Clinical trial NCT02638337
Conditions: Vaginal Dryness
Keywords: Vulvo-vaginal Atrophy menopause
Sponsor: Shionogi
Start date: 2016-01-26; Completion date: 2017-07-05
Enrollment: 631 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to evaluate the efficacy and safety of ospemifene 60 mg once daily (QD) compared with placebo in treatment of vulvo-vaginal atrophy (VVA) due to menopause in women with moderate to severe vaginal dryness as the most bothersome symptom (MBS) of VVA.

Detailed description:

Arms: arm 1: Participants will take one tablet of ospemifene 60 mg orally, once a day for 12 weeks. arm 2: Participants will take one tablet of matching placebo, orally, once a day for 12 weeks.
Interventions: intervention 1: Ospemifene intervention 2: Placebo
Intervention descriptions: intervention 1: 60 mg tablet intervention 2: Tablet identical to the ospemifene tablet without drug

Protocol documents:
Prot_000.pdf: 
 
Shionogi Study Title:  
A Phase 3, Randomized, Double-blind, Placebo controlled 
Multicenter Study to Evaluate the Efficacy and Safety of 
Ospemifene in Patients with Moderate to Severe Vaginal 
Dryness, a Symptom of Vulvo-vaginal Atrophy (VVA) due 
to Menopause 
Shionogi Study Number: 
1517I0231 
ClinicalTrials.gov 
registration No. 
NCT02638337 
Study Document  
Protocol (Version 3 dated 02 November 2016)  
 
 
History of Protocol Amendments 
 
 
Original (Version 1) 
06 October 2015 
Version 2 
11 March 2016 
1. Standardized the wording for endpoints to be consistent with previous studies and labeling 
2. Changed the limits for BMI for consistency with the demographics of the US population of 
postmenopausal women 
3. Identified the readers and clarified the process for blinding various data, e.g., photographs, 
mammograms and DXA scans  
4. Clarified the process for the pathologist’s blinded reading of the endometrial histological 
samples 
5. Improved the list of prohibited concomitant medications that might affect sex hormone 
levels including drugs involved in drug interactions and herbal supplements 
Version 3 
02 November 2016 
1. Because of very slow recruitment, the 104 week double blind, placebo controlled study 
consisting of a 12 week efficacy period followed by a 92 week safety period was shortened 
to only the 12 week efficacy period followed by a 2 week safety period. This change 
required concomitant changes throughout the protocol to text, tables, and figures, and 
adjustments to the measurements that were to be made.  
2. Made the requirement for vaginal imaging optional as it is not needed for the dryness 
endpoint 
3. Clarified the process for handling data for patients entering the study with the 11 March 
protocol and having already entered the 92 week safety period.  
 
 
 
 




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SYNOPSIS 
Study Title: 
A Phase 3, Randomized, Double-blind, Placebo-controlled Multicenter Study to 
Evaluate the Efficacy and Safety of Ospemifene in Patients with Moderate to Severe 
Vaginal Dryness, a Symptom of Vulvo-vaginal Atrophy (VVA) due to Menopause. 
Study Number: 
1517I0231  
Study Phase: 3 
Objective 
The objective of this study is to evaluate the efficacy and safety of ospemifene 60 mg 
once daily (QD) compared with placebo in treatment of vulvo-vaginal atrophy (VVA) 
due to menopause in women with moderate to severe vaginal dryness as the most 
bothersome symptom (MBS) of VVA. 
Study Design: 
This is a multicenter, randomized, double-blind, placebo-controlled study to assess the 
efficacy and safety of ospemifene 60 mg QD in postmenopausal women with vaginal 
dryness as the MBS of VVA due to menopause.    
The study was previously designed as a two part study; Part A (12 week efficacy and 
safety assessment period) and Part B (long term, 92 week safety assessment period, 
beginning at week 12 and ending at week 104). The current version of the protocol has 
been amended to remove Part B based on enrollment challenges and site feedback. 
Data will be handled as described in the Note at the end of the Synopsis. 
This study consists of 3 periods: a Screening Period of up to 4 weeks during which 
eligibility will be assessed; a Treatment Period of 12 weeks during which efficacy and 
safety will be assessed, and a Follow-up Period of 2 weeks after the last dose of study 
medication.   
Study Population: 
Approximately 600 subjects will be randomized to this study. 
Eligibility Criteria 
Postmenopausal women, 40 to 80 years old who have VVA due to menopause and 
their MBS is vaginal dryness which is moderate to severe in severity, will be able to 
participate if they meet all eligibility criteria as defined in the protocol.  
Study Drug, Dose, and Mode of Administration: 
Ospemifene tablet 60 mg QD, oral administration.  
Control Drug, Dose, and Mode of Administration: 
Placebo matching ospemifene 60 mg tablet QD, oral administration.   
Duration of Treatment: 
After screening, subjects who meet all eligibility criteria will be randomized in a 1:1 


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ratio to treatment with ospemifene 60 mg or matching placebo, once daily for 
12 weeks. 
Prohibited Concomitant Therapy: 
The following medications will be prohibited after screening and at least two weeks 
before receiving the study drug whichever is the earlier timepoint and during the 
treatment period: 
 Dietary supplements and herbal therapies with assumed clinically significant 
estrogenic vaginal effects (See Appendix 1) 
 Any hormonal products regardless of the route of administration 
 Any selective estrogen receptor modulators 
 Any vaginal lubricant or moisturizer other than that provided by the Sponsor 
for use in the study 
 Use of systemic fluconazole, rifampicin, rifabutin, carbamazepine, phenytoin, 
St John’s wort 
Efficacy Assessments: 
 Percentage of parabasal cells in the maturation index of the vaginal smear 
 Percentage of superficial cells in the maturation index of the vaginal smear 
 Vaginal pH 
 Severity of self-reported symptoms of vaginal dryness 
 Severity of VVA symptoms other than vaginal dryness (ie, dyspareunia, 
vulvar/vaginal itching/irritation, dysuria, and/or vaginal bleeding associated 
with intercourse) 
 Vaginal health index (VHI) 
 Vulvar health index (VuHI) 
 Female Sexual Function Index (FSFI)  
 Urogenital Distress Inventory (UDI-6) 
 Markers of bone metabolism 
Safety Assessments: 
Safety assessments will include gynecological examination, breast examination, 
endometrial thickness (for subjects with an intact uterus), endometrial histology, 
physical examination, vital signs, clinical laboratory tests, and adverse events (AEs).  
Statistical Methods: 
Efficacy  
For percentage of parabasal cells, percentage of superficial cells and vaginal pH, a 
Mixed-effects Model Repeated Measures (MMRM) approach will be used.  In the 
model, repeated  measurements of the change from baseline at Week 4, Week 8 and 
Week 12 will be the response variable.  Baseline value and study center may be 
modeled as covariates.  Superiority of ospemifene to placebo will be evaluated by 


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testing the mean difference between the two treatment groups at Week 12. 
For dryness as the MBS, Generalized Estimating Equations (GEE) model will be used 
to fit a marginal proportional odds model to the longitudinal ordered categorical data 
(Fitzmaurice et al., 2011).  In the model, repeated measurements of the change from 
baseline in dryness at Week 4, Week 8 and Week 12 will be the response variable.  
Baseline severity of dryness and study center may be modeled as covariates. 
Superiority of ospemifene to placebo will be evaluated by comparing the two treatment 
groups at Week 12. 
Safety 
The number and percentage of subjects who experience treatment-emergent adverse 
events (TEAEs) will be summarized by treatment group, and during Treatment Period 
and Follow-up period seperately.  Serious adverse events (SAEs) and AEs leading to 
discontinuation will be tabulated in a similar manner.  Details will be described in the 
Statistical Analysis Plan (SAP). 
Study Duration:  
Subjects may be participating in the study for up to 18 weeks. 
Date of Original Version: 06 October 2015 
Date of Version 2: 11 March 2016 
Date of Latest Amendment: 02 November 2016 
NOTE: 
For subjects consented under Protocol version 11 March 2016: 
 Dual-Energy X-ray Absorptiometry (DXA) Scan  
Bone mineral density (BMD) was determined using DXA scans.  Images of the 
hip and lumbar spine were sent to a central reader.  The date of imaging was 
entered in the eCRF.  Detailed procedures are specified in a separate document.  
Details about the central BMD laboratory are provided in Section 10.1. 
 Standard mammogram scans used to determine Breast Density .  
Breast density was determined using standard mammogram scans.  Images 
were sent to a central reader.  The date of imaging was entered in the eCRF.  
Detailed procedures are specified in a separate document.  Details about the 
central mammogram laboratory are provided in Section 10.1. For subjects who 
had a normal mammogram within 9 months prior to screening for which the 
results were available and could be sent to the central reader, do not require a 
new mammogram to be performed for eligibility assessment. 
 Early Termination Procedures  
For subjects who have completed Visit 5, the following measurements and/or 
evaluations will be made and recorded in the eCRF: 
 Record concomitant therapy 
 Assess for AEs  
 Assess symptoms of VVA 


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 Assess FSFI 
 Assess UDI-6 
 Measure vital signs (BP, pulse rate, and oral temperature performed after 
subject is in seated or in a recumbent position ≥3 minutes) including weight  
 Perform physical examination 
 Perform breast examination 
 Perform gynecological examination  
 Measure vaginal pH 
 Obtain vaginal smear for assessment of maturation index 
 Assess VHI 
 Assess VuHI 
 Obtain vulvo-vaginal imaging (optional) 
 Perform TVU and measure endometrial thickness.  Capture images to be 
sent to the central reader  
 Perform endometrial biopsy (do not perform if done within 6 months of ET 
visit) 
 Obtain blood samples for safety laboratory tests, hormone levels and serum 
markers of bone metabolism 
 Obtain urine sample for urinalysis and urinary marker of bone metabolism 
 Assess study medication returned and assess compliance with study 
medication 
 Conduct follow-up call on Day 14 after last dose of study medication 
Safety (After Visit 5) 
The subjects who experienced treatment-emergent adverse events (TEAEs) will be 
summarized by treatment group. Details will be described in the SAP. 


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TABLE OF CONTENTS 
SYNOPSIS .......................................................................................................................... 2 
TABLE OF CONTENTS .................................................................................................... 6 
LIST OF IN-TEXT TABLES ........................................................................................... 10 
LIST OF IN-TEXT FIGURES .......................................................................................... 10 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................... 11 
1. 
INTRODUCTION .................................................................................................... 14 
2. 
STUDY OBJECTIVES ............................................................................................. 16 
2.1 
Primary Objectives .......................................................................................... 16 
2.2 
Secondary Objectives ...................................................................................... 16 
3. 
INVESTIGATIONAL PLAN ................................................................................... 17 
3.1 
Overall Study Design and Plan ....................................................................... 17 
3.2 
Rationale for Study Design and Control Group .............................................. 22 
3.3 
Study Duration ................................................................................................ 22 
3.3.1 
Study Duration in Individual Subjects .................................................. 22 
3.3.2 
Planned Duration for the Study ............................................................. 22 
4. 
STUDY POPULATION SELECTION .................................................................... 23 
4.1 
Study Population ............................................................................................. 23 
4.2 
Inclusion Criteria ............................................................................................ 23 
4.3 
Exclusion Criteria ........................................................................................... 24 
4.4 
Screen Failures ................................................................................................ 26 
5. 
STUDY TREATMENT(S) ....................................................................................... 27 
5.1 
Description of Treatment(s) ............................................................................ 27 
5.1.1 
Test Drug .............................................................................................. 27 
5.1.2 
Placebo .................................................................................................. 27 
5.2 
Treatments to be Administered ....................................................................... 27 
5.3 
Selection and Timing of Dose for Each Subject ............................................. 27 
5.4 
Method of Assigning Subjects to Treatment Groups ...................................... 27 
5.5 
IxRS Blinding and Unblinding ....................................................................... 28 
5.6 
Packaging and Labeling .................................................................................. 28 
5.7 
Storage and Accountability ............................................................................. 29 
5.8 
Investigational Product Retention at Study Site ............................................. 29 
5.9 
Treatment Compliance .................................................................................... 29 
6. 
RESTRICTIONS ...................................................................................................... 31 
6.1 
Prior Therapy .................................................................................................. 31 
6.2 
Concomitant Therapy ...................................................................................... 31 
6.2.1 
Prohibited Therapy ................................................................................ 31 


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7. 
STUDY PROCEDURES AND METHODS OF ASSESSMENTS ......................... 33 
7.1 
Informed Consent ............................................................................................ 33 
7.2 
Demographics, Baseline Subject Characteristics, and Medical History ......... 33 
7.3 
Enrollment in the Study and Dispensing Study Drug ..................................... 33 
7.4 
Electronic Diary (eDiary) ............................................................................... 34 
7.5 
Efficacy Assessments ...................................................................................... 34 
7.5.1 
Percentage of Parabasal Cells and Superficial Cells in the 
Maturation Index of the Vaginal Smear ................................................ 34 
7.5.2 
Vaginal pH ............................................................................................ 35 
7.5.3 
Severity of Self-Reported VVA Symptoms .......................................... 35 
7.5.4 
Vaginal Health Index [9] (VHI; Appendix 3) ....................................... 36 
7.5.5 
Vulvar Health Index (VuHI; Appendix 4) ............................................ 36 
7.5.6 
Vaginal Imaging (Appendix 5) ............................................................. 36 
7.5.7 
Female Sexual Function Index (FSFI; Appendix 6) ............................. 37 
7.5.8 
Urinary Distress Inventory (UDI-6; Appendix 7) ................................. 37 
7.5.9 
Efficacy laboratory Tests ...................................................................... 37 
7.5.10 
Markers of Bone Metabolism ............................................................... 38 
7.5.10.1 
Markers of Bone Resorption: ...................................................... 38 
7.5.10.2 
Markers of Bone Formation: ....................................................... 38 
7.5.11 
Special Considerations Concerning Efficacy Variables ....................... 38 
7.5.11.1 
Urine Dip-Stick Test ................................................................... 38 
7.5.11.2 
Vaginal Infection ........................................................................ 39 
7.6 
Safety Assessments ......................................................................................... 39 
7.6.1 
Gynecological Examination .................................................................. 39 
7.6.2 
Breast Examination ............................................................................... 40 
7.6.3 
Cervical Cytology (Papanicolau) Smear ............................................... 40 
7.6.4 
Transvaginal Ultrasound (for Subjects with an Intact Uterus Only) .... 40 
7.6.5 
Biopsy for Endometrial Histology (for Subjects with Intact Uterus 
Only) ..................................................................................................... 41 
7.6.6 
Vaginal Bleeding .................................................................................. 42 
7.6.7 
Physical Examinations .......................................................................... 42 
7.6.8 
Vital Signs ............................................................................................. 43 
7.6.9 
Electrocardiograms/Electrocardiography ............................................. 43 
7.6.10 
Clinical Laboratory Tests ...................................................................... 43 
7.6.10.1 
Laboratory Parameters ................................................................ 43 
7.6.10.2 
Sample Collection, Storage, and Shipping ................................. 44 
7.6.11 
Adverse Events Assessments ................................................................ 44 
7.6.11.1 
Performing Adverse Events Assessments ................................... 44 


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7.6.11.2 
Timing ......................................................................................... 45 
7.6.11.3 
Severity ....................................................................................... 45 
7.6.11.4 
Relationship ................................................................................ 45 
7.6.11.5 
Expectedness ............................................................................... 46 
7.6.11.6 
Action Taken ............................................................................... 46 
7.6.11.7 
Laboratory Adverse Events ......................................................... 46 
7.6.11.8 
Serious Adverse Events .............................................................. 47 
7.6.11.9 
Special Situations: Abuse, Misuse, Overdose, and Medication 
Error ............................................................................................ 48 
7.6.11.10 
Treatment-Emergent Adverse Events ......................................... 48 
7.7 
Withdrawal of Subjects from the Study or Study Drug .................................. 48 
7.8 
Appropriateness of Measurements .................................................................. 50 
7.9 
Visit Time Window ......................................................................................... 50 
8. 
STUDY ACTIVITIES .............................................................................................. 51 
8.1 
Screening, Visit 1 (Up to 4 Weeks Prior to Randomization) .......................... 51 
8.2 
Randomization, Visit 2 (Day 1) ...................................................................... 52 
8.3 
Treatment Period, Visit 3 (Week 4) through Visit 5 (Week 12) ..................... 53 
8.3.1 
Visit 3 (Week 4) and Visit 4 (Week 8) Procedures .............................. 53 
8.3.2 
Visit 5 (Week 12) End of Study Procedures ......................................... 53 
8.4 
Telephone Call at the End of the Follow-up Period (Two Weeks after 
Treatment Period Completion) Procedures ..................................................... 54 
8.5 
Early Termination Procedures ........................................................................ 54 
9. 
PLANNED STATISTICAL METHODS ................................................................. 56 
9.1 
General Considerations ................................................................................... 56 
9.2 
Determination of Sample Size ........................................................................ 56 
9.3 
Analysis Populations ....................................................................................... 58 
9.4 
Handling of Missing Data ............................................................................... 58 
9.5 
Subject Disposition ......................................................................................... 58 
9.6 
Demographic and Baseline Characteristics .................................................... 58 
9.7 
Treatment and Treatment Compliance ............................................................ 59 
9.8 
Prior Therapy .................................................................................................. 59 
9.9 
Concomitant Therapy ...................................................................................... 59 
9.10 
Efficacy Analyses ........................................................................................... 59 
9.10.1 
Primary Efficacy Endpoints .................................................................. 59 
9.10.2 
Secondary Efficacy Endpoints .............................................................. 60 
9.10.3 
Analyses of Efficacy Endpoints ............................................................ 60 
9.10.3.1 
Statistical Analysis Methods for Primary Efficacy Endpoints ... 60 
9.10.3.2 
Other Statistical Analysis Methods for Secondary Endpoints .... 61 


