OBLIGATIONS ...........................................................................54 
14 
REFERENCES ...........................................................................................................56 


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ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse event 
BV 
Bacterial vaginosis 
CDC 
Centers for Disease Control and Prevention 
CNS 
Central nervous system 
CRO 
Clinical research organization 
CFR 
Code of Federal Regulations 
CV 
Curriculum Vitae 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
hCG 
Human chorionic gonadotropin 
HPV 
Human  papillomavirus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine device 
KOH 
Potassium hydroxide 
LEEP 
Loop electrosurgical excision procedure 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
NDA 
New Drug Application 
PP 
Per protocol 
SAE 
Serious adverse event 
STI 
Sexually transmitted infection 
SOP 
Standard operating procedure 
US 
United States 
 


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1 
INTRODUCTION AND BACKGROUND 
Bacterial vaginosis (BV) is a common vaginal infection in women. The risk of plasma cell 
endometritis in women with BV has been reported to be 15 times higher than the risk in women 
without BV (Korn 1995). The presence of atypical cells on a Pap smear is also more common in 
women with BV (Eltabbakh 1995). Untreated BV can lead to higher risk of contracting a 
sexually transmitted infection (STI) or lead to pregnancy problems (CDC Fact Sheet). 
Symptoms of BV may include unusual vaginal discharge, burning when urinating, itching around 
the outside of the vagina, and vaginal irritation. BV is typically diagnosed using Amsel’s criteria 
(Amsel 1983). The four Amsel’s criteria used to determine a clinical diagnosis of BV are as 
follows: vaginal pH > 4.5; positive “whiff” test (“fishy” odor); homogenous, nonviscous, off-
white (milky or gray) discharge; and the presence of ≥ 20% clue cells. 
Oral and topical antibiotics are used to treat BV. Metronidazole was approved for use in the U.S. 
in 1963 and is currently a first-line treatment for BV (Flagyl NDA). Gage Development 
Company, LLC is developing a drug product candidate that is designed to be therapeutically 
equivalent to the marketed drug metronidazole 0.75% vaginal gel for the treatment of BV. 


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2 
STUDY OBJECTIVES  
Primary Objective:  
The primary objective of this study to assess the therapeutic equivalence of an experimental 
formulation of a metronidazole 0.75% vaginal gel (GDC 229; test product) versus metronidazole 
0.75% vaginal gel (Oceanside Pharmaceuticals) in subjects with BV.  A vehicle (placebo) arm is 
included for assay sensitivity. 
Secondary Objectives: 
The secondary objective of this study is to evaluate the safety and tolerability of an experimental 
formulation of a metronidazole 0.75% vaginal gel (GDC 229; test product) versus metronidazole 
0.75% vaginal gel (Oceanside Pharmaceuticals) and vehicle (placebo) in subjects with BV. 


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3 
INVESTIGATIONAL PLAN 
3.1 
Description of Overall Study Design and Plan 
This is a multicenter, randomized, double-blind, vehicle-controlled, bioequivalence clinical 
endpoint study to evaluate the therapeutic equivalence, safety, and tolerability of an experimental 
formulation of a metronidazole 0.75% vaginal gel (GDC-229; test product) and the reference 
product, metronidazole 0.75% vaginal gel (Oceanside Pharmaceuticals) in generally healthy 
adult subjects with BV. The study is 30 days in duration, including a 5-day treatment period. 
There are three study visits as shown in Table 1: Entry Visit (Visit 1, day of screening and 
randomization); Post-Treatment Assessment (Visit 2, 7 to 14 days after randomization), and Test 
of Cure (Visit 3, 21 to 30 days after randomization). Including a recruitment period of seven 
months, the total study duration is approximately eight months. 
Table 1 
Visit Descriptors 
Visit Number 
Visit Name and Purpose 
Day of Study 
Visit 1 
Screening and Randomization 
Day 1 
Visit 2 
Post-Treatment Assessment 
Day 7-14 (inclusive) 
Visit 3 
Test of Cure 
Day 21 to 30 (inclusive) 
It is expected that approximately 738 subjects will be enrolled in this study and randomized into 
one of three treatment groups in a 1:1:1 ratio (246 subjects/group). One of three study treatments 
(metronidazole 0.75% vaginal gel [GDC-229; test article], marketed metronidazole 0.75% 
vaginal gel [Oceanside Pharmaceuticals], or matched placebo [i.e., GDC-229 vehicle]) will be 
administrated intravaginally once daily at bedtime for 5 consecutive days. 
3.2 
Study Design Rationale 
The study design outlined in this protocol is primarily based on the April 2013 Food & Drug 
Administration (FDA) draft guidance for the development of generic metronidazole vaginal gel, 
0.75%, equivalent to the reference listed drug Metrogel-Vaginal (NDA 020208). This guidance 
describes the eligibility criteria for subjects (including Amsel’s criteria, which are defined in 
inclusion criteria; Section 3.3.1), microbiological confirmation of disease, efficacy endpoints, 
safety considerations, and recommendations for statistical analyses. A placebo arm is included to 
demonstrate adequate study sensitivity. The dose selection and dosing regimen is based on the 
FDA approved dose.  
Safety considerations specific to the use of metronidazole are described in Section 8.2. 
3.3 
Selection of Subjects  
Approximately 738 generally healthy adult female subjects with a diagnosis of BV based on all 
four Amsel’s criteria will be recruited from approximately 40 research centers in the United 
States (US). Specific entry criteria are detailed in Section 3.3.1 and Section 3.3.2. 


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3.3.1 Inclusion Criteria 
Subjects meeting all of the following criteria at Entry Visit (Visit 1) may be considered for study 
participation: 
1. Non-pregnant female aged ≥ 18 years who is in good general health 
2. Diagnosis of BV, defined as presence of all of the following: 
a. Clinical diagnosis of BV (e.g., off-white [milky or gray], thin homogeneous 
discharge with minimal or absent pruritus and inflammation of the vulva and 
vagina); AND 
b. Saline wet mount of vaginal discharge demonstrating the proportion of clue cells 
to be ≥ 20% of the total epithelial cells; AND 
c. Vaginal secretion pH > 4.5, using pH paper that measures from 4.0 to 6.0; AND 
d. Positive (fish odor) “whiff test” after addition of a drop of 10% potassium 
hydroxide (KOH) to vaginal discharge. 
3. Willing to refrain from vaginal sexual intercourse on Days 1 to 7 (i.e., during treatment 
and for two post-treatment days) and for 48 hours prior to Visits 2 and 3.  
4. Willing to refrain from using any intravaginal product (e.g., spermicide, tampon, douche, 
feminine deodorant spray, diaphragm, vaginal ring birth control, or condom with 
spermicide or insertion into the vagina of any drug or non-drug product during 
treatment), other than study treatment for the duration of the trial.  
5. Subjects of childbearing potential who have a negative urine pregnancy test at the Entry 
Visit (Visit 1) and agree to use an acceptable form of birth control throughout the study. 
Acceptable forms of birth control include oral contraceptives (the pill), intrauterine 
devices (IUDs), contraceptive implants under the skin, patches or injections, and 
condoms without spermicide. Oral or transdermal hormonal contraceptives must be in use 
for one full cycle (e.g., four to eight weeks) prior to test article application.  Injectable or 
implanted contraceptives (e.g., Depo-Provera, Nexplanon, or hormonal IUD) must be 
injected/inserted at least seven days prior to test article application. Subjects who are not 
of childbearing potential, as defined below, must also have a negative urine pregnancy 
test prior to randomization: 
a. Postmenopausal for at least one year prior to the Entry Visit (Visit 1) (defined as 
≥ 50 years of age and amenorrheic for > one continuous year) or  
b. Surgically sterile (defined as bilateral tubal ligation, bilateral oophorectomy, or 
hysterectomy) at least 6 months before first dose or  
c. Non-surgical permanent sterilization (e.g., Essure® procedure) procedure at least 3 
months prior to first dose. 
6. The subject is willing to refrain from alcohol intake on study Days 1 to 6 (i.e., during 
treatment through first post-treatment day). 
7. Able to understand and willing to sign the informed consent form (ICF) and able to 
comply with the requirements of the protocol. 


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3.3.2 Exclusion Criteria 
Subjects meeting any of the following criteria at Screening (unless otherwise specified) will be 
excluded: 
1. Known current or recent history (i.e., within the past two years prior to the Entry Visit) of 
alcohol or substance abuse. 
2. Experienced a clinically significant medical event within 90 days prior to the Entry Visit 
(e.g., stroke, myocardial infarction, surgery). 
3. Abnormal pap or high risk human papillomavirus (HPV) within the last three months 
requiring colposcopic evaluation or treatment (e.g., Cryotherapy, loop electrosurgical 
excision procedure [LEEP], or conization of the cervix). 
4. History or presence of clinically significant central nervous system (CNS), 
cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, 
immunologic, gynecologic, dermatologic, neurologic, oncologic, or psychiatric disease, 
or any other condition that, in the opinion of the Investigator, would jeopardize the safety 
of the subject or the validity of the study results. 
5. Pregnant, lactating, or planning to become pregnant or breastfeed during the study period. 
6. Menstruating when diagnosis of BV is determined at the Entry Visit (Visit 1). 
7. Primary or secondary immunodeficiency. 
8. History of severe liver disease. 
9. History of CNS-related disorders. 
10. Evidence of any vulvovaginitis at screening other than BV (e.g., vulvovaginal 
candidiasis, Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, 
active herpes simplex, or active HPV). 
11. At the Entry Visit, the subject is receiving any antibacterial therapy unrelated to BV. 
12. Subject has received vaginal therapy within two weeks prior to the Entry Visit, or plans 
to receive vaginal therapy for the duration of the trial. 
13. Subject is or will be undergoing treatment for cervical intraepithelial neoplasia (CIN) or 
cervical carcinoma. 
14. History of hypersensitivity or allergy to metronidazole, parabens, other nitroimidazole 
derivatives, or other ingredients of the GDC-229 (metronidazole 0.75% vaginal gel), 
metronidazole 0.75% vaginal gel (Oceanside Pharmaceuticals), or vehicle gel. 
15. Use within 2 weeks prior to the Entry Visit of 1) disulfiram, 2) lithium, 3) topical or 
systemic antibiotics, or 4) topical or systemic antifungals. 
16. Use of spermicides, tampons, douches, diaphragms, condoms or other intravaginal 
product within 48 hours prior to dosing on study Day 1. 
17. Current use of anticoagulation therapy or cimetidine. 
18. Participating in a clinical trial involving an investigational product within the 30 days 
prior to the Entry Visit (Visit 1) or is planning to participate in another clinical trial 
during this study. 


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3.4 
Withdrawal of Subjects 
Subjects may withdraw from the study at any time or be withdrawn from the study at the 
discretion of the investigator should any untoward effects occur. In addition, a subject may be 
withdrawn by the investigator or the sponsor if she deviated from the protocol or for other safety 
reasons. 
Subjects withdrawing from the study will not be replaced, regardless of the reason for 
discontinuation. All reasonable efforts should be made to contact the subject if she decides to 
discontinue study treatment. 
The procedures noted in the Schedule of Assessments (Table 3) should be performed for the 
Early Termination Visit, whenever it occurs. A subject will be considered to have completed the 
study after completing the Test of Cure Visit (Visit 3). If a subject is discontinued at any time 
after entering the study, the investigator will make every effort to see the subject and complete 
the early discontinuation assessments as shown in Schedule of Assessments (Table 3) and 
Section 5.4. 
A termination electronic case report form (eCRF) page should be included for each subject who 
receives study medication, whether or not the subject completes the study. The reason for any 
early discontinuation should be indicated on the form. The primary reason for a subject 
withdrawing prematurely should be selected from the list provided in Section 6.2.  
3.5 
Study Treatments 
3.5.1 Method of Assigning Subjects to Treatments 
Subjects will be assigned a unique subject identification number during Screening. Following 
completion of the screening procedures, eligible subjects will be randomized in a blinded manner 
to one of three treatment groups in a 1:1:1 ratio. It is anticipated that approximately 246 subjects 
will be randomized to each treatment. The identity and description of study drugs are described 
in the subsections that follow. 
3.5.2 Identity of Study Drug and Treatments Administered 
All drug supplies will be provided by the Sponsor. Basic information about the study drug 
supplies is provided in Table 2. 




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3.5.3.2 Warnings 
3.5.3.2.1 Convulsive Seizures and Peripheral Neuropathy 
Convulsive seizures and peripheral neuropathy, the latter characterized mainly by numbness or 
paresthesia of an extremity, have been reported in patients treated with oral or intravenous 
metronidazole. The appearance of abnormal neurologic signs demands the prompt 
discontinuation of metronidazole vaginal gel therapy. Metronidazole vaginal gel should be 
administered with caution to patients with CNS diseases. 
3.5.3.2.2 Psychotic Reactions 
Psychotic reactions have been reported in alcoholic patients who were using oral metronidazole 
and disulfiram concurrently. Metronidazole vaginal gel should not be administered to patients 
who have taken disulfiram within the last two weeks. 
3.5.3.3 Precautions 
Metronidazole vaginal gel results in minimal peak serum levels and systemic exposure (AUCs) 
of metronidazole compared to 500 mg oral metronidazole dosing. Although these lower levels of 
exposure are less likely to produce the common reactions seen with oral metronidazole, the 
possibility of these and other reactions cannot be excluded presently. Data from well-controlled 
trials directly comparing metronidazole administered orally to metronidazole administered 
vaginally are not available. 
3.5.3.3.1 General 
Patients with severe hepatic disease metabolize metronidazole slowly. This results in the 
accumulation of metronidazole and its metabolites in the plasma. Accordingly, for such patients, 
metronidazole vaginal gel should be administered cautiously. 
Known or previously unrecognized vaginal candidiasis may present more prominent symptoms 
during therapy with metronidazole vaginal gel. Approximately 6-10% of patients treated with 
metronidazole vaginal gel developed symptomatic Candida vaginitis during or immediately after 
therapy. 
Disulfiram-like reaction to alcohol has been reported with oral metronidazole, thus the 
possibility of such a reaction occurring while on metronidazole vaginal gel therapy cannot be 
excluded. 
Metronidazole vaginal gel contains ingredients that may cause burning and irritation of the eye. 
In the event of accidental contact with the eye, rinse the eye with copious amounts of cool tap 
water. 
3.5.3.3.1.1 Information for the Patient: 
The patient should be cautioned about drinking alcohol while being treated with metronidazole 
vaginal gel. While blood levels are significantly lower with Metronidazole Vaginal Gel than with 
usual doses of oral metronidazole, a possible interaction with alcohol cannot be excluded. 


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The patient should be instructed not to engage in vaginal intercourse during treatment with this 
product (in addition, the protocol requires that the subject not engage in vaginal intercourse for 
the two days following treatment or for 48 hours prior to Visits 2 and 3). 
3.5.3.3.1.2 Drug Interactions 
Oral metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other 
coumarin anticoagulants, resulting in a prolongation of prothrombin time. This possible drug 
interaction should be considered when metronidazole vaginal gel is prescribed for patients on 
this type of anticoagulant therapy. 
In patients stabilized on relatively high doses of lithium, short-term oral metronidazole therapy 
has been associated with elevation of serum lithium levels and, in a few cases, signs of lithium 
toxicity. 
Use of cimetidine with oral metronidazole may prolong the half-life and decrease plasma 
clearance of metronidazole. 
3.5.3.3.1.3 Drug/Laboratory Test Interactions 
Metronidazole may interfere with certain types of determinations of serum chemistry values, 
such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), 
lactate dehydrogenase (LDH), triglycerides, and glucose hexokinase. Values of zero may be 
observed. All of the assays in which interference has been reported involve enzymatic coupling 
of the assay to oxidation-reduction of nicotinamide-adenine dinucleotides (NAD + NADH). 
Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole 
(322 nm) at pH 7. 
3.5.3.3.1.4 Carcinogenesis, Mutagenesis, Impairment of Fertility 
Metronidazole has shown evidence of carcinogenic activity in a number of studies involving 
chronic oral administration in mice and rats. Prominent among the effects in the mouse was the 
promotion of pulmonary tumorigenesis. This has been observed in all six reported studies in that 
species, including one study in which the animals were dosed on an intermittent schedule 
(administration during every fourth week only). At very high dose levels (approximately 
500 mg/kg/day), there was a statistically significant increase in the incidence of malignant liver 
tumors in males. Also, the published results of one of the mouse studies indicate an increase in 
the incidence of malignant lymphomas as well as pulmonary neoplasms associated with lifetime 
feeding of the drug. All these effects are statistically significant. Several long-term oral dosing 
studies in the rat have been completed. There were statistically significant increases in the 
incidence of various neoplasms, particularly in mammary and hepatic tumors, among female rats 
administered metronidazole over those noted in the concurrent female control groups. Two 
lifetime tumorigenicity studies in hamsters have been performed and reported to be negative. 
These studies have not been conducted with 0.75% metronidazole vaginal gel, which would 
result in significantly lower systemic blood levels than those obtained with oral formulations. 
Although metronidazole has shown mutagenic activity in a number of in vitro assay systems, 
studies in mammals (in vivo) have failed to demonstrate a potential for genetic damage. 


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Fertility studies have been performed in mice up to six times the recommended human oral dose 
(based on mg/m2) and have revealed no evidence of impaired fertility. 
3.5.3.3.1.5 Pregnancy: Teratogenic Effects 
Pregnancy Category B 
There has been no experience to date with the use of Metronidazole Vaginal Gel in pregnant 
patients. 
Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. No 
fetotoxicity or teratogenicity was observed when metronidazole was administered orally to 
pregnant mice at six times the recommended human dose (based on mg/m2); however, in a single 
small study where the drug was administered intraperitoneally, some intrauterine deaths were 
observed. The relationship of these findings to the drug is unknown. There are, however, no 
adequate and well-controlled studies in pregnant women. Because animal reproduction studies 
are not always predictive of human response, and because metronidazole is a carcinogen in 
rodents, this drug should be used during pregnancy only if clearly needed. 
Nursing Mothers 
Specific studies of metronidazole levels in human milk following intravaginally administered 
metronidazole have not been performed. However, metronidazole is secreted in human milk in 
concentrations similar to those found in plasma following oral administration of metronidazole. 
Because of the potential for tumorigenicity shown for metronidazole in mouse and rat studies, a 
decision should be made whether to discontinue nursing or to discontinue the drug, taking into 
account the importance of the drug to the mother. 
Pediatric Use 
Safety and effectiveness in children have not been established. 
3.5.3.4 Adverse Events 
3.5.3.4.1 Clinical Trials 
There were no deaths or serious adverse events related to drug therapy in clinical trials involving 
800 non-pregnant women who received metronidazole vaginal gel. 
In a randomized, single-blind clinical trial of 505 non-pregnant women who received 
metronidazole vaginal gel once or twice a day, 2 patients (one from each regimen) discontinued 
therapy early due to drug-related adverse events. One patient discontinued drug because of 
moderate abdominal cramping and loose stools, while the other patient discontinued drug 
because of mild vaginal burning. These symptoms resolved after discontinuation of drug. 
Medical events judged to be related, probably related, or possibly related to administration of 
metronidazole vaginal gel once or twice a day were reported for 195/505 (39%) patients. The 
incidence of individual adverse reactions were not significantly different between the two 
regimens. 
Unless percentages are otherwise stipulated, the incidence of individual adverse reactions listed 
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 Reproductive:  Vaginal discharge (12%), Symptomatic Candida cervicitis/vaginitis 
(10%), Vulva/vaginal irritative symptoms (9%), Pelvic discomfort (3%) 
 Gastrointestinal:  Gastrointestinal discomfort (7%), Nausea and/or vomiting (4%), 
Unusual taste (2%), Diarrhea/loose stools (1%), Decreased appetite (1%), Abdominal 
bloating/gas; thirsty, dry mouth 
 Neurologic:  Headache (5%), Dizziness (2%), Depression 
 Dermatologic:  Generalized itching or rash 
 Other:  Unspecified cramping (1%), Fatigue, Darkened urine 
In previous clinical trials submitted for approved labeling of Metronidazole Vaginal Gel the 
following was also reported: 
 Laboratory:  Increased/decreased white blood cell counts (1.7%) 
3.5.4 Drug Packaging and Labeling 
All packaging and labeling of study medication will be prepared in accordance with ICH E6 
Section 5.1.3. Each subject package will consist of five empty applicators and metronidazole 
0.75% vaginal gel (GDC-229; test article), or metronidazole 0.75% vaginal gel (Oceanside 
Pharmaceuticals), or vehicle (placebo) and will be labeled with identification that maintains the 
blind, randomization number, and the FDA-required caution statement for an investigational new 
drug. The investigator or designee will record the subject identification and date dispensed on the 
packaging and will record the randomization information in the subject’s source documentation. 
Instructions for use will be provided to the subject.  
3.5.5 Drug Storage  
Study medication will be stored per the reference product label at room temperature (15 to 
30°C/59-86° F) in a secure storage area at the study site. Study medication will only be 
accessible only to designated study personnel. 
3.5.6 Drug Disposal/Return 
Study medication, used and unused, with the exception of retention samples will be returned to 
the depot per instructions provided to the sites after accountability by the clinical monitor has 
been performed. 
3.5.7 Retention Samples 
Each site will be required to randomly select reserve samples from the shipment of test articles. 
Instructions regarding the number of kits to select and how to document the kits selected as 
reserve samples will be included in the shipment. Each site will then store the reserve samples 
under conditions consistent with the approved product labeling in an area segregated from the 
area where testing is conducted, with access limited to authorized personnel only. In accordance 
with 21 CFR 320.38 and 21 CFR 320.63, each reserve sample must be retained for a period of at 
least five years following the date on which the application is approved, or, if the application is 
not approved, at least five years following the date of completion of this study. 


