Conditions: Vulvovaginal Atrophy Dyspareunia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

Brief summary:
This is an unblinded study to be conducted at a single research center, San Diego Sexual Medicine. Subjects meeting inclusion and exclusion criteria will receive 60 mg ospemifene daily for twenty weeks. After the informed consent is signed, a baseline physical examination, and vulvoscopy with detailed photography of the vulva, vestibule and vagina, will be performed. Physical examination and vulvoscopy with detailed photography of the vulva, vestibule and vagina, will be repeated prospectively every 4 weeks for a total of 20 weeks. Therefore, physical examination and vulvoscopy with detailed photography of the vulva, vestibule and vagina will be performed prospectively at baseline (vulvoscopy session 1), 4 weeks (vulvoscopy session 2), 8 weeks (vulvoscopy session 3), 12, weeks (vulvoscopy session 4), 16 weeks (vulvoscopy session 5) and 20 weeks (vulvoscopy session 6) following daily administration of 60 mg ospemifene.

Detailed description:
Ospemifene is indicated for post-menopausal women diagnosed with vulvar vaginal atrophy (VVA) and dyspareunia. While ospemifene clinically significantly reduces pain associated with dyspareunia, there has been little prospective documentation using vulvoscopy with detailed photography of the visible changes to the vulva, vestibule and vaginal region with daily administration of 60 mg ospemifene in post-menopausal women with VVA and dyspareunia. This study will include a total of 6 prospective photographic sessions of the vulva, vestibule and vagina over the 20 weeks administration of 60 mg ospemifene in the study. Comparisons will be made of baseline photography (vulvoscopy session 0) with photography at 4 weeks (vulvoscopy session 1), 8 weeks (vulvoscopy session 2), 12 weeks (vulvoscopy session 3), 16 weeks (vulvoscopy session 4) and 20 weeks (vulvoscopy session 5).

Currently there have been limited prospective studies using vulvoscopy with detailed photography demonstrating visible changes to the vulva, vestibule and vagina following oral administration of 60 mg ospemifene in post-menopausal women with VVA and dyspareunia. Information regarding visible changes to the vulva, vestibule and vagina may be very important to the patient and to the health care provider to best understand the beneficial effects of ospemifene and to ensure patient compliance with treatment.

Arms:
arm 1: 60 mg ospemifene daily for 20 weeks

Interventions: intervention 1: Ospemifene
Intervention descriptions: intervention 1: FDA approved medication for the treatment of vulvovaginal atrophy and dyspareunia

Protocol document:
ICF_002.pdf: 























Prot_000.pdf: 
 
Protocol SDSM-2015-02.4 
April 4, 2016 
 
 
 
 
 
 
AN OPEN-LABEL PILOT PROSPECTIVE VULVOSCOPY WITH 
PHOTOGRAPHY STUDY OF THE VISIBLE CHANGES IN THE VULVA, 
VESTIBULE AND VAGINA PRE- AND POST- TWENTY WEEKS OF DAILY 
ADMINISTRATION OF 60 MG OSPEMIFENE IN POST-MENOPAUSAL 
WOMEN WITH DYSPAREUNIA FROM VULVAR VAGINAL ATROPHY 
 
 
 
Principal Investigator: 
 
 
Irwin Goldstein, MD 
Medical Director 
San Diego Sexual Medicine 
5555 Reservoir Drive, Suite 300 
San Diego, California 92120 
T: 619-265-8865 F: 619-265-7696 
 
 
Medical Monitor: 
 
 
Irwin Goldstein, MD 
Medical Director 
San Diego Sexual Medicine 
5555 Reservoir Drive, Suite 300 
San Diego, California 92120 
T: 619-265-8865 F: 619-265-7696 
 
 
Sponsor Contact: 
 
 
Irwin Goldstein, MD 
Medical Director 
San Diego Sexual Medicine 
5555 Reservoir Drive, Suite 300 
San Diego, California 92120 
T: 619-265-8865 F: 619-265-7696 
 


 
Protocol SDSM-2015-02.4 
April 4, 2016 
 
 
AN OPEN-LABEL PILOT PROSPECTIVE VULVOSCOPY WITH 
PHOTOGRAPHY STUDY OF THE VISIBLE CHANGES IN THE VULVA, 
VESTIBULE AND VAGINA PRE- AND POST- TWENTY WEEKS OF DAILY 
ADMINISRATION OF 60 MG OSPEMIFENE IN POST-MENOPAUSAL WOMEN 
WITH DYSPAREUNIA FROM VULVAR VAGINAL ATROPHY 
 
 
 
SUMMARY 
 
This study is Investigator initiated research (IIR) supported by a grant and study 
medication from Shionogi. 
 
