Clinical trial NCT03294538
Conditions: Atrophic Vaginitis
Sponsor: Actavis Inc.
Start date: 2016-05-18; Completion date: 2017-02-15
Enrollment: 663 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objectives of this study were to evaluate the therapeutic equivalence of the Test formulation, generic Estradiol Vaginal Cream United States Pharmacopoeia (USP), 0.01% (Teva Pharmaceuticals, United States of America) to the marketed product, Estrace® Cream estradiol vaginal cream USP, 0.01% (Warner Chilcott) in participants with atrophic vaginitis; to demonstrate the superiority of the Test and Reference (active) treatments over Placebo (vehicle) cream in participants with atrophic vaginitis; and to compare the safety of Test, Reference, and Placebo treatments in participants with atrophic vaginitis.

Detailed description:
Systemic (oral or transdermal patch administration) estrogen therapies have been shown to effectively treat symptoms of atrophic vaginitis but bear undesirable side effects including increased risk of heart attacks, stroke, endometrial cancer, and breast cancer. Topical therapies (creams and transvaginal delivery systems) provide low doses of estrogen to the vaginal mucosa to provide local relief for the symptoms of atrophic vaginitis, while reducing the unwanted side effects associated with systemic delivery systems. Low dose, topical estrogen therapy is considered most appropriate and convenient for the treatment of vaginal symptoms associated with menopause, particularly when other symptoms including bone loss or vasomotor dysfunction do not need to be targeted.

Arms: arm 1: Participants were to self-administer 2 grams (g) of generic Estradiol Vaginal Cream USP, 0.01% once daily at approximately the same time of the day for 7 consecutive days. arm 2: Participants were to self-administer 2 g of Estrace Vaginal Cream USP, 0.01% once daily at approximately the same time of the day for 7 consecutive days. arm 3: Participants were to self-administer 2 g of vehicle vaginal cream once daily at approximately the same time of the day for 7 consecutive days.
Interventions: intervention 1: Generic Estradiol Vaginal Cream USP, 0.01% intervention 2: Estrace® Vaginal Cream USP, 0.01% intervention 3: Vehicle Vaginal Cream
Intervention descriptions: intervention 1: Vaginal cream, generic formulation of the brand product. intervention 2: Vaginal cream, brand product. intervention 3: Vaginal cream, placebo. Has no active ingredient

Protocol documents:
Prot_001.pdf: 
 
 
 
 
Clinical Study Protocol with Revision 01 
 
 
A Randomized, Double-Blind, Placebo-Controlled, Parallel Design, Multiple-Site Study to 
Evaluate the Therapeutic Equivalence of Estradiol Vaginal Cream USP, 0.01% (Teva 
Pharmaceuticals, USA) to Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner 
Chilcott) in the Treatment of Atrophic Vaginitis 
 
 
Study Number 71436001 
 
NCT03294538 
 
Protocol with Revision 1 Approval Date: 18 April 2016  
 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 1 of 48 
 
 
1.0  
TITLE PAGE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Product 
Estradiol Vaginal Cream USP, 0.01% 
Design 
Randomized Double-Blind, Placebo-Controlled Parallel Design 
Population 
Up to 660 post-menopausal females aged 30-75 years inclusive  
Sponsor 
Teva Pharmaceuticals, USA 
Protocol Number 
71436001 
 Study Number 
71436001 
Protocol Date 
02-11-2015 (Rev 0) 
04-18-2016 Revision 1 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 2 of 48 
 
 
2.0  
KEY STUDY PERSONNEL AND FACILITIES 
 
Sponsor: 
 
Teva Pharmaceuticals, USA 
 
 
 
 
CRO: 
 
 
 
 
 
Sponsor’s Representative: 
 
 
 
 
 
 
 
 
 
CRO representative 
 
 
 
 
 
 
 
 
 
Medical  Monitor: 
 
 
 
 
 
 
 
 
Biostatistician: 
 
 
 
 
 
 
 
 
 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 3 of 48 
 
 
 
 
SIGNATURE PAGE 
 
We, the undersigned, have carefully read this protocol and agree that it contains all the necessary 
information required to conduct the study. The study will be performed according to this protocol 
and all applicable FDA regulations. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
  
 
 
 
 
 
 
 
 
 
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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 4 of 48 
 
 
 
 
PRINCIPAL INVESTIGATOR’S SIGNATURE 
 
I _______________________________________, agree to conduct protocol 71436001 Rev. 0 in 
accordance with FDA regulations, ICH guidelines and Good Clinical Practice. I understand that no 
deviations from the protocol may be made without the prior permission of the Sponsor (Teva 
Pharmaceuticals, USA) or 
 the 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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 5 of 48 
 
 
3.0  
TABLE OF CONTENTS 
 
1.0 
TITLE PAGE .................................................................................................................................... 1 
2.0  
KEY STUDY PERSONNEL AND FACILITIES ............................................................................ 2 
3.0  
TABLE OF CONTENTS .................................................................................................................. 5 
4.0 
SYNOPSIS ........................................................................................................................................ 8 
5.0 
STUDY SCHEMATIC ................................................................................................................... 14 
6.0 
LIST OF ABBREVIATIONS AND TERMS ................................................................................. 15 
7.0  
INTRODUCTION .......................................................................................................................... 16 
7.1 
 Disease Being Treated ............................................................................................................... 16 
7.2 
Availability and Efficacy of Already Approved Therapies ........................................................ 16 
7.3 
Scientific and Statistical Considerations ..................................................................................... 17 
7.4 
Justification for use of Placebo ................................................................................................... 17 
7.5 
Risks and Benefits ....................................................................................................................... 18 
8.0 
STUDY OBJECTIVES ................................................................................................................... 18 
9.0 
INVESTIGATIONAL PLAN ......................................................................................................... 18 
9.1 
Study Design and Plan Description ............................................................................................ 18 
9.2 
Selection of Study Design ........................................................................................................... 20 
9.3 
Selection of Study Population ..................................................................................................... 20 
9.3.1 
Inclusion Criteria................................................................................................................. 20 
9.3.2 
Exclusion Criteria ............................................................................................................... 21 
9.3.3 
Restrictions During the Study ............................................................................................. 22 
9.3.4 
Removal of Patients from the Study ................................................................................... 23 
9.4 
Treatments ................................................................................................................................... 23 
9.4.1 
Treatments Administration ................................................................................................. 23 
9.4.2 
Identity of Investigational Product ...................................................................................... 24 
9.4.3 
Method of Assigning Patients to Treatment Groups ........................................................... 25 
9.4.4 
Study Blind ......................................................................................................................... 25 
9.4.5 
Compliance ......................................................................................................................... 25 
9.5 
Study Conduct ............................................................................................................................. 26 
9.5.1 
Visit 1 (Day -14-Day 1): Screening .................................................................................... 26 
9.5.2  
Visit 2 (Day 1): Randomization .......................................................................................... 26 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 6 of 48 
 
 
9.5.3 
Visit 3 (Day 8+ 1): End of Study/Early Termination .......................................................... 27 
9.6 
Study Procedures ........................................................................................................................ 27 
9.6.1 
Informed Consent ................................................................................................................ 27 
9.6.2 
Demographics ..................................................................................................................... 28 
9.6.3 
Medical History................................................................................................................... 28 
9.6.4 
Vital Signs ........................................................................................................................... 28 
9.6.5 
Physical Exam, Pelvic Exam and Breast Exam .................................................................. 28 
9.6.6 
Rating of Symptoms............................................................................................................ 28 
9.6.7 
Concomitant Medication Use .............................................................................................. 29 
9.6.8 
Laboratory Evaluations ....................................................................................................... 29 
9.6.9 
Vaginal Cytology, pH Testing and PAP smear ................................................................... 29 
9.6.10 
Dosing Instructions and Diary ............................................................................................ 29 
9.6.11 
Dosing Compliance ............................................................................................................. 30 
9.6.12 
Dispensing Study Drug ....................................................................................................... 30 
9.7 
Adverse Events ........................................................................................................................... 30 
9.8 
Serious Adverse Events .............................................................................................................. 32 
9.8.1 
Definition of a Serious Adverse Event ................................................................................ 32 
9.8.2 
Reporting Serious Adverse Events ..................................................................................... 33 
10.0 
STATISTICAL METHODS ........................................................................................................... 35 
10.1 
Statistical Plan ............................................................................................................................. 35 
10.2 
Determination of Sample Size .................................................................................................... 36 
10.3 
Study Populations ....................................................................................................................... 36 
10.4 
Baseline Comparability ............................................................................................................... 37 
10.5 
Efficacy Endpoints ...................................................................................................................... 38 
10.6 
Therapeutic Equivalence Analysis .............................................................................................. 38 
10.7 
Superiority to Placebo Analysis .................................................................................................. 39 
10.8 
Safety Analysis ........................................................................................................................... 39 
11.0 
REGULATORY OBLIGATIONS .................................................................................................. 39 
11.1 
Institutional Review Board ......................................................................................................... 39 
11.2 
Study Documentation .................................................................................................................. 39 
11.2.1 
Protocol ............................................................................................................................... 40 
11.2.2 
Informed Consent ................................................................................................................ 40 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 7 of 48 
 
 
11.2.3 
Protocol and Informed Consent Changes ............................................................................ 40 
11.2.4 
Source Documents and Case Report Forms ........................................................................ 40 
11.2.5 
Drug Accountability ............................................................................................................ 41 
11.2.6 
Drug Storage ....................................................................................................................... 41 
11.2.7 
Reporting Safety Information to the IRB ............................................................................ 41 
11.2.8 
Record Retention................................................................................................................. 41 
11.2.9 
Study Monitoring and Auditing .......................................................................................... 41 
11.2.10 
End of the Trial ............................................................................................................... 42 
11.2.11 
Clinical Study Report ...................................................................................................... 42 
12.0 
REFERENCES ............................................................................................................................... 43 
13.0 
APPENDICES ................................................................................................................................ 44 
 
 
 
 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 8 of 48 
 
 
4.0 
SYNOPSIS 
 
Protocol Number 
71436001 
Title 
A Randomized, Double-Blind, Placebo-Controlled, Parallel Design, Multiple-
Site Study to Evaluate the Therapeutic Equivalence of Estradiol Vaginal 
Cream USP, 0.01% (Teva Pharmaceuticals, USA) to Estrace® Cream (estradiol 
vaginal cream, USP, 0.01%; Warner Chilcott) in the Treatment of Atrophic 
Vaginitis 
Objectives 
1. Evaluate the therapeutic equivalence of the Test formulation, Estradiol 
Vaginal Cream USP, 0.01% (Teva Pharmaceuticals, USA) to the marketed 
product, Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner 
Chilcott) in patients with atrophic vaginitis. 
2. Demonstrate the superiority of the Test and Reference (active) treatments 
over Placebo (vehicle) cream in patients with atrophic vaginitis. 
3. Compare the safety of Test, Reference and Placebo treatments in patients 
with atrophic vaginitis. 
Sponsor 
Teva Pharmaceuticals, USA 
Study Products 
• 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
• 
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner 
Chilcott) 
• 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
Study products will be supplied in tubes, with a calibrated plastic applicator for 
dose (2g) administration.  
Route of 
Administration 
Topical (Vaginal) 
Treatment 
Randomization 
2:2:1 (Test: Reference: Placebo) 
Patient  
Population 
Up to 660 healthy post-menopausal females aged 30-75 years inclusive with 
symptoms of vulvar and vaginal atrophy and no contraindication to estrogen 
therapy. 
Study Design 
Randomized, Double-Blind, Placebo-Controlled, Parallel Design 
Study Conduct 
Patients will administer study medication once daily for 7 days. Patients will 
visit the clinical center for a total of 3 scheduled visits:  
1. Visit 1/Screening (Day -14 to Day -1) 
2. Visit 2/Randomization (Day 1) 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 9 of 48 
 
 
3. Visit 3/End of Study (Day 8 + 1)  
Inclusion Criteria 
1. Signed Informed Consent that meets all criteria of current FDA 
regulations. 
2. Females aged 30-75 years inclusive who are postmenopausal, defined as 
follows: 
a. At least 12 months of spontaneous amenorrhea or 6 months of 
spontaneous amenorrhea with serum FSH level of > 40mIU/ml. 
b. At least 6 weeks post-surgical bilateral oophrectomy, with or 
without hysterectomy 
c. Hysterectomy without oophorectomy if of age that investigator 
believes would have naturally reached 12 months of spontaneous 
amenorrhea if uterus had remained intact.. 
3. Have ≤5% superficial cells on vaginal smear cytology. 
4. Vaginal pH > 5.0. 
5. At least one of the following patient self-assessed moderate to severe 
symptoms of vulvar and vaginal atrophy (VVA) from the following list 
that is identified by the patient as being most bothersome to her: 
a. Vaginal Dryness 
b. Vaginal and/or Vulvar Irritation/Itching 
c. Dysuria 
d. Vaginal Pain associated with sexual activity 
e. Vaginal Bleeding associated with sexual activity* 
*provided that patient is currently sexually active and plant to 
remain so throughout study. 
6. “Normal” Screening mammogram completed within 9 months before 
screening in all patients > 40 years old. 
7. Normal clinical breast examination at the Screening Visit. 
8. 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. 
9. Patients with an intact uterus should have vaginal ultrasonography results 
to confirm an inactive endometrial lining, defined as endometrial thickness 
less than  4 mm. 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 10 of 48 
 
 
Exclusion Criteria 
1. Females younger than 30 years of age or older than 75 years of age. 
2. Patients with a serum FSH level of ≤ 40mIU/ml at screening. 
3. Greater than 5% superficial cells on vaginal cytology. 
4. Vaginal pH ≤ 5. 
5. 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. 
6. Patients with an intact uterus should have vaginal ultrasonography results 
to confirm an inactive endometrial lining. Patients with an endometrial 
thickness 4 mm and greater should be excluded. 
7. Documented PAP smear conducted within the previous 12 months with 
findings that the Investigator believes would contraindicate the use of 
topical vaginal estradiol. 
8. Patients with known concurrent vaginal infections including but not 
limited to: Candida albicans, Trichomonas vaginalis, Chlamydia 
trachomatis, Neisseria gonorrhea or Gardnerella vaginalis. 
9. Patients with active vaginal herpes simplex infection or have had an 
outbreak within 30 days of the first dosing day. 
10. Patients with known, suspected or current history of carcinoma of the 
breast.  All patients over the age of 40 must have had a mammogram 
performed within 9 months of the study start and all patients will have a 
physical breast exam performed at screening. 
11. Patients with known, suspected or current history of hormone dependent 
tumor. 
12. Patients with baseline systolic blood pressure of > 150 mm Hg and/or 
diastolic pressure > 90 mm Hg. 
13. Any patient with undiagnosed vaginal bleeding or significant risk factors 
for endometrial cancer. 
14. Any history of estrogen-dependent neoplasia (e.g., endometrial cancer). 
15. History of acute thrombophlebitis or thromboembolic disorder. 
16. Any current or recent (within the previous 6 months) genital bleeding of 
unknown etiology. 
17. Any prescription treatment or over-the-counter or natural remedies for 
vaginal dryness/irritation within 28 days of screening. Products used for 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 11 of 48 
 
 
lubrication during sexual intercourse within 7 days of screening. 
18. Patients whose fasting triglyceride levels are greater than 350 mg/dL. 
19. Any patient with a history of radiation therapy or recent (within previous 6 
weeks) surgical therapy to the vaginal or cervical areas. 
20. Any known or suspected allergies that in the Investigator’s opinion would 
compromise the safety of the patient.  
21. Patients who have used vaginal hormonal products (rings, creams, gels) 
within the 28 days before screening. 
22. Any patient who has used transdermal estrogen and/or progestin therapy 
within the 28 days before screening. 
23. Patients who have used oral estrogen and/or progestin therapy or 
intrauterine progestin therapy within the 56 days before screening. 
24. Patients who have used progestin implants or estrogen alone injectable 
drug therapy within the 3 months before the screening. 
25. Patients who have used estrogen pellet therapy or progestin injectable drug 
therapy within the 6 months before screening.  
26. Patients who, in the opinion of the Investigator, would be non-compliant 
with the requirements of the study protocol. 
27. Patients who are unable or unwilling to give informed consent. 
28. Receipt of any drug as part of a research study within 30 days before 
screening. 
29. Patients who have participated in this study previously.  
Efficacy 
Endpoints 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of patients in the Per Protocol 
(PP) population that are identified as “Responders” at the end of the treatment 
period evaluated on Day 8 + 1.  
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 the PP 
population that are identified as “Treatment Success” at the end of the 
treatment period evaluated on Day 8 + 1.  
A “Treatment Success” is defined as a score of 0 or 1 at Day 8 + 1 for the 
symptom identified at baseline as the most bothersome.  This evaluation is to 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 12 of 48 
 
 
be based on patient self-assessed symptoms of vulvar and vaginal atrophy on a 
scale of 0 to 3 where 0 = none and 3 = severe. Refer to Appendix B for rating 
scales.  
 