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9.10.3.3 
Sensitivity Analyses for the GEE analysis .................................. 61 
9.11 
Safety Analyses ............................................................................................... 61 
9.11.1 
Adverse Events ..................................................................................... 61 
9.11.2 
Vital Signs ............................................................................................. 61 
9.11.3 
Clinical Laboratory Analyses ............................................................... 62 
9.11.4 
Endometrial Safety ................................................................................ 62 
9.11.5 
Other Safety Variables .......................................................................... 62 
9.12 
Interim Analysis .............................................................................................. 62 
10.  ADMINISTRATIVE CONSIDERATIONS ............................................................. 63 
10.1 
Study Administrative Structure ....................................................................... 63 
10.2 
Institutional Review Board Approval ............................................................. 64 
10.3 
Ethical Conduct of the Study .......................................................................... 65 
10.4 
Subject Information and Consent .................................................................... 65 
10.5 
Subject Confidentiality ................................................................................... 65 
10.6 
Study Monitoring ............................................................................................ 65 
10.7 
Electronic Case Report Forms and Source Documents .................................. 66 
10.7.1 
Electronic Case Report Forms .............................................................. 66 
10.7.2 
Source Data and Source Documents ..................................................... 66 
10.7.3 
External Data ........................................................................................ 67 
10.8 
Committees ..................................................................................................... 67 
10.8.1 
Visual Imaging Independent Panel Review (IPR) ................................ 67 
10.9 
Termination or Suspension of the Study ......................................................... 67 
10.9.1 
Termination or Suspension of the Entire Study .................................... 67 
10.9.2 
Termination or Suspension of the Study by Medical Institution .......... 68 
10.10  Protocol Modifications and Deviations .......................................................... 68 
10.11  Access to Source Documentation ................................................................... 69 
10.12  Data Management ........................................................................................... 69 
10.13  Retention of Data ............................................................................................ 69 
10.14  Quality Control and Assurance ....................................................................... 70 
10.15  Publication and Disclosure Policy .................................................................. 70 
10.16  Financial Disclosure ........................................................................................ 70 
11.  REFERENCE LIST .................................................................................................. 71 
Appendix 1 
Restricted Dietary and Herbal Therapies .............................................. 72 
Appendix 2 
Patient Self-Assessment of Vulvar and Vaginal Atrophy 
Questionnaire ........................................................................................ 73 
Appendix 3 
Vaginal Health Index (VHI) ................................................................. 74 
Appendix 4 
Vulvar Health Index (VuHI) ................................................................. 75 
Appendix 5 
Process for Capturing Vulvar and Vaginal Photography ...................... 76 


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Appendix 6 
Female Sexual Function Index (FSFI) Questionnaire .......................... 77 
Appendix 7 
Urinary Distress Inventory (UDI-6) ...................................................... 83 
Appendix 8 
Genital Prolapse Grading ...................................................................... 84 
Appendix 9 
Diagnostic Procedures Required in a Subject with Intact Uterus and 
Vaginal Bleeding .................................................................................. 85 
Appendix 10 
Management and Discontinuation Criteria for Abnormal Liver 
Function Tests ....................................................................................... 86 
Appendix 11 
Sponsor’s Signature .............................................................................. 90 
Appendix 12 
Investigator’s Signature ........................................................................ 91 
 
LIST OF IN-TEXT TABLES 
Table 3.1-1 
Schedule of Time and Events ..................................................... 18 
Table 7.6-1 
Laboratory Tests ......................................................................... 44 
Table 9.2-1 
Change from Baseline to Week12 in Two Pivotal Studies ......... 57 
Table 9.2-2 
Expected Power with Total Sample Size of 600 ......................... 58 
 
LIST OF IN-TEXT FIGURES 
Figure 3.1-1 
Study Schematic .......................................................................... 17 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ASC-H 
atypical squamous cells – cannot exclude HSIL 
ASCUS 
atypical squamous cells of undetermined significance 
AST 
aspartate aminotransferase 
BSAP 
bone specific alkaline phosphatase 
BIN 
bottle identification number 
BMD 
bone mineral density 
BMI 
body mass index 
BP 
blood pressure 
BSP 
bone sialoprotein 
BUN 
blood urea nitrogen 
Ca 
calcium 
CI 
confidence interval 
CK 
creatine kinase 
Cl 
chloride 
CTM 
clinical trial manager 
CTX 
C-terminal telopeptide of type 1 collagen 
DXA 
dual-energy X-ray absorptiometry 
DPD 
deoxypyridinoline 
E2 
estradiol 
ECG 
electrocardiogram/electrocardiography 
eCRF 
electronic case report form 
eDiary 
electronic diary 
eGFR 
estimated glomerular filtration rate 
FDA 
Food and Drug Administration 
FSFI 
Female Sexual Function Index 
FSH 
follicle-stimulating hormone 
GCP 
good clinical practice 
GEE 
generalized estimating equations 
GGT 
gamma glutamyl transferase 
HBsAg 
hepatitis B surface antigen 
HCT 
hematocrit 
HDL 
high-density lipoprotein 


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HDL-C 
HDL cholesterol 
HgB 
hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HPV 
human papilloma virus 
HSIL 
high-grade squamous intraepithelial lesion 
HT 
hormone therapy 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation  
IPR 
independent panel review  
IRB 
institutional review board 
ITT 
intent-to-treat 
IxRS 
interactive web or voice response system  
K 
potassium 
LDH 
lactate dehydrogenase 
LDL 
low-density lipoprotein 
LDL-C 
LDL cholesterol 
LFT 
liver function test 
LH 
luteinizing hormone 
MBS 
most bothersome symptom 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed-effects model repeated measures 
MPV 
mean platelet volume 
Na 
sodium 
NOS 
not otherwise specified 
NTX 
N-terminal telopeptide of type 1 collagen 
OTC 
over-the-counter 
P1NP 
N-terminal propeptide of type I collagen 
PAP 
Papanicolaou (Test) 
PP 
per-protocol 
QD 
once daily 
RBC 
red blood cell count 
RDW 
red blood cell distribution width 
SAE 
serious adverse event 


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SAP 
statistical analysis plan 
SD 
standard deviation 
SERM 
selective estrogen receptor modulator 
SHBG 
sex hormone binding globulin 
SIL 
squamous intraepithelial lesion 
SUSAR 
suspected unexpected serious adverse reaction 
TBL 
total bilirubin 
TC 
telephone call 
TEAE 
treatment-emergent adverse event 
TIA 
transient ischemic attack 
TRACP-5b 
tartrate-resistant acid phosphatase 5b 
TVU 
transvaginal ultrasound 
UDI 
Urogenital Distress Inventory 
ULN 
upper limit of normal 
UTI 
urinary tract infection 
VHI 
Vaginal Health Index 
VLDL 
very low-density lipoprotein 
VLDL-C 
VLDL cholesterol 
VuHI 
Vulvar Health Index 
VVA 
vulvo-vaginal atrophy 
WBC 
white blood cell count 
WHO-DD 
World Health Organization Drug Dictionary 
 


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1. INTRODUCTION 
Vulvo-vaginal atrophy (VVA) often referred to as vaginal atrophy, urogenital atrophy, or 
atrophic vaginitis, is a condition associated with the declining estrogen levels during peri- 
and post-menopause [1, 2].   
Because the vaginal wall and surrounding tissues have estrogen receptors, circulating 
estrogen levels have a direct effect on the epithelium and the underlying connective 
tissue; these affect the physiology of the vulva, vagina, and other pelvic structures [1, 2].  
Physiologic estrogen concentrations are associated with a thickened and mature vaginal 
mucosa with appropriate vaginal blood flow, lubrication, mechanical sensitivity, and 
elasticity.  Estrogen stimulation produces glycogen that is used by lactobacilli, naturally 
existing in the vagina, to produce lactic acid, which keeps vaginal pH levels low (3.5 to 
4.5).  This is part of the body’s natural defense against vaginal and urinary tract 
infections [1, 2].   
The decline in estrogen levels after menopause is followed by many histologic 
transformations including thinning of the vaginal epithelium, proliferation of connective 
tissue, fragmentation of elastin, and hyalinization of collagen.  These changes result in 
granulation, fissures, friability of the vaginal mucosa, and decreased elasticity.  Changes 
in tissue composition are not limited to the genital tract; they also occur in the urinary 
tract, as well.  Vaginal and urethral epithelia change adversely in an estrogen-deprived 
environment [2, 4].   
Genital atrophic changes include decreased maturation of the vaginal epithelial cells and 
progressive decrease in vascularity in the surrounding tissue [1, 2].  The glycogen content 
of vaginal epithelial cells decreases, resulting in reduced colonization by lactobacilli.  
This is followed by increased vaginal pH and increases the incidence of vaginal and 
urinary tract infections [2]. 
A decrease in vaginal lubrication due to hormone insufficiency is an early hallmark of 
VVA.  Genital symptoms of VVA include dryness, burning, dyspareunia, loss of vaginal 
secretions, leucorrhea, vulvar pruritus, feelings of pressure, itching, and yellow 
malodorous discharge.  Also associated with VVA are urinary symptoms including 
urethral discomfort, urinary frequency, hematuria, urinary tract infection, dysuria, and 
stress incontinence.  Over time, the lack of vaginal lubrication often results in sexual 
dysfunction and associated emotional distress [2, 3, 5, 6, 7, 8]. 
The incidence of postmenopausal women with symptoms of VVA is estimated to be from 
10% to 40% [5] up to more than 75% [2].  However, only 20% to 25% of the estimated 
symptomatic women seek medical attention [2, 6], suggesting that VVA is an 
underdiagnosed condition. 
Current treatment options for VVA include systemic hormone therapy (HT), transvaginal 
estrogen products, and non-hormonal lubricants and moisturizers [1, 2, 3].  Ospemifene is 
an oral, non-hormonal option for the treatment of dyspareunia as a symptom of VVA due 
to menopause.  Ospemifene is a selective estrogen receptor modulator (SERM) with 


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estrogenic or anti-estrogenic effects in different tissues of the body.  In the vulva, the 
vagina, and surrounding tissues, ospemifene acts as an estrogen agonist and has 
demonstrated a clinically significant increase in the number of superficial vaginal cells, a 
decrease in the number of parabasal vaginal cells, and a reduction in vaginal pH.  
Ospemifene has also demonstrated improvement in dyspareunia associated with 
postmenopausal VVA.  In one study (Study 15-50310), ospemifene therapy was 
associated with statistically significant improvement compared with placebo in vaginal 
dryness associated with postmenopausal VVA.  In a second study (Study 15-50821), 
there was a trend towards improvement relative to placebo; however, the difference 
between groups was not statistically significant.   
Over the 12 weeks of the Treatment Period, this study will assess the effect of 
ospemifene compared with placebo as treatment of vaginal dryness in postmenopausal 
women with VVA due to menopause who report vaginal dryness as the MBS. This will 
be followed by a 2-week follow up period  in which use of concomitant medication and 
adverse events will be assessed.   
 
 


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2. STUDY OBJECTIVES 
2.1 
Primary Objectives 
Objective 1: To assess the efficacy of ospemifene 60 mg daily at 12 weeks of treatment, 
relative to placebo, in the treatment of vaginal dryness, a symptom of vulvar and vaginal 
atrophy, due to menopause. 
Hypothesis: After 12 weeks of treatment, ospemifene 60 mg QD, relative to placebo, 
significantly improves all 4 co-primary efficacy endpoints: 
• 
Percentage of parabasal cells in the maturation index of the vaginal smear 
• 
Percentage of superficial cells in the maturation index of the vaginal smear 
• 
Vaginal pH 
• 
Severity of self-reported MBS of vaginal dryness  
Objective 2: To assess the safety and tolerability of ospemifene 60 mg QD during 
12 weeks of treatment, relative to placebo. 
2.2 
Secondary Objectives 
Objective 1: To assess the effect of ospemifene 60 mg relative to placebo in change from 
baseline to Week 12 on: 
• 
Severity of other VVA symptoms different from vaginal dryness (ie, dyspareunia, 
vulvar/vaginal itching/irritation, dysuria [difficult/painful urination], vaginal 
bleeding associated with intercourse) 
• 
Markers of bone metabolism 
• 
Vaginal health Index (VHI) 
• 
Vulvar health Index (VuHI)  
Objective 2: To assess the effect of ospemifene 60 mg relative to placebo in change from 
baseline to Week 12 on: 
• 
Female Sexual Function Index (FSFI) 
• 
Urinary Distress Inventory (UDI-6) 
Objective 3:  To assess the effect of ospemifene 60 mg QD, relative to placebo, over 12 
weeks on endometrial histology 


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3. INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a Phase 3 multicenter, randomized, double-blind, placebo-controlled study to 
assess the efficacy and safety of ospemifene in postmenopausal women with vaginal 
dryness as MBS of VVA due to menopause.  After screening, subjects who have ≤5% 
superficial cells in the maturation index of the vaginal smear, a vaginal pH >5.0 and 
vaginal dryness as MBS of VVA based on self-assessment, who also meet all other 
eligibility criteria, will be randomized in a 1:1 ratio to receive either ospemifene 
60 mg QD or matching placebo for 12 weeks. Randomization will be stratified by 
severity of MBS of vaginal dryness at Visit 2 and by the presence or absence of the 
uterus.  Randomization of subjects without a uterus will be limited to 60% of the study 
population. The treatment period of this study consists of a 12-week efficacy and safety 
assessment period after which the primary objective of the study will be assessed.    Two 
weeks after the last dose of study medication, subjects will have a follow-up 
visit/telephone contact to assess for adverse events and use of concomitant therapy.  
Subjects will remain in the study for up to 18 weeks.  The study design schematic is 
shown in Figure 3.1-1.  The Schedule of Time and Events is shown in  
Table 3.1-1. 
Figure 3.1-1 
Study Schematic 
 
 
TC = telephone call; R = randomization.


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Table 3.1-1 
Schedule of Time and Events 
Evaluation 
Screening 
Randomization 
Treatment 
FUq 
V1 
V2 
V3 
V4 
V5 
TC 
Within  
4 Weeks Prior to 
Day 1 a 
Day 1 
Wk 4 
Wk 8 
Wk 12/ 
ET 
Wk 14 
Informed Consent  
X 
 
 
 
 
 
Assign Subject ID Number b 
X 
 
 
 
 
 
I/E Criteria 
X 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical History c 
X 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
X 
 
Electrocardiogram 
X 
 
 
 
 
 
Breast Examination 
X 
X 
 
 
X 
 
Gynecological Examination 
Xo 
Xp 
 
 
X 
 
Safety Laboratory Tests d 
X 
X e, p 
 
 
X e 
 
Hormone Levels f 
X 
 
 
X 
 
FSH g 
X 
 
 
 
 
 
Markers of Bone Metabolism h 
 
X 
 
 
X 
 
Urinalysis 
X 
X 
 
 
X 
 
Urine Dipstick i  
X 
X 
 
 
 
 
Vital Signs (blood pressure, pulse, body 
temperature)  
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
Weight (BMI) 
X 
X 
X 
X 
X 
 
Prior Therapy 
X 
X 
 
 
 
 
Concomitant Therapy 
 
X 
X 
X 
X 
Adverse Events 
X j 
X 
X 
X 
X 
X 


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Evaluation 
Screening 
Randomization 
Treatment 
FUq 
V1 
V2 
V3 
V4 
V5 
TC 
Within  
4 Weeks Prior to 
Day 1 a 
Day 1 
Wk 4 
Wk 8 
Wk 12/ 
ET 
Wk 14 
Cervical PAP Smear  
Xo 
 
 
 
 
 
Vaginal pH 
Xo 
Xp 
X 
X 
X 
 
Vaginal Smear/  
Maturation Index 
Xo 
Xp 
X 
X 
X 
 
Vaginal Health Index (VHI) 
 
X 
X 
X 
X 
 
Vulvar Health Index (VuHI) 
 
X 
X 
X 
X 
 
Vulvo-Vaginal Imaging k 
 
X 
 
 
X 
 
Endometrial Thickness (TVU) 
X 
 
 
 
X 
 
Endometrial Histology (Biopsy) 
X 
 
 
 
X n 
 
Mammogram 
X l 
 
 
 
 
 
Dispense eDiary/Return eDiary 
 
X 
 
 
X 
 
eDiary Compliance 
 
 
X 
X 
X 
 
Assessment of symptoms of VVA 
Xo 
Xp 
X 
X 
X 
 
Dispense Study Medication 
 
X 
X 
X 
 
Dispense Lubricant 
 
X 
X 
X 
 
 
Study Medication Compliance m 
 
 
X 
X 
X 
 
Reinforce Compliance with Study Medication 
 
X 
X 
X 
 
 
Study Medication Return 
 
 
X 
X 
X 
 
Female Sexual Function Index (FSFI) 
 
X 
X 
X 
X 
 


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Evaluation 
Screening 
Randomization 
Treatment 
FUq 
V1 
V2 
V3 
V4 
V5 
TC 
Within  
4 Weeks Prior to 
Day 1 a 
Day 1 
Wk 4 
Wk 8 
Wk 12/ 
ET 
Wk 14 
Urinary Distress Inventory (UDI-6) 
 
X 
X 
X 
X 
 
ET = Early termination; FU = Follow-up; TC = Telephone call. 
a 
Enough time between Visit 1 and Visit 2 should be allowed to receive the results of tests conducted as part of Visit 1, therefore, Visit 2 should not take place 
earlier than 1 week after Visit 1.   
b 
Subject ID number will be assigned through the interactive web or voice response system (IxRS). 
c 
Medical history should be captured for the 2 years prior to screening, except for any history of cancer which should be captured regardless of the time.  
d 
Safety laboratory tests: red blood cell (RBC) count, white blood cell (WBC) count, differential, platelet count, hemoglobin (HgB), hematocrit (HCT), mean 
corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), RBC distribution width (RDW), 
mean platelet volume (MPV), albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, creatinine, estimated glomerular 
filtration rate (eGFR), total protein, glucose, uric acid, blood urea nitrogen (BUN), creatine kinase (CK), thromboplastin time, fibrinogen, antithrombin III, 
factor V Leiden (screening only), protein-C, protein-S, lipids total cholesterol, LDL cholesterol (LDL-C), HDL cholesterol (HDL-C) and triglycerides.  
e 
Subjects should be fasting for at least 8 hours prior to blood sample collection. 
f 
Hormones: Estradiol (E2), follicle stimulating hormone (FSH), luteinizing hormone (LH), sex hormone-binding globulin (SHBG), free and total testosterone 
g 
FSH values may be measured for confirmation of postmenopausal status (inclusion criterion # 3) in women ≥45 years old who do not remember the date of 
the last spontaneous menstrual period OR women who have had a hysterectomy WITHOUT oophorectomy 
h 
Markers of bone metabolism:  Markers of bone resorption: serum N-terminal telopeptide of type 1 collagen (NTX), serum C-terminal telopeptide of type 1 
collagen (CTX), serum bone sialoprotein (BSP), urinary deoxypyridinoline (DPD), and serum tartrate-resistant acid phosphatase 5b (TRACP-5b). Markers 
of bone formation: serum total alkaline phosphatase, serum bone specific alkaline phosphatase (BSAP), serum N-terminal propeptide of type 1 collagen 
(P1NP), and serum osteocalcin 
i 
 At Visits 1 and 2, in addition to obtaining a sample for urinalysis, a urine dipstick will be used to rule out urinary tract infections prior to randomization.  
Subjects otherwise eligible, who are found to have a urinary tract infection should receive treatment and may continue after confirmation of cure.  
j 
Adverse events spontaneously reported after signature of the informed consent should be captured. 
k 
Unless subject withdraws consent for Vaginal Imaging during the course of the study, if the quality of the photographs is not adequate as assessed by 
Canfield, a re-shoot should be scheduled as soon as possible but no more than seven days after the original shoot day. 
l 
May be omitted in subjects with a normal mammogram within 9 months prior to screening for which the results are available. 
m 
To be assessed based on pill count.  When there is a discrepancy between the pill count and the subject-reported compliance, the subject-reported 
compliance should be used.  
n 
Do not perform if  discontinuation (early termination) occurs PRIOR to VISIT 5 (Week 12). 
o 
Repeat after cure of infection at V1. 