 
1. INTRODUCTION 
Ospemifene is indicated for post-menopausal women diagnosed with vulvar 
vaginal atrophy (VVA) and dyspareunia.  While ospemifene clinically significantly 
reduces pain associated with dyspareunia, there has been little prospective 
documentation using vulvoscopy with detailed photography of the visible 
changes to the vulva, vestibule and vaginal region with daily administration of 60 
mg ospemifene in post-menopausal women with VVA and dyspareunia.  This 
study will include a total of 6 prospective photographic sessions of the vulva, 
vestibule and vagina over the 20 weeks administration of 60 mg ospemifene in 
the study.  Comparisons will be made of baseline photography (vulvoscopy 
session 0) with photography at 4 weeks (vulvoscopy session 1), 8 weeks 
(vulvoscopy session 2), 12 weeks (vulvoscopy session 3), 16 weeks (vulvoscopy 
session 4) and 20 weeks (vulvoscopy session 5). 
 
2. TRIAL OBJECTIVE  
The primary objective of this study is to prospectively document, using 
vulvoscopy with detailed photography, the visible changes to the vulva, vestibule 
and vaginal region in post-menopausal women with dyspareunia taking 60 mg 
daily ospemifene for twenty weeks at 6 timepoints: baseline, 4 weeks, 8 weeks, 
12 weeks,16 weeks and 20 weeks. 
 
Secondary objectives include changes in pain as noted on the pain scale 
(appendix 2) and the q-tip test, in the vestibule on visual scale (appendix 3) by 
the clinician and sexual function by subject diary (appendix 4). 
 
3. DESCRIPTION OF RESEARCH DESIGN 
 
3.1 
Overall Study Plan 
This is an unblinded study to be conducted at a single research center, San 
Diego Sexual Medicine.  Subjects meeting inclusion and exclusion criteria will 
receive 60 mg ospemifene daily for twenty weeks. After the informed consent is 


 
Protocol SDSM-2015-02.4 
April 4, 2016 
 
signed, a baseline physical examination, and vulvoscopy with detailed 
photography of the vulva, vestibule and vagina, will be performed.  Physical 
examination and vulvoscopy with detailed photography of the vulva, vestibule 
and vagina, will be repeated prospectively every 4 weeks for a total of 20 weeks.   
Therefore, physical examination and vulvoscopy with detailed photography of the 
vulva, vestibule and vagina will be performed prospectively at baseline 
(vulvoscopy session 1), 4 weeks (vulvoscopy session 2), 8 weeks (vulvoscopy 
session 3), 12, weeks (vulvoscopy session 4), 16 weeks (vulvoscopy session 5) 
and 20 weeks (vulvoscopy session 6) following daily administration of 60 mg 
ospemifene. 
 
3.2 
Study Duration 
Each eligible subject will participate in the study for approximately 20 weeks. It is 
expected this single site investigator-initiated research study will be completed 
approximately 8 months following initial approval by the Independent Review 
Board. 
 
3.3 
Independent Review Board (IRB) Approval 
Prior to conducting any study-related procedures, the Principal Investigator will 
obtain written approval from Aspire Independent Review Board for the informed 
consent form, protocol, recruitment materials, and any written information provided 
to Subjects pertaining to the procedure.   
 
3.4 
Rationale for Study Design and Subject Selection 
Currently there have been limited prospective studies using vulvoscopy with 
detailed photography demonstrating visible changes to the vulva, vestibule and 
vagina following oral administration of 60 mg ospemifene in post-menopausal 
women with VVA and dyspareunia.  Information regarding visible changes to the 
vulva, vestibule and vagina may be very important to the patient and to the health 
care provider to best understand the beneficial effects of ospemifene and to 
ensure patient compliance with treatment. 
 
This study is being conducted in an unblinded fashion because the primary 
endpoint is a collection of photographs.  All subjects will receive the same active 
drug at the same dosage. 
4. Selection and Withdrawal of Subjects 
The study population will include menopausal females with vulvar vaginal atrophy 
(VVA) causing dyspareunia.  
 
4.1 
Subject Inclusion Criteria 
All criteria below must be met in order for a Subject to be eligible for study 
participation. 
1. Subject provides written informed consent and HIPAA authorization before 
any study procedures are conducted; 


 
Protocol SDSM-2015-02.4 
April 4, 2016 
 
2. Subject is female; 
3. Subject is aged 21-80 years; 
4. Subject has a body mass index (BMI) < 37 kg/m2 
5. Subject is menopausal either naturally (at least 12 months amenorrheic) 
or 6 weeks after a bilateral salpingo-oophorectomy prior to natural 
menopause; subjects with hysterectomy only must have a serum FSH > 
40 mIU/mL;  
6. Subject has vulvovaginal atrophy with dyspareunia; 
Subject agrees to comply with the study procedures and visits. 
 