Safety Parameters  
Adverse events will be classified using standard MedDRA terminology and 
summarized by treatment group. Summary tables comparing the type, 
incidence, severity and Investigator’s opinion of relationship to the study drug 
will be prepared by treatment group. Signs and symptoms of atrophic vaginitis 
will not be considered adverse events, 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 atrophic vaginitis. .  
If sufficient data exist, adverse event frequencies will be compared between 
treatments using Fisher’s exact test or a similar test. Concomitant medication 
use during the randomized treatment period will be tabulated by patient. 
Adverse events reported during the study will be tabulated in a summary table 
listing the type, incidence, severity and Investigator’s opinion to drug 
relationship. 
Evaluation of 
Therapeutic 
Equivalence and 
Superiority 
Therapeutic Equivalence: 
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. 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. 
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). 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 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 13 of 48 
 
 
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 endpoint will be conducted for 
supportive information.  
Superiority: 
Superiority of the Test and Reference products against the Placebo for primary 
and secondary endpoints will be tested at the 5% significance level (p < 0.05; 
using two-sided, continuity-corrected Z-test) in the modified Intent-to-Treat 
(mITT) population using last observation carried forward. The superiority of 
Test and Reference treatments over the Placebo will be evaluated identically in 
separate Z-Test analyses. 
Sample Size 
Determination 
The primary statistical analysis of interest is the proportion of patients in the 
Per Protocol (PP) population that are identified as “Responders” at the end of 
the treatment period evaluated on Day 8 + 1. 
 
 
 
 
 
, a sample size of 224 patients per active group in the PP population
 
(i.e., the 90% 
confidence interval (Yates’ continuity-corrected) of the absolute difference 
between the Test and Reference “Responder” rate rates is within a defined 
equivalence range [-20%, +20%]).  
 
 
. Using a 2:1 
(active: placebo) randomization scheme, and assuming the conversion rate 
from mITT to PP will be about 90%, 250 patients in each of active groups and 
125 patients in the placebo group of the mITT population 
 
.  
 
 
 To allow for 
about 5% of patients who may drop out from the study or are otherwise non-
evaluable, up to 660 patients may be randomized to obtain 625 patients in the 
mITT population (i.e., 250 in each active group and 125 in the Placebo group). 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 14 of 48 
 
 
5.0 
STUDY SCHEMATIC 
 
 
Visit 1 
Screening 
(Day -14 to Day-1) 
Visit 2 
Randomization 
(Day 1) 
Visit 3 
End of Study 
(Day 8 + 1) or 
Early 
Termination 
Informed Consent 
X 
 
 
Demographics 
X 
 
 
Medical History 
X 
X 
 
Inclusion/Exclusion Criteria 
Review 
X 
X 
 
Vital Signs 
X 
X 
X 
Rating of Symptoms 
X 
X 
X 
Physical Exam Including 
Pelvic Exam 
X 
 
X 
Breast Exam 
X 
 
X 
Vaginal Cytology and pH 
X 
 
X 
PAP* 
X 
 
 
Serum FSH, Fasting 
Triglycerides 
X 
 
 
Mammogram** 
X 
 
 
Vaginal Ultrasound*** 
X 
 
 
Dispense/Collect  
Study Medication 
 
X 
X 
Dispense, Collect, Review 
Patient Diary 
 
X 
X 
Adverse Events 
 
 
X 
Concomitant Medications 
X 
X 
X 
* Patients who do not have documentation of a PAP smear completed within the last 12 months. 
**Patients over the age of 40 who do not have documentation of a mammogram completed within the 9 months 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 
 
 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 15 of 48 
 
 
6.0 
LIST OF ABBREVIATIONS AND TERMS 
 
Abbreviation Term 
AE 
Adverse Event 
ANDA 
Abbreviated New Drug Application 
C 
Celsius 
CRF  
Case Report Form 
CRO  
Clinical Research Organization 
eCTD 
electronic Common Technical Document 
F 
Fahrenheit 
FDA  
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
g 
gram 
GCP 
Good Clinical Practices 
ICF  
Informed Consent Form 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities  
mITT 
Modified Intent-to-Treat 
ml 
milliliter 
NDA  
New Drug Application 
OHRP 
Office of Human Rights Protection 
OTC  
Over-the-Counter 
PAP 
Papanicolaou 
PP 
Per Protocol 
SAE  
Serious Adverse Event 
SAP 
Statistical Analytical Plan 
SAS 
Statistical Analysis Software 
USA  
United States of America 
USP 
United States Pharmacopeia 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 16 of 48 
 
 
7.0  
INTRODUCTION 
7.1 
 Disease Being Treated 
Female menopause is generally characterized by various signs and symptoms associated 
with the age-related decline in reproductive hormone levels. There are many indications 
associated with the reduction in circulating estrogen levels, one of the most common 
being atrophic changes in the vaginal mucosa.1 Up to 40% of postmenopausal women 
have symptoms of atrophic vaginitis. Despite the prevalence of this condition, only 20-
25% of symptomatic women seek medical help. Therefore, this condition presents a 
significant opportunity for improving the quality of life of a large patient population.2-4 
Vaginal atrophy, also called atrophic vaginitis, is thinning, drying and inflammation of 
the vaginal walls due to a long-term and significant decline in circulating estrogen levels 
(~18 pg/ml) in the body.2 Menopause has been shown to be the leading cause of this 
condition. However, in non-menopausal women, atrophic vaginitis can result from 
interruption of ovarian estrogen production by radiation therapy, chemotherapy, 
oophorectomy or immunologic disorders. Various medications can also cause or 
contribute 
to 
vaginal 
atrophy, 
including 
tamoxifen, 
danazol 
(Danocrine®), 
medroxyprogesterone acetate, leuprolide (Lupron®), and nafarelin acetate (Synarel®).2 
Symptoms of atrophic vaginitis include vaginal dryness, burning, irritation and 
leukorrhoea. A cytologic examination of a vaginal smear is typically used to confirm 
atrophy. Patients with positive diagnosis exhibit a decreased proportion (< 5%) of 
superficial (mature, protective) cells, compared to 30-60% in healthy pre-menopausal 
females. There is also a corresponding increase in intermediate and basal/parabasal 
(immature, fragile) cells. Moreover, patients also exhibit an increase in vaginal pH from a 
usually acidic (pH 3.5-4.0) to neutral (pH 6.0-8.0). This environment is more favorable 
for the growth of vaginal infections, which potentially exacerbate symptoms of atrophic 
vaginitis.2,4 
7.2 
Availability and Efficacy of Already Approved Therapies 
Over the Counter (OTC) vaginal moisturizers and water-based lubricants are considered 
the first line of therapy for atrophic vaginitis. For the more advanced and chronic cases, 
topical (vaginal) or oral estrogen therapy is often considered. There are a number of 
prescribed estrogen replacement therapies, approved by the Food and Drug 
Administration (FDA) for the treatment of atrophic vaginitis, including oral tablets 
(Estrace®, Femtrace®), transdermal patches (Vivelle-Dot®), transvaginal rings (Estring®), 
vaginal tablets (Vagifem®) and vaginal creams (Estrace® Premarin®).1,2 
Systemic (oral/transdermal patch) estrogen therapies have been shown to effectively treat 
symptoms of atrophic vaginitis, but bear undesirable side effects including increased risk 
of heart attacks, stroke, endometrial cancer and breast cancer.5,6 Topical therapies 
(creams, transvaginal delivery systems) provide low doses of estrogen to the vaginal 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 17 of 48 
 
 
mucosa to provide local relief for the symptoms of atrophic vaginitis, while reducing the 
unwanted side effects associated with systemic delivery systems.7, 8 
Low dose, topical estrogen therapy is considered most appropriate and convenient for the 
treatment of vaginal symptoms associated with menopause, particularly when other 
symptoms including bone loss or vasomotor dysfunction do not need to be targeted.8,9 
7.3 
Scientific and Statistical Considerations 
Estrogen therapy has been demonstrated to significantly increase the percentage of 
superficial cells in the vagina. This increase in the percentage of superficial cells along 
with a corresponding decrease in parabasal and intermediate cells has been demonstrated 
to be an accurate and reliable indicator of the status of estrogen levels in the vaginal wall, 
hence a measure of therapeutic efficacy of estradiol cream in the treatment of atrophic 
vaginitis. Cytologic assessment of cell samples from the lateral vaginal wall can be used 
to calculate the number/proportion of superficial, intermediate and parabasal cells. 
Elevated vaginal pH (pH > 5), monitored by a pH strip in the vaginal cavity, has also 
been shown to be a reliable indicator of vaginal atrophy. 2,5,7-10  
Clinical studies conducted as a part of the NDA (# 020216) for a similar product, 
Premarin® Vaginal Cream, 0.625 mg/g (Wyeth-Ayerst Laboratories) indicated that there 
was a significant increase (26%) in the number of superficial cells at Week 12 (once daily 
application), compared to baseline. There was also a 58% decrease in the number of 
parabasal cells, and a significant mean reduction in vaginal pH (-1.57) compared to 
baseline. Placebo response rates for were 1% and 7% for superficial cells and parabasal 
cells respectively, and -0.26 for vaginal pH.11 
This study is designed per recommendations from two FDA draft guidances.12,13 The 
FDA Draft Guidance for Estradiol 0.01% vaginal cream (September 2014) recommends a 
primary endpoint of the study as the proportion of patients in the per protocol (PP) 
population that are identified as responders at the end of the treatment period. A 
responder is to be 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 0.5.13 The study population is 
based on the FDA draft guidance for Industry, Estrogen and Estrogen/Progestin Drug 
Products to Treat Vasomotor Symptoms and Vulvar and Vaginal Atrophy (January 
2003).12 
7.4 
Justification for use of Placebo 
To confirm the sensitivity of a clinical endpoint study to differentiate between two 
possibly bio-inequivalent products (i.e., to prevent a false positive result of 
bioequivalence) OGD/FDA recommends that a placebo group be included in such 
studies.14-16 In addition to the Test product demonstrating therapeutic equivalence to the 
Reference product, both the Test and Reference products should demonstrate statistically 
superior to the Placebo group. 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 18 of 48 
 
 
Eligible patients will have a 20% chance of being randomized to Placebo (2:2:1 
randomization scheme). There will be 132 patients randomized to the Placebo group, 
 
 
 
7.5 
Risks and Benefits 
The risks and benefits to patients enrolled in clinical research studies that include a 
placebo treatment group must be carefully considered based on three main criteria, 
namely: the disease being treated, the availability, efficacy and safety of already 
approved therapies, and the scientific and statistical requirements of the desired outcome 
of the research study. The Office of Human Rights Protection (OHRP), a Division of the 
USA Federal Government’s Department of Health and Human Services, 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 + 1 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. 
 
 
8.0 
STUDY OBJECTIVES 
1. Evaluate the therapeutic equivalence of the Test formulation, Estradiol Vaginal Cream USP, 
0.01% (Teva Pharmaceuticals, USA) to the marketed product, Estrace® Cream (estradiol 
vaginal cream, USP, 0.01%; Warner Chilcott)  in patients with atrophic vaginitis. 
2. Demonstrate the superiority of the Test and Reference (active) treatments over Placebo 
(vehicle) cream in patients with atrophic vaginitis. 
3. Compare the safety of Test, Reference and Placebo treatments in patients with atrophic 
vaginitis. 
 
9.0 
INVESTIGATIONAL PLAN 
9.1 
Study Design and Plan Description 
This randomized, double-blind, placebo-controlled, parallel group, multi-site study has been 
designed to evaluate the therapeutic efficacy and safety of a generic Estradiol Vaginal Cream 
USP, 0.01% (Teva Pharmaceuticals, USA) compared to the FDA Reference Listed Drug (RLD), 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 19 of 48 
 
 
Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) in patients with atrophic 
vaginitis. Additionally, both the Test and Reference products will be tested for superiority against 
a Placebo.  
Following the 14-day screening period, patients who continue to meet the inclusion/exclusion 
criteria will be randomized in a 2:2:1 ratio (Test: Reference: Placebo) for 7 days of treatment. Up 
to 660 eligible postmenopausal female patients with atrophic vaginitis patients will be 
randomized, to obtain an mITT population with an estimated 250 patients in each of the active 
treatment groups and 125 in the Placebo treatment group.  
Before any study-specific procedures are performed, all patients will read and sign the IRB-
approved informed consent document.  
To qualify for inclusion in the study, patients must be between the ages of 30-75 inclusive, 
postmenopausal with atrophic vaginitis assessed as moderate to severe using vaginal cytology, 
vaginal pH and patient-rated signs and symptoms. Patients cannot currently be undergoing 
treatment for atrophic vaginitis.  Patients will only be eligible to participate in the study on one 
occasion and cannot have participated in another clinical research study within 30 days of being 
screened for this study. 
At Visit 2 (Randomization), each qualified patient will be randomly assigned to one of the 
following treatment groups in a 2:2:1 ratio: 
• 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
• 
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
• 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
Study medication will be self-administered by the patient for 7 days according to the dosing 
instructions provided. Each patient will be required to dose once a day at approximately the same 
time of day for 7 consecutive days.  
During the study patients will visit the research center for a total of 3 scheduled visits:  
• 
Visit 1/Screening (Day -14 to Day -1) 
• 
Visit 2/Randomization (Day 1) 
• 
Visit 3/End of Study (Day 8+ 1) 
Vaginal cytology and vaginal pH determination will be performed as a part of clinical evaluation 
at Visits 1 and 3. Visit 3 is to be scheduled on the day following the last day of dosing. 
The primary efficacy endpoint is the proportion of patients in the per protocol (PP) population 
that are identified as “Responders” at the end of the treatment period evaluated on Day 8 + 1. 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.  