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3.5.8 Blinding and Unblinding 
This is a double-blind study. Every effort will be made to ensure that the investigator and 
subjects will be blinded to study treatment for the duration of the study. 
If the treatment assignment must be revealed for the safety of the subject or to treat an AE, the 
investigator will contact the medical monitor. A decision to break the blind must be reached by 
the medical monitor or designee and the investigator. 
The investigator or designee may break the blind independent of the medical monitor only if it is 
considered an emergency by the investigator. If this occurs, the medical monitor and the sponsor 
must be notified within 48 hours of breaking the blind. The event requiring breaking the blind 
must be documented in the eCRF, including the date the blind was broken. In addition, the 
subject will be discontinued from further study drug administration in this study. 
3.5.9 Treatment Compliance 
Subjects will be required to return unused study medication and unused applicators and subject 
compliance information will be captured. The sites will record return of study medication and 
supplies in the subject source documentation and eCRF and will retain all returned tubes and 
unused applicators for verification by the clinical monitor prior to return of study medication to 
the depot. Compliance will be assessed based on the subject’s verbal agreement on doses given 
and absence of unused applicators. 
3.5.10 Prior and Concomitant Medications 
Certain medications may interfere with study medication and will not be allowed during the 
course of the study.  
The following may not be used within two weeks of study Entry Visit (Visit 1) or during the 
study: 
 Disulfiram 
 Lithium 
 Topical or systemic antibiotics  
 Topical or systemic antifungals 
In addition to the above, the following may not be used at any time during the study: 
 Anticoagulation therapy 
 Cimetidine 
 Any intravaginal products including: Spermicides (including condoms with spermicide 
lubricants), douches, tampon, feminine deodorant spray, diaphragm, or vaginal ring birth 
control 
 Vaginal therapy 
 Any other investigational medication 
A subject with recent use of an exclusionary medication may participate if she has discontinued 
use of the drug for the number of days prior to the screening visit as specified in the 


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inclusion/exclusion criteria list. The reason for discontinuation of the medication must not be 
solely for participation in the study. All concomitant treatments will be recorded in the subject’s 
medical records, including the name of the drug, start and stop dates, and reason for use. Other 
prescriptions for the treatment of intercurrent medical conditions should be discussed with the 
medical monitor and recorded. 


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4 
STUDY PROCEDURES 
Refer to the Schedule of Assessments (Table 3) for timing of assessments. Additional details are 
provided in the sections that follow. Results of all procedures and assessments will be recorded 
in the subject’s source documentation and Electronic Data Capture (EDC) system. 
4.1 
Informed Consent 
Each subject must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the subject’s standard of care. 
4.2 
Subject Demographics, Height, and Weight 
The date of birth, race, ethnicity, and sex of the subject are to be recorded at the Entry Visit 
(Visit 1). Height will be measured only at the Entry Visit (Visit 1). Weight will be measured at 
Visits 1 and 3. 
4.3 
Medical and Gynecological History 
At the Entry Visit (Visit 1), a complete medical and gynecological history will be compiled for 
each subject, including prior and concomitant illnesses. The following information will be 
recorded:  acute and chronic history of medical and gynecological conditions, smoking, illicit 
drug and alcohol use history, menstrual cycle history, sexual history including history of 
sexually-transmitted infections (STIs) including BV, current sexual activity, previous/current 
contraceptive use, and pregnancy history. 
4.4 
Physical and Pelvic Examination 
A physical examination will be completed at Visits 1 and 3 and pelvic examinations will be 
completed at each visit.  
4.5 
Vital Signs 
Vital sign measurements will be completed at each visit. Vital sign measurements include sitting 
(after 5 to 10 minutes in this position) measurements of diastolic and systolic blood pressure, 
heart rate, respiratory rate, and oral temperature. 
4.6 
Concomitant Medications and Procedures 
Medications used by the subject will be recorded at each visit. 
See Section 3.5.10 for a list of medications prohibited during the study. 
4.7 
Adverse Events (AEs) 
Monitoring of AEs will be completed at all visits. Briefly, any untoward events reported by the 
subject or observed by the study staff following the first dose of study medication are to be 
recorded as AEs. Any untoward events that occur prior to this time are recorded in the medical 
history page of the eCRF. Refer to Section 8 for details regarding definitions, documentation, 
and reports of AEs and serious adverse events (SAEs).   


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4.7.1 Local Site Reactions 
Investigator or designee will assess treatment area and rate on a scale of 0 = absent, 1 = mild 
(slight, barely perceptible), 2 = moderate (distinct presence), and 3 = severe (marked, intense) 
the following at Visits 2 and 3:  
 Erythema 
 Petechiae 
 Erosion/ulceration 
 Edema 
The subject will be queried by the Investigator or designee for presence of the following and, if 
present, the subject will be asked to rate as described above: 
 Burning/stinging  
 Pain  
 Pruritus (itching)  
Local site reactions will be collected independently of AEs and will include any reaction that 
occurs within the treatment area.  Local site reactions that require medical intervention (e.g., 
prescription medication) or extend beyond the treatment area should be documented as an AE. 
4.8 
Clinical Laboratory Evaluations 
4.8.1 Urine Drug Screening 
At the Entry Visit (Visit 1), urine drug screening will be completed. 
4.8.2 Pregnancy Testing 
Pregnancy testing via urine hCG testing (serum hCG testing will be done only if deemed 
necessary by the PI) will be performed for each subject, regardless of childbearing potential, at 
each visit. Additional pregnancy testing may also be performed if there is any suspicion or 
clinical concern that a woman might be pregnant at any time during the study. 
4.8.3 Screening for Sexually Transmitted Infections 
At the Entry Visit (Visit 1) pelvic examination, a sample will be collected for assessment of 
sexually transmitted infections (STI) for Chlamydia trachomatis, Neisseria gonorrhoeae. 
4.8.4 Microbiological Sample 
A wet smear microbiological sample will be collected at each visit in order to determine if 
Amsel’s criteria are met/or resolved.  Evidence of any vulvovaginitis other than BV. 
(e.g., vulvovaginal candidiasis, Trichomonas vaginalis, Chlamydia trachomatis, Neisseria 
gonorrhoeae, active Herpes simplex, or active HPV will also be ruled out in order to ensure 
study eligibility.  In addition, a specimen for Gram stain will be collected at Visits 1 and 3.  
Details for collection, preparation, and evaluation of microbiological samples by the central lab 
will be provided in the study laboratory manual. 


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5 
SCHEDULE OF ASSESSMENTS AND STUDY VISIT 
PROCEDURES 
The study will include three visits: 
 Entry Visit (Visit 1) 
 Post-Treatment Assessment (Visit 2) 
 Test of Cure (Visit 3) 
Refer to Table 3, Schedule of Assessments. 
5.1 
Entry Visit (Visit 1) 
During the screening portion of the Entry Visit (Visit 1), the following should be completed:  
 Obtain written informed consent. 
 Perform urine pregnancy test. 
 Review and confirm inclusion and exclusion criteria. 
 Obtain demographic data. 
 Collect medical and gynecological history, including sexual history, information on the 
subject’s menstrual cycle, and history of STIs. 
 Obtain vital signs after sitting for 5 – 10 minutes (Section 4.5). 
 Record height and weight. 
 Record current medications and prior medications taken within three months prior to the 
start of screening, in addition to the indication for the medication and reasons for 
discontinuing medication. 
 Perform complete physical and pelvic examination including a vaginal wall inspection 
(i.e., a naked eye inspection) as well as an examination of the cervix. 
 Perform urine drug screening. 
 Collect Chlamydia and gonorrhea swab samples for central laboratory analysis. 
 Collect a swab sample for central laboratory Nugent’s analysis for BV via Gram stain. 
 Screen for presence of BV by assessing the subject for presence of the four Amsel’s 
criteria.  (Note: The four Amsel’s criteria are the only BV diagnostic criteria on which the 
decision to randomize is made; Nugent’s result is not used for randomization decisions). 
If the results of the Amsel’s screening tests are positive and the subject is eligible 
according to all other inclusion/exclusion criteria, the subject can be randomized to 
treatment: 
o Clinical diagnosis of BV (e.g., thin, homogeneous off-white [milky or grayish] 
vaginal discharge associated with minimal or absent pruritus inflammation); AND 
o Saline wet mount of vaginal discharge demonstrating the proportion of clue cells to 
be ≥ 20% of the total epithelial cells; AND 
o Vaginal secretion pH > 4.5; AND 


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o Positive “whiff test” after addition of a drop of 10% KOH to vaginal discharge. 
 Assess the saline wet mount for evidence of any vulvovaginitis other than BV. 
(e.g., vulvovaginal candidiasis, Trichomonas vaginalis, Chlamydia trachomatis, 
Neisseria gonorrhoeae, active herpes simplex, or active HPV) per laboratory manual. 
 An overall determination of the subject’s eligibility will be made based on the results of 
the assessments noted above as well as all inclusion and exclusion criteria 
(see Section 3.3). 
 Dispense study medication, explain appropriate application to subjects, and give the 
subject a copy of the Subject Dosing Instructions for Study Medication (Appendix 2). 
 Schedule the subject for Visit 2 and Visit 3 and add the visit dates to page 2 of the 
Subject Dosing Instructions for Study Medication.  Note: The subject should not be 
menstruating during the five days of study medication administration or be scheduled for 
Study Visits 2 or 3 when menstruating in order for assessments to be accurate. 
5.2 
Post-Treatment Assessment (Visit 2) 
Visit 2 will occur 7 to 14 days after randomization. During this visit, the following procedures 
will be performed: 
 Obtain vital signs after sitting for 5 – 10 minutes (Section 4.5). 
 Perform urine pregnancy test. 
 Perform pelvic examination including vaginal wall inspection (a naked eye inspection), 
examination of the cervix, and Investigator’s assessment of local site reactions. 
 Record subject-assessed local site reactions (e.g., itching, burning/stinging, localized 
pain). 
 Perform clinical test of response by assessing the subject for presence of these three of 
the Amsel’s criteria: 
o Resolution of the abnormal vaginal discharge characteristic of BV to a normal 
physiological discharge; AND 
o Negative “whiff test” after addition of a drop of 10% KOH to vaginal discharge; 
AND 
o Presence of clue cells at <20% of the total epithelial cells on microscopic examination 
of the saline wet mount. 
 Determine if vaginal pH is <4.7, which is part of the assessment of therapeutic cure 
(defined as clinical cure, vaginal pH <4.7 and bacteriological cure). 
 Record concomitant medications taken since the prior visit along with the indications for 
the medications. 
 Study medication remaining in the tube will be returned by subjects, including unused 
applicators.  Verify that the subject inserted the medication according to instructions and 
for five consecutive days. 
 Assess and record AEs. 


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 Confirm the date of the subject’s Visit 3 will still likely occur on a day that the subject is 
not expecting menstruation.  Note: The subject should not be menstruating during the five 
days of study medication administration or be scheduled for Study Visits 2 or 3 when 
menstruating in order for assessments to be accurate. 
5.3 
Test of Cure Visit (Visit 3) 
The Test of Cure Visit (Visit 3) will occur 21 to 30 days after Visit 1.  This is the last visit of the 
study. The following will be completed: 
 Perform physical examination. 
 Obtain vital signs after sitting for 5 – 10 minutes (Section 4.5). 
 Measure weight. 
 Perform urine pregnancy test. 
 Perform pelvic examination including vaginal wall inspection (a naked eye inspection), 
examination of the cervix, and Investigator’s (or designee’s) assessment of local site 
reactions. 
 Record subject-assessed local site reactions (e.g., itching, burning/stinging, localized 
pain). 
 Collect a swab sample for central laboratory Nugent’s analysis for BV via Gram stain. 
 Determine clinical cure of BV by assessing the subject for presence of the following three 
Amsel’s criteria: 
o Resolution of the abnormal vaginal discharge characteristic of BV to a normal 
physiological discharge; AND  
o Negative “whiff test” after addition of a drop of 10% KOH to vaginal discharge; 
AND 
o Presence of clue cells at <20% of the total epithelial cells on microscopic examination 
of the saline wet mount. 
 Determine if vaginal pH is <4.7, which is part of the assessment of therapeutic cure 
(defined as clinical cure, vaginal pH <4.7 and bacteriological cure). 
 Record concomitant medications taken since the prior visit along with the indications for 
the medications. 
 Assess and record AEs. 
5.4 
Early Discontinuation Visit 
At any time, if a subject decides to discontinue her participation in the study or is discontinued 
from the study for any reason, she will be advised to complete Early Termination procedures 
(i.e., all procedures noted for Visit 3) as an early discontinuation visit. The following will be 
completed: 
 Perform physical examination. 
 Obtain vital signs after sitting for 5 - 10 minutes (Section 4.5). 
 Measure weight. 


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 Perform urine pregnancy test. 
 Perform pelvic examination including vaginal wall inspection (a naked eye inspection), 
examination of the cervix, and local site reaction assessments. 
 Record subject-assessed local site reactions (e.g., itching, burning/stinging, localized 
pain). 
 Collect a swab sample for central laboratory Nugent’s analysis for BV via Gram stain.  
 Clinical test of response of BV will be determined by assessing the subject for presence 
of these three of the Amsel’s criteria: 
o Resolution of the abnormal vaginal discharge; AND  
o Negative “whiff test” after addition of a drop of 10% KOH to vaginal discharge; 
AND 
o Presence of clue cells at <20% of the total epithelial cells on microscopic examination 
of the saline wet mount. 
 Determine if vaginal pH is <4.7, which is part of the assessment of therapeutic cure 
(defined as clinical cure, vaginal pH <4.7 and bacteriological cure). 
 Study medication will be returned by the subject, including any unused applicators 
(unless previously collected). 
 Record concomitant medications taken since the prior visit along with the indications for 
the medications. 
 Assess and record AEs. 
5.5 Unscheduled Visit 
The investigator may see the subject for an unscheduled visit to manage or assess AEs. 
At this visit, the investigator or designee will: 
 Assess AEs and local site reactions since the last visit; AEs and local site reactions will 
be recorded. 
 Record any changes in the subject’s concomitant medications. 
 Confirm the next appointment (to be done at a time the subject does not expect to be 
menstruating). 
5.6 
Schedule of Assessments 
The schedule of assessments is provided in Table 3. 


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Table 3 
Schedule of Assessments 
Visit 
Visit 1 
Visit 2 
Visit 3 
 
Visit Name 
Entry 
Visit 
Post-
Treatment 
Assessment  
Test of Cure 
Early Terminationa 
Study Day(s) 
1 
7 to 14 
days 
21 to 30 
 
Informed consent 
X 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
Demographics 
X 
 
 
 
Medical and gynecological history 
X 
 
 
 
Physical examination 
X 
 
X 
X 
Pelvic examination 
X 
X 
X 
X 
Height 
X 
 
 
 
Weight 
X 
 
X 
X 
Vital signs (after sitting for 5 - 10 
mins) 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
Randomizationb 
X 
 
 
 
Dispense study medicationc and 
dosing instructions 
X 
 
 
 
Collect study medication 
 
X 
 
Xd 
Assessment of local site reactions 
 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
Urine pregnancy test 
X 
X 
X 
X 
Urine drug screen 
X 
 
 
 
Amsel’s criteria evaluations: 
 
 
 
 
 
-Assessment of vaginal 
 
discharge 
X 
X 
X 
X 
 
-KOH Whiff Test 
X 
X 
X 
X 
 
-Saline Wet Mount  
X 
X 
X 
X 
 
-pH 
X 
X 
X 
X 
Collection of samples for Nugent’s 
score based on Gram stain (send to 
central laboratory) 
X 
 
X 
X 
Collection of samples for STI 
assessmente (send to central 
laboratory) 
X 
 
 
 
a. 
At any time a subject decides to discontinue her participation in the study or is discontinued from the study for 
any other reason, she will be advised to complete the Early Termination procedures. 
b. 
Randomization to occur if the results of the full set of Amsel’s criteria are positive. 
c. 
Study medication will be dispensed at Visit 1.  The subject will be instructed to self-administer study 
medication intravaginally once daily at bedtime for 5 consecutive days. 
d. 
Unless collected at previous visit.   
e. 
Central laboratory analysis for Chlamydia trachomatis and Neisseria gonorrhoeae. 


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6 END OF STUDY CRITERIA 
At the end of each subject’s participation in the study, the investigator will complete an End of 
Study form for all completed and discontinued subjects. 
6.1 Completion of the Study 
Subjects who complete the 5-day treatment and all of the evaluations at the Assessment of 
Clinical Cure Visit (Visit 3) will be considered to have completed the study. 
6.2 Subject Discontinuation 
A subject may be withdrawn from the study prior to completion for any of the following reasons: 
 AEs 
 Abnormal laboratory values 
 Death 
 Lack of efficacy 
 Lost to follow-up 
 Noncompliance with study drug 
 Physician decision 
 Pregnancy (if applicable) 
 Protocol deviation 
 Study terminated by Sponsor 
 Withdrawal by subject; NOTE:  if the subject decides to withdraw from the study due to 
an AE then it should be classified as withdrawal due to an AE. 
 Other (e.g., any reason that may affect the outcome of the study or safety of subjects) 
If a subject withdraws prematurely for any reason, the site should make every effort to have the 
subject return for her next scheduled visit to perform all required visit activities and to collect 
and reconcile all test article. If the subject is discontinued prior to the Assessment of Clinical 
Cure Visit (Visit 3; Day 21 to 30), the site should complete the End of Study eCRFs during the 
last visit that the subject will complete. Subjects who withdraw prematurely will not be replaced. 
When a subject is withdrawn from the study for a treatment-related AE (i.e., as defined in 
Section 8.1.2), when possible, the subject should be followed until resolution or stabilization of 
the AE. If a subject is discontinued from the study due to pregnancy, the pregnancy and its 
outcome should be followed (see Section 8.1.5). 


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6.3 Study Termination 
The study may be terminated by the Sponsor. If, in the opinion of the investigator, clinical 
observations made during the study suggest that it may be unwise to continue, he or she may 
discontinue his or her participation in the study.   
If an investigator decides to terminate his or her participation, a written statement fully 
documenting the reasons for this action will be submitted to the Sponsor by the investigator 
within five working days. 
In the event that the Sponsor chooses to discontinue or terminate the study, appropriate 
notification will be given to the investigator. 


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7 
EVALUATIONS 
7.1 
Efficacy Parameters 
The primary efficacy endpoint (Clinical Cure) is the resolution of the following three abnormal 
BV signs included in Amsel’s criteria: return to normal physiological vaginal discharge as 
determined by the investigator, negative whiff test, and the presence of clue cells at <20% of the 
total epithelial cells on microscopic examination of the saline wet mount.  
The supportive secondary efficacy endpoints are the Bacteriological Cure and the Therapeutic 
Cure.  The bacteriological cure is defined as Nugent’s score <4 (via Gram stain central 
laboratory analysis). A Nugent score ≥4 is considered abnormal and represents an imbalance in 
vaginal flora that permits BV to manifest (Nugent 1991). Subjects who are responders are 
expected to achieve a normal Nugent score (i.e., 0 to 3) following treatment. 
Therapeutic cure is defined as having achieved clinical cure, vaginal pH of <4.7, and 
bacteriological cure (i.e., Nugent score of < 4 at Visit 3). 
7.2 
Safety Evaluation 
Each subject’s health status will be monitored carefully throughout the study. Baseline data 
collected will consist of the medical and gynecological history and physical examination 
findings, including pelvic examinations (to include STI screening for Chlamydia and gonorrhea). 
Vital signs include oral temperature, sitting blood pressure, heart rate, and respiratory rate. Blood 
pressure will be collected after sitting for 5 to 10 minutes and should be taken from the same arm 
at each visit. 
Weight will be recorded at the Entry Visit (Visit 1) and the Assessment of Continued Clinical 
Cure Visit (Visit 3). 
Subjects who withdraw from the study will have all safety assessments repeated except for urine 
drug and STI testing, if the subject allows. 
At every visit or contact, subjects will be questioned about how they have been feeling and any 
symptoms they have experienced. Interviews with subjects will include a review of any AE 
reported in order to obtain as much information as possible (e.g., onset date, duration, intensity). 
The AEs will be recorded at each visit in the medical records and the eCRF. See Section 8.1 for 
AE definitions and criteria, including assessments for intensity and relatedness.  In addition, 
local site reactions based on investigator examination and subject self-report will assessed at 
Visits 2 and 3. 
The principal investigator (or designated medical designee) will review each AE, assess severity 
and causality and will report it in accordance with established procedures (see Section 8.1.1.4). 
There will be strict adherence to SAE reporting (see Section 8.1.3.2). 
7.3 
Appropriateness of Measurements 
As stated in Section 3.2, the study design relied heavily on the recommendations provided in 
FDA draft guidances. 


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8 
SAFETY 
The primary method of assessing safety will be collection and analysis of AEs. AEs and SAEs 
will be carefully monitored throughout this study. 
8.1 
Adverse Events and Serious Adverse Events 
8.1.1 Definitions and Criteria 
8.1.1.1 Adverse Events (AEs) 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered related. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal product. 
Suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the AE. “Reasonable possibility” means there is evidence to suggest a causal relationship 
between the drug and the AE. A suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any AE caused by a drug. 
An adverse reaction is any AE 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. For the 
purposes of prescription drug labeling, the term adverse reaction is defined to mean “an 
undesirable effect, reasonably associated with the use of a drug that may occur as part of the 
pharmacological action or may be unpredictable in its occurrence. This definition does not 
include all AEs observed during use of a drug, only those AEs for which there is some basis to 
believe there is a causal relationship between the drug and the occurrence of the AE”. 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the RLD 
package insert or is not listed at the specificity or severity that has been observed. For example, 
under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the 
RLD package insert referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) 
if the RLD package insert listed only cerebral vascular accidents. "Unexpected," as used in this 
definition, also refers to AEs or suspected adverse reactions that are mentioned in the RLD 
package insert as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with the particular drug 
under investigation. 
Timely and complete reporting of all AEs assists 
 in identifying any 
untoward medical occurrence, thereby allowing:  
1) protection of the safety of study subjects;  
2) a greater understanding of the overall safety profile of the test article;  
3) recognition of dose-related test article toxicity; 
4) appropriate modification of study protocols;  
5) improvements in study design or procedures; and  


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6) adherence to worldwide regulatory requirements. 
Any adverse change from the study participant’s baseline condition that occurs following the 
first administration of study product is an AE. This includes the occurrence of a new AE or the 
worsening of a baseline condition, whether or not considered related to the study product. AEs 
include but are not limited to: adverse changes in the general condition of the study participant; 
signs and symptoms noted by the study participant or her caregiver; concomitant disease with 
onset or increased severity after the start of study product administration and clinically 
meaningful adverse changes in laboratory safety parameters occurring after the start of study 
product administration. Day-to-day fluctuations in pre-existing conditions that represent a 
clinically significant change in the participant’s status should be reported as AEs. 
8.1.1.2 
Local Site Reactions 
Investigator or designee will assess treatment area and rate on a scale of 0 = absent, 1 = mild 
(slight, barely perceptible), 2 = moderate (distinct presence), and 3 = severe (marked, intense) 
the following at Visits 2 and 3:  
 Erythema 
 Petechiae 
 Erosion/ulceration 
 Edema 
The subject will be queried by the Investigator or designee for presence of the following and, if 
present, the subject will be asked to rate as described above: 
 Burning/stinging  
 Pain  
 Pruritus (itching)  
Local site reactions will be collected independently of AEs and will include any reaction that 
occurs within the treatment area.  Local site reactions that require medical intervention (e.g., 
prescription medication) or extend beyond the treatment area should be documented as an AE. 
8.1.1.3 Serious Adverse Events (SAEs) 
An AE is considered “serious” if, in the view of either the investigator or sponsor, it meets the 
criteria for any of the following outcomes: 
1. Death. 
2. Life-threatening. This term refers to an event in which the participant was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if it were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization. In general, 
hospitalization signifies that the participant has been admitted (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting. 