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p 
Repeat after cure of infection at V2. 
q 
Follow-up call should occur ON Day 14 after last dose. In case subject does not respond, three follow-up attempts should be made.


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3.2 
Rationale for Study Design and Control Group 
In the US, ospemifene 60 mg is the approved dose for the treatment of dyspareunia, a 
symptom of VVA.  In a prior study (Study 15-50310), this dose demonstrated efficacy in 
the treatment of vaginal dryness due to menopause.  Therefore, subjects in the treatment 
group of this study will receive ospemifene 60 mg QD.   
For this study, placebo has been chosen as the comparator since there is no other oral 
non-hormonal therapy approved for treatment of vaginal dryness due to postmenopausal 
VVA; the current clinical standard of care is non-hormonal lubricants.  Subjects in this 
study will be provided with K-Y Jelly® to be used as needed for treatment of vaginal 
dryness.  The 12 week treatment duration is following the regulatory guidance for 
treatment of symptoms of VVA due to menopause.  
3.3 
Study Duration 
3.3.1 
Study Duration in Individual Subjects 
Subjects may be participating in the study for up to 18 weeks.  
3.3.2 
Planned Duration for the Study 
The study is expected to require approximately 60 weeks for enrollment of subjects and 
14 weeks after the last subject is randomized for a total study duration of approximately 
74 weeks.  


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4. STUDY POPULATION SELECTION 
4.1 
Study Population 
The study population will consist of approximately 600 female subjects aged ≥ 40 and 
≤ 80 years who have moderate to severe vaginal dryness, as self-reported MBS of VVA 
due to menopause.  Those who meet the following eligibility criteria may be randomized. 
4.2 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible to participate in 
the study: 
AT VISIT 1 - SCREENING VISIT: 
1. Subject understands the study procedures and risks and voluntarily agrees to 
participate by giving written informed consent. 
2. Subject is ≥40 and ≤80 years old at time of signing informed consent. 
3. Subject is a postmenopausal woman as defined by one of the following:  
a. Is ≥45 years old; her last spontaneous menstrual bleeding must have been 
≥12 months prior to screening 
b. Is ≥45 years old; she does not remember the date of her last spontaneous 
menstrual bleeding and has follicle-stimulating hormone (FSH) levels 
>40 IU/L 
c. Has had a hysterectomy WITHOUT oophorectomy and serum FSH levels 
>40 IU/L 
d. Has had a bilateral oophorectomy at least 6 weeks prior to screening 
4. The subject has 5% or fewer superficial cells in the maturation index of the 
vaginal smear. 
5. Subject has vaginal pH >5.0. 
6. Subject has moderate to severe vaginal dryness as the self-reported MBS of VVA. 
AT VISIT 2 - RANDOMIZATION: 
7. Subject has an intact uterus with double layer endometrial thickness <4 mm at 
screening, as determined by a centrally-read ultrasound OR had a hysterectomy. 
8. Subject has an intact uterus and has no evidence of hyperplasia, cancer, or other 
pathology in an endometrial biopsy OR had a hysterectomy. 
9. Subject has a negative screening mammogram (obtained at screening or within 
9 months prior to screening) and a normal clinical breast examination 
at screening. 
Note: Mammograms obtained within 9 months of screening must be available. 
10. Subject has ≤5% superficial cells in the maturation index of the vaginal smear at 
screening (results will be from Visit 1). 


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11. Subject has vaginal pH >5.0. 
12. Subject has moderate to severe vaginal dryness as the self-reported MBS of VVA. 
4.3 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria are not eligible to participate in 
the study: 
AT VISIT 1 - SCREENING VISIT: 
1. Subject has clinically significant abnormal findings in the physical examination. 
2. Subject has a body mass index (BMI) equal to or greater than 38 Kg/m2. 
3. Subject has uncontrolled hypertension (systolic blood pressure [BP] ≥140 mmHg 
or diastolic BP ≥90 mmHg on two measurements at least 5 minutes apart). 
4. Subject has clinically significant abnormal findings in the gynecological 
examination other than signs of vaginal atrophy (eg, uterine or vaginal prolapse 
≥Grade 2). 
5. Subject has uterine/vaginal bleeding of unknown origin. 
6. Subject has a vaginal infection and refuses treatment, or the infection doesn’t 
respond to the treatment. 
7. Subject has taken any of the following hormonal medications: 
a. Vaginal hormonal products (rings, creams, gels) within 14 days prior 
to screening, 
b. Oral or transdermal estrogen and/or progestin therapy within 60 days prior 
to screening, 
c. Intrauterine progestin therapy within 60 days prior to screening, 
d. Progestin implants or estrogen-alone injectable drug therapy within 90 days 
prior to screening, or 
e. Estrogen pellet therapy or progestin injectable drug therapy within 6 months 
prior to screening.  
f. Other sex hormones or medications that are expected to clinically significantly 
affect sex hormone levels within 60 days prior to screening 
8. Subject has taken a SERM (raloxifene, tamoxifen, toremifene, or clomiphene), 
tibolone, or any other medication that is expected to have clinically-significant 
estrogenic and/or antiestrogenic effects within 60 days prior to screening.  
9. Subject has regularly used any dietary supplement or herbal therapy, including 
black cohosh, soy (including soy milk), phytoestrogens, or over the counter agents 
known to possibly have estrogenic vaginal effects within 30 days prior 
to screening. 
10. Subject is currently using any of the other prohibited medications listed in 
Protocol Section 6.2.1 Prohibited Therapy. 
11. Subject consumes >14 alcoholic drinks per week. (One drink= 1.5 oz of distilled 
spirits, 12 oz of beer, or 5 oz of wine). 


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12. Subject is suspected of having or confirmed to have a malignancy or has history 
of malignancy within 10 years prior to screening (Except for non-melanoma skin 
cancer or carcinoma in situ of the cervix).  Women with a history of breast 
cancer in remission for >10 years and not taking any adjuvant therapy are eligible 
to participate. 
13. Subject has any history of thromboembolic or blood coagulation disorders. 
14. Subject has any history of cerebrovascular accident (eg, bleeding, stroke, or 
transient ischemic attack [TIA]) or cardiac ischemic disorder (eg, myocardial 
infarction, unstable angina). 
15. Subject participated in another clinical study within 30 days prior to screening. 
16. Subject has any physical or mental condition which, in the opinion of the 
Investigator, may interfere with the subject’s ability to comply with the 
study procedures. 
17. Subject has previously taken ospemifene as a treatment. 
18. Subject has any condition or situation which, in the opinion of the Investigator, 
might pose a risk to the subject or interfere with participation in the study. 
19. Subject has an abnormal Papanicolaou (PAP) test result at screening with any of 
the following findings according to the Bethesda System (2001) Classifications:  
a. Atypical Squamous Cells of Undetermined Significance (ASCUS) (human 
papilloma virus [HPV] High Risk Positive),  
b. Atypical Squamous Cells - cannot exclude high-grade squamous 
intraepithelial lesion (HSIL),  
c. Atypical Glandular Cells (Endocervical, Endometrial, not otherwise 
specified [NOS]),  
d. Low Grade squamous intraepithelial lesion (SIL),  
e. High Grade SIL,  
f. Carcinoma, or  
g. Unsatisfactory specimen (one retest will be allowed). 
20. Subject has uterine polyps. 
21. Subject has symptomatic and/or large uterine fibroids (estimated size >3 cm). 
22. Subject has clinically significant abnormalities on electrocardiogram (ECG). 
23. Subject has clinically significant abnormalities in any safety laboratory tests. 
24. Subject has liver enzyme levels (alanine aminotransferase [ALT], aspartate 
aminotransferase [AST]) > 3 times the upper limit of normal (ULN).  
25. Subject is heterozygous or homozygous for Factor V Leiden. 
26. Subject has moderate to severe renal impairment (estimated glomerular filtration 
rate [eGFR] based on Modification of Diet in Renal Disease [MDRD equation] 
< 60 mL/min/1.73 m3). 
27. Subject has a history of hepatic impairment (including chronic hepatitis C, 
hepatitis B, Child-Pugh class B, or Child-Pugh class C). 


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AT VISIT 2 – RANDOMIZATION: 
28. Subject has any condition or situation which, in the opinion of the Investigator, 
might pose a risk to the subject or interfere with participation in the study. 
4.4 
Screen Failures 
Screen failures are defined as patients who consent to participate in the study but are not 
subsequently randomized to the study drug.  Minimal information collected will include 
informed consent date, baseline subject characteristics, all of the eligibility criteria not 
met, reasons for screen failure, adverse events (AEs) that led to screen failure, and any 
serious adverse events (SAEs); these will be entered in the electronic case report form 
(eCRF). 




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At randomization, study drug treatment, ospemifene 60 mg or matching placebo, will be 
assigned in a 1:1 ratio using IxRS according to the randomization schedule.  
Randomization will be stratified by the subject’s severity of vaginal dryness (moderate or 
severe) and the presence or absence of a uterus, such that both treatment groups will have 
similar proportions of subjects with moderate or severe vaginal dryness and with or 
without a uterus at the start of the study.   
5.5 
IxRS Blinding and Unblinding 
This study will be conducted in a double-blind manner using a placebo matching the test 
drug in appearance, labeling, and packaging.  All subjects, the Investigator, all study 
personnel, and the Sponsor will be blinded to the treatment assigned at randomization 
until database lock.  Following database lock, the Sponsor will be unblinded to the 
randomization codes.   
The randomization schedule will be maintained by the IxRS in a blinded manner and will 
not be accessible to anyone until unblinding, except for the Sponsor’s drug supply 
management staff, IxRS clinical coordinator(s), and IxRS vendor staff.   
Emergency unblinding of the study drug should only be undertaken when it is critical to 
the safety and effective medical treatment of a subject.  Prior to unblinding, and if the 
situation allows it, the Investigator should try to contact the Sponsor's medical monitor in 
order to obtain additional information about the study drug.  The Investigator will contact 
the IxRS to provide the subject’s study identification information and confirm the 
necessity for unblinding.  The Investigator will subsequently be provided with the 
subject’s assigned drug treatment as well as a confidential fax or e-mail confirming this 
information.  The system will automatically inform the medical monitor, site monitor, 
Clinical Trial Manager (CTM), drug safety, and the Sponsor that a randomization code 
has been broken.   
If the blind is broken for any study subject for whatever reason, the Investigator must 
document the Subject ID, date and time of breaking the blind, and must clearly explain 
the reasons for breaking the code, and document this in the eCRF.   
The blind will be broken by designated Drug Safety personnel for an individual subject 
for purposes of submitting a suspected unexpected serious adverse reaction (SUSAR) or 
an expedited report to health authorities based on regulatory requirements.  
Once a subject is unblinded, she is no longer eligible to receive the study drug treatment 
and must be discontinued from the study and follow-up assessments must be completed. 
5.6 
Packaging and Labeling 
Study drug will be packaged in bottles that will be provided to the subject at Visits 2, 3, 
and 4. Each bottle will contain 35 tablets.  Throughout the study the same size bottle will 
be used and will be labeled in English with a label that specifies the Sponsor, the study 
number, bottle identification number (BIN), number of tablets, cautionary statement, and 
storage conditions.   


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After randomization, at Visits 2, 3, and 4, each subject will receive adequate drug supply 
to take home; this supply will be sufficient to provide the study drug until the next 
clinic visit.  Regardless of randomization assignment, all subjects will be required to take 
1 tablet of study drug every day during the treatment period. 
The Sponsor or designee will provide the Investigator with adequate quantities of the 
study drug.  The site pharmacist or medically qualified staff member will dispense the 
study drug to each subject as described in Sections 5.2, 5.3 and 5.7. 
5.7 
Storage and Accountability 
Bottles of study drug (ospemifene and placebo) should be stored at 20ºC to 25ºC (68°F to 
77°F); excursions permitted to 15°C to 30ºC (59ºF to 86ºF) and under secure conditions.    
A qualified person at the study site must be designated to receive, handle, and store the 
study drug.  The Investigator (or designee) will maintain an accurate record of the receipt 
of the study drug as shipped by the Sponsor (or designee).  One copy of this receipt will 
be returned to the Sponsor (or designee) when the contents of the study drug shipment 
have been verified. 
Upon receipt, all study drugs should be stored safely, properly, and securely in 
compliance with the specified instructions.  Only the Investigator and authorized 
associates should have access to the study drug.  
The Investigator or qualified member of the study team must maintain an accurate record 
of the study drug dispensed to and returned by the subjects.  Subjects will be asked to 
return all unused study drug and empty bottles at required study visits, at the end of the 
study, or at the time of study drug discontinuation. 
At completion of the study, a final reconciliation of all study drugs will be performed and 
all unused study drug and empty bottles will be returned or disposed of as instructed by 
the Sponsor (or designee). 
Drug accountability records will be available for verification by the designated monitors 
at each monitoring visit.  The study drug must not be used for any purpose other than for 
this study. 
5.8 
Investigational Product Retention at Study Site 
No study drug will be retained at the study site in this study.   
5.9 
Treatment Compliance 
The Investigator and/or study personnel will assess treatment compliance at each visit 
using pill counts and information provided by the subject.  The Investigator should stress 
to the subject the importance of compliance and ensure that she understands the dosing 
instructions.  Compliance checks by tablet count will be performed by qualified site 


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personnel in order to verify that the correct number of doses have been taken based on the 
actual number of days that have elapsed between designated clinic visits. 
A record of the study drug taken by the subject will be made in the eCRF as required.  In 
the event of discrepancy between the tablet count and the information provided by the 
subject, the information provided by the subject will be recorded in the eCRF.   
Based on compliance checks, a subject will be counseled by the site about the importance 
of taking the study drug as directed if < 100% of the required study drug has been taken 
by that subject.  If compliance issues persist and overall dosing compliance is < 80%, the 
Investigator may consider discontinuing the subject from the study.  
In the event a subject has interrupted or discontinued study drug, the subject must inform 
the Investigator and the rationale must be provided in the source document.  The subject 
may continue in the study after agreement with the Investigator.  If the study drug has 
been temporarily discontinued for safety reasons, the Investigator must document the 
reasons in the source document and discuss with the medical monitor prior to the subject 
reinitiating study drug.  All interruptions of study drug (≥1 day) should be captured in the 
eCRF. 
In the event a subject is withdrawn for compliance reasons (eg, missed doses or visits), 
the Investigator will notify the Sponsor or designee promptly and will make every 
effort to complete the early termination assessments and the Completion/Discontinuation 
eCRF.  The Investigator must register all subject discontinuations in the IxRS. 


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6. RESTRICTIONS 
6.1 
Prior Therapy 
Prior therapies are defined as therapies which were taken prior to the initiation of 
study treatment.   
Any prior therapy (prescription drugs, over-the-counter [OTC] drugs, herbal supplements, 
procedures without any medication) taken by the subject within 6 months prior to 
screening will be recorded in the eCRF and the information will include the name of the 
medication/procedure, administration route of drug(s), duration of treatment, and reason 
for use.  
6.2 
Concomitant Therapy 
For randomized subjects, all medications taken (prescription and OTC) and all 
procedures performed after Randomization and through the end of the study, including 
the  2-week follow up call, will be recorded in the eCRF.  The information will include 
the medication/procedure, duration of treatment and the reason for it. Additionally for 
medications, administration route of drug(s) will be captured. 
AEs requiring medication or changes to medication must be recorded on the appropriate 
eCRFs.  Medication taken for a procedure will also be included. 
6.2.1 
Prohibited Therapy 
Prohibited medications should not be taken by subjects at any time during the study. Use 
of prohibited concomitant therapy(ies) may result in study discontinuation. The following 
medications are prohibited: 
 Dietary supplements and herbal therapies with assumed clinically significant 
estrogenic vaginal effects (See Appendix 1) 
 Any form of local vaginal hormonal products 
 Any form of oral or transdermal estrogen or progestin 
 Any form of progestin implants (subdermal or intrauterine) or estrogen implants 
(pellets) 
 Any form of estrogen-alone or progestin-alone injectable drug therapy 
 Sex hormones or medications that are expected to affect clinically significant sex 
hormone levels  
 Any SERMs  
 Any vaginal lubricant or moisturizer other than that provided by the Sponsor for 
use in the study 
 Use of systemic fluconazole, rifampicin, rifabutin, carbamazepine, phenytoin, St 
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Additional medications identified that may have a significant impact on the study drug or 
the indication studied should also be prohibited at the Investigator’s discretion.   


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7. STUDY PROCEDURES AND METHODS OF ASSESSMENTS 
7.1 
Informed Consent 
The Investigator or Sub-investigator will fully explain the nature of the study to the 
subject using the institutional review board (IRB)-approved informed consent form (ICF).  
When the subject agrees to participate in the study, the subject must voluntarily sign the 
ICF prior to the initiation of any study procedures.  A copy of the signed and dated ICF 
will be given to the subject.  The signed and dated original consent form will be retained 
by the Investigator.  Informed consent will be obtained from all subjects.  A subject 
cannot be entered into the study until she has signed and dated the consent form. 
In the event a subject withdraws consent of vaginal imaging after signing ICF, the 
withdrawal will be documented on appropriate page of the already signed ICF and in the 
subject file. The photographs taken prior to withdrawal of consent will be used for study 
research purposes as described in the informed consent. 
The Investigator or Sub-investigator is responsible for ensuring that the subject 
understands the risks and benefits of participating in the study, including answering any 
questions the subject may have throughout the study and sharing any new information in 
a timely manner that may be relevant to the subject’s willingness to continue her 
participation in the study.   
7.2 
Demographics, Baseline Subject Characteristics, and 
Medical History 
Demographic data and medical history, including current medical condition(s), will be 
collected at Visit 1 (Screening) and concurrent medical signs and symptoms will be 
reviewed prior to Visit 2 (Day 1, Randomization).  
Baseline subject characteristics will be obtained and entered in the eCRF.  These include 
date of signed informed consent, date of birth, gender, race, ethnicity, duration of VVA, 
severity of symptoms of VVA and identification of the most bothersome for the subject, 
presence or absence of a uterus, prior therapy, and medical history for the 2 years prior to 
screening, except for any history of cancer.  Any history of cancer should be captured in 
the eCRF regardless of how long ago it occurred.  
Medical history may include but is not limited to evaluation for past or present 
cardiovascular, respiratory, gastrointestinal, renal, hepatic, neurological, endocrine, 
metabolic, lymphatic, hematologic, immunologic, dermatologic, psychiatric, 
genitourinary, drug abuse, or any other diseases or disorders, surgical history, and history 
of diagnosis of VVA.   
7.3 
Enrollment in the Study and Dispensing Study Drug 
At screening, after a subject signs the informed consent, the Investigator, Sub-
investigator, or designee will contact the IxRS to obtain a subject ID.   