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 20 of 48 
 
 
9.2 
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 Vulvar and Vaginal 
Atrophy (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 and any communications with OGD/FDA on how they would like such data 
analyzed. 12-16,18 
 
9.3 
Selection of Study Population 
9.3.1 
Inclusion Criteria 
1. Signed Informed Consent that meets all criteria of current FDA regulations. 
2. Females aged 30-75 years inclusive who are postmenopausal, defined as follows: 
a. At least 12 months of spontaneous amenorrhea or 6 months of spontaneous 
amenorrhea with serum FSH level of > 40mIU/ml. 
b. At least 6 weeks post-surgical bilateral oopohrectomy, with or without 
hysterectomy. 
c. Hysterectomy without oophorectomy if of age that investigator believes 
would have naturally reached 12 months of spontaneous amenorrhea if uterus 
had remained intact. 
3. Have ≤ 5% superficial cells on vaginal smear cytology. 
4. Vaginal pH > 5.0. 
5. At least one of the following patient self-assessed moderate to severe symptoms of 
vulvar and vaginal atrophy (VVA) from the following list that is identified by the 
patient as being most bothersome to her: 
a. Vaginal Dryness 
b. Vaginal and/or Vulvar Irritation/Itching 
c. Dysuria 
d. Vaginal Pain associated with sexual activity 
e. Vaginal Bleeding associated with sexual activity* 
*provided that patient is currently sexually active and plant to remain so 
throughout study. 
6. “Normal” Screening mammogram completed within 9 months before screening in all 
patients > 40 years old. 
7. Normal clinical breast examination at the Screening 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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 21 of 48 
 
 
8. 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. 
9. Patients with an intact uterus should have vaginal ultrasonography results to confirm 
an inactive endometrial lining, defined as endometrial thickness less than 4 mm. 
9.3.2 
Exclusion Criteria 
1. Females younger than 30 years of age or older than 75 years of age. 
2. Patients with a serum FSH level of ≤ 40mIU/ml at screening. 
3. Greater than 5% superficial cells on vaginal cytology. 
4. Vaginal pH ≤ 5 
5. 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. 
6. Patients with an intact uterus should have vaginal ultrasonography results to confirm 
an inactive endometrial lining. Patients with an endometrial thickness 4 mm and 
greater should be excluded. 
7. Documented PAP smear conducted within the previous 12 months with findings that 
the Investigator believes would contraindicate the use of topical vaginal estradiol. 
8. Patients with known concurrent vaginal infections including but not limited to: 
Candida albicans, Trichomonas vaginalis, Chlamydia trachomatis, Neisseria 
gonorrhea or Gardnerella vaginalis. 
9. Patients with active vaginal herpes simplex infection or have had an outbreak within 
30 days of the first dosing day. 
10. Patients with known, suspected or current history of carcinoma of the breast.  All 
patients over the age of 40 must have had a mammogram performed within 9 months 
of the study start and all patients will have a physical breast exam performed at 
screening. 
11. Patients with known, suspected or current history of hormone dependent tumor. 
12. Patients with baseline systolic blood pressure of > 150 mm Hg and/or diastolic 
pressure > 90 mm Hg. 
13. Any patient with undiagnosed vaginal bleeding or significant risk factors for 
endometrial cancer. 
14. Any history of estrogen-dependent neoplasia (e.g., endometrial cancer). 
15. History of acute thrombophlebitis or thromboembolic disorder. 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 22 of 48 
 
 
16. Any current or recent (within the previous 6 months) genital bleeding of unknown 
etiology. 
17. Any prescription treatment or over-the-counter or natural remedies for vaginal 
dryness/irritation within 28 days of screening. Products used for lubrication during 
sexual intercourse within 7 days of screening. 
18. Patients whose fasting triglyceride levels are greater than 350 mg/dL. 
19. Any patient with a history of radiation therapy or recent (within previous 6 weeks) 
surgical therapy to the vaginal or cervical areas. 
20. Any known or suspected allergies that in the Investigator’s opinion would 
compromise the safety of the patient.  
21. Patients who have used vaginal hormonal products (rings, creams, gels) within the 28 
days before screening. 
22. Any patient who has used transdermal estrogen and/or progestin therapy within the 
28 days before screening. 
23. Patients who have used oral estrogen and/or progestin therapy or intrauterine 
progestin therapy within the 56 days before screening. 
24. Patients who have used progestin implants or estrogen alone injectable drug therapy 
within the 3 months before the screening. 
25. Patients who have used estrogen pellet therapy or progestin injectable drug therapy 
within the 6 months before screening.  
26. Patients who, in the opinion of the Investigator, would be non-compliant with the 
requirements of the study protocol. 
27. Patients who are unable or unwilling to give informed consent. 
28. Receipt of any drug as part of a research study within 30 days before screening. 
29. Patients who have participated in this study previously. 
 
9.3.3 
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, over-the-counter 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 medication (e.g., vaginal antifungals). 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 23 of 48 
 
 
9.3.4 
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 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. The 
clinical report will include all reasons for early withdrawals. 
All patients who are randomized and receive study medication will be included in the safety 
analysis comparing the Test/Reference/Placebo. If a randomized patient terminates from the study 
early, all efforts will be made to complete the end of study procedures. Patients who are not 
randomized and thus do not receive study drug, do not need end of study procedures performed. 
In case of early termination the Investigator shall fully document the reason for early termination. 
Reasons for early termination may include the following: 
• 
Patient withdrew consent. 
• 
Significant adverse event that led the Investigator 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). 
• 
Pregnancy. 
• 
Significant worsening of atrophic vaginitis such that the Investigator 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 study. 
9.4 
Treatments 
9.4.1 
Treatments Administration 
Patients will be provided with verbal and written instructions on how to administer the 
study medication. Patients will be required to self-administer 2 grams of study 
medication once daily at approximately the same time of the day, for 7 consecutive days. 
The patients last dose should occur the day before visit 3.  The patient 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 g) 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 
medication, 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. 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 24 of 48 
 
 
9.4.2 
Identity of Investigational Product 
The following products will be used in this study: 
• 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
• 
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner 
Chilcott)  
• 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
All randomized study product will be blinded and packaged in sealed boxes. Each box of 
Reference product will contain a tube containing 42.5 g of study product (cream) and a 
calibrated plastic applicator for dose (2 g) administration, and each box of Test product 
will contain a tube containing 44 g of study product (cream) and a calibrated plastic 
applicator for dose (2 g) administration. Each tube will be identified by a label bearing 
the Sponsor name, protocol number, randomization number, treatment duration and a 
statement that the study medication is for Investigational Use Only. A corresponding 
label including the same randomization number will be attached to the patient’s source 
document.  
The study staff will dispense the study medication box only to those patients identified by 
the Investigator.  The study staff will instruct the patients on the use and return of study 
drug.  The patient will be instructed not to discuss the appearance of the study medication 
tube with any study personnel conducting the study visits i.e., the Investigator(s) or the 
Study Coordinator(s).  
 
 
  
 
The study medication will be shipped to each Investigator’s site from a centralized 
pharmacy.  The Principal Investigator at each site is responsible for ensuring that all 
study medications are stored in a locked, secure location, with access limited to the 
Investigator and his/her designee(s).  An accurate inventory of the study medication will 
be maintained in accordance with federal regulations.  
 
 
 
 
 
Once the site has been notified that they may do so, all unused study medication and 
empty or partially used tubes of study medication may be returned to the Sponsor or 
designee. 
Storage Conditions: Study medication is to be stored in a secure, locked location, at 
room temperature, protected from temperatures in excess of 40ºC (104ºF). 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 25 of 48 
 
 
9.4.3 
Method of Assigning Patients to Treatment Groups 
The study drug will be randomized, packaged and blinded by an independent packaging 
company. Randomization will be pre-planned according to a computer-generated 
randomization schedule.
 
 Each 
patient will be provided with one patient kit, containing 1 tube of study medication. 
Each patient will receive a screening number at Visit 1, which will be recorded in the 
patient’s CRF. At Visit 2, eligible patients will receive a randomization number (based on 
treatment assigned), which will be recorded in the CRF. 
 
. Patients will be randomized to a treatment regimen by 
assigning treatments in sequential order. At the end of the study, after all the clinical data 
has been entered and the study database has been locked, a copy of the randomization 
will be sent to the statistician. 
9.4.4 
Study Blind 
The Investigator, staff at the study site, study monitors, and data analysis/management 
personnel will be blinded to the patient assignment. To maintain the Investigator-Blind, 
the Independent Dispenser will be responsible for dispensing and collecting study 
medication.  The patient will be requested not to discuss the appearance of the study 
medication with the Investigator or study staff.  
Each study site will have at least one Independent Dispenser. The role of the Independent 
Dispenser is to dispense and collect all study medication from the patients and to ensure 
the study medication logs are completed. They should not be involved in collecting any 
efficacy data in the study thus ensuring the integrity of the study blind.  
To ensure information that could potentially bias handling of data is not disclosed at 
clinical sites, a third party will hold the randomization scheme until after database lock. 
For each patient an individual code break card describing the actual treatment will be 
provided with the study medication, to be un-blinded only in the case of medical 
emergency and should be kept at the site with the study documents until the study is 
completed. Whenever possible, the 
 Medical Monitor must be contacted before 
breaking the blind for any patient. The code break cards should be stored in a secure 
location at all times and maintained at the site for all randomized patients after the 
completion of the study. 
At the conclusion of the study, after the database has been locked, each site will be sent 
an envelope containing the full study randomization scheme that should be retained with 
the study documents in case needed during an FDA Inspection. 
9.4.5 
Compliance 
Patients will be provided with a diary to record the time and date of dosing, other 
concomitant medications and adverse events. A single dose is defined as application of 2 
g cream. Patients administering fewer than 75% (i.e., < 6), or more than 125% (i.e., > 8) 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 26 of 48 
 
 
of the required doses, or who missed > 1 dose will be considered non-compliant with 
dosing. Compliance with dosing will be verified by the use of the patient diaries. 
 
9.5 
Study Conduct  
9.5.1 
Visit 1 (Day -14-Day 1): Screening 
1. Informed Consent: Patients, who are willing to comply with study procedures will read, 
understand and sign the informed consent as appropriate. 
2. Medical History and Baseline Demographics: Patient’s demographic and medical 
history including concomitant medication use within the last 6 months will be reviewed. 
3. Vital Signs: Blood pressure, pulse, temperature and respiration rate will be recorded for 
each patient. 
4. Inclusion/Exclusion: Confirm the patient meets all inclusion/exclusion criteria. 
5. Symptom Rating: Patients will be asked to complete a rating scale to record severity of 
signs and symptoms for atrophic vaginitis. Refer to Appendix A. 
6. Physical and Pelvic Examination: A general physical exam, including a pelvic 
examination will be conducted to determine overall patient health. Refer to section 9.6.5. 
7. Vaginal Ultrasound: A vaginal ultrasound will be performed for patients with an intact 
uterus. 
8. Breast Exam: A physical breast examination will be conducted. 
9. Mammogram: Results from a mammogram performed within the last 9 months will be 
obtained. If unavailable, then a mammography will be scheduled. 
10. Vaginal Cytology and pH: A specimen will be obtained for vaginal cytology and 
vaginal pH testing will be performed. Refer to section 9.6.9.  
11. PAP smear: Obtain the results of a PAP smear conducted within the last 12 months or 
conduct a PAP smear during the pelvic exam. 
12. Blood Sample: Collect a fasted blood sample for laboratory testing (FSH and 
Triglycerides). Refer to Appendix A and Section 9.6.8. 
13. Schedule Visit 2. 
 
9.5.2  Visit 2 (Day 1): Randomization 
1. Medical History: Patient’s medical history including concomitant medication use since 
last visit will be reviewed. 
2. Inclusion/Exclusion: Confirm the patient meets all 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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 27 of 48 
 
 
3. Vital Signs: Blood pressure, pulse, temperature and respiration rate will be recorded.  
4. Symptom Rating: Patients will be asked to complete a rating scale to record severity of 
signs and symptoms for atrophic vaginitis. Refer to Appendix A. 
5. Dispense study medication, applicator, instructions and patient diary to patients eligible 
for randomization. 
6. Schedule Visit 3. 
 
9.5.3 
Visit 3 (Day 8+ 1): End of Study/Early Termination 
The patient should not dose on the day of Visit 3.  Visit 3 is to be scheduled the day after 
the last day of dosing. 
1. Concomitant Medications: Patient diary will be reviewed for concomitant medication 
use since last visit. 
2. Adverse Events: Patient diary will be reviewed and patients questioned about adverse 
events since last visit. 
3. Vital Signs: Blood pressure, pulse, temperature and respiration rate will be recorded.  
4. Symptom Rating: Patients will be asked to complete a rating scale to record severity of 
signs and symptoms for atrophic vaginitis. See Appendix A. 
5. Physical and Pelvic Examination: A general physical exam, including a pelvic 
examination will be conducted to determine overall patient health.  
6. Breast Exam: A physical breast examination will be conducted. 
7. Vaginal Cytology and pH: A specimen will be obtained for vaginal cytology and 
vaginal pH testing will be performed. See section 9.6.9. 
8. Collect Study Product: Empty/used/unused tubes of study medication and applicators 
will be collected for accountability 
9. Review Diary: Dosing compliance will be reviewed based on patient diary 
10. Review completeness of all source documents and discharge from the study. 
9.6 
Study Procedures 
9.6.1 
Informed Consent 
No patient will be entered into the study without reading, understanding, and signing an 
informed consent. For illiterate patients, verbal consent should be obtained in the 
presence of and be countersigned by a literate witness. If any other language is required, 
translation will be performed by a certified translator.  