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Complications that occur during hospitalization are AEs or SAEs as defined above. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. Hospitalization for elective treatment or procedures of a 
pre-existing condition that did not worsen from baseline is not considered an AE. 
4. Results in persistent or significant disability/incapacity. The term disability means a 
substantial disruption of a person’s ability to conduct normal life functions. This 
definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental 
trauma (e.g., sprained ankle) which may interfere or prevent everyday life functions but 
do not constitute a substantial disruption. 
5. Is a congenital anomaly/birth defect. 
Medical or scientific judgment should be exercised in deciding whether (expedited) reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the above 
definition. These medically important events should also be considered SAEs. Examples of 
medically important events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that result in hospitalizations; or development of 
drug dependency or drug abuse. 
In addition, cancer and drug overdose are included in 
 classification of an SAE. 
8.1.1.4 Unexpected Adverse Drug Reactions 
All AEs should be reported, whether or not they are considered to be related to the treatment. 
The report of AEs should include date of onset, description of the AE, severity, relation to study 
medication, action taken, outcome, and date of resolution. This information is needed to 
determine if the incidence and severity of adverse reactions is different between the test articles. 
8.1.2 Assessing Intensity and Relationship of Adverse Events 
8.1.2.1 Intensity 
The intensity of the AE will be characterized as mild, moderate, or severe using the following 
criteria: 
 Mild:  Subject was aware of the event, but was still able to do all activities 
 Moderate:  Subject had to discontinue some activities due to the event 
 Severe:  Subject was incapacitated by the event and unable to perform normal activities 
8.1.2.2 Relationship to Study Drug 
The site investigator is responsible for assessing the relationship between the AE and the study 
product. The investigator must determine whether there is a reasonable possibility that the study 
product caused or contributed to an AE. The relationship assessment, based on clinical judgment, 
often relies on the following: 
 A temporal relationship between the event and administration of study product 


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 A plausible biological mechanism for the study product to cause the AE 
 Another possible etiology of the AE 
 Previous report of similar AEs associated with the study product or other agents in the 
same class 
The terms used to assess the relationship of an AE to study drug are included in Table 4. 
Table 4 
Assessment of Causality and Relationship to Study Drug 
Causality 
Assessment 
Criteria for Assessment (note that re-challenge will not be done in this 
study) 
Related 
The experience occurs immediately following study drug administration, 
related pharmacologically (not related to underlying condition/concurrent 
disease or other drugs or chemicals) and follows a known response pattern to 
the study drug. 
Possibly Related 
The experience follows a reasonable temporal sequence from the time of drug 
administration and/or follows a known response pattern to the trial drug but 
could have been produced by other factors such as the participant’s clinical 
state, therapeutic intervention or concomitant therapy.  
Not Related 
There is not a reasonable possibility that the AE is related to the study product; 
when an AE is assessed as not related to the study product, an alternative 
etiology, diagnosis or explanation for the AE should be documented. If new 
information becomes available, the relationship of any AE should be reviewed 
again and updated, as required. 
8.1.3 Reporting Procedures and Requirements for Adverse Events 
8.1.3.1 Study Reporting Period for Adverse Events 
At every visit or contact, study staff will ask each participant how she felt since her last visit and 
indirectly ask if she has experienced any AEs. 
The reporting period for AEs is the period immediately following the signing of the ICF through 
30 days after last use of study product. 
For the purposes of study analysis, if a non-serious AE has not resolved at the end of the study-
reporting period it will be reported as still ongoing in the EDC system. However, the investigator 
must make every reasonable effort to follow the event to resolution or stabilization and report to 
. 
SAEs must be followed until resolution. Resolution of an SAE is defined as the return to baseline 
status or stabilization of the condition with the expectation that it will remain chronic. 
8.1.3.2 Recording of Adverse Events 
AEs will be reported in the EDC system using a recognized medical term or diagnosis that 
accurately reflects the event. Information recorded in the EDC system must be substantiated in 
the source documents. All AEs must be recorded in the participant’s source documents and must 
include the following information (when applicable): 


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 Specific condition or event. 
 Possible etiologies and whether the event meets criteria as an SAE and therefore requires 
immediate notification to the sponsor. (See Section 8.1.1.3 for the definition of SAEs.) 
 Indication of whether the condition was preexisting prior to study entry or not and if yes, 
whether it has worsened in severity or frequency, in which case it is reported as an AE. 
Conditions present prior to study entry that do not worsen in severity are not considered 
AEs. 
 Date of occurrence. 
 Date of resolution. If the event has not resolved at the end of the study-reporting period, it 
will be reported as still present in the EDC system. 
 AEs that change in intensity are recorded at the most severe intensity level that is 
reported by the participant. 
 Relationship to study product as evaluated by the investigator (causality assessment). 
 Action taken with the study product per the investigator medical judgment (study product 
interrupted, discontinued or none) and outcome. 
 Seriousness: An SAE, in accordance with 21 CFR 312.32 (a), means “any adverse event 
occurring at any dose that results in any of the following outcomes: death, a life 
threatening adverse drug experience, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant disability/incapacity or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-
threatening or require hospitalization may be considered a serious adverse drug 
experience when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization or development of 
drug dependency or drug abuse.” In addition, cancer and drug overdose are included in 
 classification of an SAE. 
8.1.3.3 Notification to Sponsor of Serious Adverse Events 
All SAEs will be reported promptly in accordance with the FDA regulations and recorded on the 
appropriate forms. 
WHEN ANY SAE, REGARDLESS OF RELATIONSHIP TO THE STUDY PRODUCT, IS 
ENCOUNTERED DURING THIS CLINICAL TRIAL AT AN INVESTIGATOR’S SITE, 
THE INVESTIGATOR, IN ACCORDANCE WITH 21 CFR 312.64(b), MUST NOTIFY 
 WITHIN 24 HOURS OF IDENTIFICATION/AWARENESS OF 
THE SAE BY REPORTING THE EVENT VIA THE EDC SYSTEM AND VIA THE SAE 
REPORTING FORM FOR THIS STUDY. SAE SUBMISSION SHOULD BE 
COMPLETED FOR ANY SAE THAT IS EXPERIENCED AFTER THE SUBJECT HAS 
SIGNED THE ICF, EVEN IF INVESTIGATIONAL PRODUCT HAS NOT YET BE 
ADMINISTERED. 




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8.1.3.5 Reconciliation of Safety Data 
All safety data will be reviewed throughout the study and information submitted on SAE report 
forms will be reconciled with data collected via the EDC system. Each SAE must have a 
corresponding AE recorded in the study database. Subject source documents will be reviewed 
during site audits and study monitoring visits to determine if there are any unreported AEs. 
8.1.4 Laboratory Test Abnormalities 
If an abnormal laboratory result indicated as clinically significant by the investigator is the 
reason for a subject being withdrawn from the study or requires treatment for the abnormality, 
this abnormal result must also be reported as an AE. In addition, any laboratory test result that 
meets the criteria for an SAE (see Section 8.1.1.3) must also be reported as an SAE so 
 
 can collect additional information about that abnormality, including information 
regarding relationship to test article or other causes, any action taken, and outcome. 
8.1.5 Pregnancy 
Women of childbearing potential include any female who has experienced menarche or is 18 
years of age or older and who has not undergone successful surgical sterilization (hysterectomy, 
bilateral tubal ligation [at least six months prior to initiation of treatment], or bilateral 
oophorectomy) or is not postmenopausal (defined as amenorrhea >12 consecutive months in 
women 50 years of age and older). Even women who are using one of the effective forms of 
birth control per protocol will be considered of childbearing potential. 
Women of childbearing potential must have a urine pregnancy test prior to study enrollment and 
must use an effective method of birth control during the course of the study, in a manner such 
that risk of failure is minimized. Prior to study enrollment, women of childbearing potential must 
be advised of the importance of avoiding pregnancy during the study and the potential risk 
factors for an unintentional pregnancy. The subject must sign an ICF documenting this 
discussion. 
Women of childbearing potential should be instructed to contact the investigator immediately if 
they suspect they might be pregnant (e.g., missed or late menstrual period). If a subject or 
investigator suspects that a subject may be pregnant at any time during the study, the test article 
must be withheld until the results of laboratory pregnancy testing are available. If pregnancy is 
confirmed, the subject must not receive or apply further test article and must be discontinued 
from the study. 
If following initiation of study treatment, it is subsequently discovered that a study subject was 
pregnant or may have been pregnant at the time of test article exposure, the investigator must 
immediately notify the Medical Monitor of this event, and record the pregnancy on the 
appropriate pregnancy surveillance form. The form will be sent to 
. The 
investigator must notify the IRB of any pregnancy associated with the study therapy and keep 
careful source documentation of the event. 
Protocol-required procedures for those subjects that are discontinued from the study must be 
performed on the subject unless contraindicated by pregnancy (e.g., x-ray studies). Other 
appropriate pregnancy follow-up procedures should be considered if indicated, including 


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counseling of the subject by the investigator and her managing physician or health care provider 
(e.g., obstetrician). In addition, the investigator must report to 
, on the 
appropriate 
 pregnancy surveillance form(s), any follow-up information 
regarding the course of the pregnancy, including perinatal and neonatal outcome. Although 
pregnancy itself is not an AE, any complications during pregnancy should be recorded as AEs or 
SAEs (if they fulfill the SAE criteria). Offspring should be followed for a minimum of eight 
weeks. Any congenital anomaly/birth defect in a child born to a subject exposed to the test 
article(s) should be recorded as a SAE and details documented in the pregnancy surveillance 
form. Abortion, whether accidental, therapeutic, or spontaneous should be reported as a SAE. 
8.2 
Other Safety Concerns 
The Contraindications, Warnings, Precautions, Drug Interactions, and Adverse Reactions 
associated with the use of metronidazole are described in the approved product labeling for 
metronidazole 0.75% vaginal gel (Oceanside Pharmaceutical). A brief summary of each is 
described Section 3.5.3. 


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9 
STATISTICAL AND ANALYTICAL METHODS  
The statistical analysis will be conducted by 
 in collaboration with Gage 
Development Company, LLC 
A detailed statistical analysis plan will be finalized before the code for all subjects is broken and 
prior to locking the database to expand upon the statistical methods presented below. Any 
deviations from the analysis described below will be included in the SAP, which will be included 
in Appendix 16.1.9 of the clinical study report. 
All baseline and efficacy data will be summarized and analyzed by treatment. 
9.1 
Sample Size 
Assuming the test and reference clinical cure rates are within 4% of each other, the placebo 
clinical cure rate is 20%, the test and reference clinical cure rates are at least 36% and 12.4% of 
randomized subjects do not qualify for the modified Intent-to-Treat (mITT) population, then 603 
subjects will be required to achieve at least 90% power for superiority and bioequivalence 
(Schwebke 2015; Chavoustie 2015). However, the previous studies that were used to estimate 
effect size had significant differences in study design and definition of primary endpoint.  Taking 
these differences into consideration, 738 subjects will be randomized.  The assumption of a 36% 
test and reference clinical cure rate was derived after review of the FDA statistical review of 
Metronidazole vaginal gel 1.3% (Center for Drug Evaluation and Research 2014). 
9.2 
Analysis Populations 
The following subject populations will be created: 
 Intent-to-Treat (ITT) Population:  All randomized subjects. 
 Safety Population:  All subjects who receive at least 1 dose of study drug. 
 Modified Intent-to-Treat (mITT) Population:  All randomized subjects excluding those 
who subsequently demonstrate a positive test result for other concomitant vaginal or 
cervical infections at baseline (e.g. C trachomatis, N. gonorrhoeae) which may interfere 
with the efficacy assessment for BV or who have a baseline Nugent score < 4. 
 Per Protocol (PP) Population:  Includes all subjects who qualify for the mITT population 
and who follow important components of the trial (including subjects who adhere to 
treatment and follow-up for efficacy within the prescribed timeframe). 
Subjects in the MITT population who discontinue early from the study and do not have an 
assessment of clinical cure and bacteriological cure will be included in the mITT population 
analyses as treatment failures. These subjects without outcomes, but are classified as treatment 
failures will not be included in the PP analyses.  
To establish bioequivalence, the 90% confidence interval for the primary endpoint (the 
difference in the proportion of subjects achieving a clinical cure between metronidazole 0.75% 
vaginal gel (GDC-229; test product) and metronidazole 0.75% vaginal gel (Oceanside 
Pharmaceuticals) must be within [0.20, +0.20] for dichotomous variables, using the PP 
population. 


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9.3 
Disposition of Subjects 
The number of subjects who are enrolled and treated and complete the clinical trial will be 
tabulated. A disposition graph of subjects will be provided. 
9.4 
Demographic and Other Subject Characteristics 
Subject demographics and pre-admission characteristics will be summarized descriptively. 
9.5 
Extent of Exposure 
Exposure to study product will be summarized by the number of doses used and length of time 
over which the product is used. 
9.6 
Efficacy Analyses 
9.6.1 Primary Endpoints 
The primary endpoint is the clinical cure at the Test of Cure Visit (Visit 3) and includes the 
following: 
 Resolution of the abnormal vaginal discharge to a normal physiologic discharge 
 Negative whiff test 
 Presence of clue cells at < 20% of the total epithelial cells on microscopic examination of 
the saline wet mount 
The mITT population will be used to compare both the test and reference products to placebo. 
The PP population will be used to evaluate bioequivalence between the test and reference 
products. 
To assess adequate study sensitivity the test and references products need to be statistically 
superior (p<0.05, 2-sided) to placebo using the mITT population. 
To establish bioequivalence, the 90% confidence interval for the primary endpoint (the 
difference [test-reference] in clinical cure rate) must be within [-0.20, +0.20], using the PP 
population. 
9.6.2 Secondary Endpoints 
Secondary endpoints include the following as assessed at the Test of Cure (Visit 3): 
 Nugent score of < 4  
 Responder outcome (therapeutic cure) defined as follows: 
o Clinical cure as defined in the Primary Endpoint 
o Vaginal pH < 4.7  
o Nugent score of < 4 (i.e., bacteriological cure) 
9.7 
Safety Parameters 
All safety analyses will be performed using the Safety Population. 


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9.7.1 Adverse Events 
Safety will be evaluated by incidence of premature discontinuations and AEs. Summaries will be 
provided for all AEs reported, and separately for AEs leading to study discontinuation. Serious 
AEs will be listed separately and described by narrative. 
9.7.2 Incidence of Adverse Events 
The number (percentage) of subjects with at least one AE will be presented in a frequency table. 
Summaries will also be presented by relationship to the study treatment and intensity of AE. 
9.7.3 Discontinuation Due to Adverse Events 
Subjects who are discontinued due to an AE will be listed by research center. In cases where 
multiple AEs are involved in the discontinuation, the investigator must make a determination on 
which single AE was the primary reason for discontinuation. Specific information about the AEs 
will be included in the final clinical study report. A narrative for each AE leading to 
discontinuation will be provided. 
9.7.4 Serious Adverse Events (SAEs) 
Subjects with SAEs will be listed by center with the following variables included: SAE 
description (as reported by investigator), MedDRA “included” term, MedDRA “preferred” term, 
MedDRA system-organ class (based on the “include” term), start and stop days relative to the 
date of first dose, maximum intensity, relationship to the investigational, action taken with the 
study product per the investigator’s judgment, and outcome. 
9.7.5 Deaths 
Subjects who die during the clinical trial will be listed by center with the following variables will 
be included: main reason(s) for death (as reported by the investigator), diagnosis of the SAE 
contributing to the death, date of death relative to the first day of product use, and relationship to 
investigational product. Subject SAE narratives will be part of the final clinical study report. 


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10 
MEDICAL MONITOR 
The Medical Monitor for this study is: 
 
 
 
 
 
 
 
 
The Medical Monitor will be responsible for collaborating with the investigator and Sponsor to 
make determinations regarding subject eligibility, inclusion and exclusion criteria interpretations, 
and safety issues, and for managing reporting of the SAEs that occur in the study.  A detailed 
medical monitoring plan will be written before the study begins. 


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11 
ETHICAL AND REGULATORY CONSIDERATIONS 
11.1 
Compliance with Good Clinical Practice 
All aspects of this multicenter clinical trial will be carried out in accordance with Good Clinical 
Practice (GCP) as required by the following:  United States (US) Code of Federal Regulations 
(CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR Parts 50, 54, 56, 312, and 320), 
ICH E6, and the 2013 revision of the Declaration of Helsinki. 
These guidelines are on file at 
. 
11.2 
Interactions with Institutional Review Boards (IRBs) 
This protocol will be reviewed by the IRB. This protocol and any protocol amendments, together 
with any required additional documentation (e.g., ICFs, subject information sheets, advertising 
materials, etc.), will be submitted by each site to its responsible IRB according to the applicable 
requirements at each site. The study will commence at each participating site only after its IRB 
has granted full approval. Investigators/institutions will permit trial-related monitoring, audits, 
IRB reviews, and regulatory inspection(s) and will provide direct access to source data and 
documents in order for these activities to be performed. No drug will be shipped to a site until 
written IRB authorization has been received by the Sponsor or its representative. 
11.3 
Informed Consent 
Principal investigators must provide 
 (on behalf of Gage Development 
Company, LLC) with a copy of the ICF approved by their local IRB. All translations of Informed 
Consent documents should be certified. 
Under informed consent, the subject shall understand that she is authorizing access to medical 
records as required for monitors, auditors, IRBs, and regulatory authorities. Subjects that agree to 
participate in the study must sign the ICF prior to study-specific procedures. The principles of 
informed consent will be implemented according to the 1996 revision of the Declaration of 
Helsinki, and FDA regulations. The sites must also follow Health Insurance Portability and 
Accountability Act (HIPAA) requirements in documenting subjects’ authorization for the use of 
protected health information for study purposes. 
It is the investigator's responsibility to assure that each subject is provided an explanation of the 
details contained in the informed consent statement and other locally-required documents prior to 
the individual signing the ICF certifying her voluntary participation in the trial and prior to study 
participation. Under informed consent, the subject shall understand that she is authorizing access 
to medical records as required for monitors, auditors, IRBs, and regulatory authorities. 
The subjects will be informed of their right to privacy and the fact that personal information will 
be treated as strictly confidential and will not be publicly available in accordance with HIPAA 
regulations. They will also be informed that 
 and the FDA have the right to 
inspect and possibly photocopy their medical records to verify the accuracy and completeness of 
the clinical trial results. The subject is to receive a copy of the consent form after it has been 
signed and dated. The subject’s copy can be unsigned if this is the requirement of the local IRB. 


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Prior to study participation, all study candidates will: 
 Be informed of the nature and purpose of the study. 
 Be given an explanation of the procedures to be followed in the study. 
 Be given a description of any attendant discomforts and risks reasonably to be expected 
from the study, as well as from the study product. 
 Be given an opportunity to ask any questions concerning the study. 
 Be instructed that consent to participate in the study may be withdrawn by the participant 
at any time; and that the participant may discontinue participation in the study without 
prejudice. 
 Be given a copy of the signed ICF. 
 Be given the opportunity to decide to consent or not to consent to the study without 
coercion. 
 Be given information for whom to contact if there are questions about the research, 
participant rights, or to report research-related injury.  
11.4 
Confidentiality 
The information on individual subjects arising from this study is to be considered confidential 
and transmitted to the sponsor only in a form that will not permit identification of the individual. 
Regulatory and sponsoring agencies may request access to the study records and related medical 
records of each participating subject; the subject’s identity will remain confidential to the extent 
permitted by the applicable laws and regulations. The results of the research will be released to 
public agencies including regulatory agencies, clinical investigators, and research organizations 
without reference to items identifiable to a particular subject. The results will be published such 
that the identity of the subjects will not be disclosed and cannot be ascertained. National and 
international agencies and sponsoring agencies may request access to the medical records of each 
participating subject, and if requested, the subject’s identity will remain confidential. All records 
will be kept in a secure storage area with limited access.  