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At Visit 2, after a subject is determined to be eligible according to the inclusion/exclusion 
criteria, the Investigator, Sub-investigator, or designee will contact the IxRS to randomize 
the patient.  After randomization of the subject, the Investigator, Sub-investigator, or site 
pharmacist will dispense the study drug as specified in Section 5 using the BIN provided 
by IxRS.  
7.4 
Electronic Diary (eDiary) 
During the Treatment Period, subjects will document daily in an eDiary, their use of 
study drug, use of lubricant, and sexual intercourse.  Subjects will also be asked to record 
overall satisfaction with treatment on a weekly basis.  At Visit 2, after randomization, 
subject will be asked to use an eDiary and clear instructions will be provided on how to 
use it.  Subjects will be allowed to use their own smartphone or tablet as the eDiary by 
downloading an application, as instructed by the site’s personnel.  For subjects who do 
not have a smartphone, an eDiary device will be provided.  
7.5 
Efficacy Assessments 
During the treatment phase of the study, access to the results of some key efficacy 
assessments will be restricted from the Investigators and key Sponsor personnel who are 
involved in the conduct of the study until the study database has been locked.  This is 
specified in a separate document and  follows Section II.C (Design Techniques to Avoid 
Bias) of ICH’s Guidance for Industry (E9) Statistical Principles that state that “The 
double-blind nature of some clinical trials may be partially compromised by apparent 
treatment induced effects.  In such cases, blinding may be improved by blinding 
investigators and relevant sponsor staff to certain test results...”.  In the sections below it 
is specified for which endpoints access will be limited.  Specific details of who will have 
access to each endpoint will be captured in a separate document.   
7.5.1 
Percentage of Parabasal Cells and Superficial Cells in the 
Maturation Index of the Vaginal Smear  
Vaginal smear samples will be taken from the middle third of the lateral vaginal wall and 
will be evaluated throughout the study at the central laboratory by a qualified pathologist.  
The central-laboratory pathologist will perform the cell count associated with the 
maturation index and determine the proportions of parabasal, intermediate and superficial 
cells for each sample.   
The results of the maturation index at Visit 1 (Screening) will be forwarded to the 
Investigator for the assessment of eligibility.  Date of specimen collection will be entered 
in the eCRF.  If the subject has a vaginal infection (requiring medication) at Visit 1, the 
infection should be treated, and the vaginal smear must be repeated after resolution of the 
infection and prior to randomization.  The maturation index from the infection-free 
time point will be used as the baseline value and for assessing eligibility.  
Results of the maturation index at Visit 2 (Randomization) will be used as baseline.   


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During the treatment phase of the study, access to the maturation index results will be 
restricted from the Investigators (except at Visit 1) and key Sponsor personnel involved 
in the conduct of the study until the study database has been locked.   
7.5.2 
Vaginal pH 
Vaginal pH will be measured by the Investigator using a pH indicator strip.  The pH 
measurement will be done by pressing the indicator strip against the middle third of the 
vaginal wall and read while still wet.  Two types of pH strips with different ranges will be 
provided to the study sites.  The strips with a pH range from 4 to 7 should be used first.  
If the measurement is out of the 4 to 7 range, the second pH strip with a range from 2 to 9 
should be used.  Date of specimen collection and the results will be entered in the eCRF.   
The subject will be advised to not use vaginal lubricant and not to have sexual intercourse 
within 24 hours prior to study visits.  If the subject has a vaginal infection (requiring 
medication) at screening, the pH measurement of the vagina will be repeated after 
resolution of the infection and prior to the planned randomization.  The vaginal pH from 
the infection-free time-point will be used as the baseline value and for assessing 
eligibility.  
The pH at Visit 2 will be used as baseline.   
During the treatment phase of the study, access to the pH results will be restricted from 
key Sponsor personnel involved in the conduct of the study until the study database has 
been locked.  
7.5.3 
Severity of Self-Reported VVA Symptoms 
Symptoms of VVA (vaginal dryness, vaginal and/or vulvar irritation/itching, dysuria, 
vaginal pain associated with sexual activity, and vaginal bleeding associated with sexual 
activity) will be assessed through the VVA questionnaire (see Appendix 2), to be 
completed by the subject at every visit. The severity of each symptom will be assessed as 
none, mild, moderate, or severe by the subject.  The study personnel will enter date of 
questionnaire completion and the subject’s responses in the eCRF.   
Subjects must have moderate to severe vaginal dryness at Visit 1 in order to be eligible 
for further screening procedures for the study.  Additionally, at Visit 1 and Visit 2, the 
subject will record which symptom of VVA she finds most bothersome.  To be eligible 
for the study, the subject must report vaginal dryness as her MBS at both Visits 1 and 2.   
The severity of vaginal dryness at Visit 2 will be used as baseline and for stratification 
purposes.   
During the treatment phase of the study, access to the VVA symptom data will be 
restricted from key Sponsor personnel involved in the conduct of the study until the study 
database has been locked.  


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7.5.4 
Vaginal Health Index [9] (VHI; Appendix 3) 
The Investigator will perform an evaluation of the vagina, assessing overall elasticity, 
fluid secretion, pH, condition of epithelial mucosa and moisture.  The severity of each 
characteristic will be assessed with a five-grade evaluation.  Date of evaluation and 
results of the evaluation will be entered in the eCRF. 
If the subject has a vaginal infection (needing medication) at randomization, the visual 
evaluation of the vagina will be repeated after resolution of the infection and prior to 
randomization.  The assessments from the infection-free time-point will be used as the 
baseline value. 
During the treatment phase of the study, access to the VHI data will be restricted from 
key Sponsor personnel involved in the conduct of the study until the study database has 
been locked.  
7.5.5 
Vulvar Health Index (VuHI; Appendix 4) 
Similarly to the VHI, the Investigator will perform a visual examination of the vulva, 
assessing the labia majora, labia minora, clitoris, introitus appearance and elasticity, 
color, discomfort and pain, and presence of other findings (eg, petechiae, excoriations, 
ulcers, etc.).  The severity of each characteristic will be assessed as normal/ mild/ 
moderate/ severe.  Date of evaluation and results of the evaluation will be entered in the 
eCRF.  
If the subject has a vaginal infection (needing medication) at randomization, the visual 
examination of the vulva will be repeated after resolution of the infection and prior to 
randomization.  The assessments from the infection-free time-point will be used as the 
baseline value. 
During the treatment phase of the study, access to the VuHI data will be restricted from 
key Sponsor personnel involved in the conduct of the study until the study database has 
been locked.  
7.5.6 
Vaginal Imaging (Appendix 5) 
For patients who agree to participate in the optional vaginal imaging, photographs of the 
vulva and the vagina will be taken by trained site personnel following the standard 
procedure described in Appendix 5.  
The Sponsor, in cooperation with Canfield Scientific, Inc. (Parsippany, NJ), will provide 
standardized camera equipment and photography procedures for clinical serial 
photography of the vulva and the vagina.  Photographs will be taken per the vaginal 
imaging visit schedule, as specified in the Schedule of Time and Events  
(Table 3.1-1).  The photographs will be sent electronically to Canfield as the central 
repository.  Instructions for obtaining and submitting photographs will be provided by 
Canfield. Date of visit and whether or not the pictures were taken will be entered in the 
eCRF.  After submission, Canfield will assess the quality of the photographs and will 


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provide a written confirmation of receipt of the photographs and feedback of their quality.  
If the quality of the photographs is not adequate, a re-shoot should be scheduled as soon 
as possible but no more than seven days after the original shoot day.  
Photographs will be assessed by an Independent Panel Review (IPR) in a blinded fashion 
and the results of their review will be documented.  Canfield will facilitate such review 
and will collect the data.  Access to the Canfield repository where photographs and 
results of the IPR assessment will be stored, will be restricted from the Sponsor and from 
the Investigators.   
During the treatment phase, access to the photographs and results of the IPR assessment 
will be restricted from the Investigators and key Sponsor personnel involved in the 
conduct of the study until the study database has been locked.   
Procedures to be followed by the IPR will be described in a separate document (IPR 
charter).  
7.5.7 
Female Sexual Function Index (FSFI; Appendix 6) 
Subjects will complete the Female Sexual Function Index (FSFI) [10] questionnaire and 
study personnel will enter the date of completion and the responses in the eCRF.   
7.5.8 
Urinary Distress Inventory (UDI-6; Appendix 7) 
The presence or absence of urinary symptoms (urgency, frequency, incontinence, 
retention, and pain or discomfort) will be assessed using the Urinary Distress Inventory 
(UDI-6) [11].  The subject will complete the questionnaire and the study personnel will 
enter the date of completion and the responses in the eCRF.   
7.5.9 
Efficacy laboratory Tests  
The following hormones will be measured in serum: 
 Estradiol (E2) 
 Follicle-stimulating Hormone (FSH)  
FSH levels may also be measured at Screening (Visit 1) only to confirm 
menopausal status, Inclusion Criterion #3 b. Is ≥45 years old; she does not 
remember the date of her last spontaneous menstrual bleeding and has follicle-
stimulating hormone (FSH) levels >40 IU/L OR c. Has had a hysterectomy 
WITHOUT oophorectomy and serum FSH levels >40 IU/L, as needed. 
 Luteinizing hormone (LH) 
 Sex hormone binding globulin (SHBG) 
 Free testosterone 
 Total testosterone 
The serum hormones will be analyzed by the central laboratory.  The date of specimen 
collection will be entered in the eCRF. 


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During the treatment phase of the study, access to results of hormone levels will be 
restricted from the Investigators (except FSH at Visit 1) and key Sponsor personnel 
involved in the conduct of the study until the study database has been locked.   
7.5.10 
Markers of Bone Metabolism 
Markers of bone metabolism will be measured during the Treatment Period of the study 
to assess the early effect of ospemifene on bone metabolism.  Blood and urine samples to 
measure markers of bone metabolism will be obtained and sent to a central laboratory for 
analysis.  Date of specimen collection will be entered in the eCRF. Markers of bone 
metabolism will include the following:   
7.5.10.1 
Markers of Bone Resorption: 
• Serum N-telopeptide of type 1 collagen (NTX) 
• Serum C-terminal telopeptide of type 1 collagen (CTX) 
• Serum Bone sialoprotein (BSP) 
• Urinary Deoxypyridinoline (DPD) 
• Serum tartrate-resistant acid phosphatase 5b (TRACP-5b) 
7.5.10.2 
Markers of Bone Formation: 
• Serum total alkaline phosphatase 
• Serum bone specific alkaline phosphatase (BSAP) 
• Serum aminoterminal propeptide of type 1 collagen (P1NP) 
• Serum Osteocalcin 
During the treatment phase of the study, access to results of markers of bone metabolism 
will be restricted from key Sponsor personnel involved in the conduct of the study until 
the study database has been locked.   
7.5.11 
Special Considerations Concerning Efficacy Variables 
7.5.11.1 
Urine Dip-Stick Test 
At Visits 1 and 2, a urine dip-stick test will be performed and read at the site to screen for 
a urinary tract infection (UTI). If the result indicates a UTI is present, the UTI must be 
treated to resolution before any efficacy assessments are completed.  
Any UTI diagnosed after the time of Informed Consent will be recorded as a Medical 
History or AE, and should be treated according to the clinical judgment of the 
Investigator.  Any concomitant treatments for UTI should be recorded in the eCRF. 


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7.5.11.2 
Vaginal Infection  
At all visits the sequence of procedures should follow Section 8. However, if a vaginal 
infection requiring medication (e.g. candida vaginitis) is identified at Visit 1 (screening) 
or at Visit 2 prior to randomization, the infection must be treated to resolution. After the 
vaginal infection is treated, 2 weeks (14 days) should be allowed to restore the local 
environment before continuing the screening or randomization procedures. The time 
necessary to treat the infection will not count against the 4-week duration of the screening 
period. If a vaginal infection is identified please follow these procedures: 
1. If the vaginal infection is discovered during the gynecological examination (Visit 
1 or Visit 2), the vaginal pH, the vaginal smear for maturation index, and the 
sample for cervical PAP, along with the rest of the remaining assessments for that 
visit, should not be conducted until the resolution of the infection is confirmed. 
The VVA questionnaire needs to be repeated as it should have been  conducted 
before the gynecological examination.  
2. If the infection is identified based on the results of cervical pap or vaginal smear 
for maturation index obtained at Visit 1, the infection should be treated until 
resolution. The patient should then return for an Unscheduled Visit (prior to Visit 
2) for a repeat of the VVA questionnaire, gynecological examination, vaginal pH, 
vaginal smear (maturation index), and cervical pap, to confirm eligibility.  If 
eligible based on these results the subject may continue to Visit 2.   
3. If the infection takes longer than 30 days to treat, safety laboratory tests 
(hematology and chemistry) should be repeated at an Unscheduled Visit at the 
infection-free timepoint to confirm eligibility.  If eligible based on these results 
the subject may continue to Visit 2 if the infection was diagnosed prior to Visit 2 
or continue with the outstanding procedures from Visit 2 if the infection was 
diagnosed at Visit 2.  
4. In the situations described in items 2 and 3 above, results of tests repeated 
between Visit 1 and Visit 2, at the infection-free timepoint, will be used to 
confirm eligibility (Visit 1) as well as baseline values (Visit 2) and do not need to 
be repeated again at Visit 2. The TVU, endometrial biopsy, and ECG do not need 
to be repeated even if they were assessed prior to the discovery of the infection. 
Any vaginal infection diagnosed after the time of the informed consent will be recorded 
as an AE and should be treated according to the clinical judgment of the Investigator.  
Any medication used as treatment for a vaginal infection should be recorded in the 
Concomitant Medication eCRF. 
7.6 
Safety Assessments 
7.6.1 
Gynecological Examination 
The Investigator will perform a gynecological examination as per the usual clinical 
practice. Information about all gynecological examinations must be included in the 
source documentation at the study site and be signed and dated by the Investigator or 
designee.  Only new, abnormal findings in the gynecological examination should be 


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captured in the eCRF.  Significant changes should be assessed by the Investigator or 
Sub-investigator and considered for potential reporting as an AE.  Date of examination 
will be entered in the eCRF. 
Subjects with uterine or vaginal prolapse of >Grade 2 or higher at screening should not 
be included in the study.  The recommended grading to be used for evaluation at 
screening can be found in Appendix 8. 
7.6.2 
Breast Examination  
A standard breast examination should be conducted by the Investigator.  Information 
about all breast examinations must be included in the source documentation at the study 
site and be signed and dated by the Investigator or designee.  Only new, abnormal 
findings in the breast examination should be captured in the eCRF.  Significant changes 
should be assessed by the Investigator and considered for potential reporting as an AE. 
The date of examination will be entered in the eCRF. 
7.6.3 
Cervical Cytology (Papanicolau) Smear  
Cervical smear samples will be analyzed by Cytotechnologists and a pathologist at the 
central pathology laboratory and will be classified according to the Bethesda 2001 
System.  Date of specimen collection will be entered in the eCRF.  Subjects with the 
following classifications at Visit 1 are not eligible for the study: 
 Atypical Squamous Cells of Undetermined Significance (ASCUS) (human 
papilloma virus [HPV] High Risk Positive),  
 Atypical Squamous Cells - cannot exclude high-grade squamous intraepithelial 
lesion (HSIL),  
 Atypical Glandular Cells (Endocervical, Endometrial, not otherwise 
specified [NOS]),  
 Low Grade squamous intraepithelial lesion (SIL),  
 High Grade SIL,  
 Carcinoma, and 
 Unsatisfactory specimen (one retest will be allowed). 
Detailed procedures for sample collection, handling, labeling, storage, and shipping will 
be specified in a separate document.  Details about the central pathology laboratory are 
provided in Section 10.1. 
7.6.4 
Transvaginal Ultrasound (for Subjects with an Intact Uterus Only)  
A transvaginal ultrasound (TVU) will be conducted to assess the uterus and adnexa.  
Images obtained will also be used to determine endometrial thickness at the central 
ultrasound laboratory.  Date of the TVU will be entered in the eCRF.  The TVU must be 
performed by a trained study staff member and images must be sent to a central reader.  
The results of the TVU at Visit 1 (Screening), including centrally-determined endometrial 


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thickness, will be used to assess eligibility.  The subject should not be randomized until 
the centrally read TVU result indicates the endometrial thickness (double-layer) is <4 
mm.   
If at Screening, the locally read endometrial thickness is evidently, according to the 
Investigators judgment, more than 4 mm, the subject would not be eligible for the study 
and the images from the TVU should not be sent to the central ultrasound laboratory. 
At 12 weeks (Visit 5), the TVU will be performed and the endometrial thickness (double-
layer) will be determined by a central reader following the same procedure.  If the subject 
leaves the study before Week 12, the TVU should be performed as part of the early 
termination visit.   
Any symptomatic and/or large fibroids (estimated size >3 cm) or uterine polyps observed 
in the TVU at Screening (Visit 1) will exclude the subject from the study.  Subjects with 
endometrial polyps identified during the study period will be discontinued, endometrial 
polyps should be reported as an AE, and the AE should be captured as the reason for 
discontinuation. 
Detailed procedures will be specified in a separate document.  Details about the central 
ultrasound laboratory are provided in Section 10.1. 
7.6.5 
Biopsy for Endometrial Histology (for Subjects with Intact Uterus 
Only) 
The endometrial biopsy must be obtained after the TVU is performed.  Use of oral pain 
medication is allowed before the biopsy. Local anesthesia will be used if considered 
necessary by the Investigator. The use of any concomitant medication must be recorded 
in the eCRF. Endometrial biopsy samples will be taken by the Investigator using a 
suction curette (Pipelle® or equivalent, aspiration technique). All endometrial samples 
will be shipped to the central pathology laboratory for preparation of slides. 
The endometrial biopsy performed at Visit 1 will be used to evaluate the subject’s 
eligibility for the study and to establish a baseline reading. Subjects with normal or 
atrophic endometrial histology are eligible to be randomized.  Subjects with an 
insufficient biopsy sample after a valid attempt will be eligible for the study, if the 
endometrial thickness is <4 mm in the centrally-read TVU.  If an endometrial sample 
cannot be obtained due to cervical stenosis (ie, cervical os cannot be penetrated), the 
subject is not eligible for the study. 
All endometrial histological samples (slides) will be analyzed by concurrent readings by 
three independent pathologists.  Each pathologist will be blinded to the treatment group 
and to the readings of the other pathologists. The concurrence of two of the three 
pathologists will be the final diagnosis. If there is no agreement among the three 
pathologists, the most severe pathologic diagnosis would be used as the final diagnosis. 
All pathologists will be blinded both to the study treatment and to each other’s readings 
of the histology slides.  