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 28 of 48 
 
 
9.6.2 
Demographics 
At Visit 1 each patient shall be required to provide basic demographic information 
including date of birth, gender, ethnicity and race. 
9.6.3 
Medical History 
At Visit 1 patients will be questioned about medical history, including acute and chronic 
medical history and medical history relevant to their vaginal atrophy, as well as all 
concomitant medication use within the previous 6 months. At Visit 2 medical history will 
be reviewed and updated if changes have occurred. 
9.6.4 
Vital Signs 
The patient’s vital signs will be recorded (pulse, blood pressure, temperature and 
respiration rate) at Visits 1, 2 and 3.  At Screening and Randomization blood pressure 
reading cannot exceed 150/90 to qualify for randomization. 
9.6.5 
Physical Exam, Pelvic Exam and Breast 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 and 
breast exams, any negative findings on exam should be reported as Adverse Events. 
9.6.6 
Rating of Symptoms 
At Visits 1, 2 and 3 the blinded clinical staff or Investigator will question the patient 
regarding the severity of their atrophic vaginitis 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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 29 of 48 
 
 
The worsening in severity of the signs and symptoms need not be additionally included as 
an adverse event, unless the patient requires additional treatment or the condition is an 
AE in the opinion of the Investigator. 
9.6.7 
Concomitant Medication Use 
All concomitant medication use within 6 months of Visit 1 and throughout the study will 
be recorded. 
9.6.8 
Laboratory Evaluations 
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 > 
40mIU/ml to be eligible for participation in the study. 
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. 
9.6.9 
Vaginal Cytology, pH Testing and PAP smear 
At Visits 1 and 3, a vaginal cytology specimen will be collected by scraping the right and 
left lateral vaginal walls (mid-way between the fornix and introitus) with a spatula. The 
cells and mucus will be mixed and fixed according to the instructions provided by the 
central laboratory. Samples will be sent to the central laboratory for cytology testing.  
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 study is completed.  
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. All 
Investigators will use the same type of provided pH paper (e.g., pHEM-ALERT, Gynex 
Corporation). pH paper should be able to read at a minimum 0.5 unit of pH changes.  
At Visit 1 Patients 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 (ACM Medical Lab., 
Inc.) for testing. 
9.6.10 Dosing Instructions and Diary 
Patients will be given a dosing diary with instructions on dosage administration and diary 
completion. Patients will be asked to record the time and date of each dose, AEs, and 
concomitant medications throughout the study. The diary will be reviewed by the study 
staff at Visit 3/end of 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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 30 of 48 
 
 
9.6.11 Dosing Compliance 
Dosing compliance will be checked by site staff at Visit 3 by reviewing patient diary 
entries. Patients will be considered compliant with dosing if they administer 75% (i.e. 6 
doses)-125% (i.e., 8 doses) of the required number of doses, and do not miss more than 1 
dose. 
9.6.12 Dispensing Study Drug 
An Independent Dispenser will dispense randomized study medication at Visit 2 with 
dosing instructions.  The Independent Dispenser will ensure the study medication logs are 
reported correctly.   
9.6.13 Collecting Study Drug 
Study medication tubes will be collected at Visit 3 by the Independent Dispenser . 
9.7 
Adverse Events 
The patients will be monitored throughout the study for any adverse experiences. AEs will be 
collected through both solicited and unsolicited means and subsequently coded in tabular form 
using the MedDRA Version 17.0 or higher adverse event 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 clinic staff based on observation and questioning of the patient. The 
Investigator will judge the relationship of the event to the study treatments. 
Definitions  
An adverse event is any untoward medical occurrence in a clinical investigational patient 
administered a pharmaceutical product, regardless of whether it has a causal relationship with this 
treatment. In this study, any adverse event occurring after the patient has signed the informed 
consent form should be recorded and reported as an adverse event.  
An adverse event can, therefore, be any unfavorable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of the study, or 
significant worsening of the disease under study or of any concurrent disease, whether or not 
considered related to the study drug. A new condition or the worsening of a pre-existing condition 
will be considered an adverse event. Stable chronic conditions (such as arthritis) that are present 
before study entry and do not worsen during the study will not be considered adverse events.  
Abnormal results of diagnostic procedures, including laboratory findings, are considered to be 
AEs if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event (SAE) 
• is associated with clinical signs or symptoms 
• is considered by the physician to be of clinical significance 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 31 of 48 
 
 
This includes events not seen at baseline, or worsened if present at baseline. 
Recording and Reporting Adverse Events 
For adverse event recording, the study period is defined for each patient as that time period from 
signature of the informed consent form through the follow-up period.  For this study, the 
follow-up period is defined as 30 days after the last study visit. 
All adverse events that occur during the defined study period must be recorded on the source 
documentation and transcribed onto the CRF, regardless of the severity of the event or judged 
relationship to the study drug. For serious adverse events, the Serious Adverse Event Form must 
also be completed and the serious adverse event must be reported immediately (see 
Section 9.8.2.). The investigator does not need to actively monitor patients for adverse events 
once the study has ended.  
At each contact with the patient, the investigator or designee must query the patient for adverse 
events by asking an open-ended question. All reported or observed signs and symptoms will be 
recorded individually, except when considered manifestations of a medical condition or disease 
state. A precise diagnosis will be recorded whenever possible. When such a diagnosis is made, all 
related signs, symptoms, and any test findings will be recorded collectively as a single diagnosis 
on the CRF and, if it is a serious adverse event, on the Serious Adverse Event Form. 
The clinical course of each adverse event will be monitored at suitable intervals until resolved or 
stabilized or returned to baseline, or until the patient is referred to the care of a health care 
professional, or until a determination of a cause unrelated to the study drug or study procedure is 
made. 
The onset and end dates, duration (in case of adverse event duration of less than 24 hours), action 
taken regarding study drug, treatment administered, and outcome for each adverse event must be 
recorded on the source documentation and transcribed onto the CRF.  
The relationship of each adverse event to study drug treatment and study procedures, and the 
severity and seriousness of each adverse event, as judged by the investigator, must be recorded as 
described below. 
Severity of an Adverse Event 
The severity of each adverse event must be recorded as 1 of the choices on the following scale: 
Mild:  
 
No limitation of usual activities 
Moderate:  
Some limitation of usual activities 
Severe:   
Inability to carry out usual 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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 32 of 48 
 
 
Causality Assessment of Adverse Events 
The relationship to the study treatment is characterized as: 
TERM 
DEFINITION 
CLARIFICATION 
No 
Reasonable 
Possibility 
(not related) 
This category applies to those 
adverse events which, after careful 
consideration, are clearly due to 
extraneous causes (disease, 
environment, etc.) or to those 
adverse events for which, after 
careful medical consideration at the 
time they are evaluated, are judged 
to be unrelated to the test drug. 
An adverse experience may be considered No 
Reasonable Possibility if it is clearly due to extraneous 
causes or when (must have two): 
 
It does not follow a reasonable temporal 
sequence from the administration of the IMP. 
 
It could readily have been produced by the 
subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered 
to the subject. 
 
It does not follow a known pattern of response to 
the test drug. 
 
It does not reappear or worsen when the drug is 
re-administered. 
Reasonable 
Possibility 
(related) 
This category applies to those 
adverse events which, after careful 
medical consideration at the time 
they are evaluated, are felt with a 
high degree of certainty to be related 
to the IMP. 
An adverse experience may be considered a reasonable 
possibility of being related if or when (at least three of 
the following): 
 
It follows a reasonable temporal sequence from 
administration of the IMP. 
 
It could not be reasonably explained by the 
known characteristics of the subject’s clinical 
state, environmental or toxic factors or other 
modes of therapy administered to the subject. 
 
It disappears or decreases on cessation or 
reduction in dose. There are important 
exceptions when an adverse event does not 
disappear upon discontinuation of the drug, yet 
drug-relatedness clearly exists. 
• 
It follows a known pattern of response to the 
IMP. 
 
9.8 
Serious Adverse Events 
9.8.1 
Definition of a Serious Adverse Event 
A serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes or actions: 
• 
death 
• 
a life-threatening adverse event (i.e., the patient  was at immediate risk of death from 
the event as it occurred); does not include an event that, had it occurred in a more 
severe form, might have caused death 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 33 of 48 
 
 
• 
inpatient hospitalization or prolongation of existing hospitalization means that 
hospital inpatient admission and/or prolongation of hospital stay were required for 
treatment of an adverse event, or that they occurred as a consequence of the event. 
Hospitalizations scheduled for an elective procedure or for treatment of a pre-existing 
condition that has not worsened during participation in the study will not be 
considered serious adverse events.  
• 
persistent or significant disability or incapacity (refers to a substantial disruption of 
one’s ability to conduct normal life functions) 
• 
a congenital anomaly/birth defect 
• 
an important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may jeopardize the patient and may require medical intervention 
to prevent one of the outcomes listed in this definition. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or the 
development of drug dependency or drug abuse. Note: Any suspected transmission of 
an infectious agent via a medicinal product is considered an important medical event. 
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event. 
Expectedness 
A serious adverse event that is not included in the Adverse Reaction section of the relevant 
reference safety information by its specificity, severity, outcome, or frequency is considered an 
unexpected adverse event. The reference safety information for this study is the ® Estrace® drug 
label.  
The sponsor’s Global Patient Safety & Pharmacovigilance Department will determine the 
expectedness for all serious adverse events. 
9.8.2 
Reporting Serious Adverse Events 
It is the responsibility of the CRO to report a Serious Adverse Event (SAE) to the FDA within 
proper time constraints as per the Guidance for Industry and Investigators Safety Reporting 
Requirements for INDs and BA/BE Studies.19  Confirmation of this report must then be provided 
to Teva’s study representative as well as their Pharmacovigilance department (contact 
information below). 
Any serious adverse event (SAE) that occurs after the start of the study period must be reported 
by the study site, in English, within 24 hours of becoming aware of the SAE, to the study 
representative at 
 as well as one of the contacts listed below. All serious adverse events 
occurring during the study period, whether or not considered to be related to the study drug, must 
be reported within 24 hours to the study representative at 
 as well as the two contacts 
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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 34 of 48 
 
 
 
 
Or 
 
 
 
 
 will be responsible for reporting the SAE to Teva using the following guidelines.   
PLEASE NOTE THAT EMAIL IS THE PREFERRED MEANS OF COMMUNICATION. 
 
 
 
 
Teva Pharmaceuticals USA 
 
 
 
 
 
AND 
 
Teva Pharmacovigilance 
      
 
  
These SAE reports must contain the following information: 
 
Study name/number (for EU also the Eudract number) 
 
Study Drug 
 
Investigator details (name, phone, fax, e-mail) 
 
Patient Number 
 
Patient Initials 
 
Patient Demographics 
 
Clinical Event 
o Description 
o Date of onset 
o Treatment (drug, dose, dosage form) 
o AE Relationship to study drug 
o Action taken regarding study drug in direct relationship to the AE 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 35 of 48 
 
 
Additional information may include the following: 
• 
date of first dose of study drug 
• 
date and amount of last administered dose of study drug 
• 
action taken 
• 
outcome, if known 
• 
severity 
• 
concomitant therapy (including doses, routes, and regimens) and treatment of the 
event 
• 
pertinent laboratory or other diagnostic test data  
• 
medical history 
• 
results of dechallenge/rechallenge, if known 
• 
for an adverse event resulting in death:  
• 
cause of death (whether or not the death was related to study drug) 
• 
autopsy findings (if available) 
For the purposes of SAE reporting, the study period is defined as the time period from the first 
dose through the follow-up period.  For this study, the follow-up period is defined as 30 days 
after the last study visit.  All SAEs occurring during the study period, whether or not considered 
to be related to the study drug, must be reported within 24 hours to the study representative at 
 as well as the two contacts above.  
 will report the SAE to Teva.  Even though the 
investigator does not need to actively monitor patients for adverse events once the study has 
ended, serious adverse events occurring to a patient after their treatment has ended should be 
reported to 
if the investigator becomes aware of them. 
will be responsible for notifying the Investigative sites as required.  Under 21 CFR 
320.31 (d)(3) the Investigator must inform other investigators involved in the study plus the FDA 
within 15 days of becoming aware of the occurrence of the serious AEs.  Serious AEs that occur 
with the study drugs must be reported.19 
 
10.0 
STATISTICAL METHODS 
10.1 
Statistical Plan 
A Statistical Analysis Plan (SAP) including study data report format, following FDA 
guidance “Draft Guidance on Estradiol Cream 0.01% revised Sept 2014)detailing the 
intended statistical analysis of the study data, will be prepared as a separate document 
and finalized before database lock. Any deviation from the original statistical plan will be 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 36 of 48 
 
 
described and justified in the final report, as appropriate. The procedure for accounting 
for missing, unused and spurious data will be included in the Statistical Analysis Plan. 
All statistical analysis will be conducted using SAS®, Version 9.4 or higher. 
10.2 
Determination of Sample Size 
The primary statistical analysis of interest is the proportion of patients in the Per Protocol 
(PP) population that are identified as “Responders” at the end of the treatment period 
evaluated on Day 8 + 1.  
 
 
 
 a 
sample size of 224 patients
 
 
 
  
 
 
 Using a 2:1 (active: placebo) randomization scheme, 
and assuming the conversion rate from mITT to PP will be about 90%, 250 patients in 
each of active groups and 125 patients in the placebo group of the mITT population 
 
  
 
 
 To allow for about 5% of patients who may drop out 
from the study or are otherwise non-evaluable, up to 660 patients may be randomized to 
obtain 625 patients in the mITT population (i.e., 250 in each active group and 125 in the 
Placebo group). 
10.3 
Study Populations 
10.3.1 Per-Protocol Population 
Patients will be eligible for inclusion in the PP population if they: 
• 
Met the inclusion/exclusion criteria as defined in this protocol at Visit 1 and 
2 
• 
Did not take any prohibited medications throughout the study 
• 
Did not have any significant deviations from the protocol 
• 
Did not develop any concurrent vaginal infection or illness exhibiting 
symptoms similar to atrophic vaginitis, or symptoms that in the Investigator’s 
opinion would interfere with primary and secondary endpoint assessments 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 37 of 48 
 
 
• 
Completed the last study visit (Visit 3) Day 8 + 1. 
• 
Were compliant with dosing between 75%-125% of the required doses (6 – 8 
doses), and did not miss more than 1 dose 
• 
Any patient who withdrew from the study because of lack of efficacy will be 
included in the PP population as a Non-Responder. 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). 
10.3.2 mITT  Population 
The mITT population will include all patients in the PP population, AND patients 
who: 
• 
Administered at least one dose of randomized study medication and 
• 
Had a post-randomization evaluation 
10.3.3 Safety Population 
The safety population will include all patients who are randomized and 
administered at least one dose of study drug. 
10.4 
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 
Descriptive statistics by treatment group will be presented. 
 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 38 of 48 
 
 
10.5 
Efficacy Endpoints 
Primary Efficacy Endpoint 
The primary efficacy endpoint 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 + 1. 
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 the PP population that are 
identified as “Treatment Success” at the end of the treatment period evaluated on Day 8 + 
1.  
A “Treatment Success” is defined as a score of 0 or 1 at Day 8 + 1 for the symptom 
identified at baseline as the most bothersome.  This evaluation is to be based on patient 
self-assessed symptoms of vulvar and vaginal atrophy on a scale of 0 to 3 where 0 = none 
and 3 = severe. Refer to Appendix B for rating scales. 
10.6 
Therapeutic Equivalence 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. 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. 
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). 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 endpoint will be conducted for supportive information.  