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start of the clinical trial, the investigator will complete an authorized signature sheet showing the 
signatures and handwritten initials of all individuals who are authorized to maintain study 
records and submit data using the EDC system. More detailed instructions regarding the EDC 
system will be provided by 
 in training and the instructions documents. The data 
in the database, including any updates as a result of data cleaning, will be compared to the source 
documents at subsequent monitoring visits. 
12.5 
Data Handling and Processing 
Data handling will be completed by 
. 
’ EDC system will be 
used to create, modify, maintain, archive, retrieve, and transmit study data generated for the 
clinical trial. The research centers will record clinical trial data (except for the central laboratory 
data) on an electronic web-based CRF (i.e., eCRF). Laboratory data from the central laboratory 
will be sent electronically to 
 and imported into a SAS database maintained by 
the 
’ Biometrics Department. 
’ Data Management will follow 
written SOPs for processing EDC data. Archiving of the EDC data will be done by the EDC 
vendor. 
12.6 
Confidentiality and Reporting of Results 
The information on individual subjects arising from this study is to be considered confidential 
and transmitted to the sponsor only in a form that will not permit identification of the individual. 
Regulatory and sponsoring agencies may request access to the study records and related medical 
records of each participating subject and the subject’s identity will remain confidential to the 
extent permitted by the applicable laws and regulations. All records will be kept in a secure 
storage area with limited access. 
The information obtained from the subjects that can be identified with the subject will remain 
confidential within the research team. Subject names will not be entered into the EDC system; 
instead, unique subject identifiers will be assigned to the subject. The results of the research will 
be released to public agencies including regulatory agencies, clinical investigators, and research 
organizations without reference to items identifiable to a particular subject. Medical records will 
be kept at the research center and will be available to study staff, 
, or the FDA 
only while at the study site. The results will be published such that the identity of the subjects 
will not be disclosed and cannot be ascertained. All data will only be used for the purpose for 
which it has been approved. Data collected during this study and any analyses of that data will 
not be used in any way other than those ways already approved without further approval from 
. 
12.7 
Retention of Data 
The Investigator will maintain adequate records of the study including subjects’ eCRFs, medical 
records, laboratory reports, consent form, drug disposition records, safety reports, information 
regarding participants who discontinued, and other pertinent data. All records are to be retained 
by the Investigator for a period of at least 2 years after the last approval of a marketing 
application or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product (per FDA CFR 312.62, “2 years after the 
investigation is discontinued and FDA is notified.”). These documents should be retained for a 


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longer period, however, if required by the applicable regulatory requirements or by an agreement 
with the sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to 
when these documents no longer need to be retained. The Investigator will contact 
 
 for authorization prior to destruction of any such records or in the event of accidental 
loss or destruction of any study records. 
12.8 
Publication Policy 
Data on the use of the study medication and results of all clinical and laboratory studies are 
considered private and the confidential information of Sponsor. Any publications or 
presentations that result from this study will maintain participant confidentiality. Proprietary 
information about the investigational drug is maintained under the supervision of Sponsor. 
Institutions and/or the principal investigators agree to submit all proposed publications, papers, 
abstracts, manuscripts, posters or other written materials which include data relating to the Study 
or the use of the product supplied under this Agreement (“Proposed Publication”), including 
without limitation all outlines of any proposed oral presentations with respect thereto, to the 
Sponsor at least thirty (30) days prior to either (a) submission of such Proposed Publication (b) 
any proposed oral disclosure to a third party outside of 
. The Sponsor shall have 
the right to comment on such Proposed Publications within (30) days of receipt, and such 
comments shall be considered in good faith by the principal investigators in determining the final 
form of disclosure.  Upon request of Sponsor, Institution and/or principal investigator shall delay 
publication of such Proposed Publication an additional sixty (60) days to permit Sponsor to take 
necessary actions to protect its intellectual property interests.  The Sponsor shall also have the 
right to eliminate any reference to confidential or proprietary information provided to Institutions 
and/or the principal investigators or the Study staff pursuant to this Agreement. 
12.9 
Reimbursement, Indemnity, and Insurance 
Reimbursement, indemnity, and insurance are addressed in separate documentation. 
12.10 
Adherence to the Protocol 
Except for a change that is intended to eliminate an immediate hazard to subjects, the approved 
protocol shall be conducted as described. All protocol deviations must be documented. Any 
protocol-related issues that pose an immediate or significant hazard to subjects must be reported 
to 
 on behalf of Gage Development Company, LLC immediately. 


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13 
INVESTIGATOR OBLIGATIONS 
Clinical research studies are subject to the regulations of the FDA. Prior to beginning the study, 
the investigator will be asked to demonstrate compliance with ICH E6, 8.2 and 21 CFR 312 by 
providing 
 with the signed essential documents required for the clinical trial. 
The responsibilities imposed upon investigators by the FDA are summarized in the “Statement of 
Investigator Form” (Form FDA-1572) which documents that he or she will follow the FDA 
regulations with respect to this study. 
The investigator agrees to assume the responsibilities stated on the Form FDA-1572, and 
signifies his or her agreement by signing the Form FDA-1572, these responsibilities include: 
 To conduct the study in accordance with the Study Protocol, Reference Drug Label, 
GCPs, International Conference on Harmonisation (ICH), and Declaration of Helsinki. 
 To secure prior approval of the study by an appropriate IRB. This board should be 
constituted in conformity with FDA regulations. 
 To report on the progress of the study to the IRB and to submit a final report within three 
months of the conclusion of data collection. 
 To maintain current records of the receipt, dispensing, and disposition of study product 
and to return all unused product to the sponsor or the sponsor’s designated agent. 
 To obtain a valid, fully informed, freely given written consent from each subject who 
participates in the study. 
 To maintain adequate study documentation, including hospital records, laboratory results 
and lab records, and to store these case histories for a minimum of two years following 
notification by the sponsor that all investigations have been discontinued or that the FDA 
has approved the drug application. 
 To identify all sub-investigators who will also supervise drug administration. 
 To report all AEs to the sponsor or designated agent promptly. 
 To allow inspection or copying by the FDA, sponsor, or sponsor’s designated agent of 
case histories and records of drug distribution. 
Investigator Documentation required: 
Prior to beginning the study, the investigator will be asked to comply with ICH E6, 8.2 and 21 
CFR 312 by providing the following essential documents, including but not limited to: 
1. A signed Protocol Signature Page. 
2. A signed acknowledgement of receipt of the US Prescribing Information for the reference 
drug. 
3. An IRB-approved Informed Consent. 
4. IRB approval of protocol and ICF. 
5. Form FDA 1572, fully executed, and all updates on a new fully executed Form FDA 
1572.  


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6. Current Curriculum Vitae (CV) for the principal investigator and each sub-investigator 
listed on Form FDA 1572. 
7. Medical license for principal investigator 
8. A signed declaration of any financial conflict of interest (i.e., Financial Disclosure Form, 
financial disclosure).  


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14 
REFERENCES  
Amsel R, Totten PA, Spiegel CA, et al. Nonspecific vaginitis: diagnostic criteria and microbial 
and epidemiologic associations. Am J Med. 1983;74(1):14-22. 
CDC Fact Sheet. Bacterial Vaginosis. Last reviewed 20 Dec 2016. 
https://www.cdc.gov/std/bv/bv-fact-sheet-dec-2016.pdf. 
Center for Drug Evaluation and Research. Application Number 205223Orig1s000. Statistical 
Reviews. Statistical Review and Evaluation of metronidazole vaginal gel 1.3%. Review date 
January 18, 2014. 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205223Orig1s000StatR.pdf 
Chavoustie SE, Jacobs M, Reisman HA, et al. Metronidazole vaginal gel 1.3% in the treatment 
of bacterial vaginosis:  a dose-ranging study. J Lower Genital Tract Disease. 
2015;19(2):129-134. 
Eltabbakh GH, Eltabbakh GD, Broekhuizen FF, et al. Value of wet mount and cervical cultures 
at the time of cervical cytology in asymptomatic women. Obstet Gynecol. 1995;85(4):499–503. 
Flagyl (metronidazole) NDA 012623, Approval Date 7/18/1963.  
http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=01
2623. 
Korn AP, Bolan G, Padian N, et al. Plasma cell endometritis in women with symptomatic 
bacterial vaginosis. Obstet Gynecol. 1995;85(3):387–90. 
Nugent RP, Krohn MA, and Hillier SL. Reliability of diagnosing bacterial vaginosis is improved 
by a standardized method of gram stain interpretation. J Clin Micro. 1991;29(2):297-301. 
Metronidazole 0.75% Vaginal Gel (Oceanside Pharmaceuticals) USPI. Rev. 4/2015. 
https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=526c226a-099b-4eb3-943d-
c88b2763b2c1&type=display. 
Schwebke JR, Marrazzo J, Beelen AP, et al. A Phase 3, multicenter, randomized, double-blind, 
vehicle-controlled study evaluating the safety of efficacy of metronidazole vaginal gel 1.3% in 
the treatment of bacterial vaginosis. Sexually Transmitted Diseases. 2015;42(7):376-381. 
 


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Appendix 1 
U.S. PRESCRIBING INFORMATION FOR THE REFERENCE DRUG 
METRONIDAZOLE- metronidazole gel 
Oceanside Pharmaceuticals 
---------- 
Metronidazole Vaginal Gel, 0.75% 
FOR INTRAVAGINAL USE ONLY 
NOT FOR OPHTHALMIC, DERMAL, OR ORAL USE 
DESCRIPTION 
Metronidazole Vaginal Gel is the intravaginal dosage form of the synthetic antibacterial agent, 
metronidazole, USP at a concentration of 0.75%. Metronidazole is a member of the imidazole 
class of antibacterial agents and is classified therapeutically as an antiprotozoal and antibacterial 
agent. Chemically, metronidazole is a 2-methyl-5-nitroimidazole-1-ethanol. It has a chemical 
formula of C6H9N3O3, a molecular weight of 171.16, and has the following structure: 
 
 
 
 
Metronidazole Vaginal Gel is a gelled, purified water solution, containing metronidazole at a 
concentration of 7.5 mg/g (0.75%). The gel is formulated at pH 4.0. The gel also contains 
carbomer 934P, edetate disodium, methylparaben, propylparaben, propylene glycol, and sodium 
hydroxide.  
 
Each applicator full of 5 grams of vaginal gel contains approximately 37.5 mg of metronidazole. 
 
CLINICAL PHARMACOLOGY 
 
Normal Subjects: 
Following a single, intravaginal 5 gram dose of metronidazole vaginal gel (equivalent to 37.5 mg 
of metronidazole) to 12 normal subjects, a mean maximum serum metronidazole concentration 
of 237 ng/mL was reported (range: 152 to 368 ng/mL). This is approximately 2% of the mean 
maximum serum metronidazole concentration reported in the same subjects administered a 
single, oral 500 mg dose of metronidazole (mean C = 12,785 ng/mL, range: 10,013 to 17,400 
ng/mL). These peak concentrations were obtained in 6 to 12 hours after dosing with 
metronidazole vaginal gel and 1 to 3 hours after dosing with oral metronidazole. 
 
The extent of exposure [area under the curve (AUC)] of metronidazole, when administered as a 
single intravaginal 5 gram dose of metronidazole vaginal gel (equivalent to 37.5 mg of 
metronidazole), was approximately 4% of the AUC of a single oral 500 mg dose of 
metronidazole (4977 ng-hr/mL and approximately 125,000 ng-hr/mL, respectively). 


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Dose-adjusted comparisons of AUCs demonstrated that, on a mg to mg comparison basis, the 
absorption of metronidazole, when administered vaginally, was approximately half that of an 
equivalent oral dosage. 
 
Patients with Bacterial Vaginosis: 
Following single and multiple 5 gram doses of metronidazole vaginal gel to 4 patients with 
bacterial vaginosis, a mean maximum serum metronidazole concentration of 214 ng/mL on day 1 
and 294 ng/mL (range: 228 to 349 ng/mL) on day five were reported. Steady state metronidazole 
serum concentrations following oral dosages of 400 to 500 mg BID have been reported to range 
from 6,000 to 20,000 ng/mL. 
 
Microbiology: 
The intracellular targets of action of metronidazole on anaerobes are largely unknown. The 5-
nitro group of metronidazole is reduced by metabolically active anaerobes, and studies have 
demonstrated that the reduced form of the drug interacts with bacterial DNA. However, it is not 
clear whether interaction with DNA alone is an important component in the bactericidal action of 
metronidazole on anaerobic organisms. 
 
Culture and sensitivity testing of bacteria are not routinely performed to establish the diagnosis 
of bacterial vaginosis. (See INDICATIONS AND USAGE.) 
 
Standard methodology for the susceptibility testing of the potential bacterial vaginosis 
pathogens, Gardnerella vaginalis, Mobiluncus spp., and Mycoplasma hominis, has not been 
defined. Nonetheless, metronidazole is an antimicrobial agent active in vitro against most strains 
of the following organisms that have been reported to be associated with bacterial vaginosis: 
 
Bacteroides spp. 
Gardnerella vaginalis 
Mobiluncus spp. 
Peptostreptococcus spp. 
 
INDICATIONS AND USAGE 
Metronidazole Vaginal Gel is indicated in the treatment of bacterial vaginosis (formerly referred 
to as Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, Corynebacterium 
vaginitis, or anaerobic vaginosis). 
 
NOTE: For purposes of this indication, a clinical diagnosis of bacterial vaginosis is usually 
defined by the presence of a homogeneous vaginal discharge that (a) has a pH of greater than 
4.5, (b) emits a “fishy” amine odor when mixed with a 10% KOH solution, and (c) contains clue 
cells on microscopic examination. Gram’s stain results consistent with a diagnosis of bacterial 
vaginosis include (a) markedly reduced or absent Lactobacillus morphology, (b) predominance 
of Gardnerella morphotype, and (c) absent or few white blood cells. 
 


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Other pathogens commonly associated with vulvovaginitis, e.g., Trichomonas vaginalis, 
Chlamydia trachomatis, N. gonorrhoeae, Candida albicans, and Herpes simplex virus should be 
ruled out. 
 
CONTRAINDICATIONS 
Metronidazole Vaginal Gel is contraindicated in patients with a prior history of hypersensitivity 
to metronidazole, parabens, other ingredients of the formulation, or other nitroimidazole 
derivatives. 
 
WARNINGS 
Convulsive Seizures and Peripheral Neuropathy: 
Convulsive seizures and peripheral neuropathy, the latter characterized mainly by numbness or 
paresthesia of an extremity, have been reported in patients treated with oral or intravenous 
metronidazole. The appearance of abnormal neurologic signs demands the prompt 
discontinuation of metronidazole vaginal gel therapy. Metronidazole vaginal gel should be 
administered with caution to patients with nervous system diseases.  
 
Psychotic Reactions: 
Psychotic reactions have been reported in alcoholic patients who were using oral metronidazole 
and disulfiram concurrently. Metronidazole vaginal gel should not be administered to patients 
who have taken disulfiram within the last two weeks. 
 
PRECAUTIONS 
Metronidazole Vaginal Gel affords minimal peak serum levels and systemic exposure (AUCs) of 
metronidazole compared to 500 mg oral metronidazole dosing. Although these lower levels of 
exposure are less likely to produce the common reactions seen with oral metronidazole, the 
possibility of these and other reactions cannot be excluded presently. Data from well-controlled 
trials directly comparing metronidazole administered orally to metronidazole administered 
vaginally are not available. 
 
General: 
Patients with severe hepatic disease metabolize metronidazole slowly. This results in the 
accumulation of metronidazole and its metabolites in the plasma. Accordingly, for such patients, 
metronidazole vaginal gel should be administered cautiously. 
 
Known or previously unrecognized vaginal candidiasis may present more prominent symptoms 
during therapy with metronidazole vaginal gel. Approximately 6-10% of patients treated with 
Metronidazole Vaginal Gel developed symptomatic Candida vaginitis during or immediately 
after therapy. 
 
Disulfiram-like reaction to alcohol has been reported with oral metronidazole, thus the 
possibility of such a reaction occurring while on metronidazole vaginal gel therapy cannot be 
excluded. 
 


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Metronidazole Vaginal Gel contains ingredients that may cause burning and irritation of the eye. 
In the event of accidental contact with the eye, rinse the eye with copious amounts of cool tap 
water. 
 
Information for the Patient: 
The patient should be cautioned about drinking alcohol while being treated with metronidazole 
vaginal gel. While blood levels are significantly lower with Metronidazole Vaginal Gel than with 
usual doses of oral metronidazole, a possible interaction with alcohol cannot be excluded. 
 
The patient should be instructed not to engage in vaginal intercourse during treatment with this 
product. 
 
Drug Interactions: 
Oral metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other 
coumarin anticoagulants, resulting in a prolongation of prothrombin time. This possible drug 
interaction should be considered when metronidazole vaginal gel is prescribed for patients on 
this type of anticoagulant therapy. 
 
In patients stabilized on relatively high doses of lithium, short-term oral metronidazole therapy 
has been associated with elevation of serum lithium levels and, in a few cases, signs of lithium 
toxicity. 
 
Use of cimetidine with oral metronidazole may prolong the half-life and decrease plasma 
clearance of metronidazole. 
 
Drug/Laboratory Test Interactions: 
Metronidazole may interfere with certain types of determinations of serum chemistry values, 
such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), 
lactate dehydrogenase (LDH), triglycerides, and glucose hexokinase. Values of zero may be 
observed. All of the assays in which interference has been reported involve enzymatic coupling 
of the assay to oxidation-reduction of nicotinamide-adenine dinucleotides (NAD + NADH). 
Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole 
(322 nm) at pH 7. 
 
Carcinogenesis, Mutagenesis, Impairment of Fertility: 
Metronidazole has shown evidence of carcinogenic activity in a number of studies involving 
chronic oral administration in mice and rats. Prominent among the effects in the mouse was the 
promotion of pulmonary tumorigenesis. This has been observed in all six reported studies in that 
species, including one study in which the animals were dosed on an intermittent schedule 
(administration during every fourth week only). At very high dose levels (approximately 500 
mg/kg/day), there was a statistically significant increase in the incidence of malignant liver 
tumors in males. Also, the published results of one of the mouse studies indicate an increase in 
the incidence of malignant lymphomas as well as pulmonary neoplasms associated with lifetime 
feeding of the drug. All these effects are statistically significant. Several long-term oral dosing 
studies in the rat have been completed. There were statistically significant increases in the 


PROTOCOL GDC-229-002 
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CONFIDENTIAL – PROPRIETARY INFORMATION 
 
 
 
Page 61 of 72 
incidence of various neoplasms, particularly in mammary and hepatic tumors, among female rats 
administered metronidazole over those noted in the concurrent female control groups. Two 
lifetime tumorigenicity studies in hamsters have been performed and reported to be negative. 
These studies have not been conducted with 0.75% metronidazole vaginal gel, which would 
result in significantly lower systemic blood levels than those obtained with oral formulations. 
 
Although metronidazole has shown mutagenic activity in a number of in vitro assay systems, 
studies in mammals (in vivo) have failed to demonstrate a potential for genetic damage. 
 
Fertility studies have been performed in mice up to six times the recommended human oral dose 
(based on mg/m2) and have revealed no evidence of impaired fertility. 
 
Pregnancy: Teratogenic Effects: 
 
Pregnancy Category B 
 
There has been no experience to date with the use of Metronidazole Vaginal Gel in pregnant 
patients. Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. No 
fetotoxicity or teratogenicity was observed when metronidazole was administered orally to 
pregnant mice at six times the recommended human dose (based on mg/m2); however, in a 
single small study where the drug was administered intraperitoneally, some intrauterine deaths 
were observed. The relationship of these findings to the drug is unknown. 
 
There are, however, no adequate and well-controlled studies in pregnant women. Because animal 
reproduction studies are not always predictive of human response, and because metronidazole is 
a carcinogen in rodents, this drug should be used during pregnancy only if clearly needed. 
 
Nursing Mothers: 
Specific studies of metronidazole levels in human milk following intravaginally administered 
metronidazole have not been performed. However, metronidazole is secreted in human milk in 
concentrations similar to those found in plasma following oral administration of metronidazole. 
 
Because of the potential for tumorigenicity shown for metronidazole in mouse and rat studies, a 
decision should be made whether to discontinue nursing or to discontinue the drug, taking into 
account the importance of the drug to the mother. 
 
Pediatric Use: 
Safety and effectiveness in children have not been established. 
 


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CONFIDENTIAL – PROPRIETARY INFORMATION 
 
 
 
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ADVERSE EVENTS 
 
Clinical Trials: 
 
There were no deaths or serious adverse events related to drug therapy in clinical trials involving 
800 non-pregnant women who received Metronidazole Vaginal Gel. 
 
In a randomized, single-blind clinical trial of 505 non-pregnant women who received 
Metronidazole Vaginal Gel once or twice a day, 2 patients (one from each regimen) discontinued 
therapy early due to drug-related adverse events. One patient discontinued drug because of 
moderate abdominal cramping and loose stools, while the other patient discontinued drug 
because of mild vaginal burning. These symptoms resolved after discontinuation of drug. 
 
Medical events judged to be related, probably related, or possibly related to administration of 
Metronidazole Vaginal Gel once or twice a day were reported for 195/505 (39%) patients. The 
incidence of individual adverse reactions were not significantly different between the two 
regimens. Unless percentages are otherwise stipulated, the incidence of individual adverse 
reactions listed below was less than 1%: 
 
Reproductive: 
Vaginal discharge (12%), 
Symptomatic Candida cervicitis/vaginitis (10%), 
Vulva/vaginal irritative symptoms (9%), 
Pelvic discomfort (3%). 
Gastrointestinal: 
Gastrointestinal discomfort (7%), 
Nausea and/or vomiting (4%), 
Unusual taste (2%), 
Diarrhea/loose stools (1%), 
Decreased appetite (1%), 
Abdominal bloating/gas; thirsty, dry mouth. 
Neurologic: 
Headache (5%), Dizziness (2%), Depression. 
Dermatologic: 
Generalized itching or rash. 


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CONFIDENTIAL – PROPRIETARY INFORMATION 
 
 
 
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Other: 
Unspecified cramping (1%), 
Fatigue, 
Darkened urine. 
In previous clinical trials submitted for approved labeling of Metronidazole Vaginal Gel the 
following was also reported: 
Laboratory: 
Increased/decreased white blood cell counts (1.7%). 
 
Other Metronidazole Formulations: 
 
Other effects that have been reported in association with the use of topical (dermal) formulations 
of metronidazole include skin irritation, transient skin erythema, and mild skin dryness and 
burning. None of these adverse events exceeded an incidence of 2% of patients. 
 
