Clinical trial NCT03018106
Conditions: Sexual Dysfunction, Physiological
Keywords: Female sexual disorder Aging Menopause Obstetrics/Gynecology Female urogenital disorder
Sponsor: Emory University
Start date: 2017-06-30; Completion date: 2017-09-29
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Vulvovaginal atrophy (VVA) is a condition that impacts up to 60% of the growing postmenopausal female population, and the most common symptom is dyspareunia. Vaginal estrogen is the most common treatment for VVA, but it only marginally improves overall sexual function, and many women and clinicians avoid using it because of the risks of exogenous estrogen use during menopause. Ospemifene is a non-estrogen selective estrogen receptor modulator (SERM) that is FDA-approved for treating dyspareunia related to VVA, and has shown superb improvements in overall sexual health. 104 women will be randomized to receive 12 weeks of 60mg oral ospemifene, taken daily, or 12 weeks of 0.5mg vaginal conjugated estrogens, which is placed vaginally twice per week. The improvements in sexual health and VVA symptom severity will be compared in each group. This study will help determine if ospemifene is a better treatment medication than conjugated estrogens.

Detailed description:
Female sexual dysfunction (FSD) affects 57% of postmenopausal women. Vulvovaginal atrophy (VVA) is a condition that impacts up to 60% of the growing postmenopausal female population, and the most common symptom is dyspareunia. Women with FSD are 3.84 times as likely to also have VVA. Vaginal estrogen is the most common treatment for VVA, but it only marginally improves overall sexual function, and many women and clinicians avoid using it because of the risks of exogenous estrogen use during menopause. Ospemifene is a non-estrogen selective estrogen receptor modulator (SERM) that is FDA-approved for treating dyspareunia related to VVA, and has shown superb improvements in overall sexual health. This oral medication, taken daily, improves vaginal health, and has demonstrated protective activity in the breast and bone tissues. It also has not demonstrated any carcinogenic activity in the endometrium or liver. This study hopes to determine if ospemifene is superior to conjugated estrogens in improving sexual function and vaginal atrophy symptoms.

104 women will be randomized to receive 12 weeks of 60mg oral ospemifene, taken daily, or 12 weeks of 0.5mg vaginal conjugated estrogens, which is placed vaginally twice per week. Each participant will be informed of her assigned medication, and will receive a medication coupon to help offset the cost of the medication. Each medication is FDA-approved for long-term use of at least 52 weeks. For this study, a 12-week prescription for the medication will be sent electronically to the pharmacy of the participant's choice. The improvements in sexual health and VVA symptom severity will be compared in each group.

Arms: arm 1: Women randomized to this arm will receive 60mg oral ospemifene, taken daily, for 12 weeks arm 2: Women randomized to this arm will receive 0.5mg vaginal conjugated estrogens, placed vaginally twice per week, for 12 weeks
Interventions: intervention 1: Ospemifene intervention 2: Vaginal conjugated estrogens
Intervention descriptions: intervention 1: Ospemifene is a selective estrogen receptor modulator (SERM), and it is the only SERM approved in the United States to treat moderate to severe dyspareunia associated with VVA. It is an oral medication that is taken as a 60mg tablet once daily. Food intake increases its absorption by 2 to 3-fold, and this is not impacted by the fat or calorie content of the food. It is metabolized primarily in the liver, and is excreted in feces. intervention 2: Conjugated estrogens are a mixture of several different estrogen salts derived from natural sources and blended to approximate the composition of estrogens in the urine of pregnant horses. The main components are sodium estrone sulphate and sodium equilin sulfate. Vaginal estrogen is considered the medication of choice for treating vulvovaginal atrophy (VVA).

Protocol documents:
Prot_SAP_000.pdf: 
Eto, C 
Ospemifene versus Conjugated Estrogens in the Treatment of Postmenopausal Sexual 
Dysfunction  
 
Chidimma Eto, MD 
Female Pelvic Medicine and Reconstructive Surgery, Fellow 
Emory University 
 
Gina Northington, MD, PhD 
Female Pelvic Medicine and Reconstructive Surgery, Division Director & Fellowship Director 
Associate Professor 
Emory University Hospital, Chief of Service 
 
Mary Dolan, MD, MPH, NCMP 
Department of Obstetrics & Gynecology, Associate Professor 
Menopause Clinic, Director 
Emory University 
 
 
Abstract & Relevance  
 
57% of postmenopausal women suffer from female sexual dysfunction (FSD). Vulvovaginal at-
rophy (VVA) is a condition that impacts up to 60% of the growing postmenopausal female popu-
lation, and the most common symptom is dyspareunia. Women with FSD are 3.84 times as 
likely to also have VVA. Vaginal estrogen is the most common treatment for VVA, but it only 
marginally improves overall sexual function, and many women and clinicians avoid using it be-
cause of the risks of exogenous estrogen use during menopause. Ospemifene is a SERM that 
is FDA-approved for dyspareunia related to VVA, and has shown superb improvements in over-
all sexual health. This oral medication, taken daily, improves vaginal health, and has demon-
strated protective activity in the breast and bone tissues. It also has not demonstrated any car-
cinogenic activity in the endometrium or liver. This study hopes to determine if ospemifene is su-
perior to conjugated estrogens in improving sexual function and vaginal atrophy symptoms. 104 
women will be randomized to receive 12 weeks of 60mg oral ospemifene, taken daily, or 12 
weeks of 0.5mg vaginal conjugated estrogens, which is placed vaginally twice per week. The 
improvements in sexual health and VVA symptom severity will be compared in each group. This 
study will help determine if ospemifene is a better treatment medication than conjugated estro-
gens. The implications of this study may provide an attractive alternative to the many women 
who continue to suffer from sexual dysfunction and VVA because of concerns surrounding the 
use of exogenous hormones.  
 