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 39 of 48 
 
 
10.7 
Superiority to Placebo Analysis 
Superiority of the Test and Reference products against the Placebo for primary and 
secondary endpoints will be tested at the 5% significance level (p < 0.05; using two-
sided, continuity-corrected Z-test) in the mITT population using last observation carried 
forward. The superiority of Test and Reference treatments over the Placebo will be 
evaluated identically in separate Z-Test analyses. 
10.8 
Safety Analysis 
All study patients who use at least one application of the study drugs will be included in 
the safety analysis. Adverse events will be classified using standard MedDRA 
terminology Version 17.0 or higher and summarized by treatment group. Summary tables 
comparing the type, incidence, severity and Investigator’s opinion to drug relationship 
relation will be prepared by treatment group. Signs and symptoms of atrophic vaginitis 
will not be considered adverse events, 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. If sufficient data exist, 
adverse event frequencies will be compared between treatments using Fisher’s exact test 
or a similar test. Concomitant medication use during the study will be tabulated by 
patient. Adverse events reported during the study will be tabulated in a summary table 
listing the type, incidence, severity and Investigator’s opinion to drug relationship. 
 
11.0 
REGULATORY OBLIGATIONS 
11.1 
Institutional Review Board 
The study protocol, informed consent form, Investigator's Brochure, or package insert (as 
applicable), and any specific advertising will be submitted to, and approved by, an 
Institutional Review Board (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. 
11.2 
Study Documentation 
This study will be conducted in compliance with the protocol, Good Clinical Practices 
(GCPs) 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 59th World Medical Association General Assembly, October 2008. 
The Investigator will permit trial-related monitoring, audits, IRB review and regulatory 
inspections providing direct access to source data/documents. 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 40 of 48 
 
 
11.2.1 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.  
11.2.2 Informed Consent 
An Informed Consent Form (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. For illiterate patients, 
verbal consent should be obtained in the presence of and be countersigned by a 
literate witness. 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.  
11.2.3 Protocol and Informed Consent Changes 
Revisions to the original protocol will be documented in amendments, 
incorporated as a preface to the new version and approved by the IRB. 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. Revisions to the 
original ICF will also be approved by the IRB. 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. 
11.2.4 Source Documents and 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 Case Report Forms (CRFs). A set of 
CRFs will be completed for each patient enrolled in the study. All data and CRFs 
will be reviewed, evaluated and signed by the Investigator, as required. 
The original source documents and a copy of the corresponding CRFs will be 
retained by the Investigator. Patients who terminate early from the study will 
have the Visit 3 (end of study) source/CRF completed. 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 41 of 48 
 
 
11.2.5 Drug Accountability 
All drug receipt, inventory, dispensing, dosing and reconciliation records will be 
maintained in compliance with Federal Regulations. The study drug will be 
dispensed to qualified study patients according to established procedures. Once 
the site has been notified that they may do so, all unused study medication and 
empty or partially used tubes of study medication may be returned to the Sponsor 
or designee 
11.2.6 Drug Storage 
All study drug will be stored at controlled room temperature protected from 
temperatures in excess of 40ºC (104ºF), 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 Once the site has been 
notified that they may do so, all unused study medication and empty or partially 
used tubes of study medication may be returned to the Sponsor or designee 
Retention of Reserve Samples 
Each investigator will randomly remove at least one block of study drug per 
shipment, and store as retention samples.  A block contains five patient kits (as 
the study is randomized in a 2:2:1 ratio).  
 
 The 
number of each patient kit in each block kept for retention will be noted on the 
drug accountability form. These retention samples should be stored under the 
appropriate storage conditions for a minimum of 5 years following the 
application approval or, if not approved, at least 5 years after the completion of 
the study. 
11.2.7 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 
serious adverse events occurring during the study, regardless of the assessed 
causality.19 
11.2.8 Record Retention 
All drug accountability records, CRFs, source data and related regulatory 
documents must be retained for at least ten years following completion of the 
study or for two years after the test product has been approved for marketing by 
the Food and Drug Administration.  
11.2.9 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 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 42 of 48 
 
 
collection. The clinical site will make all 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. 
11.2.10 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 drug will no 
longer be available to the patient but the Investigator can, at their discretion, 
discuss alternative treatments with the patient. 
11.2.11 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 ICH formatting standards and 
guidelines.20 ANDA summary tables will also be generated. Data sets will be 
provided in SAS® transport (.xpt) format with appropriate description (Read Me) 
files as required by FDA.20 
 
 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 43 of 48 
 
 
12.0 
REFERENCES 
 
1 
Greendale, G. A. & Judd, H. L. The menopause: health implications and clinical management. 
Journal of the American Geriatrics Society 41, 426-436 (1993). 
2 
Bachmann, G. A. & Nevadunsky, N. S. Diagnosis and treatment of atrophic vaginitis. American 
Family Physician 61, 3090-3096 (2000). 
3 
Beard, M. K. & Curtis, L. R. Libido, menopause, and estrogen replacement therapy. Postgraduate 
Medicine 86, 225-228 (1989). 
4 
Willhite, L. A. & O'Connell, M. B. Urogenital atrophy: prevention and treatment. 
Pharmacotherapy 21, 464-480 (2001). 
5 
Beard, R. J. Estrogen replacement therapy: its benefits and risks. Fertility and Contraception 3, 
37-40 (1979). 
6 
Schairer, C. et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast 
cancer risk. Jama 283, 485-491 (2000). 
7 
Handa, V. L., Bachus, K. E., Johnston, W. W., Robboy, S. J. & Hammond, C. B. Vaginal 
administration of low-dose conjugated estrogens: systemic absorption and effects on the 
endometrium. Obstetrics and Gynecology 84, 215-218 (1994). 
8 
Bachmann, G. et al. Efficacy and safety of low-dose regimens of conjugated estrogens cream 
administered vaginally. Menopause 16, 719-727, doi:10.1097/gme.0b013e3181a48c4e (2009). 
9 
Marx, P. S., G.; Wilbourn, S.; Blank, S.; Moyer, D.L.; Nett, R. Low-dose (0.3 mg) synthetic 
conjugated estrogens A is effective for managing atrophic vaginitis. Maturitas 47, 47-54 (2004). 
10 
Botsis, D., Kassanos, D., Antoniou, G., Vitoratos, N. & Zourlas, P. A. Transvaginal sonography 
in postmenopausal women treated with low-dose estrogens locally administered. Maturitas 23, 
41-45 (1996). 
11 
FDA. Summary Basis of Approval for Premarin® Vaginal Cream, 0.625 mg/g (Wyeth-Ayerst 
Laboratories), NDA # 020216.  (1993). 
12 
FDA. Draft Guidance for Industry: Estrogen and Estrogen/Progestin Drug Products to Treat 
Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms — Recommendations for 
Clinical Evaluation. U.S. Department of Health and Human Services, Center for Drug Evaluation 
and Research (CDER) (2003). 
13 
FDA. Draft Guidance for Industry: Estradiol vaginal cream 0.01%. U.S. Department of Health 
and Human Services, Center for Drug Evaluation and Research (CDER) (2014). 
14 
FDA. Guidance for Industry: Statistical Approaches to Establishing Bioequivalence. US 
Department of Health and Human Services, CDER (2001). 
15 
FDA. 21CFR 320: Types of evidence to establish bioavailability or bioequivalence Department of 
Health and Human Services (2014). 
16 
FDA. 21CFR 320 Procedures for Determining the Bioavailability or Bioequivalence of Drug 
Products. Department of Health and Human Services, Subchapter D-Drugs for Human Use 5 
(2014). 
17 
Penslar. IRB Guidebook, Office for Human Rights Protection. US Department of Health and 
Human Services (1993). 
18 
FDA. Draft Guidance for Industry: Topical Dermatological Drug Product NDAs and ANDAs ---
In Vivo Bioavailability, Bioequivalence, In Vitro Release, and Associated Studies. U.S. 
Department of Health and Human Services, Center for Drug Evaluation and Research (CDER) 
(1998). 
19 
FDA. 21CFR 312.32: IND Safety Reporting.  (2010). 
20 
ICH. Structure and Content of Clinical Study Reports E3.  Step 4 version (1996). 
 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 44 of 48 
 
 
13.0 
APPENDICES 
 
 APPENDIX A 
 
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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 45 of 48 
 
 
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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 46 of 48 
 
 
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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 47 of 48 
 
 
APPENDIX C  REVISIONS TO THE PROTOCOL 
 
Revision 
Date 
 
1 
4/18/2016 
 
The following revisions were made to the protocol dated 02/11/2015: 
- 
The Visit 3 allowable window was clarified to Day 8 + 1 
- 
An end of study breast examination was added 
 
Additionally minor typographical updates were made. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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% (Teva Pharmaceuticals, USA) to 
Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
 
 
71436001 04-18-2016 (Rev 1)   Teva Pharmaceuticals, USA   Page 48 of 48 
 
 
APPENDIX D 
PRODUCT INSERT FOR ESTRACE®  
 
 

SAP_000.pdf: 
 
 
 
 
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% (Teva 
Pharmaceuticals, USA) to Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner 
Chilcott) in the Treatment of Atrophic Vaginitis 
 
 
Study Number 71436001 
 
NCT03294538 
 
Statistical Analysis Plan Approval Date: 04 August 2016  
 


 
 
 
Estradiol Vaginal Cream USP, 0.01%                       Protocol/Study Number 71436001 
 
 
08/04/2016       
 
 Teva Pharmaceuticals, USA 
 
 
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% (Teva 
Pharmaceuticals, USA) to Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner 
Chilcott) in the Treatment of Atrophic Vaginitis 
 
Protocol Number:  71436001 
 Study Number:  71436001 
 
 
Sponsor: 
Teva Pharmaceuticals, USA 
1090 Horsham Rd 
North Wales, PA 19454 
 
 
Contract Research Organization: 
 
 
 
 
August 4, 2016 
Final Version 1.0 
 
 
 


 
 
 
Estradiol Vaginal Cream USP, 0.01%                       Protocol/Study Number 71436001 
 
 
08/04/2016       
 
 Teva Pharmaceuticals, USA 
 
 
Page 2 of 59 
 
 
SAP FINAL VERSION APPROVALS 
 
 
A Randomized, Double-Blind, Placebo-Controlled, Parallel Design, Multiple-Site Study to 
Evaluate the Therapeutic Equivalence of Estradiol Vaginal Cream USP, 0.01% (Teva 
Pharmaceuticals, USA) to Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner 
Chilcott) in the Treatment of Atrophic Vaginitis 
 
 
 
 
 
Written By: 
 
Signature: _____________________________  
 
 
 
 
 
Date:_____________________ 
Reviewed By: 
 
Signature: ____________________________ 
 
 
 
 
 
    
 
 
 
 
 
Date:_____________________ 
Approved By: 
 
Signature: ____________________________  
 
 
Teva Pharmaceuticals, USA 
 
 
 
Date:_____________________ 
 
 
 
 


 
STATISTICAL ANALYSIS PLAN 
 
Estradiol Vaginal Cream USP, 0.01%                       Protocol/Study Number 71436001 
 
 
08/04/2016       
 
 Teva Pharmaceuticals, USA 
 
 
Page 3 of 59 
Revision History 
VERSION 
DATE 
DESCRIPTION OF REVISIONS 
REVISED BY 
Draft 1.0 
July 25, 2016 
New Document 
 
Final 1.0 
August 4, 2016 
Incorporate client comments and finalize SAP 
 
 
 
 
 
  
 


 
STATISTICAL ANALYSIS PLAN 
 
Estradiol Vaginal Cream USP, 0.01%                       Protocol/Study Number 71436001 
 
 
08/04/2016       
 
 Teva Pharmaceuticals, USA 
 
 
Page 4 of 59 
List of Abbreviations and Definition of Terms 
ADaM  
 
Analysis Data Model 
AE 
 
 
Adverse Event 
C 
 
 
Celsius 
CDISC 
 
Clinical Data Interchange Standards Consortium 
CI 
 
 
Confidence Interval 
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 Population 
mL 
 
 
Milliliter 
mm 
 
 
Millimeter 
OGD  
 
Office of Generic Drugs 
PAP 
 
 
Papanicolaou 
pH 
 
 
Measure of acidity/alkalinity 
PPP 
 
 
Per-Protocol Population 
RLD  
 
Reference Listed Drug 
SAE 
 
 
Serious Adverse Event 
SAP 
 
 
Statistical Analysis Plan 
SAS 
 
 
Statistical Analysis Software 
SDTM  
 
Study Data Tabulation Model 
U.S.A  
 
United States of America 
 
 


 
 
 
Estradiol Vaginal Cream USP, 0.01%                       Protocol/Study Number 71436001 
 
 
08/04/2016       
 
 Teva Pharmaceuticals, USA 
 
 
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................................................................................................................14 
8.2.1 Analysis of Primary Efficacy Endpoint ......................................................................15 
8.2.2 Analysis of Secondary Efficacy Endpoint ..................................................................16 
8.3 Safety Analysis ...................................................................................................................17 
8.3.1 Adverse Events ............................................................................................................17 
8.3.2 Vital Signs ...................................................................................................................18 
8.4 Statistical Analysis Issues ...................................................................................................18 
8.5 Multiple Comparisons .........................................................................................................18 
8.6 Methods for Handling Missing Data ...................................................................................18 
8.7 Interim Analyses .................................................................................................................18 
9. TABLE, LISTING AND FIGURE SHELLS ............................................................................18 
T16.1.9.1 Summary of Discontinued Patients ..........................................................................21 
T16.1.9.2 Summary of Protocol Deviations  (Safety Population) ............................................22 
T16.1.9.3.1 Summary of Patients Excluded from Efficacy Analysis  (Population 
Determination) ...................................................................................................................23 
T16.1.9.3.2 Summary of Patients Included in Analysis Population by Study Center ..............24 
T16.1.9.4 Summary of Baseline Demographic Data  (Safety Population) ...............................25 
T16.1.9.5 Summary of Baseline Demographic Data  (modified Intent-to-Treat 
Population) .........................................................................................................................30 
T16.1.9.6 Summary of Baseline Demographic Data  (Per-Protocol Population) .....................30 
T16.1.9.7 Summary of Analysis Results of Primary Efficacy Endpoint  (Proportion of 
Responders Between Treatment Groups) ..........................................................................31 
T16.1.9.8 Summary of Analysis Results of Secondary Efficacy Endpoint  (Proportion 
of Treatment Successes Between Treatment Groups) .......................................................32 
T16.1.9.9 Overall Summary of Adverse Events  (Safety Population) ......................................33 


