Clinical trial NCT03332303
Conditions: Vulvar and Vaginal Atrophy
Keywords: Vaginal Dryness Vaginal and/or Vulvar Irritation/Itching Dysuria Vaginal Pain and Bleeding
Sponsor: Prasco LLC
Start date: 2017-10-26; Completion date: 2018-03-15
Enrollment: 540 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objectives of this study are to evaluate the therapeutic equivalence of the Test formulation, Estradiol Vaginal Cream 0.01% (Prasco, LLC) to the marketed product, Estrace® Cream (estradiol vaginal cream, 0.01%) in patients with vulvar and vaginal atrophy, and compare the safety of Test, Reference and Placebo treatments in patients with vulvar and vaginal atrophy.

Detailed description:

Arms: arm 1: Estradiol Vaginal Cream, USP, 0.01%, administered once daily for 7 days.

Intervention: Drug: Estradiol Vaginal Cream, USP, 0.01% arm 2: Estrace® Cream (Estradiol Vaginal Cream, USP, 0.01%), administered once daily for 7 days.

Intervention: Drug: Estrace® Cream (Estradiol Vaginal Cream, USP, 0.01%) arm 3: Placebo (Test vehicle cream) Vaginal Cream, administered once daily for 7 days.

Intervention: Drug: Placebo (Test vehicle cream) Vaginal Cream
Interventions: intervention 1: Estrace® Cream intervention 2: Estradiol Vaginal Cream intervention 3: Vehicle Cream
Intervention descriptions: intervention 1: Estrace® Cream intervention 2: Estradiol Vaginal Cream intervention 3: Vehicle Cream

Protocol documents:
Prot_002.pdf: 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 1 of 51 
 
 
1.0 TITLE PAGE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Product 
Estradiol Vaginal Cream USP, 0.01% 
Population 
Approximately 535 postmenopausal females, 30-75 years of age 
inclusive, with moderate to severe vulvar and vaginal atrophy 
Study Design 
A randomized, double-blind, placebo-controlled, multiple-site, 
parallel-design bioequivalence study with clinical endpoints 
Sponsor 
Prasco LLC 
Protocol/Study Number 
71759501 
Protocol Date 
07/25/2017 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 2 of 51 
 
 
2.0 KEY STUDY PERSONNEL AND FACILITIES 
Sponsor: 
Prasco LLC 
 
 
CRO: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 3 of 51 
 
 
 
 
 
 
 
 
 
 






CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 6 of 51 
 
 
PRINCIPAL INVESTIGATOR’S SIGNATURE 
 
 
I _______________________________________, agree to conduct protocol 71759501 Rev 0 in 
accordance with FDA regulations, ICH guidelines and GCPs. I understand that no deviations from the 
protocol may be made without the prior permission of the Sponsor (Prasco LLC) or 
 
he company managing the study. 
 
 
 
 
 
 
___________________________________  
 
 __________ 
Principal Investigator 
 
 
 
 
 
 
 
 
 
Date 
 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 7 of 51 
 
 
4.0 TABLE OF CONTENTS 
1.0 TITLE PAGE .......................................................................................................................................... 1 
2.0 KEY STUDY PERSONNEL AND FACILITIES .................................................................................. 2 
3.0 SIGNATURE PAGE .............................................................................................................................. 4 
4.0 TABLE OF CONTENTS ........................................................................................................................ 7 
5.0 SYNOPSIS ............................................................................................................................................ 10 
6.0 STUDY SCHEMATIC ......................................................................................................................... 17 
7.0 LIST OF ABBREVIATIONS AND TERMS ....................................................................................... 18 
8.0 INTRODUCTION ................................................................................................................................ 20 
8.1 Disease Being Treated ...................................................................................................................... 20 
8.2 Availability and Efficacy of Already Approved Therapies .............................................................. 20 
8.3 Scientific and Statistical Considerations ........................................................................................... 21 
8.4 Justification for use of Placebo ......................................................................................................... 21 
8.5 Risks and Benefits ............................................................................................................................. 21 
9.0 STUDY OBJECTIVES ......................................................................................................................... 22 
10.0 INVESTIGATIONAL PLAN ............................................................................................................. 22 
10.1 Study Design and Plan Description ................................................................................................ 22 
10.2 Selection of Study Design ............................................................................................................... 23 
10.3 Selection of Study Population ......................................................................................................... 23 
10.3.1 Inclusion Criteria...................................................................................................................... 23 
10.3.2 Exclusion Criteria .................................................................................................................... 24 
10.3.3 Restrictions During the Study .................................................................................................. 26 
10.3.4 Removal of Patients from the Study ........................................................................................ 26 
10.3.5 Early Terminations ................................................................................................................... 27 
10.4 Treatments....................................................................................................................................... 27 
10.4.1 Treatment Administration ........................................................................................................ 27 
10.4.2 Identity of Investigational Product ........................................................................................... 27 
10.4.3 Study Product Shipment, Storage, and Retention .................................................................... 27 
10.4.4 Method of Assigning Patients to Treatment Groups ................................................................ 28 
10.4.5 Study Blind .............................................................................................................................. 28 
10.4.6 Compliance .............................................................................................................................. 29 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 8 of 51 
 
 
10.5 Study Conduct ................................................................................................................................. 30 
10.5.1 Visit 1 (Day -28 to Day -1): Screening .................................................................................... 30 
10.5.2 Visit 2 (Day 1): Randomization ............................................................................................... 31 
10.5.3 Visit 3 (Day 8 or Day 9): End of Study or Early Termination ................................................. 31 
10.6 Study Procedures ............................................................................................................................ 32 
10.6.1 Informed Consent ..................................................................................................................... 32 
10.6.2 Medical History and Demographics ........................................................................................ 32 
10.6.3 Concomitant Medication .......................................................................................................... 32 
10.6.4 Adverse Events ........................................................................................................................ 32 
10.6.5 Vital Signs ................................................................................................................................ 32 
10.6.6 Signs and Symptoms ................................................................................................................ 32 
10.6.7 Physical Exam .......................................................................................................................... 33 
10.6.8 Vaginal Cytology and pH ........................................................................................................ 33 
10.6.9 PAP Smear ............................................................................................................................... 33 
10.6.10 Serum FSH and Fasting Triglycerides ................................................................................... 33 
10.6.11 Mammogram .......................................................................................................................... 34 
10.6.12 Vaginal Ultrasound ................................................................................................................ 34 
10.6.13 Inclusion/Exclusion Criteria Review ..................................................................................... 34 
10.6.14 Provide Patient Diary ............................................................................................................. 34 
10.6.15 Dispense Study Product ......................................................................................................... 34 
10.6.16 Collect and Review Patient Diary .......................................................................................... 34 
10.6.17 Collect Study Product ............................................................................................................ 34 
10.7 Adverse Events ............................................................................................................................... 35 
10.7.1 Adverse Event Definitions ....................................................................................................... 35 
10.7.2 Severity of Adverse Event ....................................................................................................... 36 
10.7.3 Relationship of Adverse Event ................................................................................................ 36 
10.8 Serious Adverse Events .................................................................................................................. 36 
10.8.1 Definition of a Serious Adverse Event..................................................................................... 36 
10.8.2 Reporting Serious Adverse Events and Suspected Unexpected Serious Adverse Reactions ... 37 
11.0 STATISTICAL METHODS ............................................................................................................... 38 
11.1 Statistical Plan ................................................................................................................................. 38 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 9 of 51 
 
 
11.2 Determination of Sample Size ........................................................................................................ 38 
11.3 Study Populations ........................................................................................................................... 39 
11.3.1 Per-Protocol Population ........................................................................................................... 39 
11.3.2 Modified Intent-to-Treat Population ........................................................................................ 39 
11.3.3 Safety Population ..................................................................................................................... 40 
11.4 Baseline Comparability ................................................................................................................... 40 
11.5 Efficacy Endpoints .......................................................................................................................... 40 
11.6 Efficacy Analyses ........................................................................................................................... 41 
11.7 Safety Analysis ............................................................................................................................... 42 
12.0 REGULATORY OBLIGATIONS ...................................................................................................... 42 
12.1 Institutional Review Board ............................................................................................................. 42 
12.2 Study Documentation ...................................................................................................................... 42 
12.2.1 Protocol .................................................................................................................................... 42 
12.2.2 Informed Consent ..................................................................................................................... 43 
12.2.3 Protocol and Informed Consent Changes ................................................................................. 43 
12.2.4 Source Documents and Electronic Case Report Forms ........................................................... 43 
12.2.5 Drug Accountability ................................................................................................................. 43 
12.2.6 Drug Storage ............................................................................................................................ 44 
12.2.7 Pregnancies .............................................................................................................................. 44 
12.2.8 Reporting Safety Information to the IRB ................................................................................. 44 
12.2.9 Record Retention...................................................................................................................... 44 
12.2.10 Study Monitoring and Auditing ............................................................................................. 44 
12.2.11 End of the Trial ...................................................................................................................... 45 
12.2.12 Clinical Study Report ............................................................................................................. 45 
13.0 REFERENCES ................................................................................................................................... 46 
14.0 APPENDICES .................................................................................................................................... 48 
14.1 APPENDIX A: Clinical Laboratory Testing................................................................................... 48 
14.2 APPENDIX B: Definitions and Severity ratings for Signs and Symptoms .................................... 49 
14.3 APPENDIX C: Product Insert for Estrace® .................................................................................... 51 
 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 10 of 51 
 
 
5.0 SYNOPSIS 
Protocol Number 
71759501 
Title 
A 
Randomized, 
Double-Blind, 
Placebo-Controlled, 
Parallel-Design, 
Multiple-Site Study to Evaluate the Therapeutic Equivalence of Estradiol 
Vaginal Cream USP, 0.01% (Prasco LLC) Compared to Estrace® Cream 
(Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment 
of Vulvar and Vaginal Atrophy. 
Objectives 
The objectives of this study are to: 
• 
Evaluate the therapeutic equivalence of a generic Estradiol Vaginal Cream 
USP, 0.01% (Prasco LLC) to the Reference product, Estrace® Cream 
(Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the treatment 
of vulvar and vaginal atrophy (VVA). 
• 
Demonstrate the superiority of the Test and Reference (active) treatments 
over Placebo (vehicle) treatment in patients with VVA. 
• 
Compare the safety of Test, Reference and Placebo treatments in patients 
with VVA. 
Sponsor 
Prasco LLC 
Study Products 
• 
Test: Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) 
• 
Reference: Estrace® Cream (Estradiol Vaginal Cream, USP, 0.01%) 
(Warner Chilcott) 
• 
Placebo: Placebo (Test vehicle cream) Vaginal Cream (Prasco LLC) 
Study products will be supplied in tubes, with a calibrated plastic applicator 
for dose (2 grams) administration.  
Dosage Regimen 
Patients will be instructed to apply 2 grams study product to the treatment 
area once daily for seven days. Each patient is expected to receive seven 
doses. 
Route of 
Administration 
Intravaginal 
Treatment 
Randomization 
2:2:1 (Test: Reference: Placebo) 
Patient Population 
Approximately 
 postmenopausal females, 30-75 years of age inclusive, 
with moderate to severe VVA.  
Study Design 
Randomized, double-blind, placebo-controlled, parallel-group, multiple-site 
bioequivalence study with clinical endpoints 
Study Conduct 
Eligible patients will be randomized in a 2:2:1 ratio to one of the three 
treatments (Test, Reference or Placebo). Following a 28-day screening 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 11 of 51 
 
 
period, at Visit 2 patients will be instructed to self-administer 2 grams of 
study product once daily at approximately the same time for seven 
consecutive days. During the study, patients will visit the clinical center for a 
total of three scheduled visits: 
• 
Visit 1/Screening (Day -28 to Day -1) 
• 
Visit 2/Randomization (Day 1) 
• 
Visit 3/End of Study (Day 8 or Day 9) 
Final assessments will be carried out on Day 8 or Day 9. Vaginal cytology 
and vaginal pH determination will be performed by the Investigator as a part 
of clinical evaluation at Visits 1 and 3. 
Inclusion Criteria 
1. Signed Institutional Review Boards (IRB)-approved informed consent 
form that meets all criteria of current FDA regulations. 
2. Postmenopausal females aged 30-75 years inclusive. Postmenopausal is 
defined as follows: 
a. At least 6 months of spontaneous amenorrhea. 
b. At least 6 weeks post-surgical bilateral oophrectomy, with or without 
hysterectomy. 
c. Hysterectomy without oophrectomy if of age that the Investigator 
believes would have naturally reached 12 months of spontaneous 
amenorrhea if uterus had remained intact. 
3. Patients with a serum Follicle Stimulating Hormone (FSH) level of ≥ 40 
mIU/mL at Screening. 
4. Have ≤ 5% superficial cells on vaginal smear cytology. 
5. Have a vaginal pH > 5.0. 
6. At least one of the following patient self-assessed moderate to severe 
symptoms of VVA from the following list that is identified by the patient 
as being most bothersome to her: 
• 
Vaginal Dryness 
• 
Vaginal and/or Vulvar Irritation/Itching 
• 
Dysuria 
• 
Vaginal Pain associated with sexual activity 
• 
Vaginal Bleeding associated with sexual activity (presence or 
absence) 
*Provided that patient is currently sexually active and plans to remain 
so throughout study. 
7. Have “Normal” Screening mammogram completed within 9 months 
before Screening in all patients > 40 years old, with no findings that, in 
the opinion of the Investigator, would indicate any suspicion of breast 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 12 of 51 
 
 
malignancy.  
8. Normal clinical breast examination at Screening. 
9. Patients with an intact uterus (including patients who underwent a partial 
hysterectomy) must have a documented papanicolaou (PAP) smear 
conducted within the previous 12 months with no findings that the 
Investigator believes would contraindicate the use of topical vaginal 
estradiol. 
10. Patients with an intact uterus should have vaginal ultrasonography results 
within 3 months before Screening to confirm an inactive endometrial 
lining, defined as endometrial thickness < 4 mm. 
Exclusion Criteria 
1. Significant history or current evidence of chronic infectious disease, 
system disorder, organ disorder or other medical condition that in the 
Investigator’s opinion would place the study patient at undue risk by 
participation or could jeopardize the integrity of the study evaluations. 
2. Any clinically significant laboratory finding that, in the Investigator’s 
opinion would contraindicate the use of estradiol or compromise patient 
safety. 
3. Patients with known concurrent vaginal infections including but not 
limited to: Candida albicans, Trichomonas vaginalis, Chlamydia 
trachomatis, Neisseria gonorrhea or Gardnerella vaginalis. 
4. Patients with active vaginal herpes simplex infection or have had an 
outbreak within 30 days before the Screening. 
5. Patients with known, suspected or current history of carcinoma of the 
breast. 
6. Patients with baseline systolic blood pressure of > 150 mmHg and/or 
diastolic pressure > 90 mmHg. 
7. Any patient with past or current undiagnosed vaginal bleeding or 
significant risk factors for endometrial cancer. 
8. Any history of estrogen-dependent neoplasia (e.g., endometrial cancer). 
9. Patients with known, suspected or current history of hormone dependent 
tumor. 
10. History of acute thrombophlebitis or thromboembolic disorder. 
11. Any prescription treatment for vaginal dryness/irritation within 14 days 
before Screening or any over-the-counter or natural remedies within 7 
days before Screening. 
12. Any prescription treatment for bacterial or yeast infections within 30 
days before Screening. 
13. Fasting triglyceride levels > 350 mg/dL. 
14. History of radiation therapy or recent (within previous 6 weeks) surgical 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 13 of 51 
 
 
therapy to the vaginal or cervical areas. 
15. Any known or suspected allergies that, in the Investigator’s opinion, 
would compromise the safety of the patient. 
16. Patients who have used vaginal hormonal products (rings, creams, gels) 
within the 7 days before Screening. 
17. Patients who have used transdermal estrogen and/or progestin therapy 
within the 28 days before Screening. 
18. Patients who have used oral estrogen and/ or progestin therapy or 
intrauterine progestin therapy within the 56 days before Screening. 
19. Patients who have used progestin implants or estrogen alone injectable 
drug therapy within the 3 months before Screening. 
20. Patients who have used estrogen pellet therapy or progestin injectable 
drug therapy within 6 months before Screening. 
21. History of significant alcohol abuse within 1 year prior to Screening or 
regular use of alcohol within 6 months before Screening (more than 14 
units of alcohol per week [1 unit = 150 mL of wine, 360 mL of beer, 
or 45 mL of 40% alcohol]). 
22. History of significant drug abuse within 1 year prior to Screening, use of 
soft drugs (such as marijuana) within 3 months before Screening, or hard 
drugs (such as cocaine, phencyclidine [PCP], crack, opioid derivatives 
including heroin, and amphetamine derivatives) within 1 year before 
screening. 
23. Use within 30 days of Screening with known strong CYP3A4 inducers or 
inhibitors that, in the opinion if the Investigator, may affect estrogen 
metabolism. Examples of strong CYP3A4 inhibitors are macrolide 
antibiotics such as clarithromycin and telithromycin; azole antifungals 
such as itraconazole and ketoconazole; antidepressants such as 
nefazodone; and foods such as grapefruit or grapefruit juice. Examples of 
strong CYP3A4 inducers are anticonvulsants such carbamazepine and 
phenytoin; bactericidals such as rifampin and rifabutin; and natural health 
products such as St John’s wort. 
24. Inability to understand the requirements of the study and the relative 
information or are unable or not willing to comply with the study 
protocol. 
25. Receipt of any drug as part of a research study within 30 days before 
Screening. 
26. Employees of the Investigator or research center or their immediate 
family members. 
27. Patients who have participated in this study previously. 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 14 of 51 
 
 
Efficacy 
Endpoints 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of patients in each treatment 
group that are identified as Responders at the end of the treatment period 
evaluated on Day 8 or Day 9. 
A Responder is defined as a patient with at least a 25% reduction from 
baseline in the sum of % basal/parabasal + % intermediate cells on vaginal 
cytology AND vaginal pH < 5.0 with a change from baseline vaginal pH of at 
least 0.5. 
Secondary Efficacy Endpoint 
The secondary efficacy endpoint is the proportion of patients in each 
treatment group that are considered a Treatment Success at the end of the 
treatment period evaluated on Day 8 or Day 9. 
A “Treatment Success” is defined as a score of 0 or 1 on Day 8 or Day 9 for 
the symptom identified at baseline as the most bothersome. This evaluation 
will be based on (one) patient self-assessed symptom of VVA (vaginal 
dryness, vaginal and/or vulvar irritation/itching, dysuria, or vaginal pain 
associated with sexual activity) on a scale of 0 to 3 where 0 = none and 3 = 
severe. Evaluation of vaginal bleeding during sexual activity will be based on 
a score of 1 (presence) if it is identified by the patient as the most bothersome 
symptom at baseline and a score of 0 (absent) on Day 8 or Day 9.  
 