Metronidazole Vaginal Gel affords minimal peak serum levels and systemic exposure (AUC) of 
metronidazole compared to 500 mg oral metronidazole dosing. Although these lower levels of 
exposure are less likely to produce the common reactions seen with oral metronidazole, the 
possibility of these and other reactions cannot be excluded presently. 
 
The following adverse reactions and altered laboratory tests have been reported with the oral or 
parenteral use of metronidazole: 
 
Cardiovascular: Flattening of the T-wave may be seen in electrocardiographic tracings. 
 
Central Nervous System: (See WARNINGS.) Headache, dizziness, syncope, ataxia, confusion, 
convulsive seizures, peripheral neuropathy, vertigo, incoordination, irritability, depression, 
weakness, insomnia. 
 
Gastrointestinal: Abdominal discomfort, nausea, vomiting, diarrhea, an unpleasant metallic 
taste, anorexia, epigastric distress, abdominal cramping, constipation, “furry” tongue, glossitis, 
stomatitis, pancreatitis, and modification of taste of alcoholic beverages. 
 
Genitourinary: Overgrowth of Candida in the vagina, dyspareunia, decreased libido, proctitis. 
  
Hematopoietic: Reversible neutropenia, reversible thrombocytopenia. 
 
Hypersensitivity Reactions: Urticaria; erythematous rash; flushing; nasal congestion; dryness of 
the mouth, vagina, or vulva; fever; pruritus; fleeting joint pains. 
 
Renal: Dysuria, cystitis, polyuria, incontinence, a sense of pelvic pressure, darkened urine. 


PROTOCOL GDC-229-002 
Version 01.00 Date: 23 January 2017 
 
CONFIDENTIAL – PROPRIETARY INFORMATION 
 
 
 
Page 64 of 72 
OVERDOSAGE 
There is no human experience with overdosage of metronidazole vaginal gel. Vaginally applied 
metronidazole gel, 0.75% could be absorbed in sufficient amounts to produce systemic effects. 
(See WARNINGS.) 
 
DOSAGE AND ADMINISTRATION 
The recommended dose is one applicator full of Metronidazole Vaginal Gel (approximately 5 
grams containing approximately 37.5 mg of metronidazole) intravaginally once or twice a day 
for 5 days. For once-a-day dosing, Metronidazole Vaginal Gel should be administered at 
bedtime. 
 
HOW SUPPLIED 
Metronidazole Vaginal Gel 0.75% is supplied in a 70 gram tube and packaged with 5 vaginal 
applicators. 
 
The NDC number for the 70 gram tube is 68682-455-70. 
 
Store at controlled room temperature 15° to 30°C (59° to 86°F). Protect from freezing. 
 
Clinical Studies 
 
In a randomized, single-blind clinical trial of non-pregnant women with bacterial vaginosis who 
received Metronidazole Vaginal Gel daily for 5 days, the clinical cure rates for evaluable patients 
determined at 4 weeks after completion of therapy for the QD and BID regimens were 98/185 
(53%) and 109/190 (57%), respectively. 
 
Rx Only 
Manufactured for: Valeant Pharmaceuticals North America LLC, Bridgewater, NJ 08807 
By: DPT Laboratories, Inc., San Antonio, TX 78215 
Rev. 11/14 
 


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DIRECTIONS FOR USE 
1. Filling  the applicator 
• Remove cap and puncture metal seal on tube with the pointed tip of cap. (See Figure 1) 
• Screw end of applicator onto tube. (See Figure 2) 
• Slowly squeeze gel out of tube and into applicator. Plunger will stop when the applicator 
is full. (See Figure 3) 
• Unscrew applicator and replace cap on tube. 
 
 
 
 


PROTOCOL GDC-229-002 
Version 01.00 Date: 23 January 2017 
 
CONFIDENTIAL – PROPRIETARY INFORMATION 
 
 
 
Page 66 of 72 
2. Inserting the applicator 
• The applicator may be inserted while lying on your back with your knees bent or in any 
comfortable position 
• Hold filled applicator by barrel, and gently insert into vagina as far as it will 
comfortably go. (See Figure 4) 
• Slowly press the plunger until it stops to deposit gel into vagina and then withdraw the   
applicator. 
 
 
3. Care of the applicator 
If physician prescribes twice-a-day dosing: 
• After use, pull the plunger out of the barrel. (See Figure 5) 
• Wash both plunger and barrel in warm soapy water and rinse thoroughly. 
• To reassemble applicator, gently push plunger back into barrel. 
 
IMPORTANT: 
For once-a-day dosing, apply one applicator full at bedtime. For twice-a-day dosing, apply one 
applicator full each morning and evening for five days, or as directed by physician.  


PROTOCOL GDC-229-002 
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CONFIDENTIAL – PROPRIETARY INFORMATION 
 
 
 
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WARNINGS: 
• If significant irritation develops from the use of this medication, discontinue use and consult 
your physician. 
• Do not use during pregnancy except under the supervision of a physician. 
• Keep this and all medications out of reach of children. 
• For vaginal use only. Not for use in the eyes, on the skin or in the mouth. 
Store at room temperature. Avoid exposure to extreme heat or cold. 
See end of carton and bottom of tube for lot number and expiration date. 
Manufactured for: Valeant Pharmaceuticals North America LLC, Bridgewater, NJ 08807 
By: DPT Laboratories, Inc., San Antonio, TX 78215 
Rev. 11/14 
9432501 
140410-1114 
 
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 70 gram Carton 
NDC 68682-455-70 
Rx Only 
Metronidazole Vaginal Gel, 0.75%  
with 5 applicators 
FOR INTRAVAGINAL USE ONLY. (NOT FOR OPHTHALMIC, DERMAL, OR ORAL 
USE.)  
Net Wt. 70 g 
OCEANSIDE PHARMACEUTICALS® 
 






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Page 70 of 72 
Appendix 2 
SUBJECT DOSING INSTRUCTIONS FOR STUDY MEDICATION 
SUBJECT DOSING INSTRUCTIONS FOR STUDY MEDICATION 
Bacterial Vaginosis Study  
Protocol GDC-229-002 
 
Please follow these instructions exactly as they are written below. Contact the study 
staff at the telephone number below if you have any questions about the study. 
 
Name: _________________________Phone: ____________________________ 
 
Your study medication kit includes a 70 gram tube of study medicine and 5 vaginal 
applicators. The study medicine is to be applied into the vagina using a new 
applicator each night at bedtime for five consecutive nights. You will start on the 
same day that you were given this medication by the study site.   
 
NOTE: It is important for you to continue to use the study medication during 
the prescribed 5-day treatment period unless directed to do otherwise by the 
study doctor. Do not discontinue the use of the medication unless directed so 
by the study staff. Talk to the study staff about any side effects that you 
experience. 
 
 You should not drink alcohol on Days 1 to 6 (during the five days of treatment 
and for one day afterward). 
 You should not engage in sexual intercourse 
o on Days 1 to 7 (during five days of treatment and for two days afterward) or 
o 48 hours before Visit 2 and Visit 3. 
 Do not use any intravaginal product other than study medication for the 
duration of this trial. This includes: spermicide, tampon, douche, feminine 
deodorant spray, diaphragm, vaginal ring birth control, or condom with 
spermicide. 
 Do not insert into the vagina any drug (e.g.  Monistat, etc.), or non-drug product 
during this study; also do not use any topical vaginal products (e.g., 
hydrocortisone, etc.) for the duration of this trial. 
 If you miss a dose, take the next dose at the usual time the following evening. 
Report any missed doses to the study staff at your next visit. 
 It is recommended to empty bladder completely prior to administering study drug. 
 If significant irritation develops from the use of this medication consult the study 
doctor. 
 Keep this and all medications out of reach of children. 
 Do not allow anyone else to use this study medication. 
 For vaginal use only. Not for use in the eyes, on the skin or in the mouth. 
 Store the study medication at room temperature. 




PROTOCOL GDC-229-002 
Version 01.00 Date: 23 January 2017 
 
CONFIDENTIAL – PROPRIETARY INFORMATION 
 
 
 
Page 72 of 72 
 
Step 2 Insert the applicator 
a) The applicator may be inserted while lying on your back with your knees bent or 
in any comfortable position. 
b) Hold the filled applicator by the applicator barrel and gently insert it into your 
vagina as far as it will comfortably go. (See Figure 4) 
c) Slowly press the plunger until it stops in order to insert all of the gel into your 
vagina and then withdraw the applicator. 
d) Throw away the used applicator.  Do not reuse it. 
 
 
Step 3 Return Instructions  
a) Return the tube of remaining study medication with all original packaging to the 
study site at your next visit. 
b) Return all unused applicators to the study site at your next visit.  
 

















SAP_001.pdf: 


G a g e D e v el o p m e nt                                           C O N FI D E N TI A L                                           G D C -2 2 9 -0 0 2
St ati sti c al A n al y si s Pl a n, v 3. 0
Pr ot o c ol G D C -2 2 9 -0 0 2
A M ulti c e nt er, R a n d o mi z e d, D o u bl e -Bli n d, V e hi cl e C o ntr oll e d
St u d y E v al u ati n g t h e T h er a p e uti c E q ui v al e n c e a n d S af et y of
G D C -2 2 9 (I n v e sti g ati o n al M etr o ni d a z ol e 0. 7 5 % V a gi n al G el)
a n d M etr o ni d a z ol e 0. 7 5 % V a gi n al G el i n t h e Tr e at m e nt of
B a ct eri al V a gi n o si s
St ati sti c al A n al y si s Pl a n
Pr e p ar e d f or:
G a g e D e v el o p m e nt C o m p a n y , L L C
9 4 5 0 W. Br y n M a wr A v e n u e
S uit e 6 4 0
R o s e m o nt, I L 6 0 0 1 8




G a g e D e v el o p m e nt                                           C O N FI D E N TI A L                                           G D C -2 2 9 -0 0 2
St ati sti c al A n al y si s Pl a n, v 3. 0 – P a g e ii
T A B L E O F C O N T E N T S
S T A TI S TI C A L A N A L Y SI S P L A N A P P R O V A L ............................................................... i
T A B L E O F C O N T E N T S .................................................................................................. ii
LI S T O F A B B R E VI A TI O N S ........................................................................................... i v
1. 0
I N T R O D U C TI O N.................................................................................................. 5
2. 0
P R O T O C O L S U M M A R Y ...................................................................................... 5
2. 1
B a c k gr o u n d ....................................................................................................... 5
2. 2
O bj e cti v e s ......................................................................................................... 5
2. 3
Tri al D e si g n ....................................................................................................... 5
2. 4
St u d y E n d p oi nt s ................................................................................................ 6
2. 4. 1
Pri m ar y E n d p oi nt ....................................................................................... 6
2. 4. 2
S e c o n d ar y E n d p oi nt s ................................................................................. 6
2. 5
S a m pl e Si z e C o n si d er at i o n............................................................................... 6
3. 0
S T A TI S TI C A L M E T H O D S ................................................................................... 7
3. 1
St ati sti c al H a n dli n g P oli c y ................................................................................. 7
3. 1. 1
I nt eri m S af et y R e vi e w................................................................................ 7
3. 1. 2
A n al y si s C o n v e nti o n s ................................................................................. 7
3. 2
S u bj e ct Di s p o siti o n ........................................................................................... 8
3. 3
Pr ot o c ol D e vi ati o n s ........................................................................................... 8
3. 4
A n al y si s P o p ul ati o n s ......................................................................................... 8
3. 5
D e m o gr a p hi c s a n d Pr e -Tr e at m e nt C h ar a ct eri sti c s ........................................... 9
3. 5. 1
D e m o gr a p hi c s ............................................................................................ 9
3. 5. 2
M e di c al Hi st or y ........................................................................................ 1 0
3. 5. 3
G y n e c ol o gi c al Hi st or y .............................................................................. 1 0
3. 5. 4
Pr e g n a n c y Hi st or y ................................................................................... 1 0
3. 5. 5
S u b st a n c e U s e ........................................................................................ 1 1
3. 5. 6
Pr i or M e di c ati o n s..................................................................................... 1 1
3. 6
C o n c o mit a nt M e di c ati o n s ................................................................................ 1 2
3. 7
Effi c a c y A n al y s e s ............................................................................................ 1 2
3. 7. 1
Pri m ar y Effi c a c y A n al y s e s ....................................................................... 1 2
3. 7. 2
S e c o n d ar y Effi c a c y A n al y s e s ................................................................... 1 4


G a g e D e v el o p m e nt                                           C O N FI D E N TI A L                                           G D C -2 2 9 -0 0 2
St ati sti c al A n al y si s Pl a n, v 3. 0 – P a g e iii
3. 7. 3
Ot h er O ut c o m e M e a s ur e m e nt s ................................................................ 1 4
3. 8
S af et y A n al y s e s .............................................................................................. 1 5
3. 8. 1
Tr e at m e nt E x p o s ur e a n d C o m pli a n c e ...................................................... 1 5
3. 8. 2
A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s .......................................... 1 5
3. 8. 3
L o c al Sit e R e a cti o n .................................................................................. 1 6
3. 8. 4
Vit al Si g n s a n d W ei g ht ............................................................................. 1 7
3. 8. 5
P h y si c al E x a mi n ati o n ............................................................................... 1 7
3. 8. 6
G y n e c o l o gi c al E x a m................................................................................ 1 8
3. 8. 7
Ot h er S af et y A s s e s s m e nt s ...................................................................... 1 8
4. 0
R E F E R E N C E S ................................................................................................... 1 8
5. 0
A P P E N DI C E S .................................................................................................... 2 0
5. 1
St u d y S c h e d ul e of A s s e s s m e nt s ..................................................................... 2 0
5. 2
T a bl e of C o nt e nt s f or D at a Di s pl a y ................................................................. 2 2


Gage Development                                           CONFIDENTIAL                                           GDC-229-002
Statistical Analysis Plan, v3.0 – Page iv
LIST OF ABBREVIATIONS
AE
Adverse Event
BMI
Body Mass Index
BV
Bacterial Vaginosis
CI
Confidence Interval
CSR
Clinical Study Report
DA
Drug Accountability
eCRF
Electronic Case Report Form
HEENT
Head, Eyes, Ears, Nose and Throat
ITT
Intent-To-Treat
KOH
Potassium hydroxide
LOCF
Last Observation Carried Forward
mITT
modified Intent-To-Treat
MedDRA
Medical Dictionary for Regulatory Activities
OGD
(FDA) Office of Generic Drugs
PP
Per Protocol
PT
Preferred Term
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SOC
System Organ Class
STI
Sexual Transmitted Infection
TOC
Test Of Cure
WHO
World Health Organization


G a g e D e v el o p m e nt                                           C O N FI D E N TI A L                                           G D C -2 2 9 -0 0 2
St ati sti c al A n al y si s Pl a n, v 3. 0 – P a g e 5
1. 0
I N T R O D U C TI O N
T h e p ur p o s e of t hi s d o c u m e nt i s t o d et ail t h e pl a n n e d st ati sti c al a n al y si s a n d d at a
pr e s e nt ati o n s t h at will b e p erf or m e d t o s u p p ort t h e Cli ni c al St u d y R e p ort ( C S R) f or G a g e ,
L L C st u d y pr ot o c ol G D C -2 2 9 -0 0 2 . T h e a n al y s e s d et ail e d h er ei n ar e b a s e d o n t h e st u d y
pr ot o c ol ( V er si o n 0 1. 0 0, d at e d 2 3 J A N 2 0 1 7) a n d el e ctr o ni c c a s e r e p ort f or m s ( e C R F s,
d at e d 1 6 F E B 2 0 1 7) . A n y p o st -h o c or u n pl a n n e d a n al y s e s n ot i d e ntifi e d i n t hi s S A P will
b e cl e arl y i d e ntifi e d i n t h e C S R.
2. 0
P R O T O C O L S U M M A R Y
2. 1
B a c k gr o u n d
B a ct eri al v a gi n o si s ( B V) i s a c o m m o n b a ct eri al i nf e cti o n i n w o m e n.
B V i s t y pi c all y
di a g n o s e d u si n g A m s el’ s crit eri a ( A m s el 1 9 8 3) . T h e f o ur A m s el’ s crit eri a u s e d t o
d et er mi n e a cli ni c al di a g n o si s of B V ar e a s f oll o w s: ( 1) v a gi n al p H > 4. 5; ( 2) p o siti v e “ w hiff”
t e st (“fi s h y” o d or); ( 3) h o m o g e n o u s, n o n -vi s c o u s, off -w hit e ( mil k y or gr a y) di s c h ar g e ; ( 4)
t h e pr e s e n c e of ≥2 0 % cl u e c ell s.
O r al a n d t o pi c al a nti bi oti c s ar e u s e d t o tr e at B V. M etr o ni d a z ol e w a s a p pr o v e d f or u s e i n
t h e 
Unit e d
S t at e s i n 1 9 6 3 a n d i s c urr e ntl y a fir st-li n e tr e at m e nt f or B V ( Fl a g yl
( m etr o ni d a z ol e) N D A 0 1 2 6 2 3, A p pr o v al D at e 1 8 J U L 1 9 6 3). G a g e D e v el o p m e nt C o m p a n y
i s d e v el o pi n g a dr u g pr o d u ct c a n di d at e t h at i s d e si g n e d t o b e t h er a p e uti c all y e q ui v al e nt
t o t h e m ar k et e d dr u g m etr o ni d a z ol e 0. 7 5 % v a gin al g el f or t h e tr e at m e nt of B V.
2. 2
O bj e cti v e s
T h e
pri m ar y o bj e cti v e of t hi s st u d y
i s t o a s s e s s t h e t h er a p e uti c e q ui v al e n c e of a n
e x p eri m e nt al f or m ul ati o n of a m etr o ni d a z ol e 0. 7 5 % v a gi n al g el ( G D C -2 2 9; t e st pr o d u ct)
v er s u s m etr o ni d a z ol e 0. 7 5 % v a gi n al g el ( O c e a n si d e P h ar m a c e u ti c al s) i n s u bj e ct s wit h
B V. A v e hi cl e ( pl a c e b o) ar m i s i n cl u d e d f or a s s a y s e n siti vit y p ur p o s e .
T h e s e c o n d ar y o bj e cti v e of t hi s st u d y i s t o e v al u at e t h e s af et y a n d t ol er a bilit y of G D C -
2 2 9 v er s u s m etr o ni d a z ol e 0. 7 5 % v a gi n al g el ( O c e a n si d e P h ar m a c e uti c al s) a n d v e hi cl e
( pl a c e b o) v a gi n al g el i n s u bj e ct s wit h B V.
2. 3
Tri al D e si g n
T hi s i s a m ulti c e nt er
( wit h a p pr o xi m at el y 4 0 st u d y sit e s), r a n d o mi z e d, d o u bl e-bli n d (f or
b ot h s u bj e ct s a n d i n v e sti g at or s) , v e hi cl e-c o ntr oll e d bi o e q ui v al e n c e st u d y wit h a cli ni c al
e n d p oi nt . F oll o wi n g c o m pl eti o n of t h e s cr e e ni n g pr o c e d ur e s, eli gi bl e s u bj e ct s will b e
r a n d o mi z e d i n a bli n d e d m a n n er a n d i n a 1: 1: 1 r ati o t o o n e of t hr e e tr e at m e nt ar m s :

G D C -2 2 9, t h e t e st pr o d u ct

R ef er e n c e 
pr o d u ct 
( m etr o ni d a z ol e 
0. 7 5 % 
v a gi n al 
g el
b y
O c e a n si d e
P h ar m a c e uti c al s)

V e hi cl e ( p l a c e b o) v a gi n al g el .
T h er e ar e t hr e e pl a n n e d st u d y vi sit s a s f oll o w s:
1.
St u d y e ntr y Vi sit ( D a y 1, s cr e e ni n g a n d r a n d o mi z ati o n);


G a g e D e v el o p m e nt                                           C O N FI D E N TI A L                                           G D C -2 2 9 -0 0 2
St ati sti c al A n al y si s Pl a n, v 3. 0 – P a g e 6
2.
P o st -Tr e at m e nt 
A s s e s s m e nt ( St u d y d a y s 8 -1 5, i. e.,
7 t o 1 4 d a y s aft er
r a n d o mi z ati o n), a n d
3.
T e st of C ur e ( St u d y d a y s 2 2 -3 1, i. e., 2 1 t o 3 0 d a y s aft er r a n d o mi z ati o n).
T h o u g h e arl y t er mi n ati o n c a n o c c ur a n yti m e aft er e nr oll m e nt, th e st u d y g e n er all y i s u p t o
3 1
d a y s i n d ur ati o n
f or e a c h s u bj e ct. T h e st u d y
tr e at m e nt i s t o b e a d mi ni st er e d
i ntr a v a gi n all y o n c e da il y at b e dti m e d uri n g St u d y D a y s 1 t o 5 .
All
pr o c e d ur e s a n d a s s e s s m e nt s a s s o ci at e d wit h e a c h
st u d y vi sit ar e s h o w n i n t h e
A p p e n di x 5. 1  of t hi s S A P. I n cl u di n g a r e cr uit m e nt p eri o d of a b o ut s e v e n m o nt h s, t h e st u d y
d ur ati o n i s e x p e ct e d t o b e a p pr o xi m at el y ei g ht m o nt h s .
2. 4
St u d y E n d p oi nt s
2. 4. 1
Pri m ar y E n d p oi nt
T h e pri m ar y st u d y e n d p oi nt i s “ Cli ni c al C ur e”, d efi n e d as t h e r e s ol uti o n at t h e T e st of C ur e
vi sit of t h e f oll o wi n g t hr e e a b n or m al B V si g n s i n cl u d e d i n A m s el’ s crit eri a:

R et ur n t o n or m al p h y si ol o gi c al v a gi n al di s c h ar g e a s d et er mi n e d b y t h e i n v e sti g at or

N e g ati v e w hiff t e st

T h e pr e s e n c e of cl u e c ell s at < 2 0 % of t h e t ot al e pit h eli al c ell s o n mi cr o s c o pi c
e x a mi n ati o n of t h e s ali n e w et m o u nt .
2. 4. 2
S e c o n d ar y E n d p oi nt s
T h e s e c o n d ar y effi c a c y e n d p oi nt s ar e t h e “B a ct eri ol o gi c al C ur e ” a n d t h e “T h er a p e uti c
C ur e ” at t h e T e st of C ur e vi sit ( Vi sit 3). Ba ct eri ol o gi c al C ur e i s d efi n e d a s N u g e nt’ s s c or e
< 4 ( vi a Gr a m st ai n c e ntr al l a b or at or y a n al y si s). A N u g e nt ’ s s c or e ≥4 i s c o n si d er e d
a b n or m al a n d r e pr e s e nt s a n i m b al a n c e i n v a gi n al fl or a t h at p er mit s B V t o m a nif e st
( N u g e nt 1 9 9 1). S u bj e ct s w h o ar e r e s p o n d er s ar e e x p e ct e d t o a c hi e v e a n or m al N u g e nt ’ s
s c or e (i. e., 0 t o 3) f oll o wi n g t h e st u d y tr e at m e nt.
T h er a p e uti c C ur e i s d efi n e d a s h a vi n g a c hi e v e d C li ni c al C ur e , v a gi n al p H of < 4. 7 , a n d
B a ct eri ol o gi c al C ur e (N u g e nt ’ s s c or e < 4 ) at Vi sit 3.
2. 5
S a m pl e Si z e C o n si d er ati o n
A s s u mi n g t h e t e st a n d r ef er e n c e pr o d u ct s’ C li ni c alC ur e r at e s ar e wit hi n 4 % of e a c h ot h er,
t h e pl a c e b o cli ni c al c ur e r at e i s 2 0 %, t h e t e st a n d r ef er e n ce cli ni c al c ur e r at e s ar e at l e a st
3 6 . 0% a n d 1 2. 4 % of r a n d o mi z e d s u bj e ct s d o n ot q u alif y f or t h e m o difi e d I nt e nt -t o-Tr e at
( mI T T) p o p ul ati o n ( d efi n e d i n S e cti o n 3. 4  of t hi s S A P), t h e n 6 0 3 s u bj e ct s will b e r e q uir e d
t o a c hi e v e at l e a st 9 0 % p o w er f or s u p eri orit y a n d t h er a p e uti c e q ui v al e n c e ( S c h w e b k e
2 0 1 5; C h a v o u sti e 2 0 1 5). H o w e v er, t h e pr e vi o u s st u di e s t h at w er e u s e d t o e sti m at e eff e ct
si z e h a d si g nifi c a nt diff er e n c e s i n st u d y d e si g n a n d d efi niti o n of pri m ar y e n d p oi nt. T a ki n g
t h e s e diff er e n c e s i nt o c o n si d er ati on, a p pr o xi m at el y 7 3 8 s u bj e ct s w er e pl a n n e d t o
b e
r a n d o mi z e d. T h e a s s u m pti o n of a 3 6 % t e st a n d r ef er e n c e cli ni c al c ur e r at e w a s d eri v e d
aft er r e vi e w of t h e F D A’ s St ati sti c al R e vi e w of M etr o ni d a z ol e v a gi n al g el 1. 3 % ( C e nt er f or
Dr u g E v al u ati o n a n d R e s e ar c h 2 0 1 4) .