 
STATISTICAL ANALYSIS PLAN 
 
Estradiol Vaginal Cream USP, 0.01%                       Protocol/Study Number 71436001 
 
 
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T16.1.9.10.1 Summary of Frequency of All Adverse Events by Body System  (Safety 
Population) .........................................................................................................................34 
T16.1.9.10.2 Summary of Frequency for AEs Occurring in at Least 1% of Subjects by 
Body System (Safety Population) ......................................................................................34 
T16.1.9.11 Summary of Frequency of All Adverse Events by Severity  (Safety 
Population) .........................................................................................................................35 
T16.1.9.12 Summary of Frequency of All Adverse Events by Relationship  (Safety 
Population) .........................................................................................................................36 
T16.1.9.13 Summary of Frequency of Serious Adverse Events  (Safety Population) ..............37 
T16.1.9.14 Summary of Adverse Events by Treatment  (Safety Population) ...........................38 
T16.1.9.15 Summary of Vital Signs  (Safety Population) ........................................................39 
L16.2.1 Listing of Discontinued Patients ..................................................................................40 
L16.2.2 Listing of Protocol Deviations .....................................................................................41 
L16.2.3.1 Patients Excluded from the Per-Protocol Population ...............................................42 
L16.2.3.2 Patients Excluded from the Modified Intent-to-Treat Population ............................43 
L16.2.4.1 Listing of Demographic Data ...................................................................................44 
L16.2.4.2 Listing of Patient Characteristics (Baseline Signs and Symptoms)..........................45 
L16.2.4.3 Listing of Medical History........................................................................................46 
L16.2.4.4 Listing of Concomitant Medications ........................................................................47 
L16.2.5.1 Listing of Visit Date Information .............................................................................48 
L16.2.5.2 Listing of Drug Administration ................................................................................49 
L16.2.5.3 Listing of Study Compliance ....................................................................................50 
L16.2.6.1 Listing of Vaginal Cytology Results ........................................................................51 
L16.2.6.2 Listing of Signs and Symptoms Ratings ...................................................................52 
L16.2.7 Listing of Adverse Events by Treatment Group ..........................................................53 
L16.2.8.1 Listing of Laboratory Measurements........................................................................54 
L16.2.8.2 Listing of Vaginal Ultrasonography and Mammogram............................................55 
L16.2.8.3 Listing of Vital Signs ................................................................................................56 
10. APPENDICIES ........................................................................................................................58 


 
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1. INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on the final Clinical Study Protocol 71436001 (Rev 
0) dated 02-11-2015. 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 analyses and 
presentations for this study. 
The following documents were reviewed in preparation of this SAP: 
• Final Clinical Study Protocol 71436001 (Rev 0) dated 02-11-2015 
• Case Report Form Booklet Version 1.0 for Study No. 71436001 
The reader of this SAP is encouraged to also read the clinical protocol for details on the 
conduct of this study, and the operational aspects of clinical assessments and timing for 
completing a patient in this study. 
2. OBJECTIVES 
1. Evaluate the therapeutic equivalence of the Test formulation, Estradiol Vaginal Cream 
USP, 0.01% (Teva Pharmaceuticals, USA) to the marketed product, Estrace® Cream 
(estradiol vaginal cream, USP, 0.01%; Warner Chilcott) in patients with atrophic 
vaginitis. 
2. Demonstrate the superiority of the Test and Reference (active) treatments over Placebo 
(vehicle) cream in patients with atrophic vaginitis. 
3. Compare the safety of Test, Reference and Placebo treatments in patients with atrophic 
vaginitis. 
3. OVERALL STUDY DESIGN 
This randomized, double-blind, placebo-controlled, parallel group, multi-site study has been 
designed to evaluate the therapeutic efficacy and safety of a generic Estradiol Vaginal Cream 
USP, 0.01% (Teva Pharmaceuticals, USA) compared to the FDA Reference Listed Drug (RLD), 
Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) in patients with atrophic 
vaginitis. Additionally, both the Test and Reference products will be tested for superiority against 
a Placebo.  


 
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Following the 14-day screening period, patients who continue to meet the inclusion/exclusion 
criteria will be randomized in a 2:2:1 ratio (Test: Reference: Placebo) for 7 days of treatment. Up 
to 660 eligible postmenopausal female patients with atrophic vaginitis will be randomized, to 
obtain a mITT population with an estimated 250 patients in each of the active treatment groups 
and 125 in the Placebo treatment group.  
Before any study-specific procedures are performed, all patients will read and sign the IRB-
approved informed consent document.  
To qualify for inclusion in the study, patients must be between the ages of 30-75 inclusive, 
postmenopausal with atrophic vaginitis assessed as moderate to severe using vaginal cytology, 
vaginal pH and patient-rated signs and symptoms. Patients cannot currently be undergoing 
treatment for atrophic vaginitis.  Patients will only be eligible to participate in the study on one 
occasion and cannot have participated in another clinical research study within 30 days of being 
screened for this study. 
At Visit 2 (Randomization), each qualified patient will be randomly assigned to one of the 
following treatment groups in a 2:2:1 ratio: 
• Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
• Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
• Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
Study medication will be self-administered by the patient for 7 days according to the dosing 
instructions provided. Each patient will be required to dose once a day at approximately the same 
time of day for 7 consecutive days.  
During the study patients will visit the research center for a total of 3 scheduled visits:  
• Visit 1/Screening (Day -14 to Day -1) 
• Visit 2/Randomization (Day 1) 
• Visit 3/End of Study (Day 8± 1) 
Vaginal cytology and vaginal pH determination will be performed as a part of clinical evaluation 
at Visits 1 and 3. Visit 3 is to be scheduled on the day following the last day of dosing. 
The primary efficacy endpoint is the proportion of patients in the per protocol (PP) population 
that are identified as “Responders” at the end of the treatment period evaluated on Day 8 ± 1. 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.  


 
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   Study Schematic 
 
Visit 1 
Screening 
(Day -14 to Day-1) 
Visit 2 
Randomization 
(Day 1) 
Visit 3 
End of Study 
(Day 8 ± 1) or Early 
Termination 
Informed Consent 
X 
 
 
Demographics 
X 
 
 
Medical History 
X 
X 
 
Inclusion/Exclusion 
Criteria Review 
X 
X 
 
Vital Signs 
X 
X 
X 
Rating of Symptoms 
X 
X 
X 
Physical Exam Including 
Pelvic Exam 
X 
 
X 
Breast Exam 
X 
 
 
Vaginal Cytology and pH 
X 
 
X 
PAP* 
X 
 
 
Serum FSH, Fasting 
Triglycerides 
X 
 
 
Mammogram** 
X 
 
 
Vaginal Ultrasound*** 
X 
 
 
Dispense/Collect  
Study Medication 
 
X 
X 
Dispense, Collect, 
Review Patient Diary 
 
X 
X 
Adverse Events 
 
 
X 
Concomitant Medications 
X 
X 
X 
* Patients who do not have documentation of a PAP smear completed within the last 12 months. 
**Patients over the age of 40 who do not have documentation of a mammogram completed within the 9 months 
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 
 
 


 
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4. RANDOMIZATION AND BLINDING 
The study drug will be randomized, packaged and blinded by an independent packaging 
company. Randomization will be pre-planned according to a computer-generated randomization 
schedule.
 
. Each patient will be provided 
with one patient kit, containing 1 tube of study medication. 
Each patient will receive a screening number at Visit 1, which will be recorded in the patient’s 
CRF. At Visit 2, eligible patients will receive a randomization number (based on treatment 
assigned), which will be recorded in the CRF. 
 
 Patients will be randomized to a treatment regimen by assigning treatments in sequential 
order. At the end of the study, after all the clinical data has been entered and the study database 
has been locked, a copy of the randomization 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 
The primary statistical analysis of interest is the proportion of patients in the Per Protocol (PP) 
population that are identified as “Responders” at the end of the treatment period evaluated on 
Day 8 ± 1.  
 
 
a sample size of 224 patients per active 
group in the PP population 
 to demonstrate bioequivalence (i.e., 
the 90% confidence interval (Yates’ continuity-corrected) of the absolute difference between the 
Test and Reference “Responder” rate rates is within a defined equivalence range [-20%, +20%]).  
 Using a 2:1 (active: placebo) randomization scheme, and assuming the 
conversion rate from mITT to PP will be about 90%, 250 patients in each of active groups and 
125 patients in the placebo group of the mITT population 
 to 
demonstrate superiority of active over placebo.  
 
 
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otherwise non-evaluable, up to 660 patients may be randomized to obtain 625 patients in the 
mITT population (i.e., 250 in each active group and 125 in the Placebo group). 
6. ANALYSIS POPULATION 
Per-Protocol (PP) Population 
Patients will be eligible for inclusion in the PP population if they: 
• Met the inclusion/exclusion criteria as defined in the protocol at Visit 1 and 2 
• Did not take any prohibited medications throughout the study 
• Did not have any significant deviations from the protocol 
• Did not develop any concurrent vaginal infection or illness exhibiting symptoms 
similar to atrophic vaginitis, or symptoms that in the Investigator’s opinion would 
interfere with primary and secondary endpoint assessments 
• Completed the last study visit (Visit 3) Day 8 ± 1. 
• Were compliant with dosing between 75%-125% of the required doses (6 – 8 doses), 
and did not miss more than 1 dose 
• Any patient who withdrew from the study because of lack of efficacy will be included 
in the PP population as a Non-Responder. 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). 
Modified Intent-to-Treat (mITT) Population 
 
The mITT population will include all patients in the PP population, AND patients who: 
• Administered at least one dose of randomized study medication and 
• Had a post-randomization evaluation 
Safety Population 
The safety population will include all patients who are randomized and administered at least one 
dose of study drug. 
7. STUDY ENDPOINTS 
Primary Efficacy Endpoint 


 
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The primary efficacy endpoint 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 ± 1. 
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 the PP population that are 
identified as “Treatment Success” at the end of the treatment period evaluated on Day 8 ± 1.  
A “Treatment Success” is defined as a score of 0 or 1 at Day 8 ± 1 for the symptom identified at 
baseline as the most bothersome.  This evaluation is to be based on patient self-assessed 
symptoms of vulvar and vaginal atrophy on a scale of 0 to 3 where 0 = none and 3 = severe.  
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®, Version 9.4 or higher. Datasets will be 
prepared using headings from Clinical Data Interchange Consortium (CDISC) Study Data 
Tabulation Model (SDTM) implementation for human clinical trials and ADaM (Analysis 
Dataset Model). 
8.1 Baseline Characteristics 
8.1.1 Patient Disposition 
The patient accountability and disposition information will be summarized by study treatment 
group. The number of patients enrolled, 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. 


 
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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 percentage. Baseline treatment 
comparisons will be presented using Cochran-Mantel-Haenszel test for the categorical variables, 
and Analysis of Variance 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 vaginal atrophy. At Visit 2 medical history will be 
reviewed and updated if changes have occurred. 
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.  
 


 
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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 
exam, any negative findings on exam should be reported as Adverse Events. 
Physical examination results will be listed by treatment and patient.  
8.1.6 Laboratory Evaluations 
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 > 40mIU/ml to be 
eligible for participation in the study. 
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. 
Laboratory evaluation results will be listed by treatment and patient.  
8.1.7 Dosing Compliance 
Dosing compliance will be checked by site staff at Visit 3 by reviewing patient diary entries. 
Patients will be considered compliant with dosing if they administer 75% - 125% of the required 
number of doses, and do not miss more than 1 dose. 
Drug administration and dosing compliance will be listed by treatment and patient.  
8.2 Efficacy Analyses 
The following symptoms (see Appendix A for detailed rating scales) will be evaluated at Visits 
1, 2 and 3 by the blinded clinical staff or Investigator.  
Symptoms 
Rating Scales 
Vaginal Dryness 
0=None, 1=mild, 2=moderate, 3=severe 
Vaginal/Vulvar irritation/itching 
0=None, 1=mild, 2=moderate, 3=severe 
Dysuria 
0=None, 1=mild, 2=moderate, 3=severe 
Vaginal Pain associated with Sexual Activity 
0=None, 1=mild, 2=moderate, 3=severe 
Vaginal Bleeding 
0= Absent, 1= Present 
The patients will be asked to identify which symptom is considered to be the most bothersome 
symptom at Visit 1 and Visit 2.  Vaginal Pain associated with Sexual Activity or Vaginal 


 
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Bleeding are acceptable to be considered most bothersome symptom only if patient is currently 
sexually active and plans to remain so throughout the study.   
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:  
 
 H0 :   𝑃𝑃𝑇𝑇− 𝑃𝑃𝑅𝑅< −.20  𝑜𝑜𝑜𝑜  𝑃𝑃𝑇𝑇− 𝑃𝑃𝑅𝑅 > .20     versus   
 
 HA : −.20 ≤𝑃𝑃𝑇𝑇− 𝑃𝑃𝑅𝑅≤.20 
 
 
where   𝑃𝑃𝑇𝑇  =  cure rate of test treatment  
             𝑃𝑃𝑅𝑅   =  cure rate of reference treatment.  
 