Evaluation of 
Therapeutic 
Equivalence and 
Superiority 
Primary Endpoint Analysis 
Therapeutic Equivalence: 
Therapeutic equivalence will be evaluated for both primary and secondary 
endpoints in the per-protocol (PP) population. If the 90% confidence interval 
(calculated using Yates’ continuity correction) on the absolute difference 
between the proportion of patients identified as Responders in the Test and 
Reference groups (pT - pR) is contained within the range [-20%, +20%] then 
therapeutic equivalence of the Test product to the Reference product will be 
considered to have been demonstrated. 
The same statistical approach will be conducted for analysis of the secondary 
endpoint in the PP population. 
To declare therapeutic equivalence of the Test product to the Reference 
product, equivalence must be demonstrated for only the primary endpoints in 
the PP population. 
Superiority to Placebo 
Superiority of the Test and Reference products against the Placebo product 
for the primary endpoint will be evaluated in the modified Intent-to-Treat 
(mITT) population using last observation carried forward (LOCF). If the 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 15 of 51 
 
 
proportion of Responders in the Test and the Reference product groups is 
numerically and statistically superior to that of the Placebo (p < 0.05; using a 
two-sided Cochran-Mantel-Haenszel [CMH] test, stratified by clinical site) 
then superiority of the Test and Reference products over Placebo will be 
concluded. 
The same statistical approach will be conducted for analysis of the secondary 
endpoint in the mITT population. 
To declare superiority of the Test and Reference products over Placebo, their 
superiority must be demonstrated for only the primary endpoint in the mITT 
population. 
Treatment-by-Site Interaction and Pooling of Clinical Sites 
As this is a multiple-site study, the interaction of treatment-by-site may be 
evaluated for the primary efficacy endpoint in the PP population for 
equivalence testing. The treatment-by-site interaction will be evaluated by the 
Breslow-Day test for homogeneity of the odds ratio at the 5% significance 
level (p < 0.05, 2-sided). A site(s) with a low enrollment rate(s) may be 
pooled with its geographically closest site, so as to avoid bias in the 
stratification of the sites in the CMH test and in the estimation of a treatment-
by-site interaction effect. The pooling will be done for low enrolling sites that 
account for less than 4-7% of the total number of patients in the PP 
population at the site with the highest enrolling rate in the PP population. If 
the treatment-by-site interaction term is found to be statistically significant 
(p < 0.05) for the primary endpoint, then the interaction term will also be 
assessed for clinical relevance before pooling the data across sites. This will 
include examination of Responder rates at each site where sample sizes per 
treatment may be influential in the assessment of the interaction. 
Safety Analysis 
Adverse events (AEs) will be classified using standard Medical Dictionary 
for Regulatory Activities (MedDRA) terminology Version 20.0 or higher and 
summarized by treatment group. Summary tables comparing the type, 
incidence, date of onset, date of resolution, severity, action taken, outcome 
and Investigator’s opinion of relationship to the study product will be 
prepared by treatment group. If sufficient data exist, AE frequencies will be 
compared between treatments using Fisher’s exact test or a similar test. Signs 
and symptoms of VVA will not be considered AEs, unless in the 
Investigator’s opinion, they have increased in frequency and/or severity to 
such an extent that the Investigator/patient considers that it is in the patient’s 
best interest to be dropped from continued participation in the study and 
given alternative therapy for their condition. Concomitant medication use 
during the study will be tabulated by patient.  
Sample Size 
For the primary endpoint analysis (proportion of patients in the PP population 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 16 of 51 
 
 
Determination 
that are identified as Responders at the end of the treatment period evaluated 
on Day 8 + 1), sample size is estimated for therapeutic equivalence of the 
Test to the Reference product and superiority of each of the active treatments 
groups over Placebo. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 17 of 51 
 
 
6.0 STUDY SCHEMATIC 
 
Visit 1 
(Day -28 to Day -1) 
Screening 
Visit 2 
(Day 1) 
Randomization 
Visit 3 
(Day 8 or Day 9) 
End of Study or 
Early Termination 
Informed Consent 
X 
 
 
Medical History and Demographics 
X 
 
 
Review and Assessment of 
Concomitant Medications 
X 
X 
X 
Review and Assessment of Adverse 
Events 
X 
X 
X 
Vital Signs 
X 
X 
X 
Signs and Symptoms of VVA 
X 
X 
X 
Physical Exam  
X 
 
X 
Vaginal Cytology and pH 
X 
 
X 
PAP*Smear 
X 
 
 
Serum FSH and Fasting 
Triglycerides 
X 
 
 
Mammogram† 
X 
 
 
Vaginal Ultrasound‡ 
X 
 
 
Inclusion/Exclusion Criteria Review 
X 
X  
 
Collect and Review Patient Diary 
 
X 
X 
Provide Patient Diary 
X 
X 
 
Dispense Study Product 
 
X 
 
Collect Study Product 
 
 
X 
*Patients with an intact uterus who do not have documentation of a PAP smear completed within the last 
. 
Patients over the age of 40 who do not have documentation of a mammogram completed within the  
 before Screening will have a mammogram as part of the Screening evaluations. 
‡Patients with an intact uterus will have a vaginal ultrasound as part of the Screening evaluations which 
will be reviewed before randomization.


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 18 of 51 
 
 
7.0 LIST OF ABBREVIATIONS AND TERMS 
ADaM 
Analysis Dataset Model 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ANOVA 
Analysis of variance 
C 
Celsius 
CDISC 
Clinical Data Interchange Consortium 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
eCTD 
Electronic Common Technical Document 
F 
Fahrenheit 
FDA 
Food & Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practices 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities  
mITT 
modified Intent-to-Treat  
NCR 
No Carbon Required 
NDA 
New Drug Application 
OHRP 
Office of Human Rights Protection 
OTC 
Over-the-Counter 
PAP 
Papanicolaou 
PP 
Per-Protocol 
pR 
Proportion of Subjects considered a Treatment Success in the Reference Treatment 
pT 
Proportion of Subjects considered a Treatment Success in the Test Treatment 
RS 
Reference Standard 
RSI 
Reference Safety Information  
SAE 
Serious Adverse Event 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 19 of 51 
 
 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
USA 
United States of America 
VVA 
Vulvar and Vaginal Atrophy 






CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 22 of 51 
 
 
has issued a detailed guidebook to Institutional Review Boards (IRBs) that includes discussion on the 
use of placebos in clinical studies.17 
Qualified patients have a 20% chance they may be randomized to Placebo. Randomized patients will 
be enrolled in the study for 8 or 9 days. Although the potential for any drug-related side effects of 
significance occurring during the study are low, the risk is higher in the two active treatment groups 
than in the Placebo group. 
All patients enrolled in this study will receive the benefit of free specialized medical care beyond 
standard medical treatment that would be expected through most health insurance plans. In addition, 
the patient will receive a stipend for participation to cover costs and expenses associated with trips to 
the medical facility.  
9.0 STUDY OBJECTIVES 
The objectives of this study are to: 
1. Evaluate the therapeutic equivalence of a generic Estradiol Vaginal Cream USP, 0.01% (Prasco 
LLC) to the Reference product, Estrace® Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner 
Chilcott) in the treatment of VVA. 
2. Demonstrate the superiority of the Test and Reference (active) treatments over Placebo (vehicle) 
treatment in patients with VVA. 
3. Compare the safety of Test, Reference and Placebo treatments in patients with VVA. 
10.0 INVESTIGATIONAL PLAN 
10.1 Study Design and Plan Description 
This randomized, double-blind, placebo-controlled, parallel-design, multiple-site study is designed to 
evaluate the clinical (therapeutic) effect of a generic Estradiol Vaginal Cream USP, 0.01% (Prasco 
LLC) compared to the FDA Reference Standard (RS), Estrace® Cream (Estradiol Vaginal Cream, 
USP, 0.01% (Warner Chilcott) in patients with VVA. Additionally, both the Test and Reference 
products will be tested for superiority against a Placebo. 
Before any study-specific procedures are performed, all patients will read and sign the IRB-approved 
informed consent form (ICF). 
Approximately 
 eligible postmenopausal female patients, with a confirmed diagnosis of VVA will 
be randomized in a 2:2:1 ratio (Test: Reference: Placebo) to one of the three study products as 
follows: 
• 
Test: Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) 
• 
Reference: Estrace® Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) 
• 
Placebo: Placebo (Test vehicle cream) Vaginal Cream (Prasco LLC) 
Following a 28-day screening period, at Visit 2 patients will be instructed to self-administer 2 grams 
of study product once daily at approximately the same time for seven consecutive days. 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 23 of 51 
 
 
During the study, patients will visit the clinical center for a total of three scheduled visits: 
• 
Visit 1/Screening (Day -28 to Day -1) 
• 
Visit 2/Randomization (Day 1) 
• 
Visit 3/End of Study (Day 8 or Day 9) 
Final assessments will be carried out on Day 8 or Day 9 
Vaginal cytology and vaginal pH determination will be performed by the Investigator as a part of 
clinical evaluation at Visits 1 and 3. The primary statistical analysis of interest is the proportion of 
patients in the PP population that are identified as Responders at the end of the treatment period 
evaluated on Day 8 or Day 9. A Responder is defined as a patient with at least a 25% reduction from 
baseline in the sum of % basal/parabasal + % intermediate cells on vaginal cytology AND vaginal pH 
< 5.0 with a change from baseline vaginal pH of at least 0.5. 
10.2 Selection of Study Design 
This study has been designed based on the draft FDA Guidance for Industry; Estrogen and 
Estrogen/Progestin Drug Products to Treat Vasomotor Symptoms and VVA (January 2003) and the 
Draft FDA Guidance on Estradiol Vaginal Cream (revised September 2014).12,13 Statistical analyses 
of the clinical data will be based on recommendations in the FDA Guidances.12-16,18 
10.3 Selection of Study Population 
10.3.1 Inclusion Criteria 
1. Signed IRB-approved ICF that meets all criteria of current FDA regulations. 
2. Postmenopausal females aged 30-75 years inclusive. Postmenopausal is defined as 
follows: 
a. At least 6 months of spontaneous amenorrhea. 
b. At least 6 weeks post-surgical bilateral oophrectomy, with or without 
hysterectomy. 
c. Hysterectomy without oophrectomy if of age that the Investigator believes would 
have naturally reached 12 months of spontaneous amenorrhea if uterus had 
remained intact. 
3. Patients with a serum Follicle Stimulating Hormone (FSH) level of ≥ 40 mIU/mL at 
Screening. 
4. Have ≤ 5% superficial cells on vaginal smear cytology. 
5. Have a vaginal pH > 5.0. 
6. At least one of the following patient self-assessed moderate to severe symptoms of VVA 
from the following list that is identified by the patient as being most bothersome to her: 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 24 of 51 
 
 
• 
Vaginal Dryness 
• 
Vaginal and/or Vulvar Irritation/Itching 
• 
Dysuria 
• 
Vaginal Pain associated with sexual activity 
• 
Vaginal Bleeding associated with sexual activity (presence or absence) 
*Provided that patient is currently sexually active and plans to remain so throughout 
study. 
7. Have “Normal” Screening mammogram completed within 9 months before Screening in 
all patients > 40 years old, with no findings that, in the opinion of the Investigator, would 
indicate any suspicion of breast malignancy.  
8. Normal clinical breast examination at Screening. 
9. Patients with an intact uterus (including patients who underwent a partial hysterectomy) 
must have a documented papanicolaou (PAP) smear conducted within the previous 12 
months with no findings that the Investigator believes would contraindicate the use of 
topical vaginal estradiol. 
10. Patients with an intact uterus should have vaginal ultrasonography results within 3 
months before Screening to confirm an inactive endometrial lining, defined as 
endometrial thickness < 4 mm. 
10.3.2 Exclusion Criteria 
1. Significant history or current evidence of chronic infectious disease, system disorder, 
organ disorder or other medical condition that in the Investigator’s opinion would place 
the study patient at undue risk by participation or could jeopardize the integrity of the 
study evaluations. 
2. Any clinically significant laboratory finding that, in the Investigator’s opinion, would 
contraindicate the use of estradiol or compromise patient safety. 
3. Patients with known concurrent vaginal infections including but not limited to: Candida 
albicans, Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhea or 
Gardnerella vaginalis. 
4. Patients with active vaginal herpes simplex infection or have had an outbreak within 30 
days before the Screening. 
5. Patients with known, suspected or current history of carcinoma of the breast. 
6. Patients with baseline systolic blood pressure of > 150 mmHg and/or diastolic pressure > 
90 mmHg. 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 25 of 51 
 
 
7. Any patient with past or current undiagnosed vaginal bleeding or significant risk factors 
for endometrial cancer. 
8. Any history of estrogen-dependent neoplasia (e.g., endometrial cancer). 
9. Patients with known, suspected or current history of hormone dependent tumor. 
10. History of acute thrombophlebitis or thromboembolic disorder. 
11. Any prescription treatment for vaginal dryness/irritation within 14 days before Screening 
or any OTC or natural remedies within 7 days before Screening. 
12. Any prescription treatment for bacterial or yeast infections within 30 days before 
Screening. 
13. Fasting triglyceride levels > 350 mg/dL. 
14. History of radiation therapy or recent (within previous 6 weeks) surgical therapy to the 
vaginal or cervical areas. 
15. Any known or suspected allergies that, in the Investigator’s opinion, would compromise 
the safety of the patient. 
16. Patients who have used vaginal hormonal products (rings, creams, gels) within the 7 days 
before Screening. 
17. Patients who have used transdermal estrogen and/or progestin therapy within the 28 days 
before Screening. 
18. Patients who have used oral estrogen and/ or progestin therapy or intrauterine progestin 
therapy within the 56 days before Screening. 
19. Patients who have used progestin implants or estrogen alone injectable drug therapy 
within the 3 months before Screening. 
20. Patients who have used estrogen pellet therapy or progestin injectable drug therapy 
within 6 months before Screening. 
21. History of significant alcohol abuse within 1 year prior to Screening or regular use of 
alcohol within 6 months before Screening (more than 14 units of alcohol per week 
[1 unit = 150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol]). 
22. History of significant drug abuse within 1 year prior to Screening, use of soft drugs (such 
as marijuana) within 3 months before Screening, or hard drugs (such as cocaine, 
phencyclidine [PCP], crack, opioid derivatives including heroin, and amphetamine 
derivatives) within 1 year before screening. 
23. Use within 30 days of Screening with known strong CYP3A4 inducers or inhibitors that, 
in the opinion if the Investigator, may affect estrogen metabolism. Examples of strong 
CYP3A4 inhibitors are macrolide antibiotics such as clarithromycin and telithromycin; 
azole antifungals such as itraconazole and ketoconazole; antidepressants such as 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 26 of 51 
 
 
nefazodone; and foods such as grapefruit or grapefruit juice. Examples of strong 
CYP3A4 inducers are anticonvulsants such carbamazepine and phenytoin; bactericidals 
such as rifampin and rifabutin; and natural health products such as St John’s wort. 
24. Inability to understand the requirements of the study and the relative information or are 
unable or not willing to comply with the study protocol. 
25. Receipt of any drug as part of a research study within 30 days before Screening. 
26. Employees of the Investigator or research center or their immediate family members. 
27. Patients who have participated in this study previously. 
10.3.3 Restrictions During the Study 
Patients will be instructed to refrain from the following throughout the study: 
• 
Any kind of estrogen, progesterone or androgen hormone replacement. 
• 
Any other treatments, prescription, OTC or natural products or natural methods, for the 
treatment of vaginal dryness/irritation including but not limited to vaginal lubricants, oils, 
creams, jellies, food products or saliva. 
• 
Any vaginal drug products other than the study product (e.g., vaginal anti-fungals). 
• 
Use within 30 days of Screening with known strong CYP3A4 inducers or inhibitors that, 
in the opinion if the Investigator, may affect estrogen metabolism. Examples of strong 
CYP3A4 inhibitors are macrolide antibiotics such as clarithromycin and telithromycin; 
azole antifungals such as itraconazole and ketoconazole; antidepressants such as 
nefazodone; and foods such as grapefruit or grapefruit juice. Examples of strong 
CYP3A4 inducers are anticonvulsants such carbamazepine and phenytoin; bactericidals 
such as rifampin and rifabutin; and natural health products such as St John’s wort. 
10.3.4 Removal of Patients from the Study 
Patients will be advised that they are free to withdraw from the study at any time for any reason 
or, if necessary, the Investigator or Sponsor may withdraw a patient from the study to protect the 
health of that patient. A patient may also be withdrawn for not complying with study procedures. 
Patients who withdraw or are withdrawn from the study will not be replaced. The clinical report 
will include all reasons for early withdrawals. 
Reasons for early termination may include, but are not limited to the following: 
• 
Patient withdrew consent. 
• 
Significant adverse event (AE) that led the Investigator/Sponsor or patient to withdraw 
for safety reasons. 
• 
Non-compliance with protocol requirements (e.g., use of restricted medication, not 
following dosing procedures, failure to make scheduled study visits in a timely fashion). 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 27 of 51 
 
 
• 
Pregnancy. 
• 
Significant worsening of VVA such that the Investigator/Sponsor and/or patient believe it 
is in the best interest of the patient to withdraw from the study and be provided 
alternative treatment. 
• 
Participant enrolls in another clinical trial, or is found to have previously enrolled in this 
clinical trial. 
10.3.5 Early Terminations 
If a patient terminates from the study early after being randomized, all efforts will be made to 
complete the patient's next visit study procedures. For early termination, Visit 3 (Day 8 or Day 9) 
End of Study or Early Termination (See Section 6.0) shall be completed and the Investigator shall 
fully document the reason for early termination. 
10.4 Treatments 
10.4.1 Treatment Administration 
At Visit 2, following a 28-day screening period, eligible patients will be provided with 
1 x 42.5 gram tube of study product along with verbal and written instructions on its 
administration. Patients will be required to self-administer 2 grams of study product once daily at 
approximately the same time of the day, for seven consecutive days. The last dose should be 
applied on the day before Visit 3. Patients should not dose on the day of Visit 3. 
Patients will gently squeeze the cream out of the tube and into the applicator until the required 
amount (2 grams) is filled based on the calibrated markings on the applicator. The applicator is 
then to be unscrewed from the tube and cap replaced on the tube. To deliver study product, 
patients are to lie on back and insert the applicator into the vagina and deliver the dose by 
pressing down on the plunger. The applicator is to be cleaned with mild soap and warm water 
after each application. 
Based on an approximate 2 grams application per day, 1 x 42.5 gram tube of cream should be 
sufficient to last for the full treatment period of the study (seven days). Patients will begin dosing 
on the day of Visit 2 (i.e., Day 1). 
10.4.2 Identity of Investigational Product 
The following products will be used in the study: 
• 
Test: Estradiol Vaginal Cream USP, 0.01% (Prasco LLC) 
• 
Reference: Estrace® Cream (Estradiol Vaginal Cream USP, 0.01%) (Warner Chilcott) 
• 
Placebo: Placebo (Test vehicle cream) Vaginal Cream (Prasco LLC) 
10.4.3 Study Product Shipment, Storage, and Retention 
The study product will be shipped to each Investigator’s site from a central location. The 
Principal Investigator at each site is responsible for ensuring that all study products are stored in 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 28 of 51 
 
 
locked, secure location, with access limited to the Investigator and his/her designee(s). An 
accurate inventory of the study product will be maintained in accordance with federal regulations. 
Study product will be stored in a secure, locked location, at room temperature, protected from 
temperatures in excess of 40 ºC (104 ºF). Any excursions from the permitted temperature will 
require prompt notification to 
 and thereafter 
will notify the Sponsor. 
 