 
4.2 
Subject Exclusion Criteria 
Subjects who meet any of the following criteria shall be excluded: 
 
1. Subject has a hypersensitivity to any of the ingredients of ospemifene; 
2. Subject has used ospemifene in the past; 
3. Subject has documented or suspected breast cancer, history of heart 
attack or stroke;  
4. Subject has clinically significant findings on physical examination; 
5. Subject has uncontrolled hypertension; 
6. Subject has any chronic medical condition or psychologic disorder that the 
Principal Investigator feels makes her ineligible for the study; 
7. Subject is currently on local or systemic androgen therapy including local 
or systemic testosterone (washout 14 days for local or topical androgen or 
non-depot injection, 1 month for depot, 6 months for pellet; 
8. Subject is currently on local or systemic estrogen therapy or androgen 
therapy (washout 14 days for vaginal estrogen, 60 days for 
oral/transdermal therapy); 
9. Subject is currently using a SERM or products that have estrogenic or 
anti-estrogenic effects within last month;  
10. Subject currently using itraconzole, ketoconazole, digitalis or alkaloids 
heparin or strong cytochrome P 450 3A4 inhibitors; 
11. Subject has a history of substance abuse within 12 months prior, or 
consuming > 14 alcoholic drinks per week; 
12. Subject has received an investigational drug within 30 days prior to 
signing consent; 
13. Subject has any condition or exhibits behavior that indicates to the 
Principal Investigator that the Subject is unlikely to be compliant with study 
procedures and visits. 
 
4.3 
Subject Withdrawal Criteria 
 
The Principal Investigator may discontinue a subject’s participation in the study at 
any time if it is considered in the subject’s best interest to do so.  Such a decision 
may be precipitated by adverse events, new onset illness, clinically important 
changes in vital signs, physical examinations, or laboratory tests.  Subjects who 


 
Protocol SDSM-2015-02.4 
April 4, 2016 
 
are noncompliant with study procedures and visits may also be withdrawn by the 
Principal Investigator.   
 
Subjects may withdraw from participation in the study at any time for any reason.  
A subject’s decision to withdraw will not cause the subject to lose any benefits to 
which she is entitled.  A subject who withdraws prematurely from the study will 
return to the clinic as soon as possible and before any further ospemifene 
treatment of any kind, to undergo the final visit evaluations. 
 
If a subject prematurely withdraws or is withdrawn from study participation, the 
reason for the withdrawal must be recorded on the case report form (CRF).  
Record the primary reason for premature withdrawal according to the following 
categories: 
• Adverse Event:  Subject experiences an intolerable event, which may or 
may not be related to the study medication; 
• Withdrawn Consent:  Subject withdraws from study participation for 
personal reasons (exclude adverse experience before indicating this 
category); 
• Concomitant Medication Violation:  Subject initiates, discontinues, or 
changes dosing regimen of concomitant medication in violation of the 
protocol, which, in the judgment of the Principal Investigator, may 
adversely affect evaluation of safety; 
• Lost-to-Follow-up:  Subject does not return for evaluation and no further 
contact is made by the Subject after three documented phone or email 
attempts and a final attempt by certified mail. 
• Other:  Any reason that does not fit in the above 4 categories: the reason 
will also be recorded on the CRF. 
 
5. 
Clinical Procedures 
Clinical procedures throughout the study are described in the sections below, 
and summarized briefly in Appendix 1. 
 
5.1 
Informed Consent and HIPAA 
Each potential study Subject must provide written informed consent and 
authorize release of her protected health information before any study procedure 
is conducted. 
5.1.1 Informed Consent 
An Informed Consent Form (ICF) and California Bill of Rights will be written in 
accordance with established criteria of the Aspire IRB and the appropriate federal 
regulations to describe the study plan, procedures, and risks.  The Aspire IRB 
must approve the ICF and any ICF amendments or administrative revisions 
before they are used. 


 
Protocol SDSM-2015-02.4 
April 4, 2016 
 
 
Potential subjects will be informed of the study plan and schedule and will 
provide written informed consent prior to the initiation of any study-related 
procedures.  Each subject will be afforded the opportunity to ask any questions 
about the study plan, procedures, or possible risks.  The date the consent form 
was signed by the subject and the Principal Investigator or his designee will be 
documented.  The screening procedures will be performed and recorded on the 
source documents.  No screening procedures may be initiated prior to the 
Subject signing the ICF. 
 
The original, signed ICF will be retained in the Principal Investigator’s study files.  
A copy of the signed and dated consent form will be given to each potential 
Subject. 
5.1.2 HIPAA 
In accordance with the Health Insurance Portability and Accountability Act 
(HIPAA) Privacy Rule, the Subject has the right to determine who has access to 
protected health information. 
 
Potential subjects will provide written authorization for the Principal Investigator 
to access the subject’s personal health information (PHI) for the purposes of the 
study.  Personal health information relevant to the study includes medical records 
and the results of tests and procedures.  The subject’s written authorization also 
allows sharing this information with the Food and Drug Administration (FDA), 
other regulatory agencies and the Aspire IRB.  The Subject may cancel the 
authorization in writing at any time, but will then be withdrawn from the study. 
 
An authorization form must include the following elements: 
• A description of the information to be used or disclosed; 
• Identification of the persons or class of persons authorized to make the 
disclosure(s); 
• Identification of the persons or class of persons authorized to receive the 
PHI; 
• A description of the purposes for the uses or disclosures; 
• Expiration date or event triggering expiration; 
• Individual’s signature and date; 
• A statement of the individual’s right to revoke his/her authorization; 
• A statement of consequences to the individual for refusing to sign the 
authorization; 
• A statement of the potential for the information to be re-disclosed by 
recipients and no longer protected by the Privacy Rule; and 
• If the individual will be denied access to records during the study, a 
statement that the Subject agrees to temporarily waive access to records 
during the research. 
 