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Assessment of biopsies will be made according to predefined and generally accepted 
microscopic criteria (Blaustein’s classification).  Subjects found to have endometrial 
hyperplasia or endometrial cancer at screening will be excluded from the study.  Subjects 
found to have endometrial hyperplasia or endometrial cancer during the study will be 
discontinued and endometrial hyperplasia or endometrial cancer should be reported as an 
AE, and the AE should be captured as the reason for discontinuation.  The subject will be 
referred for standard of care clinical management and followed to complete resolution 
(reports of any medical or surgical procedures and the resultant pathology must be 
provided to the Sponsor).  The interpretation of the results by the three pathologists and 
their agreement or disagreement will be managed as described above in order to 
determine the final diagnosis for all endometrial biopsies (those scheduled during the 
study and “for cause” [for example, vaginal bleeding]).   
The date of specimen collection will be entered in the eCRF.  Details about the central 
pathology laboratory are provided in Section 10.1. 
7.6.6 
Vaginal Bleeding 
If a subject reports vaginal bleeding during the study, an attempt will be made to 
determine the etiology.  The possibility of a recent biopsy or other invasive procedure or 
vaginal atrophy as a cause for the bleeding should be considered.  Visual inspection and 
gynecological examination will be performed.  If no obvious reason can be identified and 
the subject has an intact uterus, a TVU will be performed to assess possible uterine 
pathology and the thickness of endometrium.  In addition, the adnexa will be assessed.   
If the endometrium is < 4 mm, an endometrial biopsy will be performed.  If the biopsy 
yields an insufficient sample and bleeding persists, a hysteroscopy and guided biopsy will 
be performed.  If the endometrium is ≥ 4 mm, a hysteroscopy and guided biopsy will be 
performed.  The Investigator should assess the event of vaginal bleeding and its etiology 
for potential report as an AE.  In cases, where the etiology is identified, the etiology 
should be reported as the AE term.  When the etiology cannot be determined, the AE 
term should be vaginal bleeding.  All drugs and procedures used for the diagnosis and/or 
treatment of vaginal bleeding should be captured in the eCRF.  
A flowchart for the suggested process to assess vaginal bleeding in subjects with intact 
uterus is provided in Appendix 9. 
7.6.7 
Physical Examinations  
The physical examination should be performed according to the normal practice of the 
clinical study site by the Investigator.  This should include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, 
abdomen, extremities, and body weight.   
Information about all physical examinations must be included in the source 
documentation at the study site and be signed and dated by the Investigator or designee.  
Only new, abnormal findings in the physical examination should be captured in the 


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eCRF.  Significant changes in the physical examination should be assessed by the 
Investigator or Sub-investigator and considered for potential reporting as an AE. 
7.6.8 
Vital Signs  
Vital signs (BP, pulse rate, and oral temperature) will be measured by a qualified site 
staff member.  Height will be measured in centimeters and weight in kilograms.   
The BP and pulse rate will be measured after the subject has been in a sitting or 
recumbent position for ≥3 minutes.  The BP and pulse rate will be measured by the 
Investigator or designee by using a blood pressure cuff of an appropriate size.   
The Investigator or Sub-investigator will determine whether any abnormal changes from 
baseline (Visit 2) are clinically significant.  Results of BP, oral temperature, pulse rate, 
height and weight will be entered into the eCRF.  BMI will be automatically calculated in 
the eCRF. 
7.6.9 
Electrocardiograms/Electrocardiography 
A standard 12-lead ECG will be performed at screening after the subject has been in a 
supine position for at least 5 minutes.   
The Investigator or designee will be responsible for reviewing the ECG to assess whether 
it is normal or abnormal; abnormal ECG findings will be further divided into clinically 
significant and not clinically significant. 
The ECGs will be retained as source documents and must be signed and dated by the 
Investigator or designee.  Clinically significant findings observed at screening must be 
discussed with the Sponsor’s medical monitor or designee to determine whether or not to 
enroll the subject in the study and must be recorded in the eCRF if enrolled.  The date 
performed, ECG test result (normal or abnormal), and assessment of clinically significant 
findings will also be recorded in the eCRF. 
7.6.10 
Clinical Laboratory Tests 
7.6.10.1 
Laboratory Parameters 
Safety laboratory tests are shown in Table 7.6-1 and the Schedule of Time and Events, 
Table 3.1-1. 
Subjects will be in a seated or supine position during blood collection.  At Visit 1, routine 
laboratory tests may not be fasting.  Starting at Visit 2 patient should fast at least 8 hours 
prior to obtaining laboratory samples.   
At Screening, a one-time follow-up blood draw is allowed for retest of abnormal values 
that could exclude the subject from study participation.  If the retest is again abnormal, 
the subject should be excluded. 


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Table 7.6-1 
Laboratory Tests 
Category 
Evaluation Items 
Hematology Tests 
hematocrit, hemoglobin, platelet count, red blood cell (RBC) count, white blood 
cell (WBC) count with differential (eosinophil count, basophil count, neutrophil 
count, monocyte count, lymphocyte count), platelet count, mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean 
corpuscular volume (MCV), RBC distribution width (RDW), mean platelet 
volume (MPV) 
Blood Chemistry Tests ALP, ALT, AST, total bilirubin, GGT, LDH, BUN, creatinine, uric acid, sodium 
(Na), potassium (K), chloride (Cl), calcium (Ca), glucose, total protein,  
Lipids 
Total cholesterol, Low-density lipoprotein (LDL)  cholesterol, Very-low-density 
lipoprotein (VLDL) cholesterol, High-density lipoprotein (HDL) cholesterol, and 
Triglycerides 
Coagulation 
Thromboplastin time, Fibrinogen, Antithrombin III, Factor V Leiden (screening 
only), Protein-C, and Protein-S 
Urinalysis for 
Qualitative 
pH, specific gravity, color, bilirubin, glucose, ketones, nitrite, occult blood, 
protein, urobilinogen, and microscopic evaluation of sediment  
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ALP = alkaline 
phosphatase; GGT = gamma glutamyl transferase; LDH, lactate dehydrogenase; BUN, blood urea nitrogen. 
 
The Investigator or Sub-investigator will assess whether any abnormal changes from 
baseline (Visit 2) are clinically significant.  Clinically significant changes in laboratory 
parameters should be considered by the Investigator for reporting as adverse experiences 
as long as they reflect a change/worsening from baseline.  The date of specimen 
collection will also be entered in the eCRF. 
7.6.10.2 
Sample Collection, Storage, and Shipping 
A study-specific laboratory manual will detail sample collection, storage, and shipping 
procedures.  Serum or plasma samples will be stored at least one year after the date of 
database lock. 
Blood and urine samples except for the dipstick urinalysis, will be collected by the 
Investigator or designee at specified time points and sent to a central laboratory for 
processing.  Details about the central laboratory are provided in Section 10.1. 
7.6.11 
Adverse Events Assessments 
7.6.11.1 
Performing Adverse Events Assessments 
An AE is defined as any untoward medical occurrence in a subject administered a 
pharmaceutical product (including investigational drug) during the course of a clinical 
investigation.  An AE can, therefore, be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of an investigational product, whether or not considered related to the investigational 
product.   
The AEs will be found by the subject's spontaneous complaint, or as a result of non-
leading questions, physical examination, vital signs, laboratory tests, or other procedures.  


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The AEs include any occurrences that are new in onset or aggravated in severity or 
frequency from the baseline condition, or abnormal results of diagnostic procedures, 
including laboratory test abnormalities.  Conditions reported as medical history at 
baseline that worsen during the course of the study will be considered AEs.  Lack of 
efficacy determined by progression of symptoms of vaginal dryness, or dyspareunia are 
not AEs in this study.   
The AEs resulting from concurrent illnesses, concomitant medications, or progression of 
disease states must also be reported.  A procedure should not be reported as an AE; only 
the condition for which the procedure is required should be reported as an AE if it is new 
or is a worsening of a pre-existing condition.  Elective procedures for which the 
underlying condition was present at screening and has not worsened, do not constitute an 
AE.   
The Investigator or Sub-investigator is responsible for assessing AEs.  AEs should be 
fully investigated and recorded in detail including onset date, end date (if outcome is 
other than not recovered, recovering, or unknown), severity, relationship with the study 
drug, action taken due to the AE, and outcome of the AE in the eCRF. 
7.6.11.2 
Timing 
All AEs will be collected from the time of informed consent through the Follow-Up call.  
If a subject withdraws early from the study, the Investigator or Sub-investigator will 
make an effort to collect AEs for 2 weeks after the last dose of study drug.  Any AE or 
SAE ongoing 2 weeks after the last dose of study drug will be followed until resolution, 
stabilization, the condition becomes chronic, or the subject is lost to follow-up.   
7.6.11.3 
Severity 
The severity of an AE will be graded by the Investigator or Sub-investigator according to 
the following definitions: 
 Mild: A finding or symptom is minor and does not interfere with usual 
daily activities. 
 Moderate: The event is uncomfortable and causes interference with usual daily 
activity or affects clinical status. 
 Severe: The event causes interruption of the subject's usual daily activities or has 
a clinically significant effect. 
The highest severity during the period when the AE occurred will be recorded in 
the eCRF. 
7.6.11.4 
Relationship 
The relationship (causality) of AE to the study drug should be determined by the 
Investigator according to the following criteria: 


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 Related: An AE for which causal relationship with the study drug can be 
reasonably explained.  For example, the occurrence of the AE cannot be explained 
by other causative factors, the AE can be explained by the pharmacological effect 
of the study drug (eg, a similar event had been reported previously), or 
increase/decrease of the dose affect the characteristics of the AE 
(rechallenge/dechallenge), etc. 
 Not Related: An AE for which causal relationship with the study drug cannot be 
reasonably explained. 
7.6.11.5 
Expectedness 
An AE is expected if it is listed in the Adverse Reactions Section of the current 
ospemifene U.S. package insert. 
7.6.11.6 
Action Taken 
Any action taken with regard to study drug as a consequence of an adverse experience, 
drug withdrawn, drug interrupted, dose not changed or not applicable, should be captured 
in the eCRF. 
7.6.11.7 
Laboratory Adverse Events 
Abnormal laboratory test results are defined as having a value outside the reference range.  
For laboratory test results which are normal at baseline and become abnormal following 
initiation of the study or results which are abnormal at baseline and significantly worsen 
following the initiation of the study, the Investigator or Sub-investigator must also 
consider whether the results are clinically significant.  Any test results considered 
clinically significant by the Investigator or Sub-investigator should be considered for 
reporting as AEs.  If an abnormal laboratory finding is associated with other clinical 
findings for which a diagnosis can be provided, the Investigator should report only the 
diagnosis (and not the laboratory abnormality) as AEs.   
The Investigator or Sub-investigator will consider a test result clinically significant if the 
test result: 
 Leads to any of the outcomes included in the definition of an SAE (See 
Section 7.6.11.8). 
 Leads to discontinuation from the study. 
 Leads to a concomitant drug treatment or other therapy. 
 Requires additional diagnostic testing or other medical intervention. 
 Meets the management and discontinuation criteria for abnormal liver function 
tests (LFTs) identified in Appendix 10. 
In addition, when any test result meets the management and discontinuation criteria for 
liver function abnormalities (Appendix 10), the results of further assessments and 
required follow-up should be recorded in the Liver Event Form. 


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7.6.11.8 
Serious Adverse Events 
Definition 
An SAE is defined by regulation as any AE occurring at any dose that results in any of 
the following outcomes: 
 Death 
 Life-threatening condition 
 Hospitalization or prolongation of existing hospitalization for treatment 
 Persistent or significant disability/incapacity 
 Congenital anomaly/birth defect 
 Other medically important conditions that may not result in death, be life 
threatening, or require hospitalization may be considered an SAE when, based 
upon appropriate medical judgment, they may jeopardize the subject’s health and 
may require medical intervention to prevent one of the outcomes listed in the 
above definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse.   
The Investigator or Sub-investigator will determine the seriousness of AEs.  Test results 
that meet the following Hy’s law criteria are considered SAEs. 
 AST or ALT >3 × ULN and total bilirubin (TBL) >2 × ULN  
Reporting Serious Adverse Events 
All SAEs must be reported to the Sponsor in detail on the SAE form within 24 hours 
from the point in time when the Investigator first becomes aware of the SAE.  All SAEs 
must be reported regardless of causal relationship to the study drug.  A sample of the 
SAE form can be found in the Site Regulatory Binder.  Follow-up information about the 
SAE may be requested by the Sponsor.   
When reporting SAEs, the Investigator should record the diagnosis whenever possible.  
If no diagnosis is available at the time of reporting, individual signs and symptoms can 
be reported. 
In the event of any SAE reported or observed during the study, whether or not 
attributable to the study drug, site personnel must prepare an SAE Form and 
submit the completed form within 24 hours to: 
UBC Hotline 
Tel: 
 
Email: 
 
Fax: 
 
PPO
PPO
PPO


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If follow-up is required or requested, the Investigator should provide new information to 
the Sponsor's medical monitor as it becomes available using the SAE Form, then it 
should be submitted.  Discharge summaries, consultant reports, autopsy reports, and/or 
other relevant documents must be evaluated by the Investigator and all relevant 
information must be included on the follow-up SAE form.  Copies of these reports may 
also be requested by the Sponsor. 
Appropriate remedial measures should be taken by the Investigator using his/her best 
medical judgment to treat the SAE.  These measures and the subject’s response to these 
measures should be recorded.  Clinical, laboratory, and diagnostic measures should be 
used by the Investigator as needed to adequately determine the etiology of the event.  
Any SAE that occurs after the AE assessment period specified in Section 7.6.11.2 that 
is considered by the Investigator to be related to study drug must be reported to 
the Sponsor. 
The Investigator will be responsible for reporting all SAEs to the IRB.  The Sponsor will 
be responsible for reporting SAEs to the regulatory authorities, as required by the 
applicable regulatory requirements. 
7.6.11.9 
Special Situations: Abuse, Misuse, Overdose, and Medication Error 
Abuse, misuse, overdose, or medication error of the study drug (as defined below) must 
be reported by the Investigator to the Sponsor within 24 hours using a Special Situations 
Report Form. If there are associated SAEs, the Investigator will also complete an SAE 
Form and submit to the Sponsor, within 24 hours of becoming aware.  
 Abuse - Persistent or sporadic intentional excessive use of an investigational 
product that is accompanied by harmful physical or psychological effects. 
 Misuse - Intentional and inappropriate use of an investigational product at any 
dose other than as directed or indicated. 
 Overdose - Intentional or unintentional intake of a dose of investigational product 
higher than the dose assigned in the protocol.  
 Medication Error - Any unintended error in the prescribing, dispensing, or 
administration of an investigational product.  If a subject misses doses of 
investigational products, these not considered reportable as medication errors.  
7.6.11.10 
Treatment-Emergent Adverse Events 
AEs reported after the initial dose of randomized study drug will be considered 
treatment-emergent adverse events (TEAE). 
7.7 
Withdrawal of Subjects from the Study or Study Drug 
Subjects may voluntarily withdraw from the study for any reason at any time.  A subject 
may be considered withdrawn if she states an intention to withdraw, fails to return for 
visits, or becomes lost to follow-up. 


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In the event of a subject’s early withdrawal, the Investigator will promptly notify the 
Sponsor and will make every effort to determine the primary reason for the premature 
withdrawal from the study and will record this information on the 
Completion/Discontinuation eCRF.  All subjects withdrawn due to AEs will be followed 
until resolution of any AEs or at least until the unresolved AEs are judged by the 
Investigator to have stabilized, becomes chronic, or the subject is lost to follow-up.  
During the Treatment Period, the date of last dose of study drug will be entered in the 
eCRF. If the subject withdrew before the end of the Treatment Period, date of 
discontinuation and the reason for discontinuation will be entered in the eCRF. 
The following require study drug discontinuation: 
 Subject develops SAE or intolerable AE considered related to study drug or if the 
Investigator determines the subject should be withdrawn because of safety reasons 
 Subject meets Liver Discontinuation Criteria (Appendix 10) 
 Subject is lost to Follow-up 
 Subject has a protocol deviation that results in a significant risk to the subject’s 
safety 
 Subject is unblinded 
 Subject decides to discontinue her participation in the study for any reason 
 Subject is diagnosed with endometrial polyps, endometrial hyperplasia or 
endometrial cancer   
The Investigator must register all subject discontinuations in the IxRS.  In the event of a 
subject’s withdrawal, the Investigator will promptly notify the IxRS and will make every 
effort to complete the end-of-study (or early termination) assessments.  All patients 
withdrawn due to AEs will be followed until resolution or until the unresolved AEs are 
judged by the Investigator to have stabilized, the condition becomes chronic or the patient 
is lost to follow-up.  All subjects who withdraw or are discontinued from the study will 
be followed for 14 days after the last dose.  Any AEs that are ongoing 14 days after the 
last dose will be followed until resolution or until they are judged by the Investigator to 
have stabilized or the condition becomes chronic.   
For subjects who are lost to follow-up (ie, those subjects whose status is unclear because 
they fail to appear for study visits without stating an intention to withdraw), the 
Investigator should show “due diligence” by documenting in the source documents steps 
taken to contact the subject, such as dates of telephone calls, registered letters, etc. 
Subjects who have been prematurely discontinued will undergo assessments as outlined 
in Section 8.5.  A Completion/Discontinuation form must be completed for all subjects 
who discontinue prematurely or who are lost to follow-up.  


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7.8 
Appropriateness of Measurements 
All efficacy and safety evaluations selected for the study are typical of those for this 
subject population and type of investigation, and utilize widely accepted measures.  
7.9 
Visit Time Window 
Measurements for efficacy or safety endpoints will be performed according to the 
schedule as shown in Schedule of Time and Events, Table 3.1-1.   
In this study, no time windows are pre-specified.  All efforts should be made to ensure 
subjects attend the study visits according to the original visit schedule.  If it is completely 
unavoidable, and the subject must come for a visit outside of the time outlined on the 
visit schedule, the site personnel must ensure that the subject has enough study drug to 
last until the scheduled visit.  If a subject comes early or late to a study visit, the time to 
the next visit should be adjusted to align the future study visits with the original visit 
schedule.  Subjects should not be exposed to study drug for more than 12 weeks.   
 