 
 
 
 
 
 
 
 
10.4.4 Method of Assigning Patients to Treatment Groups 
All randomized study product will be blinded and packaged in sealed boxes by an independent 
packaging company. Randomization will be pre-planned according to a computer-generated 
randomization schedule. 
 
 
 
 
 
 
 
 
 
10.4.5 Study Blind 
The Investigator, staff at the study site, study monitors, and data analysis/management personnel 
will be blinded to the patient assignment. Each study site will have at least one Independent 
Dispenser. The role of the Independent Dispenser is to dispense and collect study product to/from 
the patients, maintain dispensing records, and ensure the study product logs are complete and 
accurate. The patient will be requested not to discuss the appearance of the study product with the 
Investigator or study staff. 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 29 of 51 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.4.6 Compliance 
Patients will be provided with a diary to record the time and date of dosing, other concomitant 
medications and AEs. Patients will be considered compliant if they take a total of at least six 
doses and no more than eight doses, and not more than two doses on any day. Patients taking 
fewer than 75% or more than 125% of the required doses will be considered non-compliant with 
dosing. Compliance with dosing will be verified by the use of the patient diaries. Compliance 
criteria are as outlined in the table below: 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 30 of 51 
 
 
For patients who have completed the study: 
Study Design 
Compliance Criteria 
Visit 3 
Treatment 
Duration 
Required 
Doses 
Not more than 
125% (doses) 
Not less than 75% 
(doses) 
Days 8-9 
7 days 
7 
8 
6 
For patients who are early terminated, compliance will be determined from their duration in the 
study, up to the time they are considered early terminated. For example, if a patient is dropped 
after six days of participation and starts application of study product on the day of Visit 2 (i.e., 
Day 1) and once daily for the four of the five remaining days, then percent compliance would be 
83% (4 out of 5 doses). 
10.5 Study Conduct 
10.5.1 Visit 1 (Day -28 to Day -1): Screening 
1. Informed Consent: Patients who are willing to comply with study procedures will read, 
understand and sign the ICF. 
2. Medical History and Demographics: Review the patient’s demographic and medical 
history. 
3. Concomitant Medications: Review the patient’s use of any medications in the last six 
months. 
4. Adverse Events: Patients will be questioned about any AEs experienced during the visit. 
5. Vital Signs: The patient’s vital signs will be recorded (blood pressure, pulse, temperature and 
respiration rate). 
6. Signs and Symptoms: Complete the Signs and Symptoms rating scales. See Appendix B. 
7. Physical Exam: Perform a general physical exam including pelvic exam and breast exam. 
8. Vaginal Cytology and pH: Obtain samples for vaginal cytology and pH. 
9. PAP Smear: Obtain the results of a PAP smear conducted within the last 12 months or 
conduct a PAP smear during the pelvic exam for patients with an intact uterus (including 
patients who underwent partial hysterectomy). 
10. Serum FSH and Fasting Triglycerides: Collect a fasted blood sample for FSH and 
Triglyceride testing (see Appendix A) 
11. Mammogram: Obtain results from a mammogram performed within the last nine months or 
schedule a mammogram. 
12. Vaginal Ultrasound: Perform or schedule a vaginal ultrasound for patients with an intact 
uterus which will be reviewed before randomization. 
13. Inclusion/Exclusion Criteria Review: Review inclusion/exclusion criteria. 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 31 of 51 
 
 
14. Provide Patient Diary: A diary will be provided to record AEs and concomitant medications 
and patients will receive training on completing the diary. 
15. Schedule Visit 2. 
10.5.2 Visit 2 (Day 1): Randomization 
1. Concomitant Medication: Review the patient’s use of any new or ongoing concomitant 
medications since the last visit. 
2. Adverse Events: Patients will be questioned about any health status changes/AEs since last 
visit. All AEs will be recorded. 
3. Vital Signs: The patient’s vital signs will be recorded (blood pressure, pulse, temperature and 
respiration rate). 
4. Signs and Symptoms: Complete the Signs and Symptoms ratings. See Appendix B. 
5. Inclusion/Exclusion Criteria Review: Confirm that inclusion/exclusion criteria are met. 
6. Collect and Review Patient Diary: Collect and review the previously dispensed diary. 
7. Provide Patient Diary: A diary with instructions will be provided to record date and time of 
dosing, AEs and concomitant medications. Patients will receive training on completing the 
diary.  
8. Dispense Study Product: The Independent Dispenser will dispense study product to eligible 
patients with instructions. 
9. Schedule Visit 3. 
10.5.3 Visit 3 (Day 8 or Day 9): End of Study or Early Termination 
1. Concomitant Medication: Review the patient’s use of any new or ongoing concomitant 
medications since the last visit. 
2. Adverse Events: Patients will be questioned about any health status changes/AEs since last 
visit. All AEs will be recorded. 
3. Vital Signs: The patient’s vital signs will be recorded (blood pressure, pulse, temperature and 
respiration rate). 
4. Signs and Symptoms: Complete the Signs and Symptoms ratings. See Appendix B. 
5. Physical Exam: Perform a general physical exam including pelvic exam and breast exam. 
6. Vaginal Cytology and pH: Obtain samples for vaginal cytology and pH. 
7. Collect and Review Patient Diary: Collect previously dispensed diary and review for 
compliance with the protocol. 
8. Collect Study Product: Study product tubes will be collected. 
9. Discharge from the study. 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 32 of 51 
 
 
10.6 Study Procedures 
10.6.1 Informed Consent 
At Visit 1, before performing any study-related procedures the study patient must sign the IRB-
approved ICF. The ICF will be reviewed and approved by an IRB before study commencement. 
No patient will be entered into the study without reading, understanding and signing an ICF. If 
any other language is required, translation will be performed by a certified translator and then 
approved by the IRB. 
10.6.2 Medical History and Demographics 
At Visit 1, each patient will be required to provide basic demographic information: date of birth, 
gender, ethnicity and race. Patients will also be questioned about medical history, including acute 
and chronic medical history and medical history relevant to their VVA. 
10.6.3 Concomitant Medication 
At Visit 1, patients will be questioned about current and prior medication use over the previous 6 
months. At Visits 2 and 3 patients will be questioned about ongoing or any new concomitant 
medication use. 
10.6.4 Adverse Events 
At the end of Visit 1, patients will be questioned about any AEs that may have occurred during 
the visit. At Visits 2 and 3 patients will be questioned regarding any changes in their medical 
status since their previous visit. Any significant changes will be reported as AEs. 
10.6.5 Vital Signs 
The patient’s vital signs will be recorded (pulse, blood pressure, temperature and respiration rate) 
at each visit. At Visits 1 and 2, systolic blood pressure reading cannot exceed 150 mmHg and 
diastolic blood pressure reading cannot exceed 90 mmHg. 
10.6.6 Signs and Symptoms 
At each visit, the blinded clinical staff or Investigator will question the patient regarding the 
severity of their symptoms. See Appendix B for rating scales. The following symptoms will be 
evaluated: 
• 
Vaginal Dryness 
• 
Vaginal/Vulvar irritation/itching 
• 
Dysuria 
• 
Vaginal Pain associated with Sexual Activity 
• 
Vaginal Bleeding 
The severity of each symptom will be recorded on the source documents. The patients will be 
asked to identify which symptom is considered to be the most bothersome symptom at each visit. 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 33 of 51 
 
 
At Visits 1 and 2, the most bothersome symptom must have a score of moderate or severe (for 
vaginal dryness, vaginal/vulvar irritation/itching, dysuria, or vaginal pain associated with sexual 
activity) or present (for vaginal bleeding) to be eligible for inclusion in the study. 
The worsening in severity of the Signs and Symptoms need not be additionally included as AEs 
unless the patient requires additional treatment or in the opinion of the Investigator 
10.6.7 Physical Exam 
At Visit 1, the Investigator will perform a general physical exam including pelvic exam and 
breast exam. The results of this exam should, in the Investigator’s opinion, be consistent with a 
diagnosis of estradiol deficient vaginal/vulvar atrophy for the patient to be eligible for inclusion 
in the study. Additionally, this exam should exclude the possibility that the symptoms could be 
caused by any concurrent disease (e.g., bacterial vaginosis, candida infection). Any patient 
diagnosed with, or with any suspected concurrent vaginal infection or other vaginal disease will 
be excluded from the study. At Visit 3 the Investigator will perform a general physical exam 
including pelvic exam and breast exam. Any clinically significant abnormal findings on exam 
should be reported as AEs. 
10.6.8 Vaginal Cytology and pH 
At Visits 1 and 3, a vaginal cytology specimen will be collected 
 
 
 
 
The central laboratory will report the cytology results to the investigative site before 
randomization. To protect the study blind, the central laboratory will not release the results of any 
other cytology tests other than the Screening results to either the Investigator or 
 until the 
last patient has completed the study. 
The patient’s vaginal pH will be measured by inserting standardized pH paper into the vagina and 
comparing the color change result to the manufacturer’s color chart. 
 
 
10.6.9 PAP Smear 
At Visit 1, patients with an intact uterus, including patients who underwent a partial 
hysterectomy, will have a PAP smear completed during the pelvic exam if the Investigator does 
not have results from a PAP smear completed within the last 12 months. PAP smear samples will 
be sent to the central laboratory for testing. 
10.6.10 Serum FSH and Fasting Triglycerides 
All patients will have a blood sample taken for evaluation of serum FSH levels. Serum FSH will 
be evaluated by a central clinical laboratory. Patients must have a serum FSH > 40 mIU/mL to be 
eligible for participation in the study. 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 34 of 51 
 
 
All patients will have a blood sample taken for fasting triglyceride testing. These samples will be 
sent to the central laboratory for testing. Patients with fasting triglyceride values > 350 mg/dL 
will not be eligible for inclusion in the study. 
10.6.11 Mammogram 
At Visit 1, patients > 40 years of age will have a mammogram scheduled if they do not have 
results from a mammogram in the last 9 months. Patients must have “Normal” Screening 
mammogram with no findings that, in the opinion of the Investigator, would indicate any 
suspicion of breast malignancy to be eligible for inclusion in the study. 
10.6.12 Vaginal Ultrasound 
All patients with an intact uterus will have a vaginal ultrasound performed as a part of their 
Screening evaluations which will be reviewed before randomization. Results should confirm an 
inactive endometrial lining, defined as endometrial thickness less than 4 mm. Patients with an 
endometrial thickness of 4 mm or more will be excluded from the study. 
10.6.13 Inclusion/Exclusion Criteria Review 
At Visit 1 and 2, inclusion/exclusion criteria will be reviewed to ensure patients’ eligibility for 
participation in the study. At the Investigator’s discretion, a urine pregnancy test may be done at 
study visits. At the Investigator’s discretion, a urine pregnancy test may be done at study visits. 
The test has to be negative for the patient to be included in the study or for continued 
participation in the study. 
10.6.14 Provide Patient Diary 
At Visits 1 and 2, patients will be provided with a diary to record other concomitant medications 
and AEs. The patients will also receive on-site training on completing the diary. Date and time of 
dosing should be recorded in the diary dispensed at Visit 2. 
10.6.15 Dispense Study Product 
At Visit 2 after the Investigator has determined that the study participant meets the 
inclusion/exclusion criteria for the study the Independent Dispenser will dispense one 42.5 gram 
tube of study product to the patient using the lowest patient randomization number available at 
that investigative site. 
10.6.16 Collect and Review Patient Diary 
At Visits 2 and 3, patient diaries will be collected and reviewed for compliance with the protocol. 
10.6.17 Collect Study Product 
Tubes of study product will be collected at Visit 3 and checked for compliance or evidence of 
tampering with the blind. 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 35 of 51 
 
 
10.7 Adverse Events 
The patients will be monitored throughout the study for any AEs occurring after the patient has 
signed the ICF until the last study visit of the subject. AEs will be collected through both solicited 
and unsolicited means and subsequently coded in tabular form using the Medical Dictionary for 
Regulatory Activities (MedDRA), Version 20.0 or higher AE Dictionary. The patients will be 
encouraged to report signs, symptoms, and any changes in health to the clinic staff. Severity of each 
AE will be determined by the staff based on observation and questioning of the patients. The 
Investigator will judge the relationship of the event to the study treatments. Adverse events should be 
followed up until they have resolved or stabilized. For any Serious adverse events (SAEs) still ongoing 
at the time of last visit, the Investigator should continue to follow up until the SAE has resolved or 
has stabilized / is judged permanent for SAEs considered to be related to study product (serious 
adverse drug reaction [SADRs]), and for up to 30 days after the last visit of subject for non-related 
SAEs. 
10.7.1 Adverse Event Definitions 
Adverse Event: Any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with treatment. An AE can therefore be any unfavorable and unintended sign, symptom or 
disease, temporally associated with the use of a medicinal (investigational) product, whether or 
not related to this product. This includes events not seen at baseline, or worsened even if present 
at baseline. 
Serious Adverse Event: An SAE is any untoward medical occurrence that at any dose results in 
any of the following outcomes: Death, a life-threatening AE, inpatient hospitalization or 
prolongation of existing inpatient hospitalization, persistent or significant disability / incapacity,  
a congenital anomaly / birth defect (See Section 10.8.1). 
Unexpected Adverse Event: An AE where the nature or severity of is not consistent with the 
applicable product information (e.g., Investigator’s Brochure for an unapproved investigational 
product or package insert/summary of product characteristics for an approved product). 
Adverse Drug Reaction: All noxious and unintended responses to a medical product related to 
any dose should be considered adverse drug reactions (ADRs). The response to a ‘medical 
product’ means that a causal relationship between a medicinal product and an AE is at least a 
reasonable possibility, i.e., the relationship cannot be ruled out. 
Suspected Unexpected Serious Adverse Reaction: An Unexpected Adverse Reaction is defined 
as an ADR, the nature or severity of which is not consistent with the Reference Safety 
Information. Suspected unexpected serious adverse reactions (SUSARs) are “unexpected” SAEs 
and SADRs in which the temporal relationship of the clinical event to study treatment 
administration makes a causal relationship possible, and other drugs, therapeutic interventions 
or underlying conditions do not provide a sufficient explanation for the observed event. 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 36 of 51 
 
 
The Product Insert for Estrace® Cream is inserted in the Appendix (see Appendix C). This 
document will serve as the Reference Safety Information (RSI) as a basis for expectedness 
assessment. 
10.7.2 Severity of Adverse Event 
The severity of the AE will be graded by the Investigator using the following criteria as 
guidelines: 
• 
MILD: Awareness of symptom but does not interfere with routine activities. 
• 
MODERATE: Discomfort sufficient to interfere with routine activities. Prescription drug 
therapy may have been employed to treat the AE. 
• 
SEVERE: Impossible to perform routine activities. Prescription drug therapy and/or 
hospitalization may have been employed to treat the AE 
10.7.3 Relationship of Adverse Event 
Causal relationship to the study product will be evaluated by the Investigator as follows: 
• 
Not Related: A causal relationship between the study treatment and the AE is not a 
reasonable possibility, or the subject did not take the study product. 
• 
Related: A causal relationship between the study treatment and the AE is a reasonable 
possibility, i.e. the relationship cannot be ruled out. 
10.8 Serious Adverse Events 
10.8.1 Definition of a Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose suggests a 
medically significant hazard, including any event that: 
• 
Results in death: includes all deaths, even those that appear to be completely unrelated to 
study treatment (e.g., car accident where patient is a passenger). 
• 
Is life-threatening: in the view of the Investigator, the patient is at immediate risk of death 
at the time of the event. 
• 
Results in persistent or significant disability or incapacity (substantial disruption of one’s 
ability to conduct normal life). 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
Causes congenital anomaly or birth defect. 
• 
Is an important medical event that may not be immediately life-threatening or result in 
death or hospitalization, but may jeopardize the patient or may require medical or 
surgical intervention to prevent one of the serious outcomes listed above (e.g., intensive 
treatment in an emergency room, convulsions that do not result in hospitalizations). 




CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 38 of 51 
 
 
subsequently communicated within an additional eight calendar days. All other SUSARs not 
leading to death or a threat to life will be reported to the FDA as soon as possible but within a 
maximum of 15 calendar days of first knowledge by the Sponsor. Suspected unexpected serious 
adverse reaction reports do not need to be reported in an expedited manner to any other targets for 
submission besides FDA. 
 will inform all the participating investigators of any SAEs and SUSARs reported at other 
study sites in a blinded manner. All relevant follow-up information concerning SUSARs will be 
reported by the Sponsor to the FDA as soon as possible but within a maximum of 15 calendar 
days of first knowledge by 
 on behalf of the Sponsor. 
When an SAE is classified as SUSAR, the Sponsor as well as the 
Medical Monitor must 
be contacted before breaking the blind for any patient. The blind should be broken by the 
Sponsor’s Pharmacovigilance Department only for that specific patient (regulatory unblinding). A 
duplicate copy of the unblinding envelopes shall be retained by the Sponsor’s Clinical Safety/ 
Pharmacovigilance department in order to be able to perform regulatory unblinding (peek blind) 
in case SUSAR reporting to Authorities needs to be performed. The blind will be maintained for 
persons responsible for the ongoing conduct of the study (such as the study management, 
monitors, and Investigators) and those responsible for data analysis and interpretation of results at 
the conclusion of the study, such as biometric personnel. Unblinded information will only be 
accessible to those who need to be involved in the safety reporting to relevant Competent 
Authority and Central Ethics Commitee. 
11.0 STATISTICAL METHODS 
11.1 Statistical Plan 
A Statistical Analysis Plan (SAP), detailing the intended statistical analyses of the study data, will be 
prepared as a separate document and finalized before database lock. Any deviation from the original 
SAP will be described and justified in the final report, as appropriate. The procedure for accounting 
for missing, unused and spurious data will be included in the SAP. 
All statistical analyses will be performed by 
 and conducted 
using the Statistical Analysis System (SAS®), Version 9.4 or higher. 
 
 
11.2 Determination of Sample Size 
For the primary endpoint analysis (proportion of patients in the PP population that are identified as 
Responders at the end of the treatment period evaluated on Day 8 or Day 9), sample size is estimated 
for therapeutic equivalence of the Test to the Reference product and superiority of each of the active 
treatments groups over Placebo. 
 
 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 39 of 51 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.3 Study Populations 
11.3.1 Per-Protocol Population 
The PP population will include all randomized patients who: 
• 
Met the inclusion/exclusion criteria as defined in this protocol at Visit 1 and 2. 
• 
Did not have any significant protocol deviations. 
• 
Did not develop any concurrent vaginal infection or illness exhibiting symptoms 
similar to VVA, or symptoms that in the Investigator’s opinion would interfere with 
primary and secondary endpoint assessments. 
• 
Completed the last study visit (Visit 3) within window (Day 8 or Day 9). 
• 
Were compliant with dosing between 75%-125% of the required doses. 
Any patient who withdraws from the study because of lack of efficacy will be included in the PP 
population as a Non-Responder, provided they did not have any significant protocol deviations 
that would affect treatment evaluation. 
11.3.2 Modified Intent-to-Treat Population 
The modified Intent-to-Treat (mITT) population will include all randomized patients who: 
• 
Administered at least one dose of randomized study product. 
• 
Had a post-randomization evaluation. 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 40 of 51 
 
 
11.3.3 Safety Population 
The safety population will include all patients who are randomized and received study product. 
11.4 Baseline Comparability 
Baseline comparability of all treatment groups will be evaluated separately in the PP, mITT and 
Safety populations. The following baseline demographics (determined from their initial study visit) 
will be evaluated: 
• 
Age (years) 
• 
Gender (male/female) 
• 
Ethnicity (Hispanic/non-Hispanic) 
• 
Race (White, Black/African American, Native Hawaiian or Other Pacific Islander, Asian, 
American Indian or Alaska Native, Other) 
• 
Natural or surgical menopause 
• 
Duration of postmenopausal status 
• 
Baseline signs and symptoms 
• 
Baseline % of the three major vaginal wall cell types (basal/parabasal cells, intermediate cells 
and superficial cells) 
• 
Vaginal pH 
Summary tables by treatment group will be presented. Continuous variables will be summarized 
using descriptive statistics (number of observations, median, minimum, maximum, mean and standard 
deviation). Categorical variables will be summarized using frequencies and percentage. Baseline 
treatment comparisons will be presented using Chi-Square or Cochran-Mantel-Haenszel (CMH) tests 
for the categorical variables, and Analysis of Variance (ANOVA) for the continuous variables. 
All data will be listed by treatment and patient. 
11.5 Efficacy Endpoints 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of patients in each treatment group that are identified 
as Responders at the end of the treatment period evaluated on Day 8 or Day 9. 
A “Responder” is defined as a patient with at least a 25% reduction from baseline in the sum of % 
basal/parabasal + % intermediate cells on vaginal cytology AND vaginal pH < 5.0 with a change 
from baseline vaginal pH of at least 0.5. 
Secondary Efficacy Endpoint 
The secondary efficacy endpoint is the proportion of patients in each treatment group that are 
considered a Treatment Success at the end of the treatment period evaluated on Day 8 or Day 9. 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 41 of 51 
 
 
A “Treatment Success” is defined as a score of 0 or 1 on Day 8 or Day 9 for the symptom identified 
at baseline as the most bothersome. This evaluation will be based on (one) patient self-assessed 
symptom of VVA (vaginal dryness, vaginal and/or vulvar irritation/itching, dysuria, or vaginal pain 
associated with sexual activity) on a scale of 0 to 3 where 0 = none and 3 = severe. Evaluation of 
vaginal bleeding during sexual activity will be based on a Score of 1 (presence) if it is identified by 
the patient as the most bothersome symptom at baseline and a score of 0 (absent) on Day 8 or Day 9. 
Refer to Appendix B for rating scales. 
11.6 Efficacy Analyses 
Primary Endpoint Analysis 
Therapeutic Equivalence: 
Therapeutic equivalence will be evaluated for both primary and secondary endpoints in the PP 
population. If the 90% confidence interval (calculated using Yates’ continuity correction) on the 
absolute difference between the proportion of patients identified as Responders in the Test and 
Reference groups (pT - pR) is contained within the range [-20%, +20%] then therapeutic equivalence 
of the Test product to the Reference product will be considered to have been demonstrated. 
The same statistical approach will be conducted for analysis of the secondary endpoint in the PP 
population. 
To declare therapeutic equivalence of the Test product to the Reference product, equivalence must be 
demonstrated for only the primary endpoints in the PP population. 
Superiority to Placebo 
Superiority of the Test and Reference products against the Placebo product for the primary endpoint 
will be evaluated in the mITT population using last observation carried forward (LOCF). If the 
proportion of Responders in the Test and the Reference product groups is numerically and statistically 
superior to that of the Placebo (p < 0.05; using a two-sided CMH test, stratified by clinical site) then 
superiority of the Test and Reference products over Placebo will be concluded. 
The same statistical approach will be conducted for analysis of the secondary endpoint in the mITT 
population. 
To declare superiority of the Test and Reference products over Placebo, their superiority must be 
demonstrated for only the primary endpoint in the mITT population. 
Treatment-by-Site Interaction and Pooling of Clinical Sites 
As this is a multiple-site study, the interaction of treatment-by-site may be evaluated for the primary 
efficacy endpoint in the PP population for equivalence testing. The treatment-by-site interaction will 
be evaluated by the Breslow-Day test for homogeneity of the odds ratio at the 5% significance level 
(p < 0.05, 2-sided). A site(s) with a low enrollment rate(s) may be pooled with its geographically 
closest site, so as to avoid bias in the stratification of the sites in the CMH test and in the estimation 
of a treatment-by-site interaction effect. The pooling will be done for low enrolling sites that account 
for less than 4-7% of the total number of patients in the PP population at the site with the highest 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 42 of 51 
 
 
enrolling rate in the PP population. If the treatment-by-site interaction term is found to be statistically 
significant (p < 0.05) for the primary endpoint, then the interaction term will also be assessed for 
clinical relevance before pooling the data across sites. This will include examination of “Responder” 
rates at each site where sample sizes per treatment may be influential in the assessment of the 
interaction 
11.7 Safety Analysis 
Adverse events will be classified using standard MedDRA terminology Version 20.0 or higher and 
summarized by treatment group. Summary tables comparing the type, incidence, date of onset, date of 
resolution, severity, action taken, outcome and Investigator’s opinion of relationship to the study 
product will be prepared by treatment group. If sufficient data exist, AE frequencies will be compared 
between treatments using Fisher’s exact test or a similar test. 
Signs and symptoms of VVA will not be considered AEs, unless in the Investigator’s opinion, they 
have increased in frequency and/or severity to such an extent that the Investigator/patient considers 
that it is in the patient’s best interest to be dropped from continued participation in the study and 
given alternative therapy for their condition. 
Concomitant medication use during the study will be tabulated by patient. 
12.0 REGULATORY OBLIGATIONS 
12.1 Institutional Review Board 
The study protocol, ICF, Investigator's Brochure, or package insert (as applicable), and any specific 
advertising will be submitted to, and approved by, an IRB before the start of the study. A form must 
be signed by the chairman or designee of the IRB noting the approvals. This notification of the 
board's approval along with a description by profession and gender of the board's composition will be 
provided to the Sponsor. 
12.2 Study Documentation 
This study will be conducted in compliance with the protocol; Good Clinical Practices and all 
applicable regulations, including the Federal Food, Drug and Cosmetics Act, US applicable Code of 
Federal Regulations (title 21), parts 50, 56, 312, 320, and any IRB requirements relative to clinical 
studies; and the Declaration of Helsinki, June 1964, as modified by the 64th World Medical 
Association General Assembly, October 2013.16,20-22 The Investigator will permit trial-related 
monitoring, audits, IRB review and regulatory inspections providing direct access to source 
data/documents. 
12.2.1 Protocol 
The Investigator indicated on FDA Form 1572 will act as the Principal Investigator at each study 
site. Protocols will be noted as approved by placement of the 
 Representative’s signature 
on the cover page. The Sponsor of the study will also approve the protocol by having a study-
responsible individual sign the protocol cover page. The Principal Investigator will sign the 
protocol signature page indicating their agreement to conduct the study according to the protocol. 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 43 of 51 
 
 
12.2.2 Informed Consent 
An ICF that includes all of the relevant elements currently required by FDA and local state 
regulations will be provided to each prospective study patient before enrollment into the study. 
The type and method of study, tests to be administered, any potential or possible hazards, and the 
patient's right to withdraw from the study at any time will be explained to the patients by the 
Investigator or designee. Once the Investigator or designee is assured that an individual candidate 
understands the implications of participating in this study, the patient will be asked to give 
consent by signing and dating in the appropriate areas of the ICF. The Investigator or designee 
will also sign and date the form, along with a staff member who will sign the ICF as a witness to 
verify that the patient has indeed received information. If any other language is required, 
translation will be performed by a certified translator. A copy of the ICF will be provided to the 
patient. 
12.2.3 Protocol and Informed Consent Changes 
Sponsor approved changes to the protocol or the ICF will be implemented as revisions to the 
original documents and will require additional review and approval by the IRB. Revisions to the 
original protocol will be documented in amendments, incorporated as a preface to the new 
version. Any revision that substantially alters the study design or increases potential risk to the 
patient requires the patient’s consent to continue in the study. The approvals will be processed in 
accordance with the established IRB procedures. Copies of all protocol and ICF 
amendments/revisions, along with letters noting IRB approval, will be submitted to the Sponsor. 
12.2.4 Source Documents and Electronic Case Report Forms 
All patients will be identified by initials, date of birth and a unique patient number. Source 
documents will be used to record all study-related data. Source document entries will be used to 
complete electronic case report forms (eCRFs). A set of eCRFs will be completed for each patient 
randomiazed in the study. All data and eCRFs will be reviewed, evaluated and signed by the 
Investigator. 
The original source documents and a copy of the corresponding eCRFs will be retained by the 
Investigator. Patients who terminate early from the study will have the Visit 3 (End of Study) 
source/eCRF completed. 
12.2.5 Drug Accountability 
All study product receipt, inventory, dispensing, dosing and reconciliation records will be 
maintained in compliance with federal regulations. The study product will be dispensed to 
qualified study patients according to established procedures. At the end of the study (after the 
database has been locked) all used and unused study product will be returned to Sponsor or 
designee. 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 44 of 51 
 
 
12.2.6 Drug Storage 
Study product will be stored at controlled room temperature protected from temperatures in 
excess of 40 ºC (104 ºF) in a secure place with access by authorized individuals only. The 
Investigator will be responsible for maintaining accurate records of drug receipt, dispensing, and 
return. At the end of the study, all partially used and unused study product will be returned to 
Sponsor’s designee. 
Retention of Reserve Samples 
Each Investigator will randomly remove at least one block of study product and keep for 
retention. 
 
 
 
 
 
12.2.7 Pregnancies 
If following initiation of study participation, it is subsequently discovered that a study patient is 
pregnant or may have been pregnant since the initiation of study participation (i.e. since the 
signing of ICF), the study product will be permanently discontinued. The Principal Investigator or 
designee must immediately notify the Medical Monitor of this event. Reporting timelines and 
/Sponsor contact will be consistent with SAE reporting guidelines (i.e., pregnancies will 
be reported to the Sponsor/
 within 24 hours to the contacts listed in section 10.8.2). 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
patient. Other appropriate pregnancy follow-up procedures should be considered if indicated. All 
follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome will be communicated as per the above guidelines. Infants should be followed for a 
minimum of eight weeks after birth. 
12.2.8 Reporting Safety Information to the IRB 
The Investigator must promptly report to the Investigator’s IRB all unanticipated problems 
involving risks to patients. This includes death from any cause and all SAEs occurring during the 
study, regardless of the assessed causality.23 
12.2.9 Record Retention 
All drug accountability records, eCRFs, source data and related regulatory documents must be 
retained for at least two years following completion of the study or Test product approval for 
marketing by the FDA. 
12.2.10 Study Monitoring and Auditing 
 will be responsible for monitoring the study according to Good Clinical Practice and 
applicable regulations. Monitoring visits are for the purpose of confirming adherence to the 
protocol and to verify complete and accurate data collection. The clinical site will make all 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 45 of 51 
 
 
records associated with the study available to 
 representative during such visits and 
audits. 
The study may be subject to audit by the Sponsor, Sponsor Representative or by regulatory 
authorities. If such an audit occurs the Investigator must agree to allow access to required patient 
records. By signing this protocol, the Investigator grants permission to personnel from the 
Sponsor, its representatives and appropriate regulatory authorities for on-site monitoring of all 
appropriate study documentation, as well as on-site review of study procedures. 
12.2.11 End of the Trial 
The end of the trial is defined as the time at which the last patient has completed their last visit in 
the study. Upon completion of the study, the study product will no longer be available to the 
patient but the Investigator can, at their discretion, discuss alternative treatments with the patient. 
12.2.12 Clinical Study Report 
At the end of the study a full report per requirements of Sponsor and regulatory authorities will be 
prepared which will include a narrative of the clinical conduct and results of the study, a 
statistical report including a description of the analysis performed, and other documentation as 
may be appropriate. The report will be in electronic format according to eCTD and International 
Conference on Harmonisation formatting standards and guidelines.24 






CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 48 of 51 
 
 
14.0 APPENDICES 
14.1 APPENDIX A: Clinical Laboratory Testing 
CLINICAL LABORATORY TESTING 
As part of the Screening Procedures the blood and cytology samples will be obtained for the following 
laboratory evaluations: 
Serum FSH 
Fasting Triglycerides 
Vaginal Cytology 
PAP Smear (as appropriate) 
 
All samples will be sent to the central laboratory: 
 
 
 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 49 of 51 
 
 
14.2 APPENDIX B: Definitions and Severity ratings for Signs and Symptoms  
Vaginal Dryness 
No lubrication or secretions noted on perineum or after wiping; if sexually active loss of 
lubrication during coitus. 
Score 
Severity 
Description 
0 
None 
No noticeable lack of vaginal lubrication or secretions reported or 
observed 
1 
Mild 
Episodic loss of lubrication/secretions or noticed some reduction in 
general secretions, does not interfere with daily activities 
2 
Moderate 
Symptom present most of the time, and noticeable but overall is tolerable 
and does not interfere with daily activities 
3 
Severe 
Very minimal or no natural vaginal lubrication/secretions almost all of 
the time and interferes with normal activities 
 
Vaginal/Vulvar Irritation/Itching 
Scratching or sand paper type feeling in vaginal/vulvar area. May feel uncomfortable with 
clothing or undergarments touching the perineum. 
Score 
Severity 
Description 
0 
None 
No irritation or itching reported. 
1 
Mild 
Occasional irritation/itching but does not interfere with daily activities 
2 
Moderate 
Frequent irritation/itching that can be uncomfortable but generally does 
not interfere with daily activities 
3 
Severe 
Very frequent or continuous irritation/itching of the vaginal area, may 
interfere with daily activities. 
 
Dysuria 
Pain or discomfort during urination 
Score 
Severity 
Description 
0 
None 
No pain or discomfort during urination reported. 
1 
Mild 
Occasional or slight discomfort during urination but tolerable 
2 
Moderate 
Some discomfort during urination at least 50% of the time which can be 
painful but overall tolerable. 
3 
Severe 
Urination nearly always painful, usually intolerable and causing 
disruption to daily activities 
 
 
 
 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0 07/25/2017  Prasco LLC   Page 50 of 51 
 
 
Vaginal Pain during Sexual Activity 
Suffers discomfort or pain during sexual activity that may be restrictive. 
Score 
Severity 
Description 
0 
None 
No discomfort or pain 
1 
Mild 
Some feeling of vaginal soreness or pain, during or after sexual activity. 
Does restrict frequency of or type of sexual activity. 
2 
Moderate 
Vaginal pain during sexual activity such that frequency and type of 
sexual activity have been disrupted. Lubrication may be needed for 
penetration 
3 
Severe 
Vaginal penetration very painful and impossible without vaginal 
lubrication. Discomfort such that frequency of sexual activity 
significantly reduced. 
 
Vaginal bleeding during or after sexual activity 
Score 
Severity 
Description 
0 
Absent 
No vaginal bleeding observed 
1 
Present 
Bleeding observed during or soon after vaginal activity 
 
At each visit each patient must also clearly identify which is the most bothersome sign/symptom to her, 
even if she rates two or more symptoms the same severity rating.


CONFIDENTIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the 
Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to Estrace® 
Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of Vulvar and Vaginal 
Atrophy, 71759501
 
 
71759501  Rev 0  07/25/2017  Prasco LLC   Page 51 of 51 
 
 
 
14.3 APPENDIX C: Product Insert for Estrace®  
 
 


ESTRACE® Cream   
(estradiol vaginal cream, USP, 0.01%)  
 
 
WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, 
BREAST CANCER and PROBABLE DEMENTIA 
 
 
Estrogen-Alone Therapy 
 
 
Endometrial Cancer 
 
There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed 
estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of 
endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic 
measures, including directed or random endometrial sampling when indicated, should be 
undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or 
recurring abnormal genital bleeding [see WARNINGS, Malignant Neoplasms, Endometrial 
Cancer]. 
 
Cardiovascular Disorders and Probable Dementia 
 
Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or 
dementia [see CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders, and 
Probable Dementia]. 
 
The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of 
stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) 
during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone, 
relative to placebo [see CLINICAL STUDIES and WARNINGS, Cardiovascular 
Disorders]. 
 
The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an 
increased risk of developing probable dementia in postmenopausal women 65 years of age or 
older during 5.2 years of treatment with daily CE (0.625 mg) -alone, relative to placebo. It is 
unknown whether this finding applies to younger postmenopausal women [see CLINICAL 
STUDIES and WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use]. 
 
In the absence of comparable data, these risks should be assumed to be similar for other 
doses of CE and other dosage forms of estrogens. 
 
Estrogens with or without progestins should be prescribed at the lowest effective doses and for 
the shortest duration consistent with treatment goals and risks for the individual woman. 
 
 
 
Estrogen Plus Progestin Therapy 
 
Cardiovascular Disorders and Probable Dementia 
 
Estrogen plus progestin therapy should not be used for the prevention of cardiovascular 
disease or dementia [see CLINICAL STUDIES and WARNINGS, Cardiovascular 
Disorders, and Probable Dementia]. 


The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary 
embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 
years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with 
medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see CLINICAL 
STUDIES and WARNINGS, Cardiovascular Disorders]. 
 
The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk of 
developing probable dementia in postmenopausal women 65 years of age or older during 4 
years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to 
placebo. It is unknown whether this finding applies to younger postmenopausal women [see 
CLINICAL STUDIES and WARNINGS, Probable Dementia and PRECAUTIONS, 
Geriatric Use]. 
 
Breast Cancer 
 
The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive 
breast cancer [see CLINICAL STUDIES and WARNINGS, Malignant Neoplasms, Breast 
Cancer]. 
 
In the absence of comparable data, these risks should be assumed to be similar for other 
doses of CE and MPA, and other combinations and dosage forms of estrogens and 
progestins. 
 
Estrogens with or without progestins should be prescribed at the lowest effective doses and for 
the shortest duration consistent with treatment goals and risks for the individual woman. 
 
 
 
 
 
DESCRIPTION 
Each gram of ESTRACE (estradiol vaginal cream, USP, 0.01%) contains 0.1 mg estradiol in a 
nonliquefying base containing purified water, propylene glycol, stearyl alcohol, white ceresin 
wax, mono- and di-glycerides, hypromellose 2208 (4000 cps), sodium lauryl sulfate, 
methylparaben, edetate di-sodium and tertiary-butylhydroquinone. Estradiol is chemically 
described as estra-1,3,5(10)-triene-3, 17(beta)-diol. It has an empirical formula of C18H24O2 and 
molecular weight of 272.37. The structural formula is: 
 
 
 
CLINICAL PHARMACOLOGY 
Endogenous estrogens are largely responsible for the development and maintenance of the 
female reproductive system and secondary sexual characteristics.  Although circulating estrogens 


exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal 
intracellular human estrogen and is substantially more potent than its metabolites, estrone and 
estriol at the receptor level. 
 
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which 
secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle.  After 
menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted 
by the adrenal cortex, to estrone by peripheral tissues.  Thus, estrone and the sulfate conjugated 
form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. 
 
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues.  To date, two 
estrogen receptors have been identified.  These vary in proportion from tissue to tissue. 
 
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone 
(LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. 
Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. 
 
Pharmacokinetics 
 
Absorption 
 
Estrogen drug products are absorbed through the skin, mucous membranes, and the 
gastrointestinal tract after release from the drug formulation. 
 
Distribution 
 
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are 
widely distributed in the body and are generally found in higher concentrations in the sex 
hormone target organs.  Estrogens circulate in the blood largely bound to sex hormone binding 
globulin (SHBG) and albumin. 
 
Metabolism 
 
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating 
estrogens exist in a dynamic equilibrium of metabolic interconversions.  These transformations 
take place mainly in the liver.  Estradiol is converted reversibly to estrone, and both can be 
converted to estriol, which is the major urinary metabolite.  Estrogens also undergo enterohepatic 
recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates 
into the intestine, and hydrolysis in the gut followed by reabsorption.  In postmenopausal 
women, a significant proportion of the circulating estrogens exist as sulfate conjugates, 
especially estrone sulfate, which serves as a circulating reservoir for the formation of more active 
estrogens. 
 
Excretion 


Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate 
conjugates. 
 
Special Populations 
 
No pharmacokinetic studies were conducted in special populations, including patients with renal 
or hepatic impairment. 
 
Drug Interactions 
 
In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome 
P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug 
metabolism.  Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum 
perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of 
estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine 
bleeding profile.  Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, 
itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and 
may result in side effects. 
 
CLINICAL STUDIES 
 
Women’s Health Initiative Studies 
 
The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two 
substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination 
with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The 
primary endpoint was the incidence of coronary heart disease (CHD) (defined as nonfatal MI, 
silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A 
“global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, 
endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death 
due to other cause. These substudies did not evaluate the effects of CE or CE plus MPA on 
menopausal symptoms. 
 
WHI Estrogen-Alone Substudy 
 
The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was 
observed, and it was deemed that no further information would be obtained regarding the risks 
and benefits of estrogen-alone in predetermined primary endpoints. 
Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, 
range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent 
Other), after an average follow-up of 7.1 years are presented in Table 1. 
 
 
a 
TABLE 1 -Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI 


 
 
For those outcomes included in the WHI "global index" that reached statistical significance, the 
absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more 
strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures1. 
The absolute excess risk of events included in the "global index" was a non-significant 5 events 
per 10,000 women-years. There was no difference between the groups in terms of all-cause 
mortality. 
 
No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and 
invasive breast cancer incidence in women receiving CE-alone compared with placebo was 
reported in final centrally adjudicated results from the estrogen-alone substudy, after an 
average follow-up of 7.1 years. 
 
Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an 
average follow-up of 7.1 years, reported no significant differences in distribution of stroke 
subtypes or severity, including fatal strokes, in women receiving CE-alone compared to 


placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was 
present in all subgroups of women examined2. 
 
Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect 
the overall risk benefit profile. The WHI estrogen-alone substudy stratified by age showed in 
women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [hazard ratio 
(HR) 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46– 
1.11)]. 
 
WHI Estrogen Plus Progestin Substudy 
 
The WHI estrogen plus progestin substudy was also stopped early. According to the predefined 
stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of breast 
cancer and cardiovascular events exceeded the specified benefits included in the “global 
index.” The absolute excess risk of events included in the “global index” was 19 per 10,000 
women-years. 
 
For those outcomes included in the WHI “global index” that reached statistical significance after 
5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated 
with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive 
breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer 
colorectal cancers and 5 fewer hip fractures. 
 
Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, 
range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other), 
are presented in Table 2. These results reflect centrally adjudicated data after an average follow- 
up of 5.6 years. 
 
TABLE 2 -Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of 
a,b 
WHI at an Average of 5.6 Years 


 
 
Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may 
affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age 
showed in women 50 to 59 years of age, a non-significant trend toward reduced risk for overall 
mortality [HR 0.69 (95 percent CI, 0.44-1.07)]. 
 
Women’s Health Initiative Memory Study 
 
The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy 
hysterectomized postmenopausal women 65 to 79 years of age and older (45 percent were 
65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of 
age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of 
probable dementia (primary outcome) compared to placebo. 
 
After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone 
versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for 
CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia 
as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed 
types (having features of both AD and VaD). The most common classification of probable 
dementia in the treatment group and the placebo group was AD. Since the ancillary study was 


conducted in women 65 to 79 years of age, it is unknown whether these findings apply to 
younger postmenopausal women [see BOXED WARNINGS, WARNINGS, Probable 
Dementia and PRECAUTIONS, Geriatric Use]. 
 
The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly 
healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of 
age; 35 percent were 70 to 74 years; 18 percent were 75 years of age and older) to evaluate 
the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia 
(primary outcome) compared to placebo. 
 
After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA 
versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for 
CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as 
defined in this study included AD, VaD and mixed types (having features of both AD and 
VaD). The most common classification of probable dementia in the treatment group and the 
placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of 
age, it is unknown whether these findings apply to younger postmenopausal women [see 
WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use]. 
 
When data from the two populations were pooled as planned in the WHIMS protocol, the 
reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). 
Differences between groups became apparent in the first year of treatment. It is unknown 
whether these findings apply to younger postmenopausal women [see WARNINGS, Probable 
Dementia and PRECAUTIONS, Geriatric Use]. 
 
INDICATIONS AND USAGE 
ESTRACE (estradiol vaginal cream, USP, 0.01%) is indicated in the treatment of moderate to 
severe symptoms of vulvar and vaginal atrophy due to menopause. 
 
 
 
CONTRAINDICATIONS 
ESTRACE (estradiol vaginal cream, USP, 0.01%) should not be used in women with any of the 
following conditions: 
 
1. 
Undiagnosed abnormal genital bleeding. 
2. 
Known, suspected, or history of cancer of the breast. 
3. 
Known or suspected estrogen-dependent neoplasia. 
4. 
Active DVT, PE or history of these conditions. 
5. 
Active arterial thromboembolic disease (for example, stroke, MI) or a history of these 
conditions. 
6. 
Known anaphylactic reaction or angioedema to ESTRACE (estradiol vaginal cream, 
USP, 0.01%). 
7. 
Known liver dysfunction or disease. 
8. 
Known protein C, protein S, or antithrombin deficiency, or other known 
thrombophilic disorders. 
9. 
Known or suspected pregnancy. 


 
 
WARNINGS 
See BOXED WARNINGS. 
 
Systemic absorption may occur with the use of ESTRACE (estradiol vaginal cream, USP, 
0.01%).  The warnings, precautions, and adverse reactions associated with oral estrogen 
treatment should be taken into account. 
 
1. 
Cardiovascular Disorders 
 
An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An 
increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin 
therapy. Should any of these occur or be suspected, estrogen with or without progestin therapy 
should be discontinued immediately. 
 
Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, 
hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (e.g., personal 
history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed 
appropriately. 
 
a. 
Stroke 
 
In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was 
reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to 
women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The 
increase in risk was demonstrated in year one and persisted [see CLINICAL STUDIES]. 
Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued 
immediately. 
 
Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for 
those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 
10,000 women-years) 3. 
 
In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke 
was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) 
compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women- 
years) [see CLINICAL STUDIES]. The increase in risk was demonstrated after the first year 
and persisted3. Should a stroke occur or be suspected, estrogen plus progestin therapy should be 
discontinued immediately. 
 
b. 
Coronary Heart Disease 
 
In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events 
(defined as nonfatal MI, silent MI and CHD death) was reported in women receiving estrogen- 
alone compared to placebo4 [see CLINICAL STUDIES]. 


Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant 
reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less 
than 10 years since menopause (8 versus 16 per 10,000 women-years) 3. 
 
In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased 
risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) 
compared to women receiving placebo (41 versus 34 per 10,000 women-years) 3. An increase in 
relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was 
reported in years 2 through 5 [see CLINICAL STUDIES]. 
 
In postmenopausal women with documented heart disease (n = 2,763), average age 66.7 years of 
age, in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and 
Estrogen/Progestin Replacement Study; HERS), treatment with daily CE (0.625 mg) plus MPA 
(2.5 mg) demonstrated no cardiovascular benefit.  During an average follow-up of 4.1 years, 
treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal 
women with established coronary heart disease.  There were more CHD events in the CE plus 
MPA-treated group than in the placebo group in year 1, but not during the subsequent years. 
Two thousand, three hundred and twenty one (2,321) women from the original HERS trial 
agreed to participate in an open label extension of HERS, HERS II.  Average follow-up in HERS 
II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were 
comparable among women in the CE plus MPA group and the placebo group in HERS, HERS II, 
and overall. 
 
c. 
Venous Thromboembolism 
 
In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women 
receiving daily CE (0.625 mg)-alone compared to women receiving placebo (30 versus 22 per 
10,000 women-years), although only the increased risk of DVT reached statistical significance 
(23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the 
first 2 years5 [see CLINICAL STUDIES]. Should a VTE occur or be suspected, estrogen- 
alone therapy should be discontinued immediately. 
 
In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of 
VTE was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to 
women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant 
increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 
10,000 women-years) were also demonstrated. The increase in VTE risk was observed during 
the first year and persisted 6[see CLINICAL STUDIES]. Should a VTE occur or be suspected, 
estrogen plus progestin therapy should be discontinued immediately. 
 
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type 
associated with an increased risk of thromboembolism, or during periods of prolonged 
immobilization. 
 
2. 
Malignant Neoplasms 
 
a. 
Endometrial Cancer 


 
An increased risk of endometrial cancer has been reported with the use of unopposed estrogen 
therapy in a woman with a uterus.   The reported endometrial cancer risk among unopposed 
estrogen users is about 2- to 12-times greater than in non-users, and appears dependent on 
duration of treatment and on estrogen dose.  Most studies show no significant increased risk 
associated with use of estrogens for less than one year.  The greatest risk appears associated with 
prolonged use, with increased risks of 15- to 24-fold for five to ten years or more and this risk 
has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. 
 
Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is 
important. Adequate diagnostic measures, including directed or random endometrial sampling 
when indicated, should be undertaken to rule out malignancy in postmenopausal women with 
undiagnosed persistent or recurring abnormal genital bleeding. 
 
There is no evidence that the use of natural estrogens results in a different endometrial risk 
profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen 
therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor 
to endometrial cancer. 
 
b. 
Breast Cancer 
 
The most important randomized clinical trial providing information about breast cancer in 
estrogen-alone users is the WHI substudy of daily CE (0.625 mg)-alone. In the WHI estrogen- 
alone substudy, after an average follow-up of 7.1 years, daily CE (0.625 mg)-alone was not 
associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80) 7 [see 
CLINICAL STUDIES]. 
 
The most important randomized clinical trial providing information about breast cancer in 
estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). 
After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased 
risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use 
of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. 
The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases 
per 10,000 women-years, for CE plus MPA compared with placebo. Among women who 
reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and 
the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared 
with placebo. Among women who reported no prior use of hormone therapy, the relative risk of 
invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women- 
years, for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers 
were larger, were more likely to be node positive, and were diagnosed at a more advanced stage 
in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic 
disease was rare with no apparent difference between the two groups. Other prognostic factors 
such as histologic subtype, grade and hormone receptor status did not differ between the groups8 
[see CLINICAL STUDIES]. 
 
Consistent with the WHI clinical trial, observational studies have also reported an increased risk 
of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen- 


alone therapy, after several years of use. The risk increased with duration of use, and appeared to 
return to baseline in about 5 years after stopping treatment (only the observational studies have 
substantial data on risk after stopping). Observational studies also suggest that the risk of breast 
cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as 
compared to estrogen-alone therapy. However, these studies have not generally found significant 
variation in the risk of breast cancer among different estrogen plus progestin combinations, 
doses, or routes of administration. 
 
The use of estrogen-alone and estrogen plus progestin therapy has been reported to result in an 
increase in abnormal mammograms requiring further evaluation. 
 
All women should receive yearly breast examinations by a healthcare provider and perform 
monthly breast self-examinations. In addition, mammography examinations should be scheduled 
based on patient age, risk factors, and prior mammogram results. 
 
c. 
Ovarian Cancer 
 
The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk 
of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for 
CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24). The absolute risk for CE plus 
MPA was 4 versus 3 cases per 10,000 women-years 9. In some epidemiologic studies, the use of 
estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been 
associated with an increased risk of ovarian cancer. However, the duration of exposure 
associated with increased risk is not consistent across all epidemiologic studies, and some report 
no association. 
 
3. 
Probable Dementia 
 
In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized 
women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo. 
 
After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in 
the placebo group were diagnosed with probable dementia. The relative risk of probable 
dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of 
probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years 
10 [see CLINICAL STUDIES and PRECAUTIONS, Geriatric Use]. 
 
In the WHIMS estrogen plus progestin ancillary study, a population of 4,532 postmenopausal 
women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or 
placebo. 
 
After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in 
the placebo group were diagnosed with probable dementia. The relative risk of probable 
dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk 
of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 
women-years 10 [see CLINICAL STUDIES and PRECAUTIONS, Geriatric Use]. 


When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin 
ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative 
risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Since both ancillary studies were 
conducted in women 65 to 79 years of age, it is unknown whether these findings apply to 
younger postmenopausal women 10 [see PRECAUTIONS, Geriatric Use]. 
 
4. 
Gallbladder Disease 
 
A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal 
women receiving estrogens has been reported. 
 
5. 
Hypercalcemia 
 
Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and 
bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate 
measures taken to reduce the serum calcium level. 
 
6. 
Visual Abnormalities 
 
Retinal vascular thrombosis has been reported in patients receiving estrogens.  Discontinue 
medication pending examination if there is sudden partial or complete loss of vision, or a sudden 
onset of proptosis, diplopia, or migraine.  If examination reveals papilledema or retinal vascular 
lesions, estrogens should be permanently discontinued. 
 
7. 
Anaphylactic Reaction and Angioedema 
 
Cases of anaphylaxis, which develop within minutes to hours after taking orally-administered 
estrogen and require emergency medical management, have been reported in the postmarketing 
setting. Skin (hives, pruritis, swollen lips-tongue-face) and either respiratory tract (respiratory 
compromise) or gastrointestinal tract (abdominal pain, vomiting) involvement has been noted. 
 