Let  
𝑛𝑛𝑇𝑇  =  sample size of test treatment group  
𝑐𝑐𝑛𝑛𝑇𝑇=  number of cured patients in test treatment group  
𝑛𝑛𝑅𝑅  =  sample size of reference treatment group  
𝑐𝑐𝑛𝑛𝑅𝑅=  number of cured patients in reference treatment group  
 
𝑃𝑃෠𝑇𝑇= 𝑐𝑐𝑛𝑛𝑇𝑇/𝑛𝑛𝑇𝑇  
 𝑃𝑃෠𝑅𝑅= 𝑐𝑐𝑛𝑛𝑅𝑅/𝑛𝑛𝑅𝑅 ,       and 
 
            𝑠𝑠𝑠𝑠 =  ൫𝑃𝑃෠𝑇𝑇 (1 −𝑃𝑃෠𝑇𝑇൯/𝑛𝑛𝑇𝑇 + 𝑃𝑃෠𝑅𝑅 (1 −𝑃𝑃෠𝑅𝑅)/𝑛𝑛𝑅𝑅 )
1 2
ൗ 
 
The 90% confidence interval for the difference in proportions between test and reference will be 
calculated as follows, using Yates’ correction: 
           L =  ൫𝑃𝑃෠𝑇𝑇−𝑃𝑃෠𝑅𝑅൯−1.645 𝑠𝑠𝑠𝑠−(1/𝑛𝑛𝑇𝑇 + 1/𝑛𝑛𝑅𝑅 )/2 
           U = ൫𝑃𝑃෠𝑇𝑇−𝑃𝑃෠𝑅𝑅൯+ 1.645 𝑠𝑠𝑠𝑠+ (1/𝑛𝑛𝑇𝑇 + 1/𝑛𝑛𝑅𝑅 )/2 
If the 90% confidence interval (calculated using Yates’ continuity correction) for the absolute 


 
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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. 
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. 
For the determination of superiority the proportion of patients who are considered as 
“Responders” in the test and reference product groups will each be compared to the proportion of 
“Responders” in the placebo product group. On condition that both the test and the reference 
group demonstrate statistically greater proportion of “Responders” (p< 0.05, 2-sided) than the 
placebo group then superiority shall be concluded and the sensitivity of the methodology 
confirmed. 
Summary table with frequency and percentage on the proportion of responders by treatment 
group will be presented. Treatment comparison for Test vs. Placebo and Reference vs. Placebo 
will be performed by continuity-corrected Z-tests. The superiority of Test and Reference 
treatments over the Placebo will be evaluated identically in separate Z-Test analyses. 
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). 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 


 
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must be demonstrated for only the primary endpoint. Bioequivalence testing of the secondary 
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 product to Placebo. 
Similar to the analysis for primary endpoint above, superiority of the Test and Reference 
products against the Placebo for secondary endpoints will be tested at the 5% significance level 
(p < 0.05; using two-sided, continuity-corrected Z-test) in the mITT population using last 
observation carried forward. The superiority of Test and Reference treatments over the Placebo 
will be evaluated identically in separate Z-Test analyses. 
8.3 Safety Analysis 
8.3.1 Adverse Events 
All the adverse events (AEs) reported will be coded and classified according to the MedDRA 
(Medical Dictionary for Regulatory Activities) coding dictionary (Version 17.0 or higher). Each 
adverse event is to be evaluated for date of start and end, seriousness, severity, causal 
relationship with the study drugs, action taken and outcome.   
All AEs will be listed by patient and treatment. 
The total number and percentage of patients with at least one AEs, discontinued study drug due 
to AEs, AE severity and AEs related to investigational product, serious AEs and death will be 
summarized by treatment groups and overall.  
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”. 
Should sufficient data exist, adverse event frequencies will be compared between treatments 
using the Chi-square testing (Fisher’s exact test if appropriate). 


 
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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 or end of study. 
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 Statistical Analysis Issues 
As this is a multiple-site study, treatment-by-site interaction analysis will be examined using the 
Cochran-Mantel-Haenszel Test for the primary efficacy variable, the proportion of patients in the 
PPP that are considered to be a “responder” at Visit 3. A site(s) with a low enrollment rate(s) 
may be pooled with its geographically closest site. 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 
(equivalence test) and mITT population (superiority tests) at the site with the highest enrolling 
rate. 
8.5 Multiple Comparisons 
No multiple comparison adjustment will be made in this study. 
8.6 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. 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). 
8.7 Interim Analyses 
There is no interim analysis planned in this study. 
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. These shells may not be reflective of every aspect of this study but are intended to 


 
 
 
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show the general layout of the Tables, Listings and Figures that will be included in the final 
clinical study report. Tables, Listings and Figures are numbered following the ICH structure. 
Table headers, variables names and footnotes will be modified as needed following data 
analyses. All descriptive and inferential statistical analyses will be performed using SAS® 
statistical software Version 9.4 or higher, unless otherwise noted.


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
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TABLE, LISTING AND FIGURE SHELLS 
  
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 21 of 59 
T16.1.9.1 Summary of Discontinued Patients 
 
Patients 
 
Test 
Reference 
Placebo 
Total 
Screened 
 
 
 
xxx 
Screen failures 
 
 
 
xxx 
Randomized 
xxx 
xxx 
xxx 
xxx 
Completed Study 
xxx 
xxx 
xxx 
xxx 
Terminated Early 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
Early Termination Reason 
 
 
 
 
Adverse Event 
xxx 
xxx 
xxx 
xxx 
Lack of efficacy 
xxx 
xxx 
xxx 
xxx 
Lost to Follow-Up 
xxx 
xxx 
xxx 
xxx 
etc. 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 22 of 59 
T16.1.9.2 Summary of Protocol Deviations  
(Safety Population) 
 
 
 
Test 
Reference 
Placebo 
 
Total 
Total Patients with Protocol Deviations 
xxx 
xxx 
 xxx 
 xxx 
Total Deviations 
xxx 
xxx 
xxx 
xxx 
Dosing Non-Compliance (Missed > one doses) 
xxx 
xxx 
xxx 
xxx 
Failure to meet randomization criteria 
xxx 
xxx 
xxx 
xxx 
Lost to Follow-up 
xxx 
xxx 
xxx 
xxx 
Outside Visit Window 
xxx 
xxx 
xxx 
xxx 
Patient Dosed on the Day of Visit 3 
xxx 
xxx 
xxx 
xxx 
Restricted Medication 
xxx 
xxx 
xxx 
xxx 
Total Dosing Non-Compliance 
xxx 
xxx 
xxx 
xxx 
Other 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 23 of 59 
T16.1.9.3.1 Summary of Patients Excluded from Efficacy Analysis  
(Population Determination) 
 
 
 
 
 
Test 
Reference 
Placebo 
 
Total 
  Randomized 
Total 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
  Safety Population 
Total 
xxx 
xxx 
xxx 
xxx 
  Excluded from Safety  
Did Not Dose 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
  mITT Population 
Total 
xxx 
xxx 
xxx 
xxx 
  Excluded from mITT  
Inclusion/Exclusion 
xxx 
xxx 
xxx 
xxx 
 
etc. 
 
 
 
 
 
 
 
 
 
 
  PP Population 
Total 
xxx 
xxx 
xxx 
xxx 
  Excluded from Excluded from PPP  
Restricted Medication 
xxx 
xxx 
xxx 
xxx 
 
Outside of Visit 3 Window 
 
 
 
 
etc. 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 24 of 59 
T16.1.9.3.2 Summary of Patients Included in Analysis Population by Study Center 
 
PPP 
 
mITT 
 
Safety 
Site 
No. 
Name 
Total 
Randomized 
Test 
Ref 
Placebo Total  Test 
Ref 
Placebo Total  Test 
Ref 
Placebo Total 
xx 
xxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 xxx 
xxx 
xxx 
xxx 
 xxx 
xxx 
xxx 
xxx 
xx 
xxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 xxx 
xxx 
xxx 
xxx 
 xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 
 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 25 of 59 
T16.1.9.4 Summary of Baseline Demographic Data  
(Safety Population) 
 
 
Test 
(N = xxx) 
Reference 
(N = xxx) 
Placebo 
(N = xxx) 
P-value 
Age (years) 
n 
xxx 
xxx 
xxx 
x.xxxx 
Mean ± SD 
xx.x ± xx.xx 
xx.x ± xx.xx 
xx.x ± xx.xx 
Median 
xx.x 
xx.x 
xx.x 
Range 
xx.x - xx.x 
xx.x - xx.x 
xx.x - xx.x 
Race 
American Indian or Alaska Native 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
x.xxxx 
Asian 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Black/African American 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Native Hawaiian or other Pacific Islander 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
White 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Other 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Gender 
Female 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
x.xxxx 
 
Male 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
Ethnicity 
Hispanic or Latino 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
x.xxxx 
 
Not Hispanic or Latino 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
 
N= number of patients in the treatment group;     n= number of patient with data available;      % is based on N  
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of 5 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 26 of 59 
T16.1.9.4 Summary of Baseline Demographic Data  
(Safety Population) 
 
 
 
 
 
Test 
(N = xxx) 
Reference 
(N = xxx) 
Placebo 
(N = xxx) 
P-value 
Natural or Surgical Menopause 
Natural 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
x.xxxx 
 
Surgical 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
Vaginal Dryness 
None 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
x.xxxx 
 
Mild 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Moderate 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Severe 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
Vaginal/Vulvar Irritation/Itching 
None 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
x.xxxx 
 
Mild 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Moderate 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Severe 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
 
Note:  N= number of patients in the treatment group;     n= number of patient with data available;      % is based on N  
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 2 of 5 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 27 of 59 
T16.1.9.4 Summary of Baseline Demographic Data  
(Safety Population) 
 
 
 
 
 
Test 
(N = xxx) 
Reference 
(N = xxx) 
Placebo 
(N = xxx) 
P-value 
Dysuria 
None 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
x.xxxx 
 
Mild 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Moderate 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Severe 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
Vaginal Pain during Sexual 
Activity 
None 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
x.xxxx 
 
Mild 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Moderate 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Severe 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
Most Bothersome Sign or 
Symptom 
Vaginal Dryness 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
x.xxxx 
 
Vaginal/Vulvar Irritation/Itching 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Dysuria 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Vaginal Pain during 
Sexual Activity 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Vaginal Bleeding 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 Note:  N= number of patients in the treatment group;     n= number of patient with data available;      % is based on N  
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 3 of 5 
 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 28 of 59 
T16.1.9.4 Summary of Baseline Demographic Data  
(Safety Population) 
 
 
 
 
 
Test 
(N = xxx) 
Reference 
(N = xxx) 
Placebo 
(N = xxx) 
P-value 
Vaginal Bleeding 
Absent 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
x.xxxx 
 
Present 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
Duration of Postmenopausal 
Status (Years) 
xxx 
xxx 
xxx 
xxx 
 
 
xx.x ± xx.xx 
xx.x ± xx.xx 
xx.x ± xx.xx 
xx.x ± xx.xx 
x.xxxx 
 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
xx.x - xx.x 
xx.x - xx.x 
xx.x - xx.x 
xx.x - xx.x 
 
% of basal/parabasal cells 
xxx 
xxx 
xxx 
xxx 
 
 
xx.x ± xx.xx 
xx.x ± xx.xx 
xx.x ± xx.xx 
xx.x ± xx.xx 
x.xxxx 
 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
xx.x - xx.x 
xx.x - xx.x 
xx.x - xx.x 
xx.x - xx.x 
 
Note:  N= number of patients in the treatment group;     n= number of patient with data available;      % is based on N  
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 4 of 5 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 29 of 59 
 
T16.1.9.4 Summary of Baseline Demographic Data  
(Safety Population) 
 
 
 
 
 
 
Test 
(N = xxx) 
Reference 
(N = xxx) 
Placebo 
(N = xxx) 
P-value 
% of intermediate cells 
n 
xxx 
xxx 
xxx 
x.xxxx 
 
Mean ± SD 
xx.x ± xx.xx 
xx.x ± xx.xx 
xx.x ± xx.xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
 
 
Range 
xx.x - xx.x 
xx.x - xx.x 
xx.x - xx.x 
 
% of superficial cells 
n 
xxx 
xxx 
xxx 
x.xxxx 
 
Mean ± SD 
xx.x ± xx.xx 
xx.x ± xx.xx 
xx.x ± xx.xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
 
 
Range 
xx.x - xx.x 
xx.x - xx.x 
xx.x - xx.x 
 
Vaginal pH 
n 
xxx 
xxx 
xxx 
x.xxxx 
 
Mean ± SD 
xx.x ± xx.xx 
xx.x ± xx.xx 
xx.x ± xx.xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
 
 
Range 
xx.x - xx.x 
xx.x - xx.x 
xx.x - xx.x 
 
 Note:  N= number of patients in the treatment group;     n= number of patient with data available;      % is based on N  
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 5 of 5 
 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 30 of 59 
 
Similar tables will be created for T16.1.9.5 and T16.1.9.6 
 
T16.1.9.5 Summary of Baseline Demographic Data  
(modified Intent-to-Treat Population) 
 
T16.1.9.6 Summary of Baseline Demographic Data  
(Per-Protocol Population) 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 31 of 59 
T16.1.9.7 Summary of Analysis Results of Primary Efficacy Endpoint  
(Proportion of Responders Between Treatment Groups) 
Equivalence: Per-Protocol Population 
Number of 
Patients (N) 
 
Number of 
Responders (n) 
Proportion of 
Responders (%) 
Difference Between Treatments 
Treatment  
Group 
Difference 
90% CI Evaluation 
Test 
xxx 
xxx 
xx.x% 
 
 
Reference 
xxx 
xxx 
xx.x% 
xx.x% 
xx.x – xx.x 
 
Superiority: modified Intent-to-Treat Population 
Number of 
Patients (N) 
 
Number of 
Responders (n) 
Proportion of 
Responders (%) 
Treatment vs. Placebo 
Treatment  
Group 
Difference 
P-value 
Placebo 
xxx 
xxx 
xx.x% 
 
 
Test 
xxx 
xxx 
xx.x% 
xx.x% 
x.xxxx 
 
 
 
 
 
Placebo 
xxx 
xxx 
xx.x% 
 
 
Reference 
xxx 
xxx 
xx.x% 
xx.x% 
x.xxxx 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
      Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
The 90% confidence interval for the difference in proportions between test and reference was calculated using Yates’ correction. 
 
        Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
        Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 32 of 59 
T16.1.9.8 Summary of Analysis Results of Secondary Efficacy Endpoint  
(Proportion of Treatment Successes Between Treatment Groups) 
Equivalence: Per-Protocol Population 
Treatment  
Group 
Number of 
Patients (N) 
Number of 
Treatment  
Successes (n) 
Proportion of 
Treatment  
Successes (%) 
Difference Between Treatments 
 
 
Difference 
90% CI Evaluation 
Test 
xxx 
xxx 
xx.x% 
 
 
Reference 
xxx 
xxx 
xx.x% 
xx.x% 
xx.x – xx.x 
 
Superiority: modified Intent-to-Treat Population 
Treatment  
Group 
Number of 
Patients (N) 
Number of 
Treatment  
Successes (n) 
Proportion of 
Treatment  
Successes (%) 
Treatment vs. Placebo 
 
 
Difference 
P-value 
Placebo 
xxx 
xxx 
xx.x% 
 
 
Test 
xxx 
xxx 
xx.x% 
xx.x% 
x.xxxx 
 
 
 
 
 
Placebo 
xxx 
xxx 
xx.x% 
 
 
Reference 
xxx 
xxx 
xx.x% 
xx.x% 
x.xxxx 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
      Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
The 90% confidence interval for the difference in proportions between test and reference was calculated using Yates’ correction. 
 
       Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
      Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 33 of 59 
T16.1.9.9 Overall Summary of Adverse Events  
(Safety Population) 
 
Description 
Test 
N (%) 
Reference 
N (%) 
Placebo 
N (%) 
Total 
N (%) 
Patients Randomized 
xxx 
xxx 
xxx 
xxx 
  Patients with at least one AE 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
  Discontinued study drug due to above AE 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
AEs reported 
xxx 
xxx 
xxx 
xxx 
  Mild 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
  Moderate 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
  Severe 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
  Not Related 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
  Related 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
  Death 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
  Serious AE 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
           
           Related = Probable, Possible, Unlikely  
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 34 of 59 
T16.1.9.10.1 Summary of Frequency of All Adverse Events by Body System  
(Safety Population) 
Body System 
MedDRA Term  
Test  
(N = xxx) 
 
Reference 
(N = xxx) 
   
Placebo 
(N = xxx) 
 
Fisher’s 
P-value 
Events 
Patients 
Events 
Patients 
Events 
Patients 
Patients with at least 
one AE 
Total 
xx 
xx (xx.x%)  
xx 
xx (xx.x%) 
xx 
xx (xx.x%) 
x.xxxx 
Ear and labyrinth 
disorders 
Ear pain 
xx 
xx (xx.x%)  
xx 
xx (xx.x%) 
xx 
xx (xx.x%) 
x.xxxx 
 
etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
Comparison of treatment groups is with respect to the number of patients with at least one occurrence of the AE. 
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 
 
Similar Table will be created for: 
T16.1.9.10.2 Summary of Frequency for AEs Occurring in at Least 1% of Subjects by Body System 
(Safety Population) 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 35 of 59 
T16.1.9.11 Summary of Frequency of All Adverse Events by Severity  
(Safety Population) 
 
 
Test 
# of Events 
(N=xx) 
 
Reference 
# of Events 
(N=xx) 
 
Placebo 
# of Events 
(N=xx) 
Body System 
MedDRA Term 
Mild 
Moderate 
Severe 
 
Mild 
Moderate 
Severe 
 
Mild 
Moderate 
Severe 
Total AEs 
Total 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ear and labyrinth 
disorders 
Ear pain 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Hypoacusis 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
N = Total number of events in each treatment group; Percentage is based on total number of events. 
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 36 of 59 
T16.1.9.12 Summary of Frequency of All Adverse Events by Relationship  
(Safety Population) 
 
 
Test 
# of Events 
(N=xx) 
 
Reference 
# of Events 
(N=xx) 
 
Placebo 
# of Events 
(N=xx) 
Body System 
MedDRA Term 
Related 
Not Related 
 
Related 
Not Related 
 
Related 
Not Related 
Total AEs 
Total 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
Ear and labyrinth disorders 
Ear pain 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
Hypoacusis 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
N = Total number of events in each treatment group; Percentage is based on total number of events. 
 
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Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 
 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 37 of 59 
T16.1.9.13 Summary of Frequency of Serious Adverse Events  
(Safety Population) 
Body System 
MedDRA Term 
Test 
# Events 
Reference 
# Events 
Placebo 
# Events 
Injury, poisoning and procedural complications 
Alcohol poisoning 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 38 of 59 
T16.1.9.14 Summary of Adverse Events by Treatment  
(Safety Population) 
Test: Estradiol Vaginal Cream, USP, 0.01% 
 
 
Severity 
 
Relationship to Study Drug 
Body System 
     MedDRA Term 
Mild 
n (%) 
Moderate 
n (%) 
Severe 
n (%) 
 
Related 
n (%) 
Not Related 
n (%) 
Total AEs (N=xxx) 
xx ( xx.x%) 
xx ( xx.x%) 
xx ( xx.x%) 
 
xx ( xx.x%) 
xx ( xx.x%) 
 
 
 
 
 
 
 
Ear and labyrinth disorders 
xx ( xx.x%) 
xx ( xx.x%) 
xx ( xx.x%) 
 
xx ( xx.x%) 
xx ( xx.x%) 
     Hypoacusis 
xx ( xx.x%) 
xx ( xx.x%) 
xx ( xx.x%) 
 
xx ( xx.x%) 
xx ( xx.x%) 
 etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
etc. 
 
 
 
 
 
 
     etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
N = Total AEs in Test Group 
n (%) = Number of AEs (Percent of Total AEs in Test Group) 
 
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Created on: ddmmmyy hh:mm 
Page 1 of N 
 
Note to programmer: Similar tables will be created for Reference and Placebo groups. 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 39 of 59 
T16.1.9.15 Summary of Vital Signs  
(Safety Population) 
Vital Signs 
Visit 
 
Statistic 
Test 
(N = xxx) 
Reference 
(N = xxx) 
Placebo 
(N = xx) 
Systolic Blood Pressure (mmHg) 
1 
n 
xxx 
xxx 
xxx 
 
 
Mean ± SD 
xxx.x ± xx.xx 
xxx.x ± xx.xx 
xxx.x ± xx.xx 
 
 
Median 
xxx.x 
xxx.x 
xxx.x 
 
 
Range 
xxx.x – xxx.x 
xxx.x – xxx.x 
xxx.x – xxx.x 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
Diastolic Blood Pressure (mmHg) 
 
 
 
 
 
Heart Rate (beats/min) 
 
 
 
 
 
Respiration Rate (breaths/min) 
 
 
 
 
 
Temperature (F) 
 
 
 
 
 
 
 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 40 of 59 
L16.2.1 Listing of Discontinued Patients 
Treatment  
Group 
Patient 
Randomization 
Number 
Discontinuation  
Reason 
Population 
 Test 
xx-xxxx 
Withdrew Consent 
Per-Protocol  
 
xx-xxxx 
Lost to Follow-up 
Safety  
 
 
 
 
 
 
 
 
 
 Reference 
 
 
 Placebo 
  
 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                              Page 1 of N 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 41 of 59 
L16.2.2 Listing of Protocol Deviations 
Treatment 
Group 
Patient  
Randomization  
Number 
Event Description 
Population 
Test 
xx-xxxx 
Outside Visit Window (Visit: 3) 
Per-Protocol 
 
 
 
 
 
 
 
 
 
 
 
 
Reference 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 42 of 59 
L16.2.3.1 Patients Excluded from the Per-Protocol Population 
Treatment  
Group 
Patient  
Randomization  
Number 
Exclusion Reason 
Test 
xx-xxxx 
Patient did not meet IE criterion 
 
xx-xxxx 
Patient took prohibited medications 
 
 
 
 
 
 
Reference 
 
 
Placebo 
 
 
 
 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 43 of 59 
L16.2.3.2 Patients Excluded from the Modified Intent-to-Treat Population 
Treatment  
Group 
Patient  
Randomization  
Number 
Exclusion Reason 
Test 
xx-xxxx 
Patient did not have at least one post-randomization evaluation 
 
 
 
 
 
 
 
 
 
Reference 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 44 of 59 
L16.2.4.1 Listing of Demographic Data 
Treatment 
Group 
Patient  
Randomization  
Number 
Age 
(years) 
Gender 
Ethnicity 
Race 
Natural or Surgical 
Menopause 
Test 
xx-xxxx 
30 
Female 
Not Hispanic or Latino 
Black or African American 
Natural 
 
 
 
Surgical 
 
 
 
 
 
 
 
 
 
 
 
 
Reference 
 
 
Placebo 
 
 
 
 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 45 of 59 
L16.2.4.2 Listing of Patient Characteristics (Baseline Signs and Symptoms) 
 
 
 
Baseline Signs and Symptoms Scores 
 
Baseline % 
 
 
 
Treatment 
Group 
Patient 
Rando-
mization 
Number 
 
Vaginal 
Dryness 
Vaginal/ 
Vulvar 
Irritation/ 
itching 
 
 
Dysuria 
Vaginal Pain 
Associated 
With Sexual 
Activity 
 
Vaginal 
Bleeding 
Most 
Bothersome 
Symptom 
(Baseline) 
 
 
Superficial 
Cells 
Basal/ 
para 
Basal 
Cells 
 
Intermediate 
Cells 
 
Baseline 
Vaginal 
pH 
Test 
xx-xxxx 
1 
2 
2 
2 
1 
Vaginal 
Dryness 
 
6 
0 
94 
5.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 
 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 46 of 59 
L16.2.4.3 Listing of Medical History 
Treatment 
Group 
Patient  
Randomization  
Number 
System 
Diagnosis or Surgical 
Procedure 
Start Date 
End Date 
Ongoing 
Test 
xx-xxxx 
Gynecologic 
Menopause 
2003 
2003 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                     Page 1 of N 
 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 47 of 59 
L16.2.4.4 Listing of Concomitant Medications 
 
Treatment  
Group 
Patient 
Randomization 
Number 
 
Treatment 
Area 
 
 
Medication 
Dosage 
Frequency Route 
Start/End 
Date 
Indication 
Test 
xx-xxxx 
Yes 
LISINOPRIL 
20 MG 
QD 
PO 
yyyy-mm-dd/ 
yyyy-mm-dd 
HYPERTENSION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 48 of 59 
L16.2.5.1 Listing of Visit Date Information 
 
Treatment  
Group 
Patient 
Randomization 
Number 
 
Informed Consent 
Date 
Visit 1 
Visit 2 
Visit 3 or  
Early Termination 
Test 
xx-xxxx 
yyyy-mm-dd 
yyyy-mm-dd  
yyyy-mm-dd  
yyyy-mm-dd  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 49 of 59 
L16.2.5.2 Listing of Drug Administration 
Treatment 
Group 
Patient  
Randomization  
Number 
Date of  
First Dose 
Date of 
 Last Dose 
Total Number of  
Dose Administered 
Dosing 
 Compliance 
(%) 
Test 
xx-xxxx 
yyyy-mm-dd 
yyyy-mm-dd 
xx 
xxx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 50 of 59 
L16.2.5.3 Listing of Study Compliance 
Treatment 
Group 
Patient  
Randomi- 
zation  
Number 
Dose on 
the day of 
Visit 3? 
Use any restricted 
medication for the 
treatment of 
atrophic vaginitis? 
Use any restricted 
medication other than 
for the treatment of 
atrophic vaginitis? 
Administer 
 < 6 or >8 of  
the intended 
doses? 
Miss >1  
dose 
 of study 
 medication? 
Develop any 
concurrent 
vaginal infection 
or illness? 
Require 
additional 
treatment? 
Test 
xx-xxxx 
No 
No 
No 
No 
No 
No 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 
 
 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 51 of 59 
L16.2.6.1 Listing of Vaginal Cytology Results 
 
(Test: Estradiol Vaginal Cream, USP, 0.01%) 
 
 
_________________Baseline__________________ 
_______________Visit 3____________________  
Patient 
Rando- 
mization 
Number 
Basal/ 
Parabasal 
% 
Inter- 
mediate 
% 
Basal/ 
Parabasal 
+Inter- 
mediate% 
Super-
ficial 
Cells% 
pH 
Basal/ 
Parabasal 
% 
Inter- 
mediate
% 
Basal/ 
Parabasal 
+Inter- 
mediate% 
Super-
ficial 
Cells% 
pH 
Cytology 
Changes 
From 
Baseline 
pH 
Changes 
From 
Baseline 
Responder 
Yes/No 
xx-xxxx 
69 
31 
100 
100 
7.0 
12 
43 
55 
100 
4.5 
45 
2.5 
Yes 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Programming note: table will continue for reference and placebo group 
 
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Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 52 of 59 
L16.2.6.2 Listing of Signs and Symptoms Ratings 
Treatment  
Group 
Patient 
Randomization 
Number 
 
Most Bothersome 
Symptom at Baseline 
Most Bothersome 
Score at Baseline 
Baseline Most 
Bothersome 
Symptom Score at V3 
Success 
(Yes/No) 
Test 
xx-xxxx 
Vaginal Dryness 
3 
0 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference 
 
 
 
Placebo 
 
 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 
 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 53 of 59 
L16.2.7 Listing of Adverse Events by Treatment Group 
 
 
Treatment 
group 
Patient 
Rando-
mization 
Number 
 
Body System/ 
MedDRA Term/ 
AE Term 
 
 
Treatment 
Area 
End Date 
Severity 
 
 
Relationship to 
Study Drug 
 
 
 
Outcome 
 
 
Action 
Taken 
 
Other 
Action 
Taken 
 
 
SAE? 
Test 
xx-xxxx 
NERVOUS SYSTEM 
DISORDERS/ HEADACHE/  
HEADACHE 
Yes 
yyyy-mm-dd/ 
yyyy-mm-dd 
Mild 
Not Related 
Recovered 
None 
None 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 54 of 59 
L16.2.8.1 Listing of Laboratory Measurements 
Treatment 
Group 
Patient 
Randomization 
Number 
 
Collection  
Date 
Baseline FSH 
(mIU/ml) 
Baseline Triglycerides 
(mg/dL) 
Test 
xx-xxxx 
yyyy-mm-dd 
99.0 
76 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference 
 
 
 
Placebo 
 
 
 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 
 
 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 55 of 59 
L16.2.8.2 Listing of Vaginal Ultrasonography and Mammogram 
Treatment 
Group 
Patient 
Randomization 
Number 
 
_______Vaginal Ultrasonography_______ 
    __________Mammogram___________ 
 
Collection  
Date 
Does Patient Have a  
Confirmed Inactive Uterine 
Lining of < 4 mm?* 
Collection  
Date 
Are Screening 
Mammogram Results 
Normal?** 
Test 
xx-xxxx 
yyyy-mm-dd 
Yes 
yyyy-mm-dd 
Yes 
 
xx-xxxx 
 
N/A 
 
N/A 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference 
 
Placebo 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
Note: * N/A = Patient has had a hysterectomy;      ** N/A = patient is ≤ 40 years of age 
 
 
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Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 56 of 59 
L16.2.8.3 Listing of Vital Signs 
Treatment 
Group 
Patient  
Randomization  
Number 
Visit 
Systolic BP 
(mmHg) 
 
Diastolic BP 
(mmHg) 
 
Heart Rate 
(beats/min ) 
 
Respiration Rate 
(breaths/min) 
 
Temperature 
(F) 
Test 
xx-xxxx 
1 
120 
70 
84 
18 
98.6 
 
 
2 
140 
80 
74 
18 
97 
 
 
3/EOS 
130 
87 
74 
18 
99.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                            Page 1 of N 
 
 


Teva Pharmaceuticals, USA                                                                                          
 
Estradiol Vaginal Cream USP, 0.01%                                                                                            Protocol / Study No.  71436001 
 
 
08/04/2016       
 
 
 
 Teva Pharmaceuticals, USA 
 
 
 
 
Page 57 of 59 
L16.2.8.4 Listing of Physical Examination 
 
Treatment 
Group 
Patient 
Randomization 
Number 
System 
Visit 1 
Visit 3 /EOS 
Test 
xx-xxxx 
General Appearance  
Cardiovascular  
Lungs and Thorax  
Abdominal and Gastro-Enteric  
etc 
Normal 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference 
 
 
 
Placebo 
 
 
 
 
 
 
 
Test: Estradiol Vaginal Cream, USP, 0.01% (Teva Pharmaceuticals, USA)  
Reference: Estrace® Cream (estradiol vaginal cream, USP, 0.01%; Warner Chilcott) 
Placebo: Placebo cream (Teva Pharmaceuticals, USA)  
 
Path: L:\Studies_Sas_Codes\Clinical Trial\71436001\PDF\xxx 
Created on: ddmmmyy hh:mm                                                                                                                                        Page 1 of N 


 
STATISTICAL ANALYSIS PLAN 
 
Estradiol Vaginal Cream, USP, 0.01%          
Protocol / Study No.  71436001 
 
 
08/04/2016 
 Teva Pharmaceuticals, USA.    
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.  71436001 
 
 
08/04/2016 
 Teva Pharmaceuticals, USA.    
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.