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8. STUDY ACTIVITIES 
The overall Schedule of Time and Events for this study is provided in Table 3.1-1. 
Subjects will be required to participate in both on-site clinic visits as well as a phone call 
that site personnel will schedule based on the subject’s initial randomization date.  For 
the scheduled phone call, subjects will be contacted by the Investigator or designee at the 
end of the post-study Follow-up Period.  If clinically indicated and at the Investigator’s 
discretion, the study subject may be asked to complete an unscheduled visit.  
In the sections below, activities to be performed have been listed in the order that appears 
to simplify the process for the site and the subject.  At Screening and Randomization 
visits, procedures that may exclude a subject immediately are to be conducted earlier to 
ensure subjects that will not qualify do not undergo the most invasive/uncomfortable 
procedures.   
8.1 
Screening, Visit 1 (Up to 4 Weeks Prior to Randomization) 
Screening should take place up to 4 weeks (28 days) prior to randomization.  Enough 
time between Visit 1 and Visit 2 should be allowed to receive the results of tests 
conducted as part of Visit 1, therefore, Visit 2 should not take place earlier than 1 week 
after Visit 1.  The Investigator will inform each prospective subject of the nature of 
thestudy, explain the potential risks, and obtain written informed consent from the subject 
prior to performing any study-related procedures and prior to the administration of the 
study drug. 
 Sign ICF 
 Contact IxRS to obtain subject ID number 
 Obtain urine sample for urinalysis (dipstick + central laboratory) and perform 
dipstick assessment prior to the next procedure 
 Record demographics  
 Record medical history 
 Record prior therapy 
 Assess inclusion and exclusion criteria 
 Assessment of VVA symptoms  
 Measure vital signs (BP, pulse rate, and oral temperature performed after subject 
is in seated or in a recumbent position ≥3 minutes) including height and weight 
 Perform physical examination  
 Perform breast examination 
 Perform gynecological examination 
 Measure vaginal pH 
 Obtain vaginal smear for assessment of maturation index 
 Obtain sample for cervical PAP smear 


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 Perform TVU and measure endometrial thickness   
 Perform endometrial biopsy 
 Obtain 12-lead ECG (performed in a supine position after ≥5 minutes) 
 Obtain blood samples for safety laboratory tests and FSH to confirm 
postmenopausal status in women ≥45 years old who do not remember the date of 
the last spontaneous menstrual period OR women who had a hysterectomy 
without oophorectomy.  
 Assess for AEs (with a start time after signing ICF) 
 Conduct/order mammogram  
For subjects who have a normal mammogram within 9 months prior to screening 
for which the results are available, those results can be used and a new 
mammogram is not required for eligibility assessment. 
At the time of Screening, a one-time follow-up blood draw is allowed for the retest of 
abnormal values that may exclude the subject from study participation. 
8.2 
Randomization, Visit 2 (Day 1)  
Subjects will return to the study site at Visit 2 (Day 1) for the performance of 
study related procedures, randomization and dispensing of study drug and lubricant.  All 
baseline procedures are to be performed prior to the first dose of study drug.  After Visit 
2, study subjects will be instructed to identify the most appropriate time for dosing each 
day (ie, time of day most likely to be associated with highest compliance and 
convenience).  Once the time of dosing is established, every effort should be made to take 
the study drug at approximately the same time each day.   
The following measurements and/or evaluations will be made and recorded in the eCRF: 
 Record any changes in prior therapy since screening 
 Obtain urine sample for urinalysis, dipstick, and urine markers of bone 
metabolism.  Dipstick assessment should be performed prior to the next procedure 
 Assess inclusion/exclusion criteria (including results of safety laboratory tests, 
PAP smear, and endometrial biopsy obtained at screening) 
 Assess for AEs 
 Assess symptoms of VVA 
 Assess FSFI 
 Assess UDI-6 
 Measure vital signs (BP, pulse rate, and oral temperature performed after subject 
is in seated or in a recumbent position ≥3 minutes) including weight  
 Perform physical examination 
 Perform breast examination 
 Perform gynecological examination 


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 Measure vaginal pH 
 Obtain vaginal smear for assessment of maturation index 
 Assess VHI 
 Assess VuHI 
 Obtain vulvo-vaginal imaging (optional) 
 Obtain blood samples for safety laboratory tests, hormone levels, and serum 
markers of bone metabolism 
 Dispense eDiary and instruct the subject on how to use it 
 Contact IxRS to randomize the subject 
 Dispense study medication and lubricant 
 Reinforce compliance with study medication 
8.3 
Treatment Period, Visit 3 (Week 4) through Visit 5 (Week 12) 
8.3.1 
Visit 3 (Week 4) and Visit 4 (Week 8) Procedures 
The following measurements and/or evaluations will be made and recorded in the eCRF: 
 Record any changes in concomitant therapy 
 Assess for AEs 
 Assess symptoms of VVA 
 Assess FSFI 
 Assess UDI-6 
 Measure vital signs (BP, pulse rate, and oral temperature performed after subject 
is in seated or in a recumbent position ≥3 minutes) including weight  
 Measure vaginal pH 
 Obtain vaginal smear for assessment of maturation index 
 Assess VHI  
 Assess VuHI 
 Assess eDiary compliance 
 Assess study medication returned and assess compliance with study medication 
 Dispense study medication assigned by IxRS and lubricant 
 Reinforce compliance with study medication 
8.3.2 
Visit 5 (Week 12) End of Study Procedures 
The following measurements and/or evaluations will be made and recorded in the eCRF: 
 Record concomitant therapy 
 Assess for AEs 
 Assess symptoms of VVA 


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 Assess FSFI 
 Assess UDI-6 
 Measure vital signs (BP, pulse rate, and oral temperature performed after subject 
is in seated or in a recumbent position ≥3 minutes) including weight  
 Perform physical examination 
 Perform breast examination 
 Perform gynecological examination 
 Measure vaginal pH 
 Obtain vaginal smear for assessment of maturation index 
 Assess VHI 
 Assess VuHI 
 Obtain vulvo-vaginal imaging (optional) 
 Perform TVU and measure endometrial thickness   
 Perform endometrial biopsy 
 Obtain blood samples for safety laboratory tests, hormone levels, and serum 
markers of bone metabolism 
 Obtain urine sample for urinalysis and urinary marker of bone metabolism 
 Assess eDiary compliance.  For subjects who received a device, it should be 
collected  
 Assess study medication returned and assess compliance with study medication 
8.4 
Telephone Call at the End of the Follow-up Period (Two Weeks 
after Treatment Period Completion) Procedures 
Subjects will receive a follow-up telephone call two weeks after the last dose of study 
drug.  During the phone call the study personnel will assess for AEs since the last visit.  
Any AEs should be captured in the eCRF.  If an AE is reported and needs to be followed, 
procedures described in Section 7.6.11 should be followed.  Information of concomitant 
therapy after the last dose of study drug will also be collected in the phone call. 
8.5 
Early Termination Procedures 
If a subject discontinues from the study early (i.e., before end of treatment period Visit 5), 
the following measurements and/or evaluations will be made and recorded in the eCRF: 
 Record concomitant therapy 
 Assess for AEs 
 Assess symptoms of VVA 
 Assess FSFI 
 Assess UDI-6 


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 Measure vital signs (BP, pulse rate, and oral temperature performed after subject 
is in seated or in a recumbent position ≥3 minutes) including weight  
 Perform physical examination 
 Perform breast examination 
 Perform gynecological examination  
 Measure vaginal pH 
 Obtain vaginal smear for assessment of maturation index 
 Assess VHI 
 Assess VuHI 
 Obtain vulvo-vaginal imaging (optional) 
 Perform TVU and measure endometrial thickness.  Capture images to be sent to 
the central reader  
 Obtain blood samples for safety laboratory tests, hormone levels and serum 
markers of bone metabolism 
 Obtain urine sample for urinalysis and urinary marker of bone metabolism 
 Assess study medication returned and assess compliance with study medication 
 Assess eDiary compliance. For subjects who received a device, it should be 
collected 
 
 


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9. PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
The statistical analysis will be performed by the Sponsor or designee.  Detailed statistical 
analysis methods will be specified in a statistical analysis plan (SAP) according to this 
section of the study protocol.  Analyses deviating from those outlined in the protocol will 
be clearly specified in the SAP, and the reason for deviation from the protocol will be 
described.  The SAP will be finalized before breaking the study blind.   
Unless otherwise noted, continuous variables will be summarized by using the number of 
non-missing observations, arithmetic mean, standard deviation (SD), median, minimum, 
and maximum values as descriptive statistics; categorical variables will be summarized 
by using the frequency count and the percentage of subjects in each category as 
descriptive statistics.   
All statistical tests will be performed at the 0.05 significance level using two-sided tests, 
except where otherwise noted.   
All subject study data, including data not appearing in tables, will be presented by-subject 
data listings.  In general, all tables will be presented by treatment group.  Individual 
subject data and any derived data will be presented by treatment and subject.  All 
analyses and tabulations will be performed by using SAS® Version 9.2 or higher. 
9.2 
Determination of Sample Size 
Approximately 600 subjects, about 300 subjects per arm (1:1 randomization ratio), 
will be randomized in the study.   
Table 9.2-1 shows the difference between ospemifene and placebo and the effect size in 
each of 4 co-primary endpoints, namely vaginal pH, percentage of parabasal cells and 
percentage of superficial cells in the maturation index of the vaginal smear, and MBS of 
vaginal dryness for the two pivotal studies.  
 


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Table 9.2-1 
Change from Baseline to Week12 in Two Pivotal Studies 
Primary 
Efficacy 
Variable 
Study 
Ospemifene 
Placebo 
Difference 
SDcommon 
Effect 
Size
*2)
 
MBS of Vaginal 
Dryness 
15-50310 
 
 
 
 
 
 
 
15-50821 
 
 
 
 
 
 
 
Vaginal pH 
15-50310 
 
 
 
 
 
 
 
15-50821 
 
 
 
 
 
 
 
% Parabasal 
Cells 
15-50310 
 
 
 
 
 
 
 
15-50821 
 
 
 
 
 
 
 
% Superficial 
Cells 
15-50310 
 
 
 
 
 
 
 
15-50821 
 
 
 
 
 
 
 
*1)  
Mean±SD 
*2) 
  ;   
 
For the planned study, referring to the results in  
Table 9.2-1, the effect size is assumed to be 0.27 for MBS of vaginal dryness, 0.70 for 
vaginal pH, 0.83 for % parabasal cells and 0.68 for % superficial cells.  Table 9.2-2 
shows the power of two-sided t-test with significance level of 0.05 and total sample size 
of 600 (300 for each treatment group) for each of the 4 co-primary endpoints under the 
assumed effect size.  A sample size of 600 patients provides ≥ 90% power to assess the 4 
co-primary efficacy endpoints. 
C
P
I


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Table 9.2-2 
Expected Power with Total Sample Size of 600 
 
MBS of 
Vaginal 
Dryness 
Vaginal pH 
% 
Parabasal 
Cells 
% 
Superficial 
Cells 
4 Co-Primary 
Endpoints 
Effect Size 
 
 
 
 
 
Power 
 
 
 
 
 
 
9.3 
Analysis Populations 
The following analysis populations will be analyzed for this study. 
 Safety Population includes all randomized subjects who receive at least one dose 
of the study drug.  This population will be analyzed according to the treatment the 
subjects actually received, rather than the treatment to which the subjects were 
randomized. 
 Intention-to-Treat (ITT) Population is defined as any subject that is 
randomized and receives at least one dose of study medication. All efficacy 
analyses will be based on this population.  This population will be analyzed as 
randomized. 
 Per-Protocol Population (PP) will be defined in the SAP and the PP population 
will be determined before breaking the study blind. 
The primary efficacy analysis will be done on both the ITT population and PP 
population. 
9.4 
Handling of Missing Data 
Missing data will not be imputed.  All analyses will be based on observed data.   
9.5 
Subject Disposition 
Among subjects randomized to each treatment group, the number and percent of the 
subjects who complete the study (Visit 5), and the number and percent who prematurely 
discontinue the study will be summarized.  In addition, reasons leading to study 
discontinuation will be summarized for each treatment group.  The number and percent of 
randomized subjects included in each analysis population will also be presented. For 
subjects who completed Part A and entered Part B, reasons for discontinuation will also 
be summarized. 
9.6 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized with descriptive statistics 
by treatment group for the ITT Population.  Demographic variables will include age, 
body weight, height, ethnicity, and race. 
C
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9.7 
Treatment and Treatment Compliance 
The duration of treatment exposure and percent compliance (up to Visit 5) will be 
summarized with descriptive statistics by treatment group for the ITT Population. 
9.8 
Prior Therapy 
Prior medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD).  Prior medications include all medications used prior to the first dose.  Prior 
medication will be summarized by treatment group and will be provided in Listings.  The 
number and percentage of subjects who report prior medications will be reported by 
WHO-DD classification for each of the treatment groups.   
9.9 
Concomitant Therapy 
Concomitant medications will be coded using the WHO-DD.  Concomitant medications 
will include all medications used after the first dose of study drug and those medications 
taken prior to the first dose but ending during study treatment.    
The number and percentage of subjects using concomitant medications (up to Visit 5) 
will be calculated by appropriate WHO-DD classification for each of the treatment 
groups. 
9.10 Efficacy Analyses 
The ITT Population will be the primary population for efficacy analyses.    
9.10.1 
Primary Efficacy Endpoints 
The primary efficacy endpoints will be the difference between ospemifene 60 mg QD and 
placebo in treatment of VVA due to menopause in women with moderate to 
severe vaginal dryness as the MBS of VVA at 12 weeks of treatment based upon: 
a. Change from baseline in the percentage of parabasal cells in the maturation index 
of the vaginal smear after treatment with ospemifene 60 mg QD compared with 
placebo at 12 weeks, 
b.  Change from baseline in the percentage of superficial cells in the maturation 
index of the vaginal smear after treatment with ospemifene 60 mg QD compared 
with placebo at 12 weeks, 
c. Change from baseline in the vaginal pH after treatment with ospemifene 60 mg 
QD compared with placebo at 12 weeks, and 
d. Change from baseline in the severity of self-reported MBS of vaginal dryness 
after treatment with ospemifene 60 mg QD compared with placebo at 12 weeks.   


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9.10.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints will be: 
 Change from baseline in percentage of parabasal cells in the maturation index of 
the vaginal smear after treatment with ospemifene 60 mg QD compared with 
placebo at 4 and 8 weeks,  
 Change from baseline in percentage of superficial cells in the maturation index of 
the vaginal smear after treatment with ospemifene 60 mg QD compared with 
placebo at 4 and 8 weeks, 
 Change from baseline in the vaginal pH after treatment with ospemifene 60 mg 
QD compared with placebo at 4 and 8 weeks, 
 Change from baseline in the severity of self-reported MBS of vaginal dryness 
after treatment with ospemifene 60 mg QD compared with placebo at 4 and 
8 weeks, 
 Change from baseline in the severity of other VVA symptoms other than vaginal 
dryness (ie, dyspareunia, vulvar/vaginal itching/irritation, dysuria 
[difficult/painful urination], and/or vaginal bleeding associated with intercourse) 
after treatment of ospemifene 60 mg QD compared with placebo over 12 weeks, 
 Change from baseline in markers of bone metabolism after treatment with 
ospemifene 60 mg QD compared with placebo, 
 Change from baseline in VHI after treatment with ospemifene compared 
with placebo over 12 weeks, 
 Change from baseline in VuHI after treatment with ospemifene compared 
with placebo over 12 weeks, 
 Change from baseline in FSFI after treatment with ospemifene 60 mg QD 
compared with placebo over 12 weeks, and 
 Change from baseline in UDI-6  after treatment with ospemifene 60 mg QD 
compared with placebo over 12 weeks. 
9.10.3 
Analyses of Efficacy Endpoints 
9.10.3.1 
Statistical Analysis Methods for Primary Efficacy Endpoints 
The following analyses will be performed for both of ITT and PP populations. 
For each of percentage of parabasal cells, percentage of superficial cells and vaginal pH, 
Mixed-effects Model Repeated Measures (MMRM) approach will be used. In the model, 
repeated  measurements of the change from baseline at Week 4, Week 8 and Week 12 
will be the response variable. Baseline value and study center will be modeled as 
covariates. Significance test to compare the ospemifene group with the placebo group 
will be based on the mean difference between the two groups at Week 12. 


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For the MBS of vaginal dryness, Generalized Estimating Equations (GEE) model will be 
used to fit a marginal proportional odds model to the longitudinal ordered categorical 
data (Fitzmaurice et al., 2011).  In the model, repeated measurements of the change from 
baseline in MBS of vaginal dryness at Week 4, Week 8 and Week 12 will be the response 
variable. Baseline severity of dryness and study center will be modeled as covariates. 
Significance test to compare ospemifene group to placebo group will be based on the 
mean of cumulative log odds ratio (over ordered category responses) at Week 12. 
9.10.3.2 
Other Statistical Analysis Methods for Secondary Endpoints 
For secondary efficacy endpoints, Analysis of Covariance (ANCOVA) will be used for 
observed case data, where baseline will be included as covariate.   
9.10.3.3 
Sensitivity Analyses for the GEE analysis 
In order to evaluate the robustness of the GEE analysis for the MBS of vaginal dryness, a 
sensitivity analyses using the MMRM method will be performed. 
In this analysis, ordered categorical data will be treated as continuous data. 
9.11 Safety Analyses 
9.11.1 
Adverse Events 
AEs will be classified by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA).  Of the AEs reported in the eCRF, 
TEAEs will be used for safety analyses.  The definition of TEAE is described in 
Section 7.6.11.10.   
The number of subjects who experience ≥1 TEAE, non-fatal treatment-emergent SAEs, 
significant TEAEs, TEAEs leading to withdrawal, and TEAEs with an outcome of death 
will be counted for each treatment group.  The incidences and their 95% confidence 
intervals (CIs) will be calculated using the Clopper-Pearson method.  The number of 
TEAEs counted by cases reported will also be presented.  Treatment-related TEAEs will 
be summarized by the same category as TEAEs in the overall summary. 
A summary of TEAEs by MedDRA system organ class and preferred term will be 
presented for each treatment group with the number and percent of subjects.  A summary 
of severity and outcome will be presented by system organ class and preferred term.   
All AEs, including AEs that existed prior to or after the first dose of the study drug, will 
be listed. AEs reported with an onset date prior to randomization of study drug will be 
listed separately. 
9.11.2 
Vital Signs 
Summary statistics for vital signs will be presented for each scheduled time point 
measured after randomization and for the change from baseline to each time point.  
Baseline will be the last value obtained before initial dose. 