 
Angioedema involving the tongue, larynx, face, hands and feet requiring medical intervention 
has occurred postmarketing in patients taking orally-administered estrogen. If angioedema 
involves the tongue, glottis, or larynx, airway obstruction may occur. Patients who develop an 
anaphylactic reaction with or without angioedema after treatment with oral estrogen should not 
receive oral estrogen again. 
 
8. 
Hereditary Angioedema 
 
Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary 
angioedema. 
 
 
 
PRECAUTIONS 
A. 
General 


1. 
Addition of a Progestin When a Woman Has Not Had a Hysterectomy 
 
Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, 
or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial 
hyperplasia than would be induced by estrogen treatment alone.  Endometrial hyperplasia may be 
a precursor to endometrial cancer. 
 
There are, however, possible risks that may be associated with the use of progestins with 
estrogens compared to estrogen-alone regimens.  These include a possible increased risk of 
breast cancer. 
 
2. 
Elevated Blood Pressure 
 
In a small number of case reports, substantial increases in blood pressure have been attributed to 
idiosyncratic reactions to estrogens.  In a large, randomized, placebo-controlled clinical trial, a 
generalized effect of estrogens on blood pressure was not seen. 
 
3. 
Hypertriglyceridemia 
 
In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with 
elevations of plasma triglycerides leading to pancreatitis and other complications. Consider 
discontinuation of treatment if pancreatitis occurs. 
 
4. 
Hepatic Impairment and/or Past History of Cholestatic Jaundice 
 
Estrogens may be poorly metabolized in patients with impaired liver function.  For women with 
a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution 
should be exercised and in the case of recurrence, medication should be discontinued. 
 
5. 
Hypothyroidism 
 
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels.  Women with 
normal thyroid function can compensate for the increased TBG by making more thyroid 
hormone, thus maintaining free T4 and T3 serum concentrations in the normal range.  Women 
dependent on thyroid hormone replacement therapy who are also receiving estrogens may 
require increased doses of their thyroid replacement therapy.  These women should have their 
thyroid function monitored in order to maintain their free thyroid hormone levels in an 
acceptable range. 
 
6. 
Fluid Retention 
 
Estrogens may cause some degree of fluid retention. Women with conditions that might be 
influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation 
when estrogen- alone is prescribed. 
 
7. 
Hypocalcemia 


Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen- 
induced hypocalcemia may occur. 
 
8. 
Exacerbation of Endometriosis 
 
A few cases of malignant transformation of residual endometrial implants have been reported in 
women treated post-hysterectomy with estrogen alone therapy. For patients known to have 
residual endometriosis post-hysterectomy, the addition of progestin should be considered. 
 
9. 
Exacerbation of Other Conditions 
 
Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or 
porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with 
caution in women with these conditions. 
 
B. 
Patient Information 
 
Physicians are advised to discuss the PATIENT INFORMATION leaflet with women for whom 
they prescribe ESTRACE (estradiol vaginal cream, USP, 0.01%). 
 
 
C. 
Laboratory Tests 
 
 
Serum FSH and estradiol levels have not been shown to be useful in the management of 
moderate to severe symptoms of vulvar and vaginal atrophy. 
 
D. 
Drug-Laboratory Test Interactions 
 
1.   Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; 
increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant 
activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; 
decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III 
activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen 
antigen and activity. 
2.   Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid 
hormone levels, as measured by protein-bound iodine (PBI), T4 levels (by column or by 
radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, 
reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on 
thyroid replacement therapy may require higher dose of thyroid hormone. 
3.   Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin 
(CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating 
corticosteroids and sex steroids, respectively. Free hormone concentrations, such as 
testosterone and estradiol, may be decreased. Other plasma proteins may be increased 
(angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). 
4.   Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction 
concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, 
increased triglycerides levels. 


5.   Impaired glucose tolerance. 
 
E. 
Carcinogenesis, Mutagenesis, and Impairment of Fertility 
 
Long-term continuous administration of estrogen, with and without progestin, in women with 
and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and 
ovarian cancer.  (See BOXED WARNINGS, WARNINGS and PRECAUTIONS.) 
 
Long term continuous administration of natural and synthetic estrogens in certain animal species 
increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. 
 
F. 
Pregnancy 
 
ESTRACE should not be used during pregnancy [see CONTRAINDICATIONS]. 
 
There appears to be little or no increased risk of birth defects in children born to women who 
have used estrogens and progestins as an oral contraceptive inadvertently during early 
pregnancy. 
 
G. 
Nursing Mothers 
 
ESTRACE should not be used during lactation. Estrogen administration to nursing women has 
been shown to decrease the quantity and quality of the breast milk.  Detectable amounts of 
estrogens have been identified in the milk of women receiving estrogen therapy.  Caution should 
be exercised when ESTRACE is administered to a nursing woman. 
 
H. 
Pediatric Use 
 
ESTRACE Vaginal Cream is not indicated in children. Clinical studies have not been conducted 
in the pediatric population. 
 
I. 
Geriatric Use 
 
 
There have not been sufficient numbers of geriatric patients involved in studies utilizing 
ESTRACE to determine whether those over 65 years of age differ from younger subjects in their 
response to ESTRACE. 
 
The Women’s Health Initiative Study 
 
In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was 
a higher relative risk of stroke in women greater than 65 years of age [see CLINICAL 
STUDIES and WARNINGS]. 
 
In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] 
versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast 


cancer in women greater than 65 years of age [see CLINICAL STUDIES and 
WARNINGS]. 
 
The Women’s Health Initiative Memory Study 
 
In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there 
was an increased risk of developing probable dementia in women receiving estrogen-alone 
or estrogen plus progestin when compared to placebo [see CLINICAL STUDIES and 
WARNINGS]. 
 
Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown 
whether these findings apply to younger postmenopausal women 10 [see CLINICAL 
STUDIES and WARNINGS]. 
 
ADVERSE REACTIONS 
 
See BOXED WARNINGS, WARNINGS and PRECAUTIONS. 
 
Systemic absorption may occur with the use of ESTRACE.  The warnings, precautions, and 
adverse reactions associated with oral estrogen treatment should be taken into account. 
 
The following adverse reactions have been reported with estrogen and/or progestin therapy. 
 
1. 
Genitourinary System 
 
Abnormal uterine bleeding or spotting; dysmenorrhea or pelvic pain, increase in size of uterine 
leiomyomata; vaginitis, including vaginal candidiasis; change in cervical secretion; cystitis-like 
syndrome; application site reactions of vulvovaginal discomfort including burning and irritation; 
genital pruritus; ovarian cancer; endometrial hyperplasia; endometrial cancer. 
 
2. 
Breasts 
 
Tenderness, enlargement, pain, nipple discharge,  fibrocystic breast changes; breast cancer. 
 
3. 
Cardiovascular 
 
Deep and superficial venous thrombosis; pulmonary embolism; myocardial infarction; stroke; 
increase in blood pressure. 
 
4. 
Gastrointestinal 
 
Nausea, vomiting; abdominal cramps, bloating; increased incidence of gallbladder disease. 
 
5. 
Skin 
 
Chloasma that may persist when drug is discontinued;  loss of scalp hair; hirsutism;  rash. 
 
6. 
Eyes 


 
 
Retinal vascular thrombosis, intolerance to contact lenses. 
 
7. 
Central Nervous System 
 
Headache; migraine; dizziness; mental depression; nervousness; mood disturbances; irritability; 
dementia. 
 
8. 
Miscellaneous 
 
Increase or decrease in weight; glucose intolerance; edema; arthralgias; leg cramps; changes in 
libido; urticaria; exacerbation of asthma; increased triglycerides; hypersensitivity (including 
erythema multiforme). 
 
OVERDOSAGE 
 
Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain, 
drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose 
consists of discontinuation of ESTRACE therapy together with institution of appropriate 
symptomatic care. 
 
 
DOSAGE AND ADMINISTRATION 
 
 
Use of ESTRACE alone or in combination with a progestin, should be limited to the shortest 
duration consistent with treatment goals and risks for the individual woman.  Postmenopausal 
women should reevaluate periodically as clinically appropriate to determine if treatment is still 
necessary.  For treatment of vulvar and vaginal atrophy associated with the menopause, the 
lowest dose and regimen that will control symptoms should be chosen and medication should be 
discontinued as promptly as possible.  For women who have a uterus, adequate diagnostic 
measures, including directed and random endometrial sampling when indicated, should be 
undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal 
genital bleeding. 
 
Usual Dosage: The usual dosage range is 2 to 4 g (marked on the applicator) daily for one or two 
weeks, then gradually reduced to one half initial dosage for a similar period. A maintenance 
dosage of 1 g, one to three times a week, may be used after restoration of the vaginal mucosa has 
been achieved. 
 
NOTE: The number of doses per tube will vary with dosage requirements and patient 
handling. 
 
 
 
HOW SUPPLIED 
ESTRACE (estradiol vaginal cream, USP, 0.01%). 
N 0430-3754-14: Tube containing 1 ½ oz (42.5 g) with a calibrated plastic applicator for 
delivery of 1, 2, 3, or 4 g. 


 
Store at room temperature 20° to 25°C (59° to 77°F). Protect from temperatures in excess 
of 40°C (104° F). 
 
Keep ESTRACE Vaginal Cream out of the reach of children. 
REFERENCES 
1.   Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in 
Postmenopausal Women With Hysterectomy: Results From the Women’s Health Initiative 
Randomized Trial. J Bone Miner Res. 2006;21:817-828. 
2.   Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women’s Health 
Initiative. Circulation. 2006;113:2425-2434. 
3.   Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by 
Age and Years Since Menopause. JAMA. 2007;297:1465-1477. 
4.   Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med. 
2006;166:357-365. 
5.   Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a 
Uterus. Arch Int Med. 2006;166:772-780. 
6.   Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 
2004;292:1573-1580. 
7.   Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and 
Mammography Screening in Postmenopausal Women With Hysterectomy. JAMA. 
2006;295:1647-1657. 
8.   Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and 
Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234-3253. 
9.   Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and 
Associated Diagnostic Procedures. JAMA. 2003;290:1739-1748. 
10. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and 
Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:29472958. 
 
Distributed By: 
Allergan USA, Inc. 
Irvine, CA 92612 
 
© 2017 Allergan. All rights reserved. 
Revised: 05/2017 


ESTRACE® CREAM 
Rx only 
(estradiol vaginal cream, USP, 0.01%) 
INFORMATION FOR THE PATIENT 
Read this PATIENT INFORMATION before you start using ESTRACE Vaginal Cream and 
read what you get each time you refill your ESTRACE Vaginal Cream prescription.  There may 
be new information.  This information does not take the place of talking with your healthcare 
provider about your menopausal symptoms or your treatment. 
 
 
What is the most important information I should know about ESTRACE Vaginal 
Cream (an estrogen hormone)? 
 
• Using estrogen-alone may increase your chance of getting cancer of the uterus 
(womb). Report any unusual vaginal bleeding right away while you are using 
ESTRACE Vaginal Cream. Vaginal bleeding after menopause may be a warning 
sign of cancer of the uterus (womb). Your healthcare provider should check any 
unusual vaginal bleeding to find out the cause. 
• Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia 
(decline in brain function) 
• Using estrogen-alone may increase your chances of getting strokes or blood clots 
• Using estrogen-alone may increase your chance of getting dementia, based on a study 
of women age 65 years of age or older 
• Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes or 
dementia 
• Using estrogens with progestins may increase your chances of getting heart attacks, 
strokes, breast cancer, or blood clots 
• Using estrogens with progestins may increase your chance of getting dementia, based 
on a study of women age 65 years of age or older 
• You and your healthcare provider should talk regularly about whether you still need 
treatment with ESTRACE Vaginal Cream 
 
 
 
 
 
What is ESTRACE Vaginal Cream? 
 
ESTRACE Vaginal Cream is a medicine that contains an estrogen hormone. 
 
What is ESTRACE Vaginal Cream used for? 
ESTRACE Vaginal Cream is used after menopause to: 
• Treat moderate to severe menopausal changes in and around the vagina 
You and your healthcare provider should talk regularly about whether you still need 
treatment with ESTRACE Vaginal Cream to control these problems. 


Who should not use ESTRACE Vaginal Cream? 
Do not start using ESTRACE Vaginal Cream if you: 
 
• Have unusual vaginal bleeding 
 
• Currently have or have had certain cancers 
Estrogens may increase the chances of getting certain types of cancers, including 
cancer of the breast or uterus.  If you have or have had cancer, talk with your 
healthcare provider about whether you should use ESTRACE Vaginal Cream. 
 
• Had a stroke or heart attack 
 
• Currently have or have had blood clots 
 
• Currently have or have had liver problems 
 
• Have been diagnosed with a bleeding disorder 
 
• Are allergic to ESTRACE Vaginal Cream or any of its ingredients 
See the list of ingredients in ESTRACE Vaginal Cream at the end of this leaflet. 
 
• Think you may be pregnant 
 
Tell your healthcare provider: 
 
• If you have unusual vaginal bleeding 
Vaginal bleeding after menopause may be a warning sign of cancer of the uterus 
(womb). Your healthcare provider should check any unusual vaginal bleeding to find 
out the cause. 
 
• About all of your medical problems 
Your healthcare provider may need to check you more carefully if you have certain 
conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, 
endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high 
calcium levels in your blood. 
 
• About all the medicines you take 
This includes prescription and nonprescription medicines, vitamins, and herbal 
supplements.  Some medicines may affect how ESTRACE Vaginal Cream works. 
ESTRACE Vaginal Cream may also affect how your other medicines work. 
 
• If you are going to have surgery or will be on bed rest. 
You may need to stop using ESTRACE Vaginal Cream. 


• If you are breastfeeding 
The estrogen hormone in ESTRACE Vaginal Cream can pass into your breast milk. 
 
 
 
How should I use ESTRACE Vaginal Cream? 
ESTRACE Vaginal Cream is a cream that you place in your vagina with the applicator provided 
with the cream. 
 
• Take the dose recommended by your healthcare provider and talk to him or her about 
how well  that dose is working for you 
 
• Estrogens should be used at the lowest dose possible for your treatment only as long as 
needed. You and your healthcare provider should talk regularly (for example, every 3 to 6 
months) about the dose you are using and whether you still need treatment with 
ESTRACE Vaginal Cream 
 
• Step 1. Remove the cap from the tube. (There is no seal on tube) 
 
• Step 2. Do not separate plunger from applicator. 
 
• Step 3. Screw threaded end of applicator onto the open tube until secure. 
 
• Step 4. Position upright in order to view the calibrated gram amounts. 
 
• Step 5. Gently squeeze tube from the bottom to expel the prescribed amount of 
ESTRACE Vaginal cream into the applicator. As cream is squeezed out, plunger will rise 
to indicate amount of grams. 
 
• Step 6. Unscrew applicator from tube. 
 
• Step 7. Replace cap on tube. 
 
• Step 8. Lie on back with knees drawn up. To deliver medication, gently insert applicator 
deeply into vagina and press plunger downward to its original position. 
 
• Step 9. To cleanse applicator: Pull plunger to remove it from barrel. Wash with mild soap 
and warm water (DO NOT BOIL OR USE HOT WATER) 
 
 
What are the possible side effects of ESTRACE Vaginal Cream? 
 
Although ESTRACE Vaginal Cream is only used in and around the vagina, the risks associated 
with oral estrogens should be taken into account. 
 
Side effects are grouped by how serious they are and how often they happen when you are 
treated. 


 
 
Serious, but less common side effects include: 
• Heart attack 
• Stroke 
• Blood clots 
• Dementia 
• Breast cancer 
• Cancer of the lining of the uterus (womb) 
• Cancer of the ovary 
• High blood pressure 
• High blood sugar 
• Gallbladder disease 
• Liver problems 
• Enlargement of benign tumors of the uterus (“fibroids”) 
• Severe allergic reaction 
 
Call your healthcare provider right away if you get any of the following warning signs or 
any other unusual symptoms that concern you: 
• New breast lumps 
• Unusual vaginal bleeding 
• Changes in vision or speech 
• Sudden new severe headaches 
• Severe pains in your chest or legs with or without shortness of breath, weakness and 
fatigue 
• Swollen lips, tongue or face 
 
Less serious, but common side effects include: 
• Headache 
• Breast pain 
• Irregular vaginal bleeding or spotting 
• Stomach or abdominal cramps, bloating 
• Nausea and vomiting 
• Hair loss 
• Fluid retention 
• Vaginal yeast infection 
• Reactions from inserting ESTRACE Vaginal Cream, such as vaginal burning, irritation, 
and itching 
 
These are not all the possible side effects of ESTRACE Vaginal Cream. For more information, 
ask your healthcare provider or pharmacist for advice about side effects. You may report side 
effects to FDA at 1-800-FDA-1088. 
 
What can I do to lower my chances of a serious side effect with ESTRACE Vaginal Cream? 
• Talk with your healthcare provider regularly about whether you should continue using 


ESTRACE Vaginal Cream. 
 
• If you have a uterus, talk with your healthcare provider about whether the addition of a 
progestin is right for you. The addition of a progestin is generally recommended for a 
woman with a uterus to reduce the chance of getting cancer of the uterus. 
 
• See your healthcare provider right away if you get vaginal bleeding while using 
ESTRACE Vaginal Cream. 
 
• Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your 
healthcare provider tells you something else.  If members of your family have had breast 
cancer or if you have ever had breast lumps or an abnormal mammogram, you may need 
to have breast exams more often. 
 
• If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are 
overweight, or if you use tobacco, you may have higher chances for getting heart disease. 
Ask your healthcare provider for ways to lower your chances for getting heart disease. 
 
General information about safe and effective use of ESTRACE Vaginal Cream 
Medicines are sometimes prescribed for conditions that are not mentioned in patient information 
leaflets.  Do not use ESTRACE Vaginal Cream for conditions for which it was not prescribed. 
Do not give ESTRACE Vaginal Cream to other people, even if they have the same symptoms 
you have.  It may harm them. 
 
Keep ESTRACE Vaginal Cream out of the reach of children. 
 
This leaflet provides a summary of the most important information about ESTRACE Vaginal 
Cream. If you would like more information, talk with your healthcare provider or pharmacist. 
You can ask for information about ESTRACE Vaginal Cream that is written for health 
professionals.  You can get more information by calling the toll free number 1-800-678-1605. 
 