 
Protocol SDSM-2015-02.4 
April 4, 2016 
 
The original, signed HIPAA authorization form will be retained in the Principal 
Investigator’s study files.  A copy of the signed and dated form will be given to 
each potential Subject. 
 
 
5.2 
Subject Screening (Visit 1) 
Candidates for enrollment will be screened within 28 days prior to enrollment.  
Before initiation of any test procedures, Subjects will be fully informed of the 
study plan, procedures, and risks involved in participating in the study.  Each 
potential Subject will be required to read and to indicate her understanding by 
signing and dating the ICF prior to initiation of any screening procedures.  
 
The site will maintain an ongoing screening log of all subjects who provide written 
informed consent.  The screening log will include each Subject’s initials, date of 
birth, and screening number (assigned sequentially), including reason for exclusion 
if the subject is determined to be ineligible for the study.  If the subject does not 
have a middle name, a dash will be used instead of that initial (e.g., J-S).  The 
subject will be identified on source documents by initials and the assigned Subject 
number.  
 
Screening procedures will consist of the following: 
• Medical history, including surgical procedures, tobacco, alcohol, and 
medication use (prescription and non-prescription drugs, nutritional 
supplements, herbals, or investigational drugs); 
• Measurement of height (inches) and weight (pounds) in indoor clothing 
without shoes; recorded to the nearest whole unit; 
• Vital signs (blood pressure, pulse, respiration rate, and oral temperature); 
• Pain scale; 
• Urinalysis; 
• Clinical laboratory tests estradiol, LH, FSH (the same clinical laboratory 
will be used throughout the study):  
• Physical examination including review of systems and breast and 
gynecologic exam;  
• Vulvoscopy including detailed photograph(s) of the vulva, vestibule and 
vagina region and pain scale/Q-tip testing; 
• Visual scale. 
 
The Principal Investigator will review all screening assessments and sign and 
date all reports.  Any clinically significant abnormalities will be indicated by the 
abbreviation CS on the report.  Results that are not clinically significant will be 
identified as NCS. The Principal Investigator will review all inclusion and 
exclusion requirements and document the eligibility of each Subject to participate 
further. 
 


 
Protocol SDSM-2015-02.4 
April 4, 2016 
 
5.3 
Study Restrictions 
 
The restrictions listed below will be applied from study drug administration 
through study termination.  The Principal Investigator will determine if a deviation 
from the restrictions warrants Subject withdrawal from the study.  
 
From screening through completion of the last study procedures, Subjects may 
not do the following: 
• use of any prescription hormone (any administration); 
• change any prescription medication without notifying the Principal 
Investigator; 
• use any over-the-counter products, vitamins or herbal and/or nutritional 
supplements; 
• use any investigational drug or medical device products; 
• use any drugs of abuse. 
 
5.4 
Study Day 0 (Visit 2) 
 
Subject meeting inclusion and exclusion criteria may enroll any time after 
screening up to 28 days after consent is signed: 
• Measure vital signs (blood pressure, pulse, respiration rate, and oral 
temperature); 
• Assess any change in concomitant medication since screening visit; 
• Complete pain scale; 
• Vulvoscopy including detailed photograph(s) of the vulva, vestibule and 
vagina region and pain scale/Q-tip testing; 
• Complete visual scale; 
• Educate subject as to how study medication is administered (taken 
each morning); 
• Dispense study medication (35 tabs), diaries (10) and lubricant; 
• Assess adverse events. 
 
 
5.5 
Study Days 28 ± 7, 56 ± 7, 84 ± 7, 112 ± 7 (Visits 3, 4, 5, 6) 
 
Each Subject will report to the Principal Investigator’s office on study Days 28, 
56, 84 and 112 ± 7 for the following procedures at each visit: 
• Measure vital signs (blood pressure, pulse, respiration rate, and oral 
temperature); 
• Assess any change in concomitant medication;  
• Complete pain scale; 
• Vulvoscopy including photograph(s) of the vulvar vestibule region and 
pain scale/Q-tip testing; 
• Complete visual scale; 


 
Protocol SDSM-2015-02.4 
April 4, 2016 
 
• Collect medication and calculate compliance (reeducate Subject on 
medication administration if compliance is <80% or >120%); 
• Collect diaries; 
• Dispense study medication (35 tabs), new diaries and new lubricant; 
• Assess adverse events. 
 
 
5.6 
Study Day 140 ± 7 (Visit 7) or Early Termination Visit 
 
On Study Day 140 ± 7 each Subject will report to the Principal Investigator’s 
office for the following procedures: 
• Measure vital signs (blood pressure, pulse, respiration rate, and oral 
temperature); 
• Assess any change in concomitant medication;  
• Complete pain scale; 
• Perform physical examination including review of systems and breast and 
gynecologic exam;  
• Vulvoscopy including photograph(s) of the vulva, vestibule and vagina 
region and pain scale/Q-tip testing; 
• Complete visual scale; 
• Collect medication and calculate compliance; 
• Collect diaries; 
• Assess adverse events. 
 