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9.11.3 
Clinical Laboratory Analyses  
Summary statistics for laboratory test data will be presented for each scheduled time 
point measured after randomization and for the change from baseline to each time point.  
Baseline will be the last value obtained before initial dose. 
Qualitative laboratory test data at baseline and at planned visits will be classified 
according to test category. 
9.11.4 
Endometrial Safety 
Summary statistics for endometrial thickness and endometrial histology will be presented 
for each scheduled time point measured after randomization and for the change from 
baseline to each time point.  Baseline will be the last value obtained before initial dose. 
9.11.5 
Other Safety Variables 
Other clinical safety variables (e.g., gynecological examination, ECG and weight) will be 
summarized with descriptive statistics for each scheduled time point measured after 
randomization and for the change from baseline to each time point.  Baseline will be the 
last value obtained before initial dose. 
9.12 Interim Analysis 
No interim analysis is planned for this study. 




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CENTRAL ULTRASOUND:   
BioClinica 
100 Overlook Center, 3rd Floor 
Princeton, NJ  08540 
 
CENTRAL ENDOMETRIAL HISTOLOGY 
READER: 
EUROFINS 
2430 New Holland Pike 
Lancaster, PA 17601 
 
ELECTRONIC DIARIES: 
New England Survey Systems 
1415 Beacon Street 
Brookline, MA 02446 
 
*CENTRAL (DXA) BMD READER: 
BioClinica 
100 Overlook Center, 3rd Floor 
Princeton, NJ  08540 
 
*CENTRAL BREAST DENSITY READER: 
BioClinica 
100 Overlook Center, 3rd Floor 
Princeton, NJ  08540 
*Central Readers were utilized for Protocol versions 06 October 2015 and 11 March 2016 
 
10.2 Institutional Review Board Approval 
The IRB will safeguard the rights, safety, and well-being of the subjects by reviewing the 
following study documents: the protocol, ICF, written information about subject 
recruitment procedures (if applicable), other written information given to the subjects, 
Investigator’s Brochure, safety updates, annual progress reports (if applicable), and any 
significant revisions to these documents.  The Investigator or the Sponsor will provide 
these study documents to the IRB.  The IRB will be appropriately constituted in 
accordance with ICH good clinical practice (GCP), and local requirements, as applicable.  
The study will be undertaken only after IRB has given full approval and the Sponsor has 
received a copy of the approval.   
Amendments to the protocol will be subject to the same requirements as the initial review.  
The Investigator will submit all periodic reports and updates as required by the IRB.  The 
Investigator will inform the IRB of any reportable AEs. 


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10.3 Ethical Conduct of the Study 
This study will be conducted in accordance with all appropriate regulatory requirements 
and under the protocol approved by an IRB.  The study will be conducted in accordance 
with current ICH GCP, all appropriate subject privacy requirements, and the ethical 
principles that are outlined in the Declaration of Helsinki.   
10.4 Subject Information and Consent 
The Sponsor will provide the Investigators with a proposed ICF that complies with ICH 
GCP guidelines and regulatory requirements.  The Sponsor must agree to any changes to 
the proposed consent form suggested by the Investigator prior to submission to the IRB, 
and the IRB approved version must be provided to the site monitor after IRB approval. 
The Investigator will generate a site-specific ICF for the study.  The consent form will 
include all the elements required by ICH GCP and any additional elements required by 
local regulations; this will be reviewed and approved by the appropriate IRB before use.  
The Investigator or Sub-investigator will explain the nature, purpose and methods, 
reasonable anticipated benefits, and potential hazards of the study to the subject in simple 
terms by using the consent form before the subject is entered into the study.  The method 
of obtaining and documenting informed consent will comply with ICH GCP and all 
applicable regulatory requirements.   
10.5 Subject Confidentiality  
Procedures for protecting subject privacy must adhere to applicable data privacy laws and 
regulations.  In order to maintain subject privacy, all eCRFs, study drug accountability 
records, study reports, and communications will identify the subject by the subject 
number.  The Investigator will grant the site monitors and auditors of the Sponsor or 
designee and regulatory authorities access to all source documents for verification of data 
collected in the eCRFs and for verification of the data collection process.  The subject’s 
confidentiality will be maintained and will not be made publicly available to the extent 
permitted by the applicable laws and regulations.  The Investigator and the Sponsor will 
be responsible for ensuring that sensitive information is handled in accordance with local 
requirements (eg, Health Insurance Portability and Accountability Act [HIPAA]).  
Appropriate consent and authorizations for use and disclosure and/or transfer (if 
applicable) of protected information must be obtained. 
Data about subjects collected on eCRFs during the study will be documented in an 
anonymous manner and the subject will only be identified by subject number.  In the 
emergent or rare event that for safety or regulatory reasons it is necessary to identify a 
subject, the Sponsor and the Investigator are bound to keep this information confidential. 
10.6 Study Monitoring 
The Sponsor or designee will monitor the study to ensure the study is conducted in 
accordance with GCP requirements and the protocol.  Study monitoring will be 
performed by a representative of the Sponsor (site monitor) through on-site monitoring 


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visits as frequently as necessary and frequent communications (e-mail, letter, telephone, 
and fax).  The site monitor will review data recorded in the eCRFs, verify the eCRF 
entries with direct access to source documents, collect any safety/efficacy information 
about subjects, verify that amounts of unused study drug are accurate, and check 
retention of source documents and essential documents.   
The Investigator agrees to permit such monitoring as well as audits or reviews by 
regulatory authorities, the IRB, or the Sponsor. 
10.7 Electronic Case Report Forms and Source Documents 
10.7.1 
Electronic Case Report Forms 
The eCRFs for each subject who signed informed consent will be provided and historic 
information and study data, which are specified by the protocol, will be recorded on 
eCRFs by the Investigator or designee.  All subject data from study visits must be 
collected on source documents and are promptly entered in the eCRFs in accordance with 
the specific instructions given.  All eCRF entries will be performed by an Investigator, 
Sub-investigator, or study coordinator who is authorized for documentation.  Data should 
be entered within 72 hours after each subject’s visit. 
When queries are generated to the participating medical institutions for resolution by the 
Sponsor or designee, eCRF data will be changed or a response will be recorded in 
accordance with the specific instructions given.  The Investigator must ensure that data 
reported in the eCRF is accurate, complete, legible, and timely and must sign the eCRFs 
to verify the integrity of the data recorded. 
A list of the reference ranges for all laboratory tests to be undertaken will be a part of the 
documentation to be collected prior to the initiation of study.  The list of reference ranges 
for all laboratory tests should be updated if they are changed during the study.  If a 
central laboratory has been selected to perform any or all tests, it is essential that all 
reference ranges for the laboratory tests to be analyzed at the laboratory should also 
be collected.   
10.7.2 
Source Data and Source Documents 
Source documentation supporting eCRF data should indicate the subject’s participation in 
the study and should document the dates and details of study procedures, AEs, and 
subject status.  However, the following data can be directly recorded on an eCRF as 
source data:  
 Reason for use of prior therapy or concomitant therapy 
 Severity, seriousness, causal relationship to the study drug of AE 
 Any comments inserted into eCRF 
 Automatically-calculated data in eCRF (age, BMI)  


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The Investigator must maintain source documents such as laboratory reports, and 
complete medical history and physical examination reports.  All the source documents 
are accessible for verification by the site monitor, auditor, the IRB, inspections of 
regulatory authority.  Direct access to these documents must be guaranteed by the 
Investigator, Sub-investigator, or study coordinator, who must provide support at all 
times for these activities.  For all sources of original data required to complete the eCRF, 
the nature and location of the source documents will be identified by the Sponsor and the 
site staff.  If electronic records are maintained at the medical institution, the method of 
verification must be specified in document within the medical institution.   
10.7.3 
External Data  
The following data will be reported in documents/data bases separate from eCRFs.   
 eDiary 
 Results of cervical cytology (PAP) smear 
 Results of vaginal smear 
 Results of vaginal imaging 
 Results of TVU 
 Results of DXA scan 
 Results of breast mammogram 
 Results of biopsy for endometrial histology 
 Results of clinical laboratory tests including serum hormone levels and markers of 
bone metabolism 
10.8 Committees 
10.8.1 
Visual Imaging Independent Panel Review (IPR) 
An Independent Panel Review (IPR) will be established and will be composed by three 
experts in obstetrics and gynecology.  This panel will independently review vulvo-
vaginal photographs of all subjects at all scheduled time points in a random and blinded 
fashion.  Details of IPR composition, roles and responsibilities, and processes will be 
documented in a separate IPR charter. 
10.9 Termination or Suspension of the Study 
10.9.1 
Termination or Suspension of the Entire Study 
The Sponsor may prematurely terminate or suspend the study at any time for the 
following reasons:   
 Ensuring safety of the study is difficult due to safety concerns (eg, occurrence of 
many serious treatment-related TEAEs) 
 Achieving the purpose of the study is considered impossible (eg, interim data 
suggesting lack of efficacy/safety, inadequate recruitment of subjects) 


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If the study is prematurely terminated or suspended, the Sponsor should promptly inform 
the Investigators.  The Investigator or Sub-investigator should promptly inform the 
participating subjects and change the study treatment to other appropriate therapy(ies).   
For withdrawal criteria for individual subjects, see Section 7.7. 
10.9.2 
Termination or Suspension of the Study by Medical Institution 
The Investigator may prematurely terminate or suspend the study in the medical 
institution with agreement of the Sponsor at any time when the Investigator considers that 
ensuring safety of the study is difficult due to safety concerns (eg, occurrence of 
many SAEs). 
The Sponsor may request the Investigator to prematurely terminate or suspend the study 
in the medical institution at any time when major violations/deviations of protocol, other 
procedures, and GCP guidelines were not improved. 
If the study is prematurely terminated or suspended, the Investigator or Sub-investigator 
should promptly inform the corresponding IRB and participating subjects and change the 
study treatment to other appropriate therapy(ies).   
The entire study may be discontinued at the discretion of the Sponsor based on the 
occurrence of the following:  
 AEs unknown to date with respect to their nature, severity, and duration;  
 Increased frequency and/or severity and/or duration of known AEs;  
 Medical or ethical reasons affecting the continued performance of the study;  
 Difficulties in recruitment of subjects; or 
 Cancellation of drug development by the Sponsor 
10.10 Protocol Modifications and Deviations 
The Investigator will conduct the study in compliance with the protocol provided by the 
Sponsor and approval/favorable opinion given by the IRB and the regulatory 
authority(ies).  Modifications to the protocol should not be performed without agreement 
of both the Investigator and the Sponsor.  Changes to the protocol will require written 
IRB approval/favorable opinion prior to implementation, except when the modification is 
needed to eliminate immediate hazard(s) to subjects.   
The Investigator or Sub-investigator should document any deviation from the protocol 
and the reason.  If the Investigator deviates from the protocol or make a change of the 
protocol to eliminate an immediate hazard(s) to subjects, the record should be 
immediately submitted to the Sponsor, the medical institution, and the IRB by the 
Investigator and the IRB will provide expedited review and approval/favorable opinion.  
After the Investigator obtained approval/favorable opinion of the IRB, the Investigator 
should obtain a written agreement of the Sponsor through the medical institution.  The 


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Sponsor will submit all protocol modifications to the regulatory authority (ies) via an 
Amendment in accordance with the governing regulations. 
When deviation from the protocol is required to eliminate immediate hazard(s) to 
subjects, the Investigator will contact the Sponsor, if circumstances permit, to discuss the 
planned course of action.  Any deviations from the protocol must be fully documented on 
source documentation. 
10.11 Access to Source Documentation 
The site monitors, the auditors, the IRB, and regulatory authorities are able to directly 
access all source documents and other study documentation for study monitoring, on-site 
audit, or inspection.  Direct access to these documents must be guaranteed by the 
Investigator, Sub-investigator, or study coordinator, who must provide support at all 
times for these activities. 
The Investigator must inform the study subject that his/her study-related records may be 
reviewed by the above individuals without violating the subject’s privacy of personal 
health information in compliance with HIPAA of 1996 US regulations. 
10.12 Data Management 
The Sponsor or designee will be responsible for data management and data analysis.  
These procedures are specified in a separate document. 
10.13 Retention of Data 
The study documents must be maintained as specified in the ICH GCP and as required by 
the applicable regulatory requirements.  The Investigator and study center should take 
measures to prevent accidental or premature destruction of these documents. 
If the Sponsor is granted manufacturing and marketing approval for the drug, the Sponsor 
will promptly notify the head of the study center in writing. 
Records will be retained for the longest of the following periods: 
 At least 2 years after the last marketing application approval 
 2 years after formal discontinuation of the clinical development of the 
investigational product 
 Other period according to applicable local laws, regulations, and other regulatory 
requirements, whichever is latest 
However, the duration of retention may be prolonged in accordance with an agreement 
with the Sponsor. 
These records will be available for copying and inspection if requested by a properly 
authorized employee of the Food and Drug Administration (FDA) or other government 
regulatory agency, in accordance with federal regulations.  The Investigator must notify 


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the Sponsor prior to transfer or in cases of accidental loss or destruction of any study 
records.  If the Investigator withdraws from the responsibility of keeping the study 
records, custody must be transferred to a person willing to accept the responsibility. The 
Sponsor must be notified in writing if a custodial change occurs. 
10.14 Quality Control and Assurance 
The Sponsor or designee will implement and maintain quality control and quality 
assurance procedures with written standard operating procedures to ensure that the study 
is conducted and data are generated, documented, and reported in compliance with the 
protocol, ICH GCP, and applicable regulatory requirements. 
This study will be conducted in accordance with the provisions of the Declaration of 
Helsinki and all revisions thereof; in accordance with the ICH GCP and as required by 
the applicable regulatory requirements. 
Necessary training for the study will be provided to investigator's meeting and study 
center personnel prior to the initiation of the study. 
10.15 Publication and Disclosure Policy 
All information regarding ospemifene supplied by the Sponsor to the Investigator is 
privileged and confidential.  The Investigator agrees to use this information to 
accomplish the study and will not use it for other purposes without consent from the 
Sponsor.  It is understood that there is an obligation to provide the Sponsor with complete 
data obtained during the study.  The information obtained from the clinical trial will be 
used toward the development of ospemifene and may be disclosed to regulatory 
authority(ies), other Investigators, corporate partners, or consultants as required. 
The Sponsor will retain ownership of all data.  All proposed publications based on the 
study will be subject to the Sponsor's approval requirements. 
The key design elements of this protocol will be posted in a publicly accessible database, 
eg, ClinicalTrials.gov.  
10.16 Financial Disclosure 
Information concerning financial disclosure for Investigators will be addressed in a 
separate agreement between the Sponsor and the Investigator. 
In accordance with the applicable regulations (21 CFR Parts 54, 312, 314, 320, 330, 601, 
807, 812, 814, and 860), the Sponsor will provide the FDA with: Certification, that no 
financial arrangements with an Investigator or Sub-investigator have been made where 
compensation could affect study outcome; that the Investigator or Sub-investigator has no 
proprietary interest in the tested product; that the Investigator or Sub-investigator does 
not have a significant equity interest in the Sponsor of the covered study; and that the 
Investigator has not received significant payments of other sorts, and/or disclosure of 
specified financial arrangements and any steps taken to minimize the potential for bias. 


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11. REFERENCE LIST 
1. Willhite LA, O'Connell MB. Urogenital Atrophy: Prevention and Treatment. 
Pharmacotherapy 2001;21(4):464-80. 
2. Pandit L, Ouslander JG. Postmenopausal Vaginal Atrophy and Atrophic Vaginitis. 
Am J Med Sci 1997;314(4):228-31. 
3. Bachmann GA, Nevadunsky NS. Diagnosis and Treatment of Atrophic Vaginitis. 
American Family Physician 2000;61:3090-6. 
4. Iosif CS, Batra S, Ek A, Astedt B. Estrogen Receptors in the Human Female Lower 
Urinary Tract. Am J Obstet Gyneco1 1981;141:817-20. 
5. Greendale GA, Judd JL. The menopause: Health implications and clinical 
management. J Am Geriatr Soc 1993;41:426-36. 
6. Cardozo L, Bachmann G, McClish D, Fonda D, Birgerson L. Meta-Analysis of 
Estrogen Therapy in the Management of Urogenital Atrophy in Postmenopausal 
Women: Second Report of the Hormones and Urogenital Therapy Committee. Obstet 
Gyneco1 1998;92(4):722-7. 
7. Berg G, Gottqall M, Hammar M, Lindgren R. Climacteric Symptoms Among Women 
Aged 60-62 in Linkoping, Sweden, in 1986. Maturitas 1988;10:193-9.  
8. Rekers H, Drogendijk AC, Valkenburg HA, Riphagen F. The Menopause, Urinary 
Incontinence and Other Symptoms of the Genito-Urinary Tract. Maturitas 
1992;15:101-11. 
9. Bachmann G. Urogenital ageing: an old problem newly recognized. Maturitas 
1995;22 Suppl:S1-S5. 
10. Rosen R, Brown C, Heiman J, et al. The Female Sexual Function Index (FSFI): A 
Multidimensional Self-Report Instrument for the Assessment of Female Sexual 
Function. J Sex &Marital Ther 2000;26:191-208. 
11. Uebersax JS, Wyman JF, Shumaker SA, McClish DK, Fantl JA. Short forms to assess 
life quality and symptom distress for urinary incontinence in women: The 
incontinence impact questionnaire and the urogenital distress inventory. Continence 
Program for Women Research Group. Neurourol Urodyn 1995;14(2):131-9. 
 
 


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Appendix 1 
Restricted Dietary and Herbal Therapies 
Soy (Glycine max) 
Flaxseed (Linum usitatissimum) 
Nettle root (Urtica dioica) 
Pygeum (Pygeum africanum) 
Beta-sitosterol 
Licorice (Glycyrrhiza glabra) 
Ginseng 
Tribulus (Tribulus terrestris) 
Red clover (Trifolium pretense) 
Chasteberry (Vitex agnus-castus) 
Japanese knotweed (Polygonum cuspidatum) 
Black Cohosh (Cimicifuga racemosa) 
Hops (Humulus lupulus) 
Dong Quai (Angelica sinensis) 
Fo-Ti (Polygonum multiflorum) 
Kudzu (Pueraria lobata) 
Alfalfa (Medicago sativa) 
Mung bean sprout (Vigna radiate) 
Sicklepod (Cassia obtusifolia) 
Turkish rhubarb root (Rheum palmatum) 
Phytoestrogens: 
- 
Isoflavones (biochanin A, daidzein, genistein) 
- 
Resveratrol 
- 
Coumestrol 


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Appendix 2 
Patient Self-Assessment of Vulvar and Vaginal 
Atrophy Questionnaire 
Have you had the following symptoms in the past month? (or since the last visit?) 
If yes, please indicate if the most severe episode of the symptom was mild, moderate or 
severe. 
Please choose one option per question. 
 