G a g e D e v el o p m e nt                                           C O N FI D E N TI A L                                           G D C -2 2 9 -0 0 2
St ati sti c al A n al y si s Pl a n, v 3. 0 – P a g e 7
3. 0
S T A TI S TI C A L M E T H O D S
3. 1
St ati sti c al H a n dli n g P oli c y
3. 1. 1
I nt eri m S af et y R e vi e w
N o f or m al i nt eri m a n al y si s will b e c o n d u ct e d .  A bli n d e d M e di c al M o nit or
will p eri o di c all y
p erf or m a bli n d e d r e vi e w of  a d v er s e e v e nt d at a.
3. 1. 2
A n al y si s C o n v e nti o n s
T hi s s e cti o n d et ail s g e n er al
a p pr o a c h e s t o
b e u s e d f or t h e st ati sti c al a n al y s e s.
D e p art ur e s fr o m t h e s e g e n er al
a p pr o a c h e s m a y b e
o utli n e d i n t h e s p e cifi c d et ail e d
s e cti o n s of t hi s st ati sti c al a n al y si s pl a n , a n d will t a k e pr e c e d e n c e o v er t h e g e n er al
a p pr o a c h e s.
T h e f oll o wi n g a p pr o a c h e s will b e a p pli e d t o all d at a pr e s e nt ati o n s a n d
a n al y s e s.

D at a li sti n g s will b e pr o vi d e d f or all C R F d at a wit h o n e li sti n g f or o n e C R F p a n el. All
d at a li sti n g s will b e s ort e d f or pr e s e nt ati o n i n t h e or d er of sit e i d e ntifi er (I D), s u bj e ct
I D, a n d d at e of pr o c e d ur e or e v e nt.

St ati sti c al s u m m ar y t a bl e s will b e pr o vi d e d f or m o st C R F d at a , a n d g e n er at e d f or e a c h
of t h e 3 tr e at m e nt gr o u p s , a n d f or o v er all s u bj e ct s (i. e., 3 gr o u p s c o m bi n e d) w h e n
a p pr o pri at e .

S u m m ar y st ati sti c s will c o n si st of t h e n u m b er a n d p er c e nt a g e of r e s p o n s e s i n e a c h
c at e g or y f or di s cr et e
( c at e g ori c al) v ari a bl e s, a n d t h e
n u m b er of n o n -mi s si n g
o b s er v ati o n s ( n), m e a n, m e di a n, st a n d ar d d e vi ati o n ( S D), mi ni m u m, a n d m a xi m u m
(a b br e vi at e d a s “6 -n u m b er st ati sti c s ”) f or c o nti n u o u s v ari a bl e s.

All m e a n v al u e s will b e f or m att e d t o o n e m or e d e ci m al pl a c e s t h a n t h e m e a s ur e d
v al u e, a n d s t a n d ar d d e vi ati o n v al u e s will b e f or m att e d t o t w o m or e d e ci m al pl a c e s
t h a n t h e 
m e a s ur e d v al u e. F or m e di a n v al u e s, t h e s a m e d e ci m al pl a c e a s t h e
m e a s ur e d v al u e s will b e r e p ort e d, if t h at is f e a sibl e wit h o ut l o s i n ga c c ur a c y; ot h er wi s e,
m e di a n v al u e s will b e f or m att e d t o o n e m or e d e ci m al pl a c e t h a n t h e m e a s ur e d v al u e s .

All p er c e nt a g e s will b e r o u n d e d t o o n e d e ci m al pl a c e.
T h e n u m b er a n d p er c e nt a g e
of
c at e g ori c al
r e s p o n s e s will b e pr e s e nt e d i n t h e f or m X X ( X X. X), w h er e t h e
p er c e nt a g e i s i n t h e p ar e nt h e s e s.
T h e d e n o mi n at or f or p er c e nt a g e c al c ul ati o n s will
b e t h e n u m b er of n o n -mi s si n g o b s er v ati o n s ( n) w h e n t hi s n u m b er i s s h o w n, or will b e
t h e t ot al s a m pl e si z e of t h e r el e v a nt tr e at m e nt gr o u p f or t a bl e s li k e a d v er s e e v e nt s,
m e di c al hi st ori e s, or ot h er t a bl e s w h er e t hi s n u m b er of n o n -mi s si n g o b s er v ati o n s ( n)
i s n ot pr e s e nt e d.

All st ati sti c al t e st s will u s e a si g nifi c a n c e l e v el o f = 0. 0 5 .  T w o-t ail e d t e st s will b e
p erf or m e d f or all a n al y s e s t h at u s e st ati sti c al t e sti n g.

All p -v al u e s will b e r o u n d e d t o 3 d e ci m al pl a c e s.  All p -v al u e s t h at r o u n d t o 0. 0 0 0 will
b e pr e s e nt e d a s ‘ < 0. 0 0 1’ , a n d p -v al u e s t h at r o u n d t o 1. 0 0 0 will b e pr e s e nt e d a s
‘ > 0. 9 9 9’.  A n y p-v al u e 0. 0 5 will b e c o n si d er e d st ati sti c all y si g nifi c a nt a n d will b e
m ar k e d wit h o n e a st eri s k ( e. g., 0. 0 2 5*) .


G a g e D e v el o p m e nt                                           C O N FI D E N TI A L                                           G D C -2 2 9 -0 0 2
St ati sti c al A n al y si s Pl a n, v 3. 0 – P a g e 8

All a n al y si s a n d s u m m ar y t a bl e s will h a v e t h e p o p ul ati o n s a m pl e si z e i n t h e c ol u m n
h e a di n g.

B a s eli n e i s d efi n e d a s t h e l a st d at a p oi nt o n or b ef or e t h e d a y of r a n d o mi z ati o n.

C al c ul ati n g c h a n g e fr o m b a s eli n e t o a vi sit will b e d o n e a s f oll o w s: C h a n g e
fr o m
B a s eli n e = O b s er v e d v al u e at t h e v i sit – B a s eli n e v al u e .

S u bj e ct s w h o h a v e o nl y b a s eli n e ( wit h o ut a n y p o st -b a s eli n e m e a s ur e m e nt s)
f or a
p ar a m et er at a vi sit , or o nl y h a v e p o st-b a s eli n e v al u e f or a p ar a m et er at a vi sit, will b e
e x cl u d e d fr o m t h e s u m m ar y of c h a n g e fr o m b a s eli n e b y vi sit f or t h at p ar a m et er .

V er si o n 9. 4 of S A S or hi g h er will b e t h e st ati sti c al s oft w ar e p a c k a g e u s e d t o pr o d u c e
all st ati sti c al a n al y si s t a bl e s a n d d at a li sti n g s.
3. 2
S u bj e ct Di s p o siti o n
S u bj e ct di s p o siti o n will b e s u m m ari z e d a s f oll o w s: f or t h e All S cr e e n e d p o p ul ati o n wit h
t h e f oll o wi n g d at a:

N u m b er of i nf or m c o n s e nt e d s u bj e ct s i n e a c h of t h e f oll o wi n g 4 gr o u p s:

S cr e e n f ail ur e s

Pl a c e b o

G D C -2 2 9

M etr o ni d a z ol e

S u m m ar y of s cr e e n f ail ur es b y t h e r e a s o n f or i n eli gi bilit y f or s cr e e n f ail e d s u bj e ct s

T h e n u m b er a n d p er c e nt a g e of r a n d o mi z e d s u bj e ct s w h o c o m pl et e d or di s c o nti n u e d
pr e m at ur el y fr o m t h e st u d y, t h e n u m b er a n d p er c e nt a g e of s u bj e ct s w h o di s c o nti n u e d
b y e a c h r e a s o n f or all s u bj e ct s.

A li sti n g of r a n d o mi z e d s u bj e ct s w h o di s c o nti n u e d pr e m at ur el y fr o m t h e st u d y . T h e
li sti n g will i n cl u d e i nf or m ati o n a b o ut st u d y sit e I D n u m b er , s u bj e ct I D n u m b er, a g e ,
n u m b er of d o s e s u s e d, a n d r e a s o n f or di s c o nti n u ati o n.

T h e n u m b er a n d p er c e nt a g e of r a n d o mi z e d s u bj e ct s at e a c h st u d y vi sit.

T h e n u m b er of r a n d o mi z e d s u bj e ct s w h o w er e e nr oll e d , c o m pl et e d or di s c o nti n u e d
pr e m at ur el y at e a c h st u d y sit e .
T h e
Di s p o siti o n
p a g e
of t h e
C R F will b e u s e d t o d et er mi n e
t h o s e s u bj e ct s t h at
di s c o nti n u e d pr e m at ur el y fr o m t h e st u d y.
3. 3
Pr ot o c ol D e vi ati o n s
Pr ot o c ol d e vi ati o n s will b e s u m m ari z e d b y t y p e of d e vi ati o n s li st e d o n t h e C R F . B ot h t h e
n u m b er of d e vi ati o n e v e nt s a n d di sti n ct n u m b er a n d p er c e nt a g e of s u bj e ct s will b e
pr e s e nt e d
f or e a c h t y p e of d e vi ati o n b y tr e at m e nt gr o u p a n d f or all
Int e nt -t o-T r e at
s u bj e ct s .
3. 4
A n al y si s P o p ul ati o n s
All S cr e e n e d
P o p ul ati o n : all s u bj e ct s w h o
si g n e d C o n s e nt F or m a n d s cr e e n e d at t h e
st u d y sit e s.


Gage Development                                           CONFIDENTIAL                                           GDC-229-002
Statistical Analysis Plan, v3.0 – Page 9
Intent-to-Treat (ITT) Population: All randomized subjects.
Safety Population: All randomized subjects who received at least 1 dose of study drug.
If the drug accountability is unknown (e.g., due to being lost to follow-up after being
randomized) then subjects will be assumed to have taken study drug and included in the
safety population. Subjects reporting 0 doses will be excluded.
Modified Intent-to-Treat (mITT) Population: a subset of the Safety Population who also
met all 4 Amsel’s criteria at baseline, but excluding those who subsequently demonstrate
a positive or indeterminate test result for other concomitant vaginal or cervical infections
at baseline (e.g. C. trachomatis, N. gonorrhoeae) which may interfere with the efficacy
assessment for BV, or who have a baseline Nugent’s score < 4. If baseline STI value is
missing, use the Post-Treatment Assessment Visit infection test result. Subjects without
a Nugent’s score at baseline will be excluded from the mITT population.
Per Protocol (PP) Population: All mITT subjects except for those who had at least one of
the protocol deviations listed below. If lack of efficacy (LOE) is the discontinuation reason
and the subject took at least 3 doses, then the subject will be included in PP as a treatment
failure and then the 6 protocol deviations below will not exclude those subjects:
1. Used topical or systemic antimicrobial drugs after randomization, this includes the
following drug classes: antimycotics, antibacterials, antiprotozoals, gynecological
anti-infectives, antiseptics and antifungals.
2. Used non-study vaginal products during the study
3. Did not start treatment within 2 days of randomization
4. Took less than 5 doses of study drug
5. Test of cure visit (V3) was not in the Study Day 22 – 31 window, i.e., Visit 3 was
not 21 – 30 days after randomization
6. Test of cure visit (V3) not done
Other important violations that represent material non-compliance with study drug or
protocol that would impact the primary and secondary efficacy endpoints will be reviewed
prior to database lock (i.e., before unblinding). These will be documented in the
Evaluability Memo which will be included in the clinical study report.
Subjects in the mITT population who discontinue early from the study, and do not have
an assessment of Clinical Cure or Bacteriological Cure will be included in the mITT
population as treatment failures. These subjects without actual outcomes, but are
classified as treatment failures will not be included in the PP analysis population.
3.5
Demographics and Pre-Treatment Characteristics
Subject demographics and pre-treatment characteristics will be summarized for the ITT
analysis population, and some of these summaries may also be done for other
populations when deemed important.
3.5.1
Demographics
A summary of demographics and subject characteristics will be created for the ITT,
Safety, mITT, and PP populations, and include age, race, ethnicity, height, weight, and
body mass index (BMI) at the study entry visit with:


G a g e D e v el o p m e nt                                           C O N FI D E N TI A L                                           G D C -2 2 9 -0 0 2
St ati sti c al A n al y si s Pl a n, v 3. 0 – P a g e 1 0

6 -n u m b er st ati sti c s ( n u m b er of n o n -mi s si n g o b s er v ati o n s, 
m e a n, 
m e di a n, S D,
mi ni m u m, a n d m a xi m u m) f or a g e, h ei g ht, b a s eli n e w ei g ht, b a s eli n e B MI (t o b e
c al c ul at e d, s e e f or m ul a i n S e cti o n 3. 8. 4 ) b y tr e at m e nt gr o u p a n d f or all s u bj e ct s.

A g e will b e c al c ul at e d ( wit h t h e I N T C K f u n cti o n i n S A S® ) u si n g t h e st u d y e ntr y vi sit
d at e a n d t h e d at e of birt h. S u bj e ct a g e ( y e ar s) will al s o b e c at e g ori z e d a s 1 8 -2 0, 2 1 -
3 0, 3 1 -4 0, 4 1 -5 0, 5 1 + , a n d t h e n s u m m ari z e d c at e g ori c all y al o n g wit h r a c e, et h ni cit y.

B MI at t h e st u d y e ntr y vi sit will al s o b e c at e g ori z e d a s: U n d er w ei g ht (< 1 8. 5 ), N or m al
(1 8. 5 – 2 4. 9 ), O v er w ei g ht (2 5. 0 – 2 9. 9 ), a n d O b e s e
(≥3 0. 0). T h e n u m b er a n d
p er c e nt a g e of s u bj e ct s i n e a c h of t h e s e c at e g ori e s will b e pr e s e nt e d b y tr e at m e nt
gr o u p a n d f or all s u bj e ct s .
3. 5. 2
M e di c al Hi st or y
M e di c al hi st or y d at a will b e c o d e d b y u si n g t h e M e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s
(M e d D R A ) V er si o n 2 0 .0 . T h e c o di n g s will b e r e vi e w e d b y q u alifi e d m e di c al p er s o n n el ,
a n d t h e n s u m m ari z e d b y s y st e m or g a n cl a s s ( S O C) a n d pr ef err e d t er m ( P T) a n d b y t h e
m e di c al hi st or y st at u s
“ O n g oi n g”, or “ R e s ol v e d” b y tr e at m e nt gr o u p a n d f or all s u bj e ct s .
If a s u bj e ct r e p ort s m or e t h a n o n e S O C/ P T, t h at s u bj e ct will b e c o u nt e d o nl y o n c e t o w ar d
t h e st at u s “ O n g oi n g” f or t h e s u m m ar y of t h at S O C/ P T.
3. 5. 3
G y n e c ol o gi c al Hi st or y
G y n e c ol o gi c al
hi st or y d at a will b e s u m m ari z e d f or k e y p ar a m et er s c oll e ct e d i n t h e C R F,
wit h c at e g ori c al ( q u alit ati v e ) p ar a m et ers a s :

I s t h er e a hi st or y of B a ct eri al V a gi n o si s ?

I s t h er e a hi st or y of S e x u all y Tr a n s mitt e d I nf e cti o n s ?
a n d c o nti n u o u s ( q u a ntit ati v e) p ar a m et er s a s :

A p pr o xi m at e n u m b er of ti m e s ( p er m o nt h) y o u h a v e v a gi n al i nt er c o ur s e

C urr e nt t ot al n u m b er of s e x u al p art n er s
T h e n u m b er a n d p er c e nt a g e of I T T s u bj e ct s will b e pr o vi d e d b y tr e at m e nt gr o u p a n d f or
all s u bj e ct s f or e a c h r e s p o n s e t o t h e q u e sti o n f or c at e g ori c al d at a, a n d 6 -n u m b er st ati sti c s
f or c o nti n u o u s d at a.
3. 5. 4
Pr e g n a n c y Hi st or y
Pr e g n a n c y hi st or y d at a i n cl u d e s o nl y 2 p ar a m et er s:

N u m b er of ti m es s u bj e ct h a s b e e n pr e g n a nt

D at e l a st pr e g n a n c y e n d e d.
T h e fir st p ar a m et er will b e s u m m ari z e d b y 6 -n u m b er st ati sti c s a n d al s o c at e g ori c all y ( a s
0, 1, 2, 3, et c.) f or I T T s u bj e ct s. T h e s e c o n d o n e’ s Y e ar p art ( e. g., 1 9 9 8) will b e u s e d t o
g et “N u m b er of y e ar s si n c e t h e l a st pr e g n a n c y e n d e d ”, w hi c h i s t o b e a p pr o xi m at e d a s
2 0 1 7 – Y e ar of l a st p r e g n a n c y e n d e d. T h e n t h e “N u m b er of y e ar s si n c e t h e l a st pr e g n a n c y
e n d e d ” will b e s u m m ari z e d b y 6 -n u m b er s t ati sti c s.