If a Subject terminates study participation or is withdrawn from the study by the 
Principal Investigator before visit 7, the Subject should return to the Principal 
Investigator's office as soon as possible for the following procedures: 
 
• Measure vital signs (blood pressure, pulse, respiration rate, and oral 
temperature); 
• Assess any change in concomitant medication;  
• Complete pain scale; 
• Assess any change in concomitant medication since screening visit;  
• Perform physical examination including review of systems and breast and 
gynecologic exam;  
• Vulvoscopy including photograph(s) of the vulva, vestibule and vagina 
region and pain scale/Q-tip testing; 
• Complete visual scale; 
• Collect medication and calculate compliance; 
• Collect diaries; 
• Assess adverse events. 
 


 
Protocol SDSM-2015-02.4 
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6 
Adverse Event Assessment  
 
6.1 
Adverse Events 
 
An adverse event (AE) is any undesirable sign, symptom, medical condition, or 
laboratory abnormality occurring after the Subject has taken the first dose of 
study medication, whether the event is considered study medication-related or 
not.  Medical conditions or diseases present before starting study medication are 
only considered adverse events if they worsen after starting study medication.  
The Principal Investigator will follow all Subjects who experience an adverse 
event until the Subject’s medical condition returns to normal or until a clinically 
satisfactory resolution is obtained. 
 
Adverse events are classified in several ways: as either serious or non-serious, 
and either expected or unexpected.  Serious adverse events (SAEs) include 
those that result in death, are life threatening, require inpatient hospitalization or 
result in prolongation of an existing hospitalization, result in persistent or 
significant disability or incapacity, require medical or surgical intervention to 
prevent one of the outcomes described above, are congenital anomalies or birth 
defects, or are medically important events or reactions (see Section 7.2).  Non-
serious adverse events are those adverse events that do not meet the above 
criteria for serious adverse events.  Expected adverse events are those events 
that have been previously observed and are described in the current prescribing 
information for the study medication.  Unexpected adverse events are those 
events that are not listed in the prescribing information, or are not consistent with 
the specificity or severity described in the current prescribing information. 
 
Any abnormality that, in the judgment of the Principal Investigator or a physician 
identified on Form FDA 1572, impacts the health, safety, or well-being of the 
study participant such that immediate follow-up (e.g., additional testing or 
treatment intervention) is warranted is considered a clinically significant 
abnormality.  A determination of clinical significance is independent of whether or 
not the abnormality is considered causally related to the use of the study 
medication. 
 
6.2 
Serious Adverse Events 
 
A SAE is defined by federal regulation as any AE that results in any of the 
following outcomes: 
1. 
Death 
2. 
Life threatening (Subject is at risk of death at the time the event 
occurs) 
3. 
Persistent/significant disability or incapacity (substantial disruption of 
a person’s ability to conduct normal life functions) 
4. 
Inpatient hospitalization or prolongation of an existing hospitalization. 


 
Protocol SDSM-2015-02.4 
April 4, 2016 
 
5. 
Congenital anomaly or birth defect. 
 
Additionally, important medical events that may not result in death, be life 
threatening, or require hospitalization may be considered a SAE when, based 
upon appropriate medical judgment, they may jeopardize the Subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. 
 
Any SAE occurring in a Subject after providing informed consent and until 30 
days after completing the study must be reported to the Aspire IRB.  The 
reporting period may be extended if there is a strong suspicion of a study 
medication reaction.  Reports of overdosage must be monitored and reported as 
an SAE. 
 
6.3 
Adverse Event Reporting 
 
All adverse events, whether volunteered by the Subject, discovered during 
general questioning by the Principal investigator, or detected through a physical 
examination or other means, will be recorded in the clinic chart (source 
document) and on the Adverse Events CFR.  Each description of an adverse 
event will include: 
1. 
Duration: start and stop dates 
2. 
Expectedness  
3. 
Severity: events will be classified as either mild (causing no limitation 
in normal activities), moderate (causing some limitation in normal 
activities), or severe (causing significant limitation in or the inability to 
perform normal activities) 
4. 
Action taken 
5. 
Relationship to the study medication:  not related, possibly related, or 
probably related 
6. 
Outcome: resolved, continuing requiring no treatment, continuing 
requiring treatment, hospitalization, or death 
 
Whenever possible, adverse events causing premature study discontinuation 
should be followed to resolution. 
 
All SAEs occurring during the study and up to 28 days after the Subject 
completes the study (visit on Day 84 or earlier) must be reported to the Aspire 
IRB within 1 week of learning of the event with the exception of death which must 
be reported within 24 hours.  Additionally, the Principal investigator must provide 
any other AE notification required by the IRB.  Each SAE is to be recorded on a 
SAE worksheet along with follow-up records.  Examples of follow-up records may 
include photocopies of hospital records, consultation reports, autopsy findings, 
laboratory reports, and a summary of the outcome of the reaction.  
 


 
Protocol SDSM-2015-02.4 
April 4, 2016 
 
6.4 
Risks 
 
The risks to Subjects in this study are those associated with in the package insert 
for ospemifene:  hot flashes, vaginal discharge, muscle spasms and increased 
sweating.  Less common but serious side effects include stroke, blood clots and 
cancer of the lining of the uterus. 
 