Symptom 
None 
Mild 
Moderate 
Severe 
Vaginal Dryness? 
 
 
 
 
Vaginal and/or Vulvar 
Irritation or Itching? 
 
 
 
 
Difficult or Painful Urination? 
 
 
 
 
Vaginal Pain Associated with 
Sexual Activity? 
 
 
 
 
Vaginal Bleeding Associated 
with Sexual Activity? 
 
 
 
 
 
Which symptom is the most bothersome to you? Please choose one symptom that was 
indicated above as moderate or severe. (Ask at Visits 1 and 2 [Screening & 
Randomization]) 
Vaginal Dryness? 
 
Vaginal and/or Vulvar Irritation or 
Itching? 
 
Difficult or Painful Urination? 
 
Vaginal Pain Associated with Sexual 
Activity? 
 
Vaginal Bleeding Associated with Sexual 
Activity? 
 


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Appendix 3 
Vaginal Health Index (VHI) 
 
1 
2
3
4
5 
Overall 
Elasticity 
None 
Poor 
Fair 
Good 
Excellent 
Fluid 
Secretion 
None 
Scant 
Superficial 
Moderate 
Normal 
pH 
>6.1 
5.6–6.0 
5.1–5.5 
4.7–5.0 
≤4.6 
Epithelial 
Mucosa 
Petechiae 
before 
contact 
Bleeds with 
light contact 
Bleeds with 
scraping 
Not friable, 
thin mucosa 
Not friable,
normal 
mucosa 
Moisture 
None, 
mucosa 
inflamed 
None, 
mucosa not 
inflamed 
Minimal 
Moderate 
Normal 


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Appendix 4 
Vulvar Health Index (VuHI) 
 
Normal (0) 
Mild (1)
Moderate (2)
Severe (3)
Labia Majora 
Normal 
Mild loss 
Moderate loss 
Severe loss or 
disappeared 
Labia Minora 
Normal 
Mild loss 
Moderate loss 
Severe loss or 
disappeared 
Clitoris 
Normal size 
Mild decrease 
in size 
Moderate 
decrease in size 
Severe 
decrease or 
undetected 
Introitus & 
Elasticity 
Normal 
Mild decrease 
or stenosis 
Moderate 
decrease or 
stenosis 
Severe 
decrease or 
stenosis 
Color 
Normal 
Mild pallor 
Moderate pallor 
Severe pallor 
Discomfort & 
Pain 
None 
Mild during 
intercourse 
Moderate 
during 
intercourse 
Moderate 
during 
intercourse 
and any 
discomfort 
intensity 
beyond 
intercourse 
Other 
Findings 
(Petechiae, 
Excoriation, 
Ulceration, 
etc.) 
None 
Mild 
Moderate 
Severe 


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Appendix 5 
Process for Capturing Vulvar and Vaginal 
Photography 
 
 
 
Subject’s Visit: 
Digital images 
taken at site 
Images 
submitted to 
Canfield 
electronically 
Images 
monitored by 
Canfield Project 
Team 
Images quality 
checked by 
Canfield Project 
Team 
Feedback 
provided to site 
via report form 
 


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Appendix 6 
Female Sexual Function Index (FSFI) Questionnaire 
 
Subject ID _______________________________ Date ____________ 
 
INSTRUCTIONS: These questions ask about your sexual feelings and responses during 
the past 4 weeks. Please answer the following questions as honestly and clearly as 
possible. Your responses will be kept completely confidential. In answering these 
questions the following definitions apply: 
 
Sexual activity can include caressing, foreplay, masturbation and vaginal intercourse. 
Sexual intercourse is defined as penile penetration (entry) of the vagina. 
 
Sexual stimulation includes situations like foreplay with a partner, self-stimulation 
(masturbation), or sexual fantasy. 
 
CHECK ONLY ONE BOX PER QUESTION. 
 
Sexual desire or interest is a feeling that includes wanting to have a sexual experience, 
feeling receptive to a partner's sexual initiation, and thinking or fantasizing about having 
sex. 
 
1. 
Over the past 4 weeks, how often did you feel sexual desire or interest? 
 
☐ Almost always or always 
☐  Most times (more than half the time) 
☐ Sometimes (about half the time) 
☐ A few times (less than half the time) 
☐ Almost never or never 
 
2. 
Over the past 4 weeks, how would you rate your level (degree) of sexual desire or 
interest? 
 
☐ Very high 
☐ High  
☐ Moderate  
☐ Low 
☐ Very low or none at all 


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Sexual arousal is a feeling that includes both physical and mental aspects of sexual 
excitement. It may include feelings of warmth or tingling in the genitals, lubrication 
(wetness), or muscle contractions. 
 
3. 
Over the past 4 weeks, how often did you feel sexually aroused ("turned on") 
during sexual activity or intercourse? 
 
☐ No sexual activity 
☐ Almost always or always 
☐ Most times (more than half the time) 
☐ Sometimes (about half the time) 
☐ A few times (less than half the time) 
☐ Almost never or never 
 
4. 
Over the past 4 weeks, how would you rate your level of sexual arousal ("turn 
on") during sexual activity or intercourse? 
 
☐ No sexual activity 
☐ Very high 
☐ High 
☐ Moderate 
☐ Low 
☐ Very low or none at all 
 
5. 
Over the past 4 weeks, how confident were you about becoming sexually aroused 
during sexual activity or intercourse? 
 
☐ No sexual activity 
☐ Very high confidence 
☐ High confidence 
☐ Moderate confidence 
☐ Low confidence 
☐ Very low or no confidence 
 
6. 
Over the past 4 weeks, how often have you been satisfied with your arousal 
(excitement) during sexual activity or intercourse? 
 
☐ No sexual activity 
☐ Almost always or always 
☐ Most times (more than half the time) 
☐ Sometimes (about half the time) 
☐ A few times (less than half the time) 
☐ Almost never or never 


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7. 
Over the past 4 weeks, how often did you become lubricated ("wet") during 
sexual activity or intercourse? 
 
☐ No sexual activity 
☐ Almost always or always 
☐ Most times (more than half the time) 
☐ Sometimes (about half the time) 
☐ A few times (less than half the time) 
☐ Almost never or never 
 
8. 
Over the past 4 weeks, how difficult was it to become lubricated ("wet") during 
sexual activity or intercourse? 
 
☐ No sexual activity 
☐ Extremely difficult or impossible 
☐ Very difficult 
☐ Difficult 
☐ Slightly difficult 
☐ Not difficult 
 
9. 
Over the past 4 weeks, how often did you maintain your lubrication ("wetness") 
until completion of sexual activity or intercourse? 
 
☐ No sexual activity 
☐ Almost always or always 
☐ Most times (more than half the time) 
☐ Sometimes (about half the time) 
☐ A few times (less than half the time) 
☐ Almost never or never 
 
10. 
Over the past 4 weeks, how difficult was it to maintain your lubrication 
("wetness") until completion of sexual activity or intercourse? 
 
☐ No sexual activity 
☐ Extremely difficult or impossible 
☐ Very difficult 
☐ Difficult 
☐ Slightly difficult 
☐ Not difficult 
 
 
 
 


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11. 
Over the past 4 weeks, when you had sexual stimulation or intercourse, how often 
did you reach orgasm (climax)? 
 
☐ No sexual activity 
☐ Almost always or always 
☐ Most times (more than half the time) 
☐ Sometimes (about half the time) 
☐ A few times (less than half the time) 
☐ Almost never or never 
 
12. 
Over the past 4 weeks, when you had sexual stimulation or intercourse, how 
difficult was it for you to reach orgasm (climax)? 
 
☐ No sexual activity 
☐ Extremely difficult or impossible 
☐ Very difficult 
☐ Difficult 
☐ Slightly difficult 
☐ Not difficult 
 
13. 
Over the past 4 weeks, how satisfied were you with your ability to reach orgasm 
(climax) during sexual activity or intercourse? 
 
☐ No sexual activity 
☐ Very satisfied 
☐ Moderately satisfied 
☐ About equally satisfied and dissatisfied 
☐ Moderately dissatisfied 
☐ Very dissatisfied 
 
14. 
Over the past 4 weeks, how satisfied have you been with the amount of emotional 
closeness during sexual activity between you and your partner? 
 
☐ No sexual activity 
☐ Very satisfied 
☐ Moderately satisfied 
☐ About equally satisfied and dissatisfied 
☐ Moderately dissatisfied 
☐ Very dissatisfied 
 
 
 
 


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15. 
Over the past 4 weeks, how satisfied have you been with your sexual relationship 
with your partner? 
 
☐ Very satisfied 
☐ Moderately satisfied 
☐ About equally satisfied and dissatisfied 
☐ Moderately dissatisfied 
☐ Very dissatisfied 
 
16. 
Over the past 4 weeks, how satisfied have you been with your overall sexual life? 
 
☐ Very satisfied 
☐ Moderately satisfied 
☐ About equally satisfied and dissatisfied 
☐ Moderately dissatisfied 
☐ Very dissatisfied 
 
17. 
Over the past 4 weeks, how often did you experience discomfort or pain during 
vaginal penetration? 
 
☐ Did not attempt intercourse 
☐ Almost always or always 
☐ Most times (more than half the time) 
☐ Sometimes (about half the time) 
☐ A few times (less than half the time) 
☐ Almost never or never 
 
18. 
Over the past 4 weeks, how often did you experience discomfort or pain 
following vaginal penetration? 
 
☐ Did not attempt intercourse 
☐ Almost always or always 
☐ Most times (more than half the time) 
☐ Sometimes (about half the time) 
☐ A few times (less than half the time) 
☐ Almost never or never 
 
 
 
 
 
 
 


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19. 
Over the past 4 weeks, how would you rate your level (degree) of discomfort or 
pain during or following vaginal penetration? 
 
☐ Did not attempt intercourse 
☐ Very high 
☐ High 
☐ Moderate 
☐ Low 
☐ Very low or none at all 
 
Thank you for completing the questionnaire 
 
 


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Appendix 7 
Urinary Distress Inventory (UDI-6) 
 
Do you experience, and, if so, how much are you bothered by: 
 
1. Frequent urination? 
 
Yes ☐ 
No ☐ 
If Yes, how much does it bother you? 
not at all ☐ 
slightly ☐ 
 moderately ☐  
greatly ☐ 
 
2. Urine leakage related to the feeling of urgency? 
 
Yes ☐ 
No ☐ 
If Yes, how much does it bother you? 
not at all ☐  slightly ☐  
moderately ☐  
greatly ☐ 
 
3. Urine leakage related to physical activity, coughing, or sneezing? 
 
Yes ☐ 
No ☐ 
If Yes, how much does it bother you? 
not at all ☐  slightly ☐  
moderately ☐ 
greatly ☐ 
 
4. Small amounts of urine leakage (drops)? 
 
Yes ☐  
No ☐ 
If Yes, how much does it bother you? 
not at all ☐  slightly ☐  
moderately ☐ 
greatly ☐ 
 
5. Difficulty emptying your bladder? 
 
Yes ☐  
No ☐ 
 
If Yes, how much does it bother you? 
not at all ☐ 
slightly ☐  
moderately ☐  
greatly ☐ 
 
6. Pain or discomfort in the lower abdominal or genital area? 
 
Yes ☐ 
No ☐ 
If Yes, how much does it bother you? 
not at all ☐  slightly ☐ 
moderately ☐ 
greatly ☐


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Appendix 8 
Genital Prolapse Grading 
The following grading will be used for evaluation at screening 
(patient should have an empty bladder and Valsalva strain maximally). 
 
Uterine Prolapse: 
Grade 0 - Normally positioned cervix or vaginal apex 
Grade 1 - Less than half way to the hymenal ring 
Grade 2 - More than half way to the hymenal ring 
Grade 3 - At the hymenal ring 
Grade 4 - Halfway or greater outside the hymenal ring 
 
Vaginal Prolapse (cysto[urethra]cele or rectocele): 
Grade 0 - Normal 
Grade 1 - Some bulging during Valsalva, no symptoms 
Grade 2 - Size approximately hen`s egg 
Grade 3 - Approaching hymenal level, bulging “out” 
Grade 4 - Clearly visible outside 


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Appendix 9 
Diagnostic Procedures Required in a Subject with 
Intact Uterus and Vaginal Bleeding 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial bleeding episode ==> 
Transvaginal ultrasound 
Subsequent bleeding episodes 
Endometrium˂ 4 mm 
Endometrium≥4 mm 
Endometrial biopsy 
Bleeding persists 
Sufficient sample 
Insufficient sample 
Hysteroscopy and guided 
biopsy 
Bleeding ended 
No further procedures 
Send biopsy to the central laboratory for evaluation; further procedures based on the result. 


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Appendix 10 
Management and Discontinuation Criteria for 
Abnormal Liver Function Tests 
Management and Discontinuation Criteria for Abnormal Liver Function tests have been 
designed to ensure subject safety and evaluate liver event etiology. (See Guidance for 
Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, Food and Drug 
Administration [FDA]: 2009)  
1. 
Abnormal Liver Chemistry Criteria: 
The Investigator or Sub-investigator must review study subject laboratories to identify if 
any levels meet the following criteria: 
a. AST or ALT >5 × ULN 
b. AST or ALT >3 × ULN and total bilirubin (TBL) >2 × ULN (SAE)  
c. AST or ALT >3 × ULN with signs or symptoms compatible with hepatitis or 
hypersensitivity (eg, fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, jaundice, fever, rash, eosinophilia [>5%]) 
2. 
Action to be Taken by Investigator: 
If any abnormal liver chemistry criterion is met, the Investigator or Sub-investigator must 
do the following: 
 Subjects must be instructed to discontinue study medication immediately.  The 
Investigator or Sub-investigator should not re-challenge the subject with the 
investigational product without consulting the Sponsor. 
 Following the initial observed elevation, every effort should be made to have the 
subject return to the clinic within 72 hours to repeat liver function chemistries and 
for further hepatic evaluation.   
 Every effort should be made to have the subjects must be monitored 2 to 3 times 
per week until liver function chemistries (ALT, AST, ALP, total bilirubin) 
resolve, stabilize or return to within the normal range or to baseline levels. 
 This event must be reported to the Sponsor as soon as possible but no later than 
24 hours of learning after its occurrence on the Liver Event Form.  
 Consultation with a specialist such as a hepatologist is considered. 
 Liver imaging (ie, ultrasound, magnetic resonance imaging (MRI), computerized 
tomography) is considered. 
 For criteria b, termed “Hy’s law,” the case must be reported as an SAE.  
3. 
Follow-up Examination: 
If any of the abnormal liver chemistry criteria are met, the following assessments should 
be performed at the follow-up visit(s) and documented in the Liver Event Form: 
 


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 Clinical symptoms course 
- 
Concomitant medications: OTC (over-the-counter drug)/herbal/dietary 
supplements (start and stop dates) 
 Alcohol use 
 Risk factors for nonalcoholic steatohepatitis (NASH) such as diabetes, obesity 
and hypertriglyceridemia 
 Autoimmune hepatitis/cholangitis 
 Wilson's disease 
 Laboratory Assessments 
– Viral hepatitis serology 
o Hepatitis A IgM antibody 
o Hepatitis B surface antigen (HBs antigen) and Hepatitis B core antibody 
(HBc antibody) 
o Hepatitis C RNA 
o Hepatitis E IgM antibody 
o Cytomegalovirus IgM antibody 
o Epstein-Barr viral capsid antigen IgM antibody 
– For subjects with total bilirubin of >1.5 ULN, conjugated bilirubin should 
be measured. 
– Complete blood count with differential to assess for eosinophilia 
The Investigator or Sub-investigator must not re-challenge the subject with the 
investigational product without consulting the Sponsor. 


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AST or ALT >5xULN and 
≤8xULN
AST or ALT >8xULN
Plus total Bilirubin >2xULN 
(or PT-INR >1.5 if 
measured)
With signs or symptoms 
compatible with hepatitis or 
hypersensitivity
• Patients must be instructed to hold study medication immediately. 
• The investigator or subinvestigator should not re-challenge the patient with the investigational product without consulting the sponsor.
• Following the initial observed elevation, every effort should be made to have the patient return to the clinic within 72 hours to repeat liver function 
chemistries and for further hepatic evaluation  
• Patients must be monitored 2 to 3 times per week until liver function chemistries (ALT, AST, ALP, total bilirubin) resolve, stabilize or return to 
within the normal range or to baseline levels. 
• Consultation with a specialist such as a hepatologist is considered.
• Liver imaging (ie, ultrasound, magnetic resonance imaging (MRI), computerized tomography) is considered.
•
Discontinue IP 
•
Report  to the sponsor within 72 hours on the Liver Event  Form 
•
Report as AE or SAE 
•
Discontinue IP
•
Report as SAE 
•
Report  to the sponsor 
within 72 hours on the 
Liver Event  Form
AST or ALT >3xULN
Abnormal Liver Chemistry Criteria: Algorithm


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Appendix 12 
Investigator’s Signature  
Study Title: 
A Phase 3, Randomized, Double-blind, Placebo-
controlled Multicenter Study to Evaluate the Efficacy 
and Safety of Ospemifene in Patients with Moderate 
to Severe Vaginal Dryness, a Symptom of Vulvo-
vaginal Atrophy (VVA) due to Menopause 
Study Number: 
1517I0231 
Date of Original: 
06 October 2015 
Date of Version 2: 
Date of Latest Amendment: 
11 March 2016 
02 November 2016 
 
I have read the protocol described above.  I agree to comply with all applicable 
regulations and to conduct the study as described in the protocol.  
Signed: 
 
 
 
 
 
 
Date:  
 
 
 
 
Printed Name: ____________________________________ 
Title:   ____________________________________ 
Affiliation: ________________________________ 
 
 
 

SAP_001.pdf: 
 
Shionogi Study Title:  
A Phase 3, Randomized, Double-blind, Placebo controlled 
Multicenter Study to Evaluate the Efficacy and Safety of 
Ospemifene in Patients with Moderate to Severe Vaginal 
Dryness, a Symptom of Vulvo-vaginal Atrophy (VVA) due 
to Menopause 
Shionogi Study Number: 
1517I0231 
ClinicalTrials.gov 
registration No. 
NCT02638337 
Study Document  
Statistical Analysis Plan   17 August 2017