G a g e D e v el o p m e nt                                           C O N FI D E N TI A L                                           G D C -2 2 9 -0 0 2
St ati sti c al A n al y si s Pl a n, v 3. 0 – P a g e 1 1
3. 5. 5
S u b st a n c e U s e
S u b st a n c e u s e i n cl u d e to b a c c o , al c o h ol, a n d illi cit dr u g s. C at e g ori c al r e s p o n s e s, e. g.,
“N e v er ”, “C urr e nt ”, or “F or m er ”, will b e s u m m ari z e d b y n u m b er a n d p er c e nt a g e of
I T T
s u bj e ct s i n e a c h r e s p o n s e/c at e g or y b y tr e at m e nt gr o u p a n d f or all s u bj e ct s .
3. 5. 6
Pri or M e di c ati o n s
All m e di c ati o n s t a k e n b y t h e s u bj e ct f or o n e m o nt h pri or t o r a n d o mi z ati o n (pr e -st u d y) a n d
d uri n g t h e s t u d y will b e r e c or d e d o n t h e pri or a n d c on c o mit a nt m e di c ati o n C R F p a g e.
P ri or m e di c ati o n s ar e m e di c ati o n s t h at w er e t a k e n u p t o o n e m o nt h b ef or e r a n d o mi z ati o n,
a n d c o n c o mit a nt 
m e di c ati o n s ar e 
m e di c ati o n s t a k e n o n or aft er t h e
s u bj e ct w a s
r a n d o mi z e d.
M e di c ati o n s will b e c o d e d t o t h e t h er a p e uti c dr u g cl a s s e s a n d g e n eri c dr u g n a m e s b y
u si n g t h e W orl d H e alt h Or g a ni z ati o n ( W H O) Dr u g Di cti o n ar y, M ar c h 2 0 1 6 v er si o n. T h e
c o di n g s will b e
r e vi e w e d b y q u alifi e d 
m e di c al
p er s o n n el , a n d t h e n s u m m ari z e d b y
tr e at m e nt gr o u p a n d f or all s u bj e ct s wit h th e n u m b er a n d p er c e nt a g e of I T T s u bj e ct s w h o
h a d pri or m e di c ati o n s t h at w er e c o d e d t o e a c h g e n eri c dr u g n a m e a n d t h er a p e uti c dr u g
cl a s s, a s w ell a s t h e n u m b er a n d p er c e nt a g e of s u bj e ct s w h o h a d a t l e a st o n e pri or
m e di c ati o n .  S u bj e ct s r e p orti n g m or e t h a n o n e dr u g i n e a c h dr u g cl a s s/ g e n eri c n a m e ar e
o nl y c o u nt e d o n c e t o t h at dr u g cl a s s/ g e n eri c n a m e.
Pri or m e di c ati o n s will b e al s o b e s u m m ari z e d b y t h e d e s c e n di n g or d er of fr e q u e n ci e s
(t ot al n u m b er of I T T s u bj e ct s) f or dr u g cl a s s (i. e., no g e n eri c dr u g n a m e s pr o vi d e d) .
F or t h e p ur p o s e of a s s e s si n g pri or a n d c o n c o mit a nt m e di c ati o n s,
t h e f oll o wi n g r ul e s will
b e u s e d f or p arti al or mi s si n g m e di c ati o n st art a n d st o p d at e s.
D = D a y, Y = Y e ar, M = M o nt h
P ar a m et er
Mi s si n g
C o m m e nt s
I m p ut ati o n
St art d at e
D o nl y
M a n d Y s a m e a s M a n d Y
of fir st d o s e of st u d y dr u g
D at e of fir st d o s e of st u d y dr u g
M a n d/ or Y n ot s a m e a s
d at e of fir st d o s e of st u d y
dr u g
Fir st d a y of m o nt h
M a n d D
Y s a m e a s Y of fir st d o s e of
st u d y dr u g
D at e of fir st d o s e of st u d y dr u g
Y n ot s a m e a s Y of fir st
d o s e of st u d y dr u g
U s e J a n 0 1 of Y
M, D, a n d Y
N o n e - d at e c o m pl et el y
mi s si n g
D a y pri or t o d at e of fir st d o s e of st u d y
dr u g


G a g e D e v el o p m e nt                                           C O N FI D E N TI A L                                           G D C -2 2 9 -0 0 2
St ati sti c al A n al y si s Pl a n, v 3. 0 – P a g e 1 2
St o p d at e
D o nl y
M a n d Y s a m e a s M a n d Y
of l a st d o s e of st u d y dr u g
D at e of l a st d o s e of st u d y dr u g
M a n d/ or Y n ot s a m e a s
d at e of l a st d o s e of st u d y
dr u g
L a st d a y of m o nt h
M a n d D
Y s a m e a s Y of l a st d o s e of
st u d y dr u g
D at e of l a st d o s e of st u d y dr u g
Y n ot s a m e a s Y of l a st
d o s e of st u d y dr u g
U s e D e c 3 1 of Y
M, D, a n d Y
N o n e - d at e c o m pl et el y
mi s si n g a n d N O T o n g oi n g
D at e of l a st d o s e of st u d y dr u g
3. 6
C o n c o mit a nt M e di c ati o n s
A s d efi n e d i n t h e a b o v e S e cti o n 3. 5. 6 , c o n c o mit a nt m e di c ati o n s ar e m e di c ati on s t a k e n
o n or aft er t h e s u bj e ct w a s r a n d o mi z e d t o st u d y tr e at m e nt. Si mil ar t o pri or m e di c ati o n s,
c o n c o mit a nt m e di c ati o n s will b e s u m m ari z e d f or S af et y p o p ul ati o n s b y t h e n u m b er a n d
p er c e nt a g e of s u bj e ct s i n e a c h c o d e d dr u g n a m e a n d dr u g cl a s s . T h e y will al s o b e
s u m m ari z e d b y t h e d e s c e n di n g or d er of fr e q u e n ci e s (t ot al n u m b er of S af et y s u bj e ct s) f or
dr u g cl a s s (i. e., n o g e n eri c dr u g n a m e s pr o vi d e d) .
A m e di c ati o n m a y b e b ot h “ pri or” a n d “ c o n c o mit a nt” if
a s u bj e ct t o o k it pri or t o t h e
r a n d o mi z ati o n ( pr e-st u d y)
a n d al s o u s e d it a g ai n o n/ aft er r a n d o mi z ati o n . A n ot h er
s u m m ar y t a bl e wit h u ni q u e n u m b er a n d p er c e nt a g e of s u bj e ct s f or e a c h tr e at m e nt gr o u p
a n d all s u bj e ct s
will b e pr e s e nt e d
f or 
m e di c ati o n s b el o n gi n g t o b ot h “ pri or” a n d
“ c o n c o mit a nt” (i. e., a m e di c ati o n will n ot b e i n cl u d e d i n t h e t a bl e u nl e s s a s u bj e ct t o o k it
b ef or e r a n d o mi z ati o n a s w ell a s o n or aft er r a n d o mi z ati o n) .
3. 7
Effi c a c y A n al y s e s
T h e mI T T p o p ul ati o n will b e u s e d t o c o m p ar e b ot h t h e t e st a n d r ef er e n c e pr o d u ct s t o
pl a c e b o. T h e P P p o p ul at i o n will b e u s e d t o e v al u at e t h er a p e uti c e q ui v al e n c e b et w e e n t h e
t e st a n d r ef er e n c e pr o d u ct.
3. 7. 1
Pri m ar y Effi c a c y A n al y s e s
Pri m ar y effi c a c y e n d p oi nt i s t h e “ Cli ni c al Cur e ” at t h e T e st of C ur e ( T O C) vi sit ( Vi sit 3)
a n d i n cl u d e s t h e f oll o wi n g 3 p ar a m et er s fr o m t h e “ St u d y Pr o c e d ur e” C R F p a g e :

R e s ol uti o n of t h e a b n or m al v a gi n al di s c h ar g e t o a n or m al p h y si ol o gi c di s c h ar g e ,
w hi c h
i s fr o m t h e v ari a bl e S P C D B V
(W a s t h er e cli ni c al di a g n o si s of b a ct eri al
v a gi n o si s ? ), wit h v al u e of “ N o”

N e g ati v e w hiff t e st , w hi c h i s fr o m t h e v ari a bl e S P W T (W a s t h er e a p o siti v e w hiff
t e st aft er a d di n g a dr o p of 1 0 % K O H t o v a gi n al di s c h ar g e ?), wit h v al u e of “ N o”


G a g e D e v el o p m e nt                                           C O N FI D E N TI A L                                           G D C -2 2 9 -0 0 2
St ati sti c al A n al y si s Pl a n, v 3. 0 – P a g e 1 3

Pr e s e n c e of cl u e c ell s at < 2 0 % of t h e t ot al e pit h eli al c ell s o n 
mi cr o s c o pi c
e x a mi n ati o n of t h e s ali n e w et m o u nt , w hi c h i s fr o m t h e v ari a bl e S P S W M , wit h v al u e
of “ N o”.
T o i n v e sti g at e t h er a p e uti c e q ui v al e n c e, t h e 9 0 % c o nfi d e n c e i nt er v al ( CI) f or diff er e n c e ,
[t e st - r ef er e n c e], i n pr op orti o n of s u bj e ct s a c hi e vi n g “ C li ni c al C ur e”
will b e c al c ul at e d ,
u si n g t h e P P a n al y si s p o p ul ati o n . A d o pt e d fr o m F D A
Offi c e of G e n eri c Dr u g s
Dr aft
Pr o d u ct 
S p e cifi c
G ui d a n c e
f or 
G e n eri c 
Dr u g 
D e v el o p m e nt 
o n 
M etr o ni d a z ol e
( R e c o m m e n d e d A pril 2 0 1 3) d o c u m e nt , th e c o m p o u n d h y p ot h e si s t o b e t e st e d h er e i s:
If t h e l ow er li mit L ≥– 0. 2 0 a n d u p p er li mit U ≤0. 2 0, w e will r ej e ct n ull h y p ot h e si s H0 a n d
cl ai m t h e bi o e q ui v al e n c e (“ T h er a p e uti c E q ui v al e n c e”) of t e st tr e at m e nt G D C-2 2 9 a n d
r ef er e n c e tr e at m e nt.
T w o -si d e d 9 0 % c o nfi d e n c e i nt er v al ( CI), wit h c o nti n uit y c orr e cti o n, f or t h e “ Cli ni c al C u r e”
r at e of e a c h tr e at m e nt ar m will al s o b e pr e s e nt e d , wit h t h e f oll o wi n g f or m ul a:


G a g e D e v el o p m e nt                                           C O N FI D E N TI A L                                           G D C -2 2 9 -0 0 2
St ati sti c al A n al y si s Pl a n, v 3. 0 – P a g e 1 4
,
w h er e p i s t h e p er c e nt a g e ( pr o p orti o n) of s u bj e ct s wit h “ Cli ni c al C ur e”, z
α / 2 i s t h e
st a n d ar d n or m al di stri b uti o n’ s 5 t h p er c e ntil e ( wit h α = 0. 1), a n d n i s t h e a n al y si s
p o p ul ati o n si z e i n t h e r el e v a nt tr e at m e nt gr o u p , wit h st a n d ar d err or f or t h e pr o p orti o n.
.
P R O C F R E Q ( S A S 9. 4) will b e e m pl o y e d f or t h e a n al y si s.
Pr o p orti o n of s u bj e ct s wit h
“Cli ni c al C ur e ” i n t e st pr o d u ct G D C -2 2 9 a n d r ef er e n c e dr u g will al s o b e c o m p ar e d a g ai n st
t h at i n pl a c e b o gr o u p , a n d p v al u e s fr o m c hi -s q u ar e t e st, or Fi s h er’ s e x a ct t e st - if a n y
c ell s h a v e e x p e ct e d fr e q u e n c y of < 5 , will b e pr e s e nt e d.
A s a p ar a m et er f or d et er mi ni n g
a d e q u at e st u d y s e n siti vit y, b ot h t e st pr o d u ct a n d t h e r ef er e n c e dr u g n e e d to h a v e h i g h er
“ Cli ni c al Cur e ” rat e s t h a n pl a c e b o a n d wit h p v al u e s < 0. 0 5 , u si n g t h e mI T T a n al y si s
p o p ul ati o n
a n d
L a st 
O b s er v ati o n 
C arr i e d F or w ar d
(L O C F ), 
w hi c h 
m e a n s if n o
a s s e s s m e nt s ar e a v ail a bl e at E n d of Tri al vi sit ( eit h er Vi sit 3 f or c o m pl et er s, or E arl y
T er mi n ati o n ( v i sit 4) f or di s c o nti n u e d s u bj e ct s), t h e n t h e Vi sit 2 a s s e s s m e nt r e s ult s will b e
u s e d . A 9 5 % CI f or t h e “ Cli ni c al Cur e ” r at e of e a c h tr e at m e nt ar m will b e pr e s e nt e d f or
mI T T s u bj e ct s.
T h e f or m ul a f or t hi s 9 5 % CI will b e t h e s a m e a s a b o v e 9 0 % CI e x c e pt f or
r e pl a ci n g t h e α v al u e wit h 0. 0 5.
3. 7. 2
S e c o n d ar y Effi c a c y A n al y s e s
T h e e n d p oi nt s f or s e c o n d ar y effi c a c y a n al y s e s ar e

B a ct eri ol o gi c a l C ur e , i. e., N u g e nt’ s s c or e < 4

T h er a p e uti c C ur e , d efi n e d a s f oll o w s:
o
Cli ni c al c ur e a s d efi n e d i n t h e Pri m ar y E n d p oi nt
o
V a gi n al p H < 4. 7
o
N u g e nt ’ s s c or e < 4 (i. e., B a ct eri ol o gi c al C ur e)
T ot al n u m b er a n d pr o p orti o n of s u bj e ct s a c hi e vi n g “B a ct eri ol o gi c al C ur e ”, “T h er a p e uti c
C ur e ” ( al s o e a c h of t h e 3 c o m p o n e nt s) will b e pr e s e nt e d f or mI T T
p o p ul ati o n a s w ell a s
P P p o p ul ati o n b y st u d y vi sit a n d tr e at m e nt ar m .
N u g e nt’ s s c or e will al s o b e s u m m ari z e d c at e g ori c all y b y it s r a w s c or e ( 0, 1, 2, …, 1 0).
All
r e s ult s fro m t h e A m s el’ s 4 crit eri a will al s o b e s u m m ari z e d c at e g ori c all y (“ Y e s”/ “N o”) b y
st u d y vi sit a n d tr e at m e nt ar m f or b ot h mI T T p o p ul ati o n a n d P P p o p ul ati o n .
3. 7. 3
Ot h er O ut c o m e M e a s ur e m e nt s
T h e ot h er a s s e s s m e nt s a s f oll o w s ( e a c h wit h “ Y e s”, or “ N o” a n s w er) o n “ St u d y Pr o c e d ur e”
f or m will b e pr e s e nt e d i n d at a li sti n g :

W a s t h er e a v a gi n al s e cr eti o n wit h p H gr e at er t h a n 4. 5 ?

W a s t h e s ali n e w et m o u nt a s s e s s e d f or e vi d e n c e of a n y ot h er v ul v o v a gi nit i s ot h er
t h a n B V ?


G a g e D e v el o p m e nt                                           C O N FI D E N TI A L                                           G D C -2 2 9 -0 0 2
St ati sti c al A n al y si s Pl a n, v 3. 0 – P a g e 1 5

Di d t h e w et m o u nt c o nt ai n a n y e vi d e n c e f or c a n di di a si s, Tri c h o m o n a s v a gi n ali s,
C hl a m y di a tr a c h o m ati s, N ei s s eri a g o n orr h o e a e, a cti v e h er p e s si m pl e x, or a cti v e
H P V ?

W a s t h e uri n e dr u g s cr e e n p erf or m e d ?

W er e a n y of t h e r e s ult s p o siti v e ?

I n t h e l a st 4 8 h o ur s h a v e y o u u s e d a n y s p er mi ci d e s, t a m p o n s, d o u c h e s,
di a p hr a g m s, c o n d o m s or ot h er i ntr a v a gi n al pr o d u ct ?

Si n c e y o ur l a st vi sit h a v e y o u u s e d a n y s p er mi ci d e s, t a m p o n s, d o u c h e s,
di a p hr a g m s, c o n d o m s or ot h er i ntr a v a gi n al pr o d u ct ?

H a v e y o u h a d i nt er c o ur s e wit hi n t h e 4 8 h o ur s pri or t o a vi sit ?
3. 8
S af et y A n al y s e s
All s af et y a n al y s e s will b e p erf or m e d f or t h e S af et y p o p ul ati o n u nl e s s n ot e d ot h er wi s e .
3. 8. 1
Tr e at m e nt E x p o s ur e a n d C o m pli a n c e
E x p o s ur e t o st u d y tr e at m e nt will b e s u m m ari z e d c at e g ori c all y b y

t h e n um b er of d o s e s
(1, 2, 3, et c. ) a ct u all y u s e d

t h e l e n gt h of ti m e ( # of d a y s) o v er w hi c h t h e pr o d u ct i s u s e d.
T h e l e n gt h of ti m e o v er w hi c h t h e pr o d u ct i s u s e d will b e c al c ul at e d a s Tr e at m e nt St o p
D at e – Tr e at m e nt St art D at e + 1.
Tr e at m e nt C o m pli a n c e f or e a c h s u bj e ct i n S af et y p o p ul ati o n will b e c al c ul at e d a s :
N u m b er of d o s e s a ct u all y u s e d / 5 x 1 0 0 % ,
w h er e d e n o mi n at or 5 i s t h e t ot al n u m b er of d o s e s s u p p o s e d t o b e t a k e n b y a r a n d o mi z e d
s u bj e ct i n t hi s st u d y. T h e f oll o wi n g i nf or m ati o n f or e a c h tr e at m e n t gr o u p will b e pr e s e nt e d
f or Tr e at m e nt C o m pli a n c e:

S i x-n u m b er st ati sti c s ( s a m pl e si z e, m e a n, m e di a n, S D, mi ni m u m, a n d m a xi m u m)

T h e n u m b er a n d p er c e nt a g e of s u bj e ct s i n e a c h of t h e f oll o wi n g 4 c at e g ori e s of
tr e at m e nt c o m pli a n c e: < 6 0 %,
6 0 %
- < 1 0 0 %, 1 0 0 % , a nd > 1 0 0 % .
All d r u g a c c o u nt a bilit y ( D A) d at a o n D A f or m will b e pr e s e nt e d i n a d at a li sti n g.
3. 8. 2
A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s
A tr e at m e nt-e m er g e nt a d v er s e e v e nt , ( T E A E) i s a n y s y m pt o m, si g n, ill n e s s, or e x p eri e n c e
t h at d e v el o p s or w or s e n s i n s e v erit y a n d/ or fr e q u e n c y aft er t h e st u d y tr e at m e nt st art e d .
A s eri o u s a d v er s e e v e nt (S A E ) i s a n y a d v er s e e v e nt t h at r e s ult s i n a n y of t h e f oll o wi n g
o ut c o m e s: D e at h ; i m m e di at e t hr e at t o lif e; i n p ati e nt h o s pit ali z ati o n or pr ol o n g ati o n of a n
e xi sti n g 
h o s pit ali z ati o n ;
p er si st e nt 
or 
si g nifi c a nt 
di s a bilit y/i n c a p a cit y ;
c o n g e nit al
a n o m al y/ birt h d ef e ct ; ot h er s eri o u s ( m e di c al i m p ort a nt) A E s. All A E s will b e c o d e d wit h
s y st e m or g a n cl a s s ( S O C) a n d pr ef err e d t er m ( P T) fr o m t h e M e d D R A V er si o n 2 0 . 0. T h e
c o di n g s will b e r e vi e w e d b y q u alifi e d m e di c al p er s o n n el .
I n ci d e n c e of A E s a n d S A E s will b e s u m m ari z e d b y S O C a n d P T wit h t h e n u m b er a n d
p er c e nt a g e of s u bj e ct s wit h e a c h S O C a n d P T b y tr e at m e nt ar m . T h e f oll o wi n g t a bl e s will
b e pr e s e nt e d f or S af et y p o p ul ati o n:


G a g e D e v el o p m e nt                                           C O N FI D E N TI A L                                           G D C -2 2 9 -0 0 2
St ati sti c al A n al y si s Pl a n, v 3. 0 – P a g e 1 6

A E s b y S O C a n d P T

A E s t h at l e d t o st u d y di s c o nti n u ati o n or d e at h b y S O C a n d P T

A E s b y S O C a n d P T b y s e v erit y

A E s b y S O C a n d P T b y r el at e d n e s s t o t h e st u d y tr e at m e nt

A E s i n d e s c e n di n g or d er of S O C fr e q u e n ci e s ( n o P T di s pl a y e d)

A E s i n d e s c e n di n g or d er of P T fr e q u e n ci e s ( n o S O C di s pl a y e d)
All t h e a b o v e t a bl e s ( e x c e pt f or w h er e s p e cifi e d) ar e c o u nti n g n u m b er of di sti n ct s u bj e ct s
i n e a c h S O C a n d P T. S u bj e ct s r e p orti n g m or e t h a n o n e A E / S A E i n e a c h P T
will b e
c o u nt e d o nl y o n c e t o t h at P T , u si n g t h e m o st s e v er e i nt e n sit y, f or u ni q u e n u m b er of
s u bj e ct s c o u nti n g .  T h e o nl y e x c e pti o n t o t hi s will b e f or t h e s u m m ar y b y r el at e d n e s s t o
t h e st u d y tr e at m e nt, wh er e s u bj e ct s will b e c o u nt e d o nl y o n c e u si n g t h e str o n g e st
r el at e d n e s s t o t h e st u d y tr e at m e nt f or t h e p ur p o s e of c o u nti n g di sti n ct n u m b er of s u bj e ct s.
T h e s a m e pri n ci pl e al s o will b e a p pli e d t o t h e s u m m ar y at t h e S O C l e v el.
A n o v er all A E hi g h -l e v el s u m m ar y t a bl e will al s o b e pr o vi d e d f or S af et y p o p ul ati o n s wit h
t ot al n u m b er a n d p er c e nt a g e of di sti n ct s u bj e ct s ( b ut n o S O C or P T ) f or

A E s e v erit y ( Mil d, M o d er at e, S e v er e)

A E r el at e d n e s s ( N ot R el at e d, P o s si bl y R el at e d , R el at e d )

S A E

D e at h, or d i s c o nti n u e d st u d y d u e t o a n y A E
A n ot h er hi g h -l e v el s u m m ar y t a bl e f or S af et y p o p ul ati o n will pr e s e nt t h e c o u n t s of e v e nt s
(n ot di sti n ct s u bj e ct s) a s t h e f oll o wi n g c h art. N ot e t h at e a c h p er c e nt a g e, if pr o vi d e d, i s
b a s e d o n t h e n u m b er o n t h e o n e w h er e “( 1 0 0. 0)” i s di s pl a y e d . T hi s A E s u m m ar y t a bl e,
d o n e f or e a c h tr e at m e nt gr o u p a n d all S af et y
s u bj e ct s, pr o vi d e s t h e c r o s s r ef er e n c e
b et w e e n e v er y l e v el of r el at e d n e s s a n d s e v erit y.
R el at e d n e s s (t o t h e
st u d y tr e at m e nt)
A E S e v erit y
Mil d
M o d er at e
S e v er e
T ot al # ( %) of
E v e nt s
N ot R el at e d
x x
x x
x x
x x ( x. x)
P o s si bl y R el at e d
x x
x x
x x
x x ( x. x)
R el at e d
x x
x x
x x
x x ( x. x)
T ot al # ( %) of
E v e nt s
x x
x x
x x
x x ( 1 0 0. 0)
T w o li sti n g-st yl e t a bl e s , o n e i s f or S A E s , a n d t h e ot h er i s f or A E s t h at l e d t o pr e m at ur e
st u d y di s c o nti n u ati o n, will al s o b e pr e s e nt e d, wit h t h e d et ail s a b o ut t h e e v e nt o n s et d at e,
r e s ol v e d d at e, st u d y d a y of o n s et si n c e t h e st u d y tr e at m e nt ( c al c ul at e d a s O n s et D at e –
R a n d o mi z ati o n D at e + 1 ), s e v erit y, o ut c o m e, m e di c al i nt er v e nti o n n e e d e d f or t h e A E, a n d
r el at e d n e s s t o t h e st u d y tr e at m e nt, a s w ell a s ot h er s u p p orti v e dat a s u c h a s t h e s u bj e ct’ s
a g e a n d n u m b er of d a y s o n t h e st u d y .
3. 8. 3
L o c al Sit e R e a cti o n
L o c al sit e r e a cti o n s i n cl u d e a n y r e a cti o n t h at o c c ur s wit hi n t h e tr e at m e nt ar e a of s u bj e ct s .
L o c al sit e r e a cti o n s ar e pr e s p e cifi e d i n t h e pr ot o c ol a n d will b e c oll e ct e d i n d e p e n d e ntl y of


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St ati sti c al A n al y si s Pl a n, v 3. 0 – P a g e 1 7
a d v er s e e v e nt s.  L o c al sit e r e a cti o n s t h at r e q uir e m e di c al i nt er v e nti o n or e xt e n d b e y o n d
t h e tr e at m e nt ar e a will b e d o c u m e nt e d a s a d v er s e e v ent s. A t Vi sit s 2 (P o st -Tr e at m e nt
A s s e s s m e nt ) a n d 3 (T e st of C ur e ), su bj e ct s will b e a s s e s s e d at tr e at m e nt ar e a f or t h e
f oll o wi n g 7 s y m pt o m s :

Er yt h e m a

P et e c hi a e

Er o si o n/ ul c er ati o n

E d e m a

B ur ni n g/ sti n gi n g

P ai n

Pr urit u s (it c hi n g)
S u bj e ct s n e e d t o r at e t h e m a s

1 = A b s e nt,

2 = M il d ( sli g ht, b ar el y p er c e pti bl e),

3 = M o d er at e ( di sti n ct pr e s e n c e), or

4 = S e v er e ( m ar k e d, i nt e n s e) .
T h e s e d at a, al o n g wit h t h e f oll o wi n g 2 q u e sti o n s o n t h e s a m e C R F, will b e s u m m ari z e d
c at e g ori c all y b y vi sit .