7. 
Study Medication and Accountability 
 
The Principal Investigator is responsible for study medication at the 
investigational site, including storage, accountability, record keeping, and 
reconciliation. 
 
7.1 
Study Medication 
 
Ospemifene (Osphena®) 60 mg tablets will be provided by Shionogi 
Pharmaceuticals, in sufficient quantity to dose all Subjects. 
 
The ospemifene tablets provided for this study will be taken from commercial 
drug supply. 
 
7.2 
Study Medication Blinding 
 
This is an open-label (unblinded) study and no blinding of study medication is 
required. 
 
7.3 
Study Medication Labeling 
 
Each envelope of medication provided to each Subject will be marked as to 
subject (initials and subject number), visit number and date of dispensing. 
 
7.4 
Study Medication Storage 
 
Ospemifene will be stored in a cool, dry place. The study medication shall be 
stored in a securely locked, substantially constructed enclosure to which access 
is limited.  The Principal Investigator shall take adequate precautions, including 
locked storage, to prevent theft or diversion of the study medication, consistent 
with CFR Title 21, part 312.69. 
 
7.5 
Study Medication Handling 
 
Study medication will be shipped to the investigational site after the granting 
agency (Shionogi Pharmaceuticals) has received the required study documents 
in accordance with regulatory requirements. 


 
Protocol SDSM-2015-02.4 
April 4, 2016 
 
 
All study medication is to be administered in accordance with the protocol and 
only to enrolled Subjects.  Only authorized personnel may supply the study 
medication to each Subject. 
 
7.6 
Study Medication Accountability 
 
All study medications will be Subject to inventory upon receipt, and stored in 
accordance with Section 8.4.  Applicable regulatory requirements for this study 
will be enforced by the Principal Investigator or designated site personnel 
through the study.  The Principal Investigator (or designee) will document the 
date, Subject identification, and lot number used each time drug is dispensed for 
Subject use. 
 
Throughout the study, the Principal Investigator will maintain an accounting of all 
study medication.  The Principal Investigator must not destroy any unused study 
medication. The Principal Investigator will return all unopened study medication 
and a copy of the completed drug disposition form to Shionogi Pharmaceuticals. 
 
8. 
Statistical Methods 
 
8.1 
Determination of Sample Size 
 
The sample size of 10 menopausal Subjects was chosen for this study based on 
this being a pilot study and this sample size will be sufficient to prospectively 
document visible changes to the vulva, vestibule and vagina in post-menopausal 
women with VVA and dyspareunia.  There will be a total of 6 photographic 
sessions of the vulva, vestibule and vagina over the 20 weeks of the study.  The 
photograph(s) at baseline (vulvoscopy session 0) will be compared to 
photographs at 4 weeks (vulvoscopy session 1), 8 weeks (vulvoscopy session 2), 
12 weeks (vulvoscopy session 3), 16 weeks (vulvoscopy session 4) and 20 
weeks (vulvoscopy session 5). 
 
8.2  
Photographic Data 
 
Changes to the vulva, vestibule and vagina will be examined prospectively by 
comparing photographs of post-menopausal women with VVA and dyspareunia 
at 4 weeks, 8 weeks, 12 weeks, 16 weeks and 20 weeks while on treatment with 
60 mg ospemifene. The proportion of subjects with improvement will be tabulated 
by scheduled visit. 
 
8.3  
Patient Reported Outcomes 
 


 
Protocol SDSM-2015-02.4 
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Mean pain score will be summarized at each scheduled visit. Subjects will also 
be categorized at each visit as having more pain, the same pain, or less pain 
compared to baseline. 
 
Mean scores will be summarized for each item of the visual scale at each 
scheduled visit. Subjects will also be categorized at each visit as worsened, 
unchanged, or improved compared to baseline for each item of the visual scale 
at each scheduled visit. 
 
For each subject, the proportion of total sexual events with a ‘yes’ response since 
the last scheduled visit will be calculated for each diary question at each 
scheduled visit.  
 
8.4   Safety Data 
 
Safety data will be summarized for each Subject enrolled in the study. 
 
9.   Administrative Issues 
 
9.1 
Changes to the Protocol 
 
Any change or addition to this protocol requires a written protocol amendment 
that must be approved by the Aspire IRB before implementation.   Only in the 
event of an emergency should a deviation from the protocol occur for an 
individual Subject.  Such a deviation will be for the Subject in the emergency 
situation and for that Subject only. A description of the deviation from the protocol 
and the reason for it will be recorded in the source documents. 
 
 
9.2 
Monitoring Procedures 
 
The Principal Investigator and site personnel will complete all CRFs in a timely 
manner following completion of each Subject visit to facilitate documentation of 
study procedures and review of the CRFs. 
 
9.3 
Access to Data Source/Documentation 
 
The Principal Investigator will permit representatives of the Aspire IRB and/or the 
FDA (or other regulatory authority) to inspect the facilities and records relevant to 
this study, including Subject charts, either during the study or after its completion. 
 