What are the ingredients in ESTRACE Vaginal Cream? 
Each gram of ESTRACE Vaginal Cream contains 0.1 mg estradiol in a nonliquefying base 
containing purified water, propylene glycol, stearyl alcohol, white ceresin wax, mono- and di- 
glycerides, hypromellose 2208 (4000 cps), sodium lauryl sulfate, methylparaben, edetate di- 
sodium and tertiary-butylhydroquinone. 
 
HOW SUPPLIED 
ESTRACE® (estradiol vaginal cream, USP, 0.01%). 
N0430-3754-14: Tube containing 1 ½ oz (42.5 gram) with a calibrated plastic applicator for 
delivery of 1, 2, 3, or 4 gram. 
 
NOTE: The number of doses per tube will vary with dosage requirements and patient 
handling. 


Store at room temperature 20° to 25°C (59° to 77°F). Protect from temperatures in excess 
of 40° C (104° F). 
 
Distributed By: 
Allergan USA, Inc. 
Irvine, CA 92612 
 
© 2017 Allergan. All rights reserved. 
Revised: 05/2017 
 

SAP_003.pdf: 


 
STATISTICAL ANALYSIS PLAN 
 
Estradiol Vaginal Cream USP, 0.01%                                 Protocol/Study Number 71759501 
 
 
01/17/2018       
             
 Prasco LLC 
              
 
Page 1 of 59 
                      
STATISTICAL ANALYSIS PLAN 
             
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to 
Evaluate the Therapeutic Equivalence of Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) to 
Estrace® Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the Treatment of 
Vulvar and Vaginal Atrophy 
 
Protocol Number:  71759501 
 Study Number:  71759501 
 
 
Sponsor: 
Prasco LLC 
6125 Commerce Court 
Mason, OH 45040 
 
Contract Research Organization: 
 
 
 
 
 
January 17, 2018 
Final Version 1.0 
 
 
 






 
STATISTICAL ANALYSIS PLAN 
 
Estradiol Vaginal Cream USP, 0.01%                                 Protocol/Study Number 71759501 
 
 
01/17/2018       
             
 Prasco LLC 
              
 
Page 4 of 59 
List of Abbreviations and Definition of Terms 
ADaM  
 
Analysis Data Model 
AE 
 
 
Adverse Event 
ANOVA 
 
Analysis of variance 
C 
 
 
Celsius 
CDISC 
 
Clinical Data Interchange Standards Consortium 
CI 
 
 
Confidence Interval 
CMH  
 
Cochran-Mantel-Haenszel 
CRF 
 
 
Case Report Form 
CRO  
 
Contract Research Organization 
dL 
 
 
Deciliter 
F 
 
 
Fahrenheit 
FDA  
 
Food & Drug Administration 
FSH 
 
 
Follicle-stimulating hormone 
Hg 
 
 
Mercury 
ICF 
 
 
Informed Consent Form 
ICH 
 
 
International Conference on Harmonisation 
LOCF  
 
Last Observation Carried Forward 
mcg 
 
 
Microgram 
MedDRA 
 
Medical Dictionary for Regulatory Activities  
mg 
 
 
Milligram 
mITT  
 
modified Intent-to-Treat 
mL 
 
 
Milliliter 
mm 
 
 
Millimeter 
OGD  
 
Office of Generic Drugs 
PAP 
 
 
Papanicolaou 
pH 
 
 
Measure of acidity/alkalinity 
PP 
 
 
Per-Protocol 
RS  
 
 
Reference Standard 
SAE 
 
 
Serious Adverse Event 
SAP 
 
 
Statistical Analysis Plan 
SAS 
 
 
Statistical Analysis Software 
SDTM  
 
Study Data Tabulation Model 
U.S.A  
 
United States of America 
VVA  
 
Vulvar and Vaginal Atrophy 
 
 


 
STATISTICAL ANALYSIS PLAN 
 
Estradiol Vaginal Cream USP, 0.01%                                 Protocol/Study Number 71759501 
 
 
01/17/2018       
             
 Prasco LLC 
              
 
Page 5 of 59 
TABLE OF CONTENTS 
1. INTRODUCTION .......................................................................................................................7 
2. OBJECTIVES ..............................................................................................................................7 
3. OVERALL STUDY DESIGN .....................................................................................................7 
4. RANDOMIZATION AND BLINDING....................................................................................10 
5. SAMPLE SIZE ..........................................................................................................................10 
6. ANALYSIS POPULATION ......................................................................................................11 
7. STUDY ENDPOINTS ...............................................................................................................11 
8. STATISTICAL ANALYSIS METHODS .................................................................................12 
8.1 Baseline Characteristics ......................................................................................................12 
8.1.1 Patient Disposition ......................................................................................................12 
8.1.2 Demographic and Other Baseline Characteristics .......................................................13 
8.1.3 Medical History ...........................................................................................................13 
8.1.4 Concomitant Medications ...........................................................................................13 
8.1.5 Physical Exam .............................................................................................................14 
8.1.6 Laboratory Evaluations ...............................................................................................14 
8.1.7 Dosing Compliance .....................................................................................................14 
8.2 Efficacy Analyses................................................................................................................15 
8.2.1 Analysis of Primary Efficacy Endpoint ......................................................................15 
8.2.2 Analysis of Secondary Efficacy Endpoint ..................................................................16 
8.2.3 Treatment-by-Site Interaction and Pooling of Clinical Sites ......................................17 
8.3 Safety Analysis ...................................................................................................................17 
8.3.1 Adverse Events ............................................................................................................17 
8.3.2 Vital Signs ...................................................................................................................18 
8.4 Multiple Comparisons .........................................................................................................18 
8.5 Methods for Handling Missing Data ...................................................................................18 
8.6 Interim Analyses .................................................................................................................18 
9. TABLE, LISTING AND FIGURE SHELLS ............................................................................19 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
STATISTICAL ANALYSIS PLAN 
 
Estradiol Vaginal Cream USP, 0.01%                                 Protocol/Study Number 71759501 
 
 
01/17/2018       
             
 Prasco LLC 
              
 
Page 6 of 59 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10. APPENDICIES ........................................................................................................................58 
 
 
 
 
 
 
 


 
STATISTICAL ANALYSIS PLAN 
 
Estradiol Vaginal Cream USP, 0.01%                                 Protocol/Study Number 71759501 
 
 
01/17/2018       
             
 Prasco LLC 
              
 
Page 7 of 59 
1. INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on the final Clinical Study Protocol 71759501 (Rev 
0) dated 07-25-2017. The SAP provides details on the planned statistical methodology for the 
analysis of the study data. The SAP also outlines the statistical programming specifications for 
the tables, listings and figures. 
This SAP describes the study endpoints, derived variables, anticipated data transformations and 
manipulations, and other details of the analyses not provided in the study protocol. This SAP 
therefore outlines in detail all other aspects pertaining to the planned statistical analyses and 
presentations for this study. 
The following documents were reviewed in preparation of this SAP: 
 Final Clinical Study Protocol 71759501 (Rev 0) dated 07-25-2017 
 Case Report Form Booklet Version 1.0 for Study No. 71759501 
2. OBJECTIVES 
The objectives of this study are to: 
1. Evaluate the therapeutic equivalence of a Test product, the generic Estradiol Vaginal 
Cream USP, 0.01% (Prasco LLC) to the Reference product, Estrace® Cream 
(Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) in the treatment of VVA. 
2. Demonstrate the superiority of the active treatments (Test and Reference) over 
Placebo (vehicle) treatment in patients with VVA. 
3. Compare the safety of Test, Reference and Placebo treatments in patients with VVA. 
3. OVERALL STUDY DESIGN 
This randomized, double-blind, placebo-controlled, parallel-design, multiple-site study is 
designed to evaluate the clinical (therapeutic) effect of a Test product, a generic Estradiol 
Vaginal Cream USP, 0.01% (Prasco LLC) compared to the FDA Reference Standard (RS), 
Estrace® Cream (Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in patients with VVA. 
Additionally, both the Test and Reference products will be tested for superiority against a 
Placebo. 
Before any study-specific procedures are performed, all patients will read and sign the IRB-
approved informed consent form (ICF). 
Approximately 
 eligible postmenopausal female patients, with a confirmed diagnosis of VVA 
will be randomized in a 
 to one of the three study products 
as follows: 


 
STATISTICAL ANALYSIS PLAN 
 
Estradiol Vaginal Cream USP, 0.01%                                 Protocol/Study Number 71759501 
 
 
01/17/2018       
             
 Prasco LLC 
              
 
Page 8 of 59 
 Test: Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) 
 Reference: Estrace® Cream (Estradiol Vaginal Cream, USP, 0.01%) (Warner Chilcott) 
 Placebo: Placebo (Test vehicle cream) Vaginal Cream (Prasco LLC) 
Following a 28-day screening period, at Visit 2 patients will be instructed to self-administer 
2 grams of study product once daily at approximately the same time for seven consecutive days. 
During the study, patients will visit the clinical center for a total of three scheduled visits: 
 Visit 1/Screening (Day -28 to Day -1) 
 Visit 2/Randomization (Day 1) 
 Visit 3/End of Study (Day 8 or Day 9) 
Final assessments will be carried out on Day 8 or Day 9. 
Vaginal cytology and vaginal pH determination will be performed by the Investigator as a part of 
clinical evaluation at Visits 1 and 3. The primary statistical analysis of interest is the proportion 
of patients in the PP population that are identified as Responders at the end of the treatment 
period evaluated on Day 8 or Day 9. A Responder is defined as a patient with at least a 25% 
reduction from baseline in the sum of % basal/parabasal + % intermediate cells on vaginal 
cytology AND vaginal pH < 5.0 with a change from baseline vaginal pH of at least 0.5. 
 
 


 
STATISTICAL ANALYSIS PLAN 
 
Estradiol Vaginal Cream USP, 0.01%                                 Protocol/Study Number 71759501 
 
 
01/17/2018       
             
 Prasco LLC 
              
 
Page 9 of 59 
   Study Schematic 
 
Visit 1 
(Day -28 to Day -1) 
Screening 
Visit 2 
(Day 1) 
Randomization 
Visit 3 
(Day 8 or Day 9) 
End of Study or 
Early Termination 
Informed Consent 
X 
 
 
Medical History and 
Demographics 
X 
 
 
Review and Assessment of 
Concomitant Medications 
X 
X 
X 
Review and Assessment of 
Adverse Events 
X 
X 
X 
Vital Signs 
X 
X 
X 
Signs and Symptoms of VVA 
X 
X 
X 
Physical Exam  
X 
 
X 
Vaginal Cytology and pH 
X 
 
X 
PAP*Smear 
X 
 
 
Serum FSH and Fasting 
Triglycerides 
X 
 
 
Mammogram† 
X 
 
 
Vaginal Ultrasound‡ 
X 
 
 
Inclusion/Exclusion Criteria 
Review 
X 
X  
 
Collect and Review Patient Diary 
 
X 
X 
Provide Patient Diary 
X 
X 
 
Dispense Study Product 
 
X 
 
Collect Study Product 
 
 
X 
*Patients with an intact uterus who do not have documentation of a PAP smear completed within 
the 
. 
†Patients over the age of 
 who do not have documentation of a mammogram completed within 
the 
 before Screening will have a mammogram as part of the Screening evaluations. 
‡Patients with an intact uterus will have a vaginal ultrasound as part of the Screening evaluations 
which will be reviewed before randomization. 
 


 
STATISTICAL ANALYSIS PLAN 
 
Estradiol Vaginal Cream USP, 0.01%                                 Protocol/Study Number 71759501 
 
 
01/17/2018       
             
 Prasco LLC 
              
 
Page 10 of 59 
4. RANDOMIZATION AND BLINDING 
Patients who meet the inclusion criteria and none of the exclusion criteria at Visits 1 and 2 will 
be assigned a randomization number. The randomization number will 
 
. Randomization numbers will be assigned immediately before dispensing of study 
product and in ascending sequential order, beginning with the lowest available number at the 
study site. Each patient kit and each dispensed study tube should include 
 
on the label. 
All randomized study product 
 
 
 
 
 
 
At the end of the study, after all the clinical data have been entered and the study database has 
been locked, a copy of the randomization schedule will be sent to the statistician. 
The Investigator, staff at the study site, study monitors, and data analysis/management personnel 
will be blinded to the patient assignment. 
5. SAMPLE SIZE 
For the primary endpoint analysis (proportion of patients in the PP population that are identified 
as Responders at the end of the treatment period evaluated on Day 8 or Day 9), sample size is 
estimated for therapeutic equivalence of the Test product to the Reference product and 
superiority of each of the active treatments groups over Placebo. 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 


 
STATISTICAL ANALYSIS PLAN 
 
Estradiol Vaginal Cream USP, 0.01%                                 Protocol/Study Number 71759501 
 
 
01/17/2018       
             
 Prasco LLC 
              
 
Page 11 of 59 
 
 
 
 
 
 
 
 
6. ANALYSIS POPULATION 
Per-Protocol (PP) Population 
The PP population will include all randomized patients who: 
 Met the inclusion/exclusion criteria as defined in the protocol at Visit 1 and 2. 
 Did not have any significant protocol deviations. 
 Did not develop any concurrent vaginal infection or illness exhibiting symptoms similar 
to VVA, or symptoms that in the Investigator’s opinion would interfere with primary and 
secondary endpoint assessments. 
 Completed the last study visit (Visit 3) within window (Day 8 or Day 9). 
 Were compliant with dosing between 
 of the required doses. 
Any patient who withdraws from the study because of lack of efficacy will be included in the PP 
population as a Non-Responder, provided they did not have any significant protocol deviations 
that would affect treatment evaluation. 
Modified Intent-to-Treat (mITT) Population 
 
The modified Intent-to-Treat (mITT) population will include all randomized patients who: 
 Administered at least one dose of randomized study product. 
 Had a post-randomization evaluation. 
Safety Population 
The safety population will include all patients who are randomized and received study product. 
7. STUDY ENDPOINTS 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of patients in each treatment group that are 
identified as Responders at the end of the treatment period evaluated on Day 8 or Day 9. 


 
STATISTICAL ANALYSIS PLAN 
 
Estradiol Vaginal Cream USP, 0.01%                                 Protocol/Study Number 71759501 
 
 
01/17/2018       
             
 Prasco LLC 
              
 
Page 12 of 59 
A “Responder” is defined as a patient with at least a 25% reduction from baseline in the sum of 
% basal/parabasal + % intermediate cells on vaginal cytology AND vaginal pH < 5.0 with a 
change from baseline vaginal pH of at least 0.5. 
Secondary Efficacy Endpoint 
The secondary efficacy endpoint is the proportion of patients in each treatment group that are 
considered a Treatment Success at the end of the treatment period evaluated on Day 8 or Day 9. 
A “Treatment Success” is defined as a score of 0 or 1 on Day 8 or Day 9 for the symptom 
identified at baseline as the most bothersome. This evaluation will be based on (one) patient self-
assessed symptom of VVA (vaginal dryness, vaginal and/or vulvar irritation/itching, dysuria, or 
vaginal pain associated with sexual activity) on a scale of 0 to 3 where 0 = none and 3 = severe. 
Evaluation of vaginal bleeding during sexual activity will be based on a Score of 1 (presence) if 
it is identified by the patient as the most bothersome symptom at baseline and a score of 0 
(absent) on Day 8 or Day 9. 
Baseline is defined as the symptom score at Randomization Visit 2. 
8. STATISTICAL ANALYSIS METHODS 
If not otherwise specified, statistical significance is defined as p < 0.05 and is two-tailed. Data 
will be summarized with respect to demographic and baseline characteristics, efficacy variables 
and safety variables. 
For categorical variables, the number and percent of each category within a parameter will be 
calculated for non-missing data. For continuous variables, statistics will include n, mean, 
standard deviation, median, minimum and maximum values. 
All statistical analyses will be conducted using SAS®, 
 
 
 
 
8.1 Baseline Characteristics 
8.1.1 Patient Disposition 
The patient disposition information will be summarized by study treatment group. The number of 
patients randomized, and the number of patients in each analysis population will be tabulated. In 
addition, completion status and primary reason for withdrawal will be summarized by study 
treatment group. 


 
STATISTICAL ANALYSIS PLAN 
 
Estradiol Vaginal Cream USP, 0.01%                                 Protocol/Study Number 71759501 
 
 
01/17/2018       
             
 Prasco LLC 
              
 
Page 13 of 59 
8.1.2 Demographic and Other Baseline Characteristics 
Baseline comparability of all treatment groups will be evaluated separately in the PP, mITT and 
Safety populations. The following baseline demographics (determined from their initial study 
visit) will be evaluated: 
 Age (years) 
 Gender (male/female) 
 Ethnicity (Hispanic/non Hispanic) 
 Race (White, Black/African American, Native Hawaiian or Other Pacific Islander, 
Asian, American Indian or Alaska Native, Other) 
 Natural or surgical menopause 
 Duration of postmenopausal status 
 Baseline signs and symptoms 
 Baseline % of the three major vaginal wall cell types (basal/parabasal cells, 
intermediate cells and superficial cells)  
 Vaginal pH 
Summary tables by treatment group will be presented. Continuous variables will be summarized 
using descriptive statistics (n, mean, standard deviation, median, minimum, maximum).  
Categorical variables will be summarized using frequencies and percentages.  
Baseline treatment comparisons will be presented using Chi-Square test for the categorical 
variables, and Analysis of Variance (ANOVA) for the continuous variables. 
All data will be listed by treatment and patient. 
8.1.3 Medical History 
At Visit 1, patients will be questioned about medical history, including acute and chronic 
medical history and medical history relevant to their VVA. 
Medical history data will be listed by treatment and patient. 
8.1.4 Concomitant Medications 
At Visit 1, patients will be questioned about all concomitant medication use within the previous 
6 months. At Visits 2 and 3, patients will be questioned about ongoing or any new concomitant 
medication use. 
 