Di d t h e l o c al si t e r e a cti o n e xt e n d b e y o n d t h e tr e at m e nt ar e a a n d w a s r e c or d e d a s
a n A E ? (“ Y e s”, “ N o”)

Di d t h e l o c al sit e r e a cti o n r e q uir e m e di c al i nt er v e nti o n ? (“ Y e s”, “ N o”)
3. 8. 4
Vit al Si g n s a n d W ei g ht
Vit al si g n s 
m e a s ur e m e nt s , d o n e at all st u d y vi sit s, i n cl u d e h e art
rat e , p ul s e r at e,
re s pir at or y rat e , b o d y t e m p er at ur e, s y st oli c a n d di a st oli c bl o o d pr e s s ur e s , i n a d diti o n t o
h ei g ht a n d w ei g ht . B MI ( u nit: k g/ m 2 ) will b e c al c ul at e d fr o m h ei g ht (i n c h) a n d w ei g ht (l b):
B MI = W ei g ht (l b) / ( H ei g ht (i n c h e s))
2 x 7 0 3
T h e n it will b e c at e g ori z e d a s: U n d er w ei g ht (< 1 8. 5 ), N or m al (1 8. 5 – 2 4. 9 ), O v er w ei g ht
(2 5. 0 – 2 9. 9 ), a n d O b e s e (≥3 0. 0). B ot h n u m eri c al a n d c at e g ori c al s u m m ari e s f or B MI will
b e pr e s e nt e d.
T h e 6 -n u m b er s u m m ar y st ati sti c s f or c o nti n u o u s v ari a bl e s a n d t h eir
c h a n g e s fr o m b a s eli n e, a s w ell a s t h e n u m b er a n d p er c e nt a g e of s u bj e ct s i n e a c h B MI
c at e g or y will b e pr e s e nt e d b y st u d y vi sit a n d tr e at m e nt ar m .
3. 8. 5
P h y si c al E x a mi n ati o n
P h y si c al e x a mi n ati o n will b e p erf or m e d at all st u d y v i sit s i n t h e f oll o wi n g b o d y ar e a s:

D er m at ol o gi c al

R e s pir at or y

H. E. E. N. T

C ar di o v a s c ul ar

G a str oi nt e sti n al

H e p ati c/ Bil iar y

G e nit o uri n ar y/ R e pr o d u cti v e


G a g e D e v el o p m e nt                                           C O N FI D E N TI A L                                           G D C -2 2 9 -0 0 2
St ati sti c al A n al y si s Pl a n, v 3. 0 – P a g e 1 8

R e n al

N e ur ol o gi c al/ P s y c h ol o gi c al

M u s c ul o s k el et al

M et a b ol i c

H e m at ol o gi c al

I m m u n ol o gi c al/ All er gi e s

R e c e nt Tr a u m a ( p a st 3 m o nt h s)

Pri or S ur g er y

C o n g e nit al

Ot h er
T h e e x a m i n ati o n r e s ult s (“ Nor m al ”, “ Ab n or m al ”), a n d c h a n g e s fr o m b a s eli n e (“I m pr o v e d”
– if “ A b n or m al” at b a s eli n e a n d “ N or m al” at p o st-b a s eli n e, “ N o C h a n g e”, “ W or s e n e d” – if
“ N or m al” at b a s eli n e a n d “ A b n or m al” at p o st-b a s eli n e), will b e s u m m ari z e d b y pr e s e nti n g
th e n u m b er a n d p er c e nt a g e of s u bj e ct s i n e a c h c at e g or y b y b o d y ar e a a n d tr e at m e nt a t
e a c h st u d y vi sit .
3. 8. 6
G y n e c ol o gi c al E x a m
G y n e c ol o gi c al e x a m will b e d o n e at e a c h st u d y vi sit i n t h e f oll o wi n g ar e a s:

Br e a st s

A d n e x a e

V ul v a

V a gi n al w all

C er vi x

Ut er u s

R e ct al
T h e e x a mi n ati o n r e s ult s (“ N or m al”, “ A b n or m al”), a n d c h a n g e s fr o m b a s eli n e (“I m pr o v e d”
– if “ A b n or m al” at b a s eli n e a n d “ N or m al” at p o st-b a s eli n e, “ N o C h a n g e”, “ W or s e n e d” – if
“ N or m al” at b a s eli n e a n d “ A b n or m al” at p o st-b a s eli n e), will b e s u m m ari z e d c at e g ori c all y
b y vi sit .
F or “ A b n or m al” r e s ult s, a f u rt h er q u e sti o n “ W a s t h e r e s ult cli ni c all y si g nifi c a nt ?” will al s o
b e s u m m ari z e d wit h n u m b er  of “ Y e s” s u bj e ct s.
3. 8. 7
Ot h er S af et y A s s e s s m e nt s
Ot h er st u d y a s s e s s m e nt s, s u c h a s pr e g n a n c y t e st
( a n d pr e g n a n c y o ut c o m e, if k n o w n),
a n d uri n e dr u g s cr e e n will b e pr o vi d e d i n d at a li sti n g s.
4. 0
R E F E R E N C E S
1.
A m s el R, T ott e n P A, S pi e g el C A, et al. N o n s p e cifi c v a gi niti s: di a g n o sti c crit eri a a n d
mi cr o bi al a n d e pi d e mi ol o gi c a s s o ci ati o n s. A m J M e d. 1 9 8 3; 7 4( 1): 1 4 -2 2.
2.
C e nt er f or Dr u g E v al u ati o n a n d R e s e ar c h. A p pli c ati o n N u m b er 2 0 5 2 2 3 Ori g 1 s 0 0 0.
St ati sti c al R e vi e w s. St ati sti c al R e vi e w a n d E v al u ati o n of m etr o ni d a z ol e v a gi n al g el
1. 3 %. R e vi e w d at e J a n u ar y 1 8, 2 0 1 4.


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Statistical Analysis Plan, v3.0 – Page 19
3.
Chavoustie SE, Jacobs M, Reisman HA, et al. Metronidazole vaginal gel 1.3% in
the treatment of bacterial vaginosis: a dose-ranging study. J Lower Genital Tract
Disease. 2015;19(2):129-134.
4.
Korn AP, Bolan G, Padian N, et al. Plasma cell endometritis in women with
symptomatic bacterial vaginosis. Obstet Gynecol. 1995;85(3):387–90.
5.
Nugent RP, Krohn MA, and Hillier SL. Reliability of diagnosing bacterial vaginosis is
improved by a standardized method of gram stain interpretation. J Clin Micro.
1991;29(2):297-30.
6.
Schwebke JR, Marrazzo J, Beelen AP, et al. A Phase 3, multicenter, randomized,
double-blind, vehicle-controlled study evaluating the safety of efficacy of
metronidazole vaginal gel 1.3% in the treatment of bacterial vaginosis. Sexually
Transmitted Diseases. 2015;42(7):376-381.


G a g e D e v el o p m e nt                                           C O N FI D E N TI A L                                           G D C -2 2 9 -0 0 2
St ati sti c al A n al y si s Pl a n, v 3. 0 – P a g e 2 0
5. 0
A P P E N DI C E S
5. 1
S t u d y Sc h e d ul e of A s s e s s m e nt s
Vi sit
Vi sit 1
Vi sit 2
Vi sit 3
Vi sit N a m e
E ntr y
Vi sit
P o st -
Tr e at m e nt
A s s e s s m e nt
T e st of C ur e
E arl y
T er mi n ati o n a
St u d y D a y( s)
1
8 t o 15 d a y s
2 2 t o 31 d a y s
I nf or m e d c o n s e nt
X
I n cl u si o n/ e x cl u si o n crit eri a
X
D e m o gr a p hi c s
X
M e di c al a n d g y n e c ol o gi c al
hi st or y
X
P h y si c al e x a mi n ati o n
X
X
X
P el vi c e x a mi n ati o n
X
X
X
X
H ei g ht
X
W ei g ht
X
X
X
Vit al si g n s ( aft er sitti n g f or 5 - 1 0
mi n s)
X
X
X
X
C o n c o mit a nt m e di c ati o n s
X
X
X
X
R a n d o mi z ati o n b
X
Di s p e n s e st u d y m e di c ati o n c a n d
d o si n g i n str u cti o n s
X
C oll e ct st u d y m e di c ati o n
X
X d
A s s e s s m e nt of l o c al sit e r e a cti o n s
X
X
X
A d v er s e e v e nt s
X
X
X
X
Uri n e pr e g n a n c y t e st
X
X
X
X
Uri n e dr u g s cr e e n
X
A m s el’ s crit eri a e v al u ati o n s:
-A s s e s s m e nt of v a gi n al
di s c h ar g e
X
X
X
X
-K O H W hiff T e st
X
X
X
X
-S ali n e W et M o u nt
X
X
X
X
-p H
X
X
X
X
C oll e cti o n of s a m pl e s f or N u g e nt’ s
s c or e b a s e d o n Gr a m st ai n ( s e n d t o
c e ntr al l a b or at or y)
X
X
X
C oll e cti o n of s a m pl e s f or S TI
a s s e s s m e nt e ( s e n d t o c e ntr al
l a b or at or y)
X
a.
At a n y ti m e a s u bj e ct d e ci d e s t o di s c o nti n u e h er p arti ci p ati o n i n t h e st u d y or i s di s c o nti n u e d fr o m t h e
st u d y f or a n y ot h er r e a s o n, s h e will b e a d vi s e d t o c o m pl et e t h e E arl y T er mi n ati o n pr o c e d ur e s.
b.
R a n d o mi z ati o n t o o c c ur if t h e r e s ult s of t h e f ull s et of A m s el’ s crit eri a ar e p o siti v e.
c.
St u d y m e di c ati o n will b e di s p e n s e d at Vi sit 1.  T h e s u bj e ct will b e i n str u ct e d t o s elf -a d mi ni st er st u d y
m e di c ati o n i ntr a v a gi n all y o n c e d ail y at b e dti m e f or 5 c o n s e c uti v e d a y s.
d.
U nl e s s c oll e ct e d at pr e vi o u s vi sit.


G a g e D e v el o p m e nt                                           C O N FI D E N TI A L                                           G D C -2 2 9 -0 0 2
St ati sti c al A n al y si s Pl a n, v 3. 0 – P a g e 2 1
e.
C e ntr al l a b or at or y a n a l y si s f or C hl a m y di a tr a c h o m ati s a n d N ei s s eri a g o n orr h o e a e.


G a g e D e v el o p m e nt                                           C O N FI D E N TI A L                                           G D C -2 2 9 -0 0 2
St ati sti c al A n al y si s Pl a n, v 3. 0 – P a g e 2 2
5. 2
T a bl e of C o nt e nt s f or D at a Di s pl a y
F oll o w i n g i s t h e li st of pl a n n e d t a bl e s a n d li sti n g s. T a bl e s will b e n u m b er e d a c c or di n g t o
t h e n o m e n cl at ur e u s e d t o s u p p ort t h e fi n al C S R . T h e d at a s et s i n t h e O G D G ui d a n c e will
b e cr e at e d a n d u s e d i n o ur pr o gr a m mi n g of t h e t a bl e s i n t hi s S A P.
T h e f or m at of e a c h u ni q u e t a bl e i s pr o vi d e d i n a s e p ar at e d o c u m e nt of “ T a bl e S h ell s”, b ut
n o d at a li sti n g s h ell s ar e pr o vi d e d. Fi n al o ut p ut s m a y b e sli g htl y diff er e nt i n l a y o ut fr o m
t h at of ill u str at e d i n “ T a bl e S h ell s”. Th e t a bl e s h ell s will n ot b e a m e n d e d t o m at c h t h e
a ct u al t a bl e s i n s u c h c a s e s.
T a bl e
N u m b er
T a bl e Titl e
A n al y si s
P o p ul ati o n
1 4. 1. 1
S u m m ar y of S u bj e ct Di s p o siti o n a n d R e a s o n s f or
Di s c o nti n u ati o n
All S cr e e n e d
1 4. 1. 1 . 1
S cr e e n F ail ur e R e a s o n S u m m ar y
S cr e e n
F ail ur e
1 4. 1. 2
Li st of S u bj e ct s W h o Pr e m at ur el y Di s c o nti n u e d t h e St u d y
I T T
1 4. 1. 3
S u m m ar y of S u bj e ct Di s p o siti o n b y St u d y Sit e
I T T
1 4. 1. 4
N u m b er a n d P er c e nt a g e of S u bj e ct s at E a c h Vi sit
I T T
1 4. 1. 5
S u m m ar y of Pr ot o c ol D e vi ati o n s
I T T
1 4. 1. 6
S u m m ar y of A n al y si s P o p ul ati o n s
I T T
1 4. 1. 7
D e m o gr a p hi c s
I T T
1 4. 1. 7 S
D e m o gr a p hi c s
S af et y
1 4. 1. 7 M
D e m o gr a p hi c s
mI T T
1 4. 1. 7 P
D e m o gr a p hi c s
P P
1 4. 1. 8 . 1
M e di c al Hi st or y
I T T
1 4. 1. 8 . 2
G y n e c ol o gi c al Hi st or y
I T T
1 4. 1. 8. 3
Pr e g n a n c y Hi st or y
I T T
1 4. 1. 8. 4
S u b st a n c e U s e
I T T
1 4. 1. 9. 1 C
N u m b er a n d P er c e nt a g e of S u bj e ct s wit h Pri or M e di c ati o n
U s e b y Dr u g Cl a s s i n D e s c e n di n g Or d er of Fr e q u e n ci e s
I T T
1 4. 1. 9. 1 G
N u m b er a n d P er c e nt a g e of S u bj e ct s wit h Pri or M e di c ati o n
U s e b y Dr u g G e n eri c N a m e i n D e s c e n di n g Or d er of
Fr e q u e n ci e s
I T T
1 4. 1. 9. 1
N u m b er a n d P er c e nt a g e of S u bj e ct s wit h Pri or M e di c ati o n
U s e b y Dr u g Cl a s s a n d G e n eri c N a m e
I T T
1 4. 1. 9 .2 C
N u m b er a n d P er c e nt a g e of S u bj e ct s wit h C o n c o mit a nt
M e di c ati o n U s e
b y Dr u g Cl a s s i n D e s c e n di n g Or d er of
Fr e q u e n ci e s
S af et y


Gage Development                                           CONFIDENTIAL                                           GDC-229-002
Statistical Analysis Plan, v3.0 – Page 23
14.1.9.2G
Number and Percentage of Subjects with Concomitant
Medication Use by Drug Generic Name in Descending
Order of Frequencies
Safety
14.1.9.2
Number and Percentage of Subjects with Concomitant
Medication Use by Drug Class and Generic Name
Safety
14.1.9.3C
Number and Percentage of Subjects with Prior Medications
Also Used After the Randomization by Drug Class in
Descending Order of Frequencies
Safety
14.1.9.3G
Number and Percentage of Subjects with Prior Medications
Also Used After the Randomization by Drug Name in
Descending Order of Frequencies
Safety
14.1.9.3
Number and Percentage of Subjects with Prior Medications
Also Used After the Randomization by Drug Class and
Generic Name
Safety
14.2.1
Analysis of Therapeutic Equivalence
PP
14.2.2
Analysis of Study Sensitivity
mITT
14.2.3M
Summary of Bacteriological Cure and Therapeutic Cure
mITT
14.2.3P
Summary of Bacteriological Cure and Therapeutic Cure
PP
14.2.4M
Nugent’s Score and Amsel’s Criteria Summary by Study
Visit
mITT
14.2.4P
Nugent’s Score and Amsel’s Criteria Summary by Study
Visit
PP
14.3.0
Treatment Exposure and Compliance
Safety
14.3.1.1
Overall Number and Percentage of Subjects with Adverse
Events
Safety
14.3.1.2
Overall Number of Adverse Events by Severity and
Relatedness to the Study Treatment
Safety
14.3.1.3C
Summary of Adverse Events by System Organ Class in
Descending Order of Frequencies
Safety
14.3.1.3P
Summary of Adverse Events by Preferred Term in
Descending Order of Frequencies
Safety
14.3.1.4
Summary of Adverse Events by System Organ Class and
Preferred Term
Safety
14.3.1.5C
Summary of Adverse Events by System Organ Class and
by Severity
Safety
14.3.1.5
Summary of Adverse Events by System Organ Class and
Preferred Term and by Severity
Safety
14.3.1.6C
Summary of Adverse Events by System Organ Class and
by Relatedness to the Study Treatment
Safety


G a g e D e v el o p m e nt                                           C O N FI D E N TI A L                                           G D C -2 2 9 -0 0 2
St ati sti c al A n al y si s Pl a n, v 3. 0 – P a g e 2 4
1 4. 3. 1. 6
S u m m ar y of A d v er s e E v e nt s b y S y st e m Or g a n Cl a s s a n d
Pr ef err e d T er m a n d b y R el at e d n e s s t o t h e St u d y Tr e at m e n t
S af et y
1 4. 3. 2. 1
Li st of S eri o u s A d v er s e E v e nt s
S af et y
1 4. 3. 2. 2
Li st of A d v er s e E v e nt s t h at L e d t o Pr e m at ur e St u d y
Di s c o nti n u ati o n
S af et y
1 4. 3. 5
L o c al Sit e R e a cti o n
S af et y
1 4. 3. 6
Vit al Si g n s a n d W ei g ht
S af et y
1 4. 3. 7
P h y si c al E x a mi n ati o n
S af et y
1 4. 3. 8
G y n e c ol o gi c al E x a mi n ati o n
S af et y
Li sti n g
N u m b er
Li sti n g Titl e
A n al y si s
P o p ul ati o n
1 6. 2. 1. 1
S u bj e ct I nf or m ati o n
All S cr e e n e d
1 6. 2. 1. 2
I n cl u si o n / E x cl u si o n Crit eri a N ot M et
All S cr e e n e d
1 6. 2. 1. 3
S u bj e ct Di s p o siti o n
I T T
1 6. 2. 1. 4
S u bj e ct St u d y Vi sit s
I T T
1 6. 2. 2
Pr ot o c ol D e vi ati o n s
I T T
1 6. 2. 3
S u bj e ct s E x cl u d e d fr o m t h e Effi c a c y A n al y si s
I T T
1 6. 2. 4. 1
D e m o gr a p hi c s
I T T
1 6. 2. 4. 2
M e di c al Hi st or y
I T T
1 6. 2. 4. 3
G y n e c ol o g i c al Hi st or y
I T T
1 6. 2. 4. 4
Pr e g n a n c y Hi st or y
I T T
1 6. 2. 4. 5
Pri or a n d C o n c o mit a nt M e di c ati o n s
I T T
1 6. 2. 4. 6
S u b st a n c e U s e
I T T
1 6. 2. 5. 1
Dr u g A c c o u nt a bilit y
I T T
1 6. 2. 5. 2
Tr e at m e nt E x p o s ur e
I T T
1 6. 2. 6. 1
St u d y Pr o c e d ur e s
I T T
1 6. 2. 7. 1 A
A d v er s e E v e nt s – P art A
I T T
1 6. 2. 7. 1 B
A d v er s e E v e nt s – P art B
I T T
1 6. 2. 7. 2
L o c al Sit e R e a cti o n
I T T
1 6. 2. 8. 1
N u g e nt’ s S c or e s
I T T
1 6. 2. 8. 2
S e x u al Tr a n s mitt e d I nf e cti o n T e st s
I T T
1 6. 2. 9. 1
Vit al Si g n s
I T T
1 6. 2. 9. 2
P h y si c al E x a mi n ati o n
I T T
1 6. 2. 9. 3
G y n e c ol o gi c al E x a mi n ati o n
I T T
1 6. 2. 9. 4
Pr e g n a n c y T e st
I T T


Gage Development                                           CONFIDENTIAL                                           GDC-229-002
Statistical Analysis Plan, v3.0 – Page 25
16.2.9.5
Pregnancy Notification
ITT
16.2.9.6
Pregnancy Outcome
ITT