9.4   Quality Control and Quality Assurance 
 


 
Protocol SDSM-2015-02.4 
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The Principal Investigator must provide the documents listed below before drug 
can be shipped and the study initiated: 
• Original Form FDA 1572 completed and signed by the Principal 
Investigator; 
• Current medical license for each physician appearing on Form FDA 1572; 
• Copy of IRB correspondence documenting approving the protocol, 
informed consent form, recruitment materials and any instructions for the 
Subject regarding the procedure, and any other documents reviewed 
and/or required by the IRB. 
 
9.5 
Ethics 
 
This study will be conducted in accordance with current Good Clinical Practice 
(GCP), with the Code of Federal Regulations (CFR Title 21, Parts 50, 54, 56, 
312, and 314).  Current GCP is consistent with the ethical principles described in 
the current version of the Declaration of Helsinki. 
 
Requirements for Independent Review Board (IRB) review and obtaining 
informed consent are described in Sections 3.3 and 5.1, respectively.  
 
9.6  
Case Report Forms, Data Handling, and Recordkeeping 
 
The following procedures will be employed related to recording of data: 
• Relevant information determined at each Subject visit is to be recorded on 
source documents/CRFs.   
• Data recorded on CRFs will be documented in an anonymous fashion with 
the Subject identified only by her Subject number and initials. 
• All CRFs are to be completed in a neat, legible manner to ensure accurate 
communication of data.  A black pen is preferred to ensure clarity of any 
reproduced copies.  Any change or corrections made on the CRFs must 
be dated and initialed by the person making the change.  In such cases, 
the best procedure is to cross out the original entry with a single line.  Do 
not erase, overwrite, or obliterate, by any means, the original entry. 
• CRFs and any data queries should accurately reflect Subject data records 
(source documents). 
• The completed CRF set for each Subject is to be reviewed by the Principal 
Investigator for completeness and accuracy.  The Principal Investigator 
will sign and date the last CRF page to indicate this review was 
performed. 
 
9.7  
Retention of Data, Documents, and Study Medication 
 
In compliance with CFR Title 21, part 312.57(c), the Principal Investigator will 
retain all study-related materials for at least 2 years after study completion.  
Study-related materials include, but are not limited to, medical records (i.e., the 


 
Protocol SDSM-2015-02.4 
April 4, 2016 
 
source data), completed case report forms, medication accountability records, 
and reserve samples of investigational medication.  Study medication will be 
stored securely under the storage conditions described in Section 8.4. 
 
10.    References 
 
1. Bachmann GA, Komi JO, Ospemifene Study Group, Ospemifene 
effectively treats vulvaginal atrophy in postmenopausal women; results 
from a pivotel phase 3 study.  Menopause 2010;17:480-6.  
2. Portman DJ, Bachmann GA, Simon JA and Ospemifene Study Group, 
Ospemifene, a novel selective estrogen receptor modulator for treating 
dyspareunia associated with postmenopausal vulvar and vaginal atrophy.  
Menopause 2013;20:623-30. 
3. Goldstein SR, Bachmann GA, Koninckx PR, Lin VH, Portman DJ, 
Ylikorkala O and Ospemifene Study Group.  Climacteric 2014;17:173-82. 
4. James A. Simon, MD,1 Vivian H. Lin, MD,2 Cathy Radovich, BS,2 Gloria 
A. Bachmann, MD,3 and The Ospemifene Study GroupOne-year long-
term safety extension study of ospemifene for the treatment of vulvar and 
vaginal atrophy in postmenopausal women with a uterus, Menopause: The 
Journal of The North American Menopause Society, Vol. 20, No. 4, pp. 
418-427. 
 


 
Protocol SDSM-2015-02.4 
April 4, 2016 
 
Appendix 1:  Schedule of Study Procedures 
 
Study DAY: 
Up to -28 
0 
28 ± 7 
56 ± 7 
84 ± 7 
112 ± 7 
140 ± 7 
 or ET 
Visit 
1 
2 
3 
4 
5 
6 
7 
Procedure 
 
 
 
 
 
 
 
ICF & HIPAA 
X 
 
 
 
 
 
 
I/E Criteria 
X 
X 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
 
X 
Breast/Gyn exam 
X 
 
 
 
 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Height & weight 
X 
 
 
 
 
 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
Pain scale 
X 
X 
X 
X 
X 
X 
X 
Clinical  
laboratory tests2 
X 
 
 
 
 
 
X 
Vulvoscopy with 
photography 
X 
X 
X 
X 
X 
X 
X 
Visual Scale 
X 
X 
X 
X 
X 
X 
X 
Q-tip test 
X 
X 
X 
X 
X 
X 
X 
Dispense study 
drug  
 
X 
X 
X 
X 
X 
 
Dispense diaries  
 
X 
X 
X 
X 
X 
 
Dispense lubricant 
 
X 
X 
X 
X 
X 
 
Collect/reconcile 
medication 
 
 
X 
X 
X 
X 
X 
Calculate 
compliance 
 
 
X 
X 
X 
X 
X 
Collect diaries 
 
 
X 
X 
X 
X 
X 
Collect AE data 
X 
X 
X 
X 
X 
X 
X 
ET = early termination 
For detailed study procedures, see Section 5, Clinical Procedures. 
 