 
STATISTICAL ANALYSIS PLAN 
 
Estradiol Vaginal Cream USP, 0.01%                                 Protocol/Study Number 71759501 
 
 
01/17/2018       
             
 Prasco LLC 
              
 
Page 14 of 59 
All prior and concomitant medications taken since screening until the end of the study will be 
listed by treatment and patient. 
8.1.5 Physical Exam 
At Visit 1, the Investigator will perform a general physical exam including pelvic exam and 
breast exam. At Visit 3, the Investigator will perform a general physical exam including pelvic 
and breast exam. Any clinically significant abnormal findings on this exam should be reported as 
adverse events (AEs). 
Physical examination results will be listed by treatment and patient.  
8.1.6 Laboratory Evaluations 
At Visit 1, all patients will have a blood sample taken for evaluation of serum FSH levels. Serum 
FSH will be evaluated by a central clinical laboratory. 
 
 
All patients will have a blood sample taken for fasting triglyceride testing. These samples will be 
sent to the central laboratory for testing. 
 
 
Laboratory evaluation results will be listed by treatment and patient.  
8.1.7 Dosing Compliance 
Patients will be considered compliant if they take a total of at least six doses and no more than 
eight doses, and not more than two doses on any day. Patients taking fewer than 75% or more 
than 125% of the required doses will be considered non-compliant with dosing. Compliance with 
dosing will be verified by the use of the patient diaries. Compliance criteria are as outlined in the 
table below: 
For patients who have completed the study: 
Study Design 
Compliance Criteria 
Visit 3 
Treatment 
Duration 
Required 
Doses 
Not more than 
125% (doses) 
Not 
less 
than 
75% (doses) 
Days 8-9 
7 days 
7 
8 
6 
For patients who are early terminated, compliance will be determined from their duration in the 
study, up to the time they are considered early terminated. For example, if a patient is dropped 
after six days of participation and starts application of study product on the day of Visit 2 (i.e., 
Day 1) and once daily for the four of the five remaining days, then percent compliance would be 
83% (4 out of 5 doses). 


 
STATISTICAL ANALYSIS PLAN 
 
Estradiol Vaginal Cream USP, 0.01%                                 Protocol/Study Number 71759501 
 
 
01/17/2018       
             
 Prasco LLC 
              
 
Page 15 of 59 
Drug administration and dosing compliance will be listed by treatment and patient.  
8.2 Efficacy Analyses 
8.2.1 Analysis of Primary Efficacy Endpoint 
Therapeutic Bioequivalence Analysis 
Therapeutic equivalence of the Test product to the Reference product based on the primary 
endpoint will be evaluated in the PP population after the end of treatment on Day 8 ± 1.  
Based on the usual method used in OGD for binary outcomes, the 90% confidence interval for 
the difference in success proportions between test and reference treatment should be contained 
within [-0.20, +0.20] in order to establish equivalence.  
 
The compound hypothesis to be tested is:  
 
               
                  
        versus   
 
            
       
    
 
 
where       =  cure rate of test treatment  
                  =  cure rate of reference treatment.  
 
Let  
    =  sample size of test treatment group  
   =  number of cured patients in test treatment group  
    =  sample size of reference treatment group  
   =  number of cured patients in reference treatment group  
 
    
        
     
       ,       and 
 
                                                   
    
 
The 90% confidence interval for the difference in proportions between test and reference will be 
calculated as follows, using Yates’ correction: 
                              
                    
             
               
                    


 
STATISTICAL ANALYSIS PLAN 
 
Estradiol Vaginal Cream USP, 0.01%                                 Protocol/Study Number 71759501 
 
 
01/17/2018       
             
 Prasco LLC 
              
 
Page 16 of 59 
If the 90% confidence interval (calculated using Yates’ continuity correction) for the absolute 
difference between the proportion of patients considered as “Responders” (at least a 25% 
reduction from baseline in the sum of % basal/parabasal + % intermediate cells on vaginal 
cytology AND vaginal pH < 5.0 with a change from baseline vaginal pH of at least 0.5) in the 
Test and Reference groups is contained within the range [-20%, +20%] then bioequivalence of 
the Test product to the Reference product will be considered to have been demonstrated for the 
primary endpoint.  
To declare therapeutic equivalence of the Test product to the Reference product, equivalence 
must be demonstrated for only the primary endpoints in the PP population. 
Superiority to Placebo Analysis 
The mITT population and LOCF will be used to evaluate the superiority of both the Test and 
Reference product to Placebo. LOCF will apply to each parameter of the endpoint. 
Summary table with frequency and percentage on the proportion of responders by treatment 
group will be presented. If the proportion of Responders in the Test and the Reference product 
groups is numerically and statistically superior to that of the Placebo (p < 0.05; using a two-sided 
CMH test, stratified by clinical site) then superiority of the Test and Reference products over 
Placebo will be concluded. 
To declare superiority of the Test and Reference products over Placebo, their superiority must be 
demonstrated for only the primary endpoint in the mITT population. 
8.2.2 Analysis of Secondary Efficacy Endpoint 
Therapeutic Bioequivalence Analysis 
Similar to the analysis for primary endpoint above, therapeutic equivalence of the Test product to 
the Reference product based on the secondary endpoint will be evaluated in the PP population 
after the end of treatment on Day 8 ± 1.  
Secondary analysis will compare the proportion of patients considered to be a “Treatment 
Success” for their most bothersome symptom.  A “Treatment Success” is defined as a score of 0 
or 1 at Day 8 for the symptom identified at baseline as the most bothersome). Baseline is defined 
as the symptom score at Randomization Visit 2. If the 90% confidence interval (calculated using 
Yates’ continuity correction) for the absolute difference between the proportion of patients 
considered as “Treatment Success” in the Test and Reference groups is contained within the 
range [-20%, +20%] then bioequivalence of the Test product to the Reference product will be 
considered to have been demonstrated for the secondary endpoint. 
To declare therapeutic equivalence of the Test product to the Reference product, bioequivalence 
must be demonstrated for only the primary endpoint. Bioequivalence testing of the secondary 


 
STATISTICAL ANALYSIS PLAN 
 
Estradiol Vaginal Cream USP, 0.01%                                 Protocol/Study Number 71759501 
 
 
01/17/2018       
             
 Prasco LLC 
              
 
Page 17 of 59 
endpoint will be conducted for supportive information.  
Superiority to Placebo Analysis 
The mITT population and LOCF will be used to evaluate the superiority of both the Test and 
Reference products to Placebo. 
Summary table with frequency and percentage on the proportion of responders by treatment 
group will be presented. If the proportion of Responders in the Test and the Reference product 
groups is numerically and statistically superior to that of the Placebo (p < 0.05; using a two-sided 
CMH test, stratified by clinical site) then superiority of the Test and Reference products over 
Placebo will be concluded. 
8.2.3 Treatment-by-Site Interaction and Pooling of Clinical Sites 
As this is a multiple-site study, the interaction of treatment-by-site may be evaluated for the 
primary efficacy endpoint in the PP population for equivalence testing. The treatment-by-site 
interaction will be evaluated by the Breslow-Day test for homogeneity of the odds ratio at the 5% 
significance level (p < 0.05, 2-sided). A site(s) with a low enrollment rate(s) may be pooled with 
its geographically closest site, so as to avoid bias in the stratification of the sites in the CMH test 
and in the estimation of a treatment-by-site interaction effect. The pooling will be done for low 
enrolling sites that account for less than 4-7% of the total number of patients in the PP 
population at the site with the highest enrolling rate in the PP population. If the treatment-by-site 
interaction term is found to be statistically significant (p < 0.05) for the primary endpoint, then 
the interaction term will also be assessed for clinical relevance before pooling the data across 
sites. This will include examination of Responder rates at each site where sample sizes per 
treatment may be influential in the assessment of the interaction. 
8.3 Safety Analysis 
8.3.1 Adverse Events 
All the AEs reported will be coded and classified according to the Medical Dictionary for 
Regulatory Activities (MedDRA) coding dictionary (Version 20.0 or higher). Each AE is to be 
evaluated for date of start and end, seriousness, severity, causal relationship with the study drug, 
action taken and outcome.   
All AEs will be listed by patient and treatment. 
The total number and percentage of patients with at least one AE, discontinued study drug due to 
AEs, AE severity, AEs related to investigational product, serious adverse events (SAEs), and 
death will be summarized by treatment groups.  


 
STATISTICAL ANALYSIS PLAN 
 
Estradiol Vaginal Cream USP, 0.01%                                 Protocol/Study Number 71759501 
 
 
01/17/2018       
             
 Prasco LLC 
              
 
Page 18 of 59 
A summary table of the number and percent of patients with AEs by system organ class, 
preferred term, and treatment group will be presented. Each patient will be counted only once 
within each preferred term. 
A frequency summary table of the number of AEs by system organ class, preferred term, 
severity, and treatment group will be presented. Severity will be classified as “Mild”, 
“Moderate”, or “Severe”.  
Similarly, a frequency summary table of the number of AEs by system organ class, preferred 
term, and relationship to a study drug, and treatment group will be presented. Relationship to a 
study drug will be classified as “Related” or “Not Related”. 
Adverse event frequencies will be compared between treatments using the Fisher’s exact test. 
8.3.2 Vital Signs 
The patient’s vital signs will be recorded (pulse, blood pressure, temperature and respiration 
rate) at Visits 1, 2, and 3. 
Descriptive summaries (n, mean, standard deviation, minimum, median and maximum) will be 
provided by treatment and visit. The summary table will be based on safety population 
randomized. 
All data will be listed by treatment and patient. 
8.4 Multiple Comparisons 
No multiple comparison adjustment will be made in this study. 
8.5 Methods for Handling Missing Data 
For demographic and baseline characteristics, each variable will be analyzed using all available 
data. Patients with missing data will be excluded only from analyses for which data are not 
available. 
Any patient who withdrew from the study because of lack of efficacy will be included in the PP 
population as a Non-Responder, provided they did not have any significant protocol deviations 
that would affect treatment evaluation. Patients who discontinue early for other reasons should 
be excluded from the PP population and included in the mITT population using Last Observation 
Carried Forward (LOCF). 
8.6 Interim Analyses 
There is no interim analysis planned in this study. 


 
STATISTICAL ANALYSIS PLAN 
 
Estradiol Vaginal Cream USP, 0.01%                                 Protocol/Study Number 71759501 
 
 
01/17/2018       
             
 Prasco LLC 
              
 
Page 19 of 59 
9. TABLE, LISTING AND FIGURE SHELLS 
The following shells are provided in order to provide a framework for the display of data from 
this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 


Prasco LLC                                                                                                                    
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71759501 
 
 
01/17/2018       
 
 
 
 Prasco LLC  
 
 
 
 
Page 20 of 59 
 
 
 
 
 
 
 
TABLE, LISTING AND FIGURE SHELLS 
  
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 2 1 of 5 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
   
 
 
 
 
 
   
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                             
 
 
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 2 2 of 5 9 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
   
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
   
 
 
 
 
 
   
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                             
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 2 3 of 5 9 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                             
 
 
 


Prasco LLC                                                                                                                    
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71759501 
 
 
01/17/2018       
 
 
 
 Prasco LLC  
 
 
 
 
Page 24 of 59 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                            
 
 
 
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 2 5 of 5 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
      
  
 
 
 
 
 
 
                                                                                                                                             
 
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 2 6 of 5 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
      
  
 
 
 
 
 
 
                                                                                                                                             
 
 
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 2 7 of 5 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
      
  
 
 
 
 
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 2 8 of 5 9 
 
                                                                                                                                             
 
 
 
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 2 9 of 5 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
      
  
 
 
 
 
 
 
 
                                                                                                                                             
 
 
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 3 0 of 5 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
      
  
 
 
 
 
 
 
                                                                                                                                             
 
 
 
 


Prasco LLC                                                                                                                    
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71759501 
 
 
01/17/2018       
 
 
 
 Prasco LLC  
 
 
 
 
Page 31 of 59 
 
 
 
 
 
 
 
 
 
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 3 2 of 5 9 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
 
 
 
  
 
 
        
 
        
                                                                                                                                             
 
 
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 3 3 of 5 9 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
 
 
 
  
 
 
       
 
      
                                                                                                                                            
 
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 3 4 of 5 9 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
                     
 
 
 
 
 
 
                                                                                                                                             
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 3 5 of 5 9 
  
 
 
  
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                             
 
 
 


Prasco LLC                                                                                                                    
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71759501 
 
 
01/17/2018       
 
 
 
 Prasco LLC  
 
 
 
 
Page 36 of 59 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                            
 


Prasco LLC                                                                                                                    
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71759501 
 
 
01/17/2018       
 
 
 
 Prasco LLC  
 
 
 
 
Page 37 of 59 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                            
 
 
 
 


Prasco LLC                                                                                                                    
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71759501 
 
 
01/17/2018       
 
 
 
 Prasco LLC  
 
 
 
 
Page 38 of 59 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                            
 
 
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 3 9 of 5 9 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                             
 
 
 


Prasco LLC                                                                                                                    
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71759501 
 
 
01/17/2018       
 
 
 
 Prasco LLC  
 
 
 
 
Page 40 of 59 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                              
 
 
 


Prasco LLC                                                                                                                    
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71759501 
 
 
01/17/2018       
 
 
 
 Prasco LLC  
 
 
 
 
Page 41 of 59 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                            
 
 
 


Prasco LLC                                                                                                                    
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71759501 
 
 
01/17/2018       
 
 
 
 Prasco LLC  
 
 
 
 
Page 42 of 59 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                            
 
 
 


Prasco LLC                                                                                                                    
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71759501 
 
 
01/17/2018       
 
 
 
 Prasco LLC  
 
 
 
 
Page 43 of 59 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                            
 
 
 


Prasco LLC                                                                                                                    
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71759501 
 
 
01/17/2018       
 
 
 
 Prasco LLC  
 
 
 
 
Page 44 of 59 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                            
 
 
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 4 5 of 5 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                             
 
 
 
 


Prasco LLC                                                                                                                    
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71759501 
 
 
01/17/2018       
 
 
 
 Prasco LLC  
 
 
 
 
Page 46 of 59 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                     
 
 
 
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 4 7 of 5 9 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                             
 
 
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 4 8 of 5 9 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                             
 
 
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 4 9 of 5 9 
 
 
 
  
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                             
 
 
 


Prasco LLC                                                                                                                    
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71759501 
 
 
01/17/2018       
 
 
 
 Prasco LLC  
 
 
 
 
Page 50 of 59 
 
 
 
  
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
              
 
 
              
 
 
              
 
 
 
                                                                                                                                            
 
 
 
 
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 5 1 of 5 9 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
                                                                                                                                             
 
 
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 5 2 of 5 9 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                             
 
 
 
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 5 3 of 5 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                             
 
 
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 5 4 of 5 9 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                             
 
 
 
 
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 5 5 of 5 9 
 
 
 
 
 
 
 
 
    
 
 
  
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
 
 
 
 
                                                                                                                                             
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 5 6 of 5 9 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                             
 
 
 


Pr asc o L L C                                                                                                                    
 
Estr a di ol V a gi n al Cre a m U S P, 0. 0 1 %                                                                                            Pr ot oc ol / St u d y N o.  7 1 7 5 9 5 0 1 
 
 
0 1 / 1 7/ 2 0 1 8        
  
  
 
 Prasc o L L C   
  
  
  
  
Pa ge 5 7 of 5 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                         
 


 
STATISTICAL ANALYSIS PLAN 
 
Estradiol Vaginal Cream, USP, 0.01%          
Protocol / Study No.  71759501 
 
 
01/17/2018 
 Prasco LLC    
Page 58 of 59 
10. APPENDICIES 
Appendix A:  Definitions and Severity Ratings For Signs and Symptoms 
Vaginal Dryness 
No lubrication or secretions noted on perineum or after wiping; if sexually active loss of 
lubrication during coitus. 
Score 
Severity 
Description 
0 
None 
No noticeable lack of vaginal lubrication or secretions reported or 
observed 
1 
Mild 
Episodic loss of lubrication/secretions or noticed some reduction in 
general secretions, does not interfere with daily activities 
2 
Moderate Symptom present most of the time, and noticeable but overall is 
tolerable and does not interfere with daily activities 
3 
Severe 
Very minimal or no natural vaginal lubrication/secretions almost 
all of the time and interferes with normal activities 
 
 
Vaginal/Vulvar Irritation/Itching 
Scratching or sand paper type feeling in vaginal/vulvar area. May feel uncomfortable 
with clothing or undergarments touching the perineum. 
Score 
Severity 
Description 
0 
None 
No irritation or itching reported. 
1 
Mild 
Occasional irritation/itching but does not interfere with daily 
activities 
2 
Moderate Frequent irritation/itching that can be uncomfortable but generally 
does not interfere with daily activities 
3 
Severe 
Very frequent or continuous irritation/itching of the vaginal area, 
may interfere with daily activities. 
 
 
Dysuria 
Pain or discomfort during urination 
Score 
Severity 
Description 
0 
None 
No pain or discomfort during urination reported. 
1 
Mild 
Occasional or slight discomfort during urination but tolerable 
2 
Moderate Some discomfort during urination at least 50% of the time which 
can be painful but overall tolerable. 
3 
Severe 
Urination nearly always painful, usually intolerable and causing 
disruption to daily activities 
 
 


 
STATISTICAL ANALYSIS PLAN 
 
Estradiol Vaginal Cream, USP, 0.01%          
Protocol / Study No.  71759501 
 
 
01/17/2018 
 Prasco LLC    
Page 59 of 59 
Vaginal Pain during Sexual Activity 
Suffers discomfort or pain during sexual activity that may be restrictive. 
Score 
Severity 
Description 
0 
None 
No discomfort or pain 
1 
Mild 
Some feeling of vaginal soreness or pain, during or after sexual 
activity. Does restrict frequency of or type of sexual activity. 
2 
Moderate Vaginal pain during sexual activity such that frequency and type of 
sexual activity have been disrupted. Lubrication may be needed for 
penetration 
3 
Severe 
Vaginal penetration very painful and impossible without vaginal 
lubrication. Discomfort such that frequency of sexual activity 
significantly reduced. 
 
 
Vaginal bleeding during or after sexual activity 
Score 
Severity 
Description 
0 
Absent 
No vaginal bleeding observed 
1 
Present 
Bleeding observed during or soon after vaginal activity 
 
 
At each visit each patient must also clearly identify which is the most bothersome   
sign/symptom to her, even if she rates two or more symptoms the same severity rating.