 


 
Protocol SDSM-2015-02.4 
April 4, 2016 
 
Appendix 2:  Pain Scale 
 
 
 
      I---------------------------------I---------------------------------I---------------------------------I 
     0  
 
      1  
 
       2  
 
        3  
 
no pain 
 
   mild  
          moderate 
 
    severe 
 
 


 
Protocol SDSM-2015-02.4 
April 4, 2016 
 
Appendix 3:  Visual Scale 
 
 
Observation 
 
 
0 - none 
 
1 - mild 
 
2 - moderate 
 
3 - severe 
 
Petechiae 
 
 
 
 
 
 
Pallor 
 
 
 
 
 
 
Friability 
 
 
 
 
 
 
Dryness 
 
 
 
 
 
 
Redness 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Protocol SDSM-2015-02.4 
April 4, 2016 
 
Appendix 4:  Diary 
 
 
 
Initials ___________  Number ___________  Date _______________________ 
 
 
 
 
Please complete after each sexual event, answering all questions. 
 
 
 
If you experienced dryness before were you less dry? ☐Yes   ☐ No   ☐ N/A 
 
 
Did you use lubricant during this activity?  
 
☐Yes   ☐ No    
 
 
Did you experience pain/discomfort during foreplay? ☐Yes   ☐ No   ☐ N/A 
 
 
Did you experience pain during masturbation?   
☐Yes   ☐ No   ☐ N/A 
 
 
Did you experience pain during oral sex?  
 
☐Yes   ☐ No   ☐ N/A 
 
 
Did you experience pain during intercourse?  
 
☐Yes   ☐ No   ☐ N/A 
 
 
Did you stop early because of discomfort?  
 
☐Yes   ☐ No    
 
 
 
 
 
 
 

SAP_001.pdf: 
AN OPEN-LABEL PILOT PROSPECTIVE VULVOSCOPY WITH PHOTOGRAPHY 
STUDY OF THE VISIBLE CHANGES IN THE VULVA, VESTIBULE AND VAGINA PRE- 
AND POST- TWENTY WEEKS OF DAILY ADMINISTRATION OF 60 MG 
OSPEMIFENE IN POST-MENOPAUSAL WOMEN WITH DYSPAREUNIA FROM 
VULVAR VAGINAL ATROPHY 
 
 
 
 
 
 
 
 
 
 
 
 
NCT 02784613 
April 4, 2016 
 
 


Each subject’s baseline and end of the study vulvoscopic photographs were subsequently 
assessed using a four-point rating scale, the vulvoscopic genital tissue appearance (VGTA) scale. 
The VGTA scale has not been validated. This scale assesses ten different parameters of the 
appearance of the genital tissue including loss of labia majora, loss of labia minora, decreased 
size of glans clitoris, prominence of urethral meatus, stenosis of introitus, vestibular pallor, 
vestibular erythema, loss of vestibular moisture, loss of vaginal rugae, and loss of prominence 
of the anterior vaginal wall (Table 2). Each subject could score between 0 and 30 total points on 
the VGTA at each visit. A higher score of the VGTA scale was considered consistent with a worse 
vulvoscopic genital tissue appearance. 
 
Baseline physical examination was performed as part of the screening. The physical exam 
included performance of a cotton-tipped swab testing where the examiner applied gentle 
pressure at each location of the vestibule: 1:00, 3:00, 5:00, 6:00, 7:00, 9:00, and 11:00 o’clock. 
The subject was asked to rate her pain on a scale from 0 to 3. Aggregate pain scores at baseline 
and study end were compared using the Wilcoxon signed-rank test. 
 
Baseline sexual function diary data concerning dryness and sexual pain were collected.  The 
questions of the sexual function diary have not been validated. For 4 weeks prior to each study 
visit, subjects recorded yes or no answers to the following questions for each sexual encounter: 
1) did the subject experience dryness before and were you now less dry, 2) did the subject use 
lubricant during this sexual activity, 3) did the subject experience pain/discomfort during 
foreplay? 4) did the subject experience pain during masturbation, 5) did the subject experience 
pain during oral sex, 6) did the subject experience pain during intercourse, and 7) did the 
subject stop early because of discomfort. Diaries were collected and new ones administered at 
each subsequent visit.  The number of total sexual events, as well as percentage of total sexual 
events with pain or lubrication difficulty was compared for diaries collected at week 0 and week 
20 using the Wilcoxon signed-rank test. 
 
At the completion of the study, the photographs were sorted by subject number and date of 
exam and assessed by the principal investigator, a sexual medicine physician, who had not 
examined any of the women in person. He assigned scores to the photographs using pre-
determined Likert scales for the 10 parameters of VGTA scale (Table 2).  Differences in pre-and 
post-treatment scores were compared using Wilcoxon signed-rank test for non-parametric 
matched pairs. All tests of significance were 2-tailed with p<0.05 considered significant. All 
analyses were performed in Stata®, version 13.