Introduction 
 
In May 2013, the Board of Directors of the International Society for the Study of Women's Sex-
ual Health (ISSWSH) and the Board of Trustees of The North American Menopause Society 
(NAMS) endorsed the term genitourinary syndrome of menopause (GSM). This term encom-
passes the numerous changes that occur as a result of the decrease in estrogen and other sex 
steroids, including vaginal atrophy and sexual dysfunction [1]. In a cross-sectional study of US 
postmenopausal women, those with sexual dysfunction were 4 times more likely to have vulvo-
vaginal atrophy [2]. With the rising elderly population, the impact of VVA and sexual dysfunction 
on quality of life and health care costs is a growing issue. In 2000, there were 26.25 million 
women over the age of 60 years old, and this number is expected to almost double by the year 
2030 [3]. Currently VVA affects up to 60% of postmenopausal women, and its most common 
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symptom is dyspareunia [4,5]. Further, if left untreated, it can increase rates of infection, and 
negatively impact a woman’s sexual health and quality of life [6]. While only 25% of women with 
VVA seek medical advice, only 3% of women reveal problems with sexual health without being 
prompted [7,8].  
 
There are several established methods of treatment for VVA. Vaginal estrogen is considered the 
treatment of choice. While several studies have shown that vaginal estrogen does not increase 
serum estrogen levels above postmenopausal values, there is still significant controversy sur-
rounding the use of estrogen and the risk of breast cancer and uterine cancer [9,10]. This study 
is important because we hope to prove a non-estrogen medication to be an effective non-hor-
monal alternative therapy for vulvovaginal atrophy.   
 
In 2013, Ospemifene was approved by the Food and Drug Administration for the treatment of 
moderate to severe dyspareunia that is due to menopause [10]. Ospemifene is a non-estrogen 
selective estrogen receptor modulator (SERM). SERMs are estrogen receptor (ER) agonist/an-
tagonists that typically induce the desirable effects of estrogen while avoiding estrogen-related 
adverse effects. Unlike other drugs in this class, Ospemifene has been shown to have signifi-
cant estrogenic agonist effects on the vagina and bone, but antagonist effects on breast tissue 
[6]. Furthermore, it significantly improves overall sexual function [12]. Despite this promising 
medical profile, it remains a second or third line of therapy to treat VVA. More research is 
needed to determine if ospemifene is an acceptable, and possibly a favorable, alternative to 
vaginal estrogen for the treatment of vulvovaginal atrophy, especially if there is any concern for 
sexual function. In this research study, we aspire to determine the efficacy of ospemifene com-
pared to a vaginal estrogen.  The primary aim of this research is to compare female sexual func-
tion as measured by a validated instrument in women randomized to receive ospemifene and 
vaginal estrogen.  Secondary aims include comparing markers of vaginal health and safety in 
both treatment groups. 
 
Hypothesis  
 
Ospemifene is a nonhormonal alternative that has proven to significantly improve sexual health 
and vulvovaginal atrophy, yet vaginal estrogen is still considered the first-line therapy. Our null 
hypothesis is that ospemifene has a similar efficacy as vaginal conjugated estrogens for improv-
ing sexual function in postmenopausal women who have vulvovaginal atrophy.  
 
Specific Aims 
 
Specific Aim 1: To compare the efficacy of ospemifene and vaginal conjugated estrogens on fe-
male sexual function. Ospemifene is the only non-estrogen that is FDA-approved to treat 
dyspareunia in postmenopausal women. Further, studies report a significant improvement in 
sexual health in patients that are treated with ospemifene [12]. However, vaginal estrogen ther-
apy (with conjugated equine estrogen or estradiol) remains the most commonly prescribed treat-
ment for dyspareunia.  To our knowledge, a direct comparison of ospemifene and local vaginal 
estrogen therapy on postmenopausal female sexual function has not been performed.  We hy-
pothesize that ospemifene provides a greater improvement in sexual function in postmenopau-
sal women with dyspareunia and VVA. 
 
Specific Aim 2: To compare the effects of ospemifene and vaginal conjugated estrogens on 
symptoms of VVA. We hypothesize that treatment with either ospemifene or vaginal conjugated 
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estrogens will demonstrate comparable improvements in VVA symptoms.  In the population ran-
domly treated with vaginal conjugated estrogens or ospemifene in specific aim 1, we will com-
pare the change from baseline and between groups. 
 
Significance 
 
Female Sexual Dysfunction 
 
Traditionally, female sexual dysfunction (FSD) is defined as the disorder of desire, arousal, pain 
and/or muted orgasm in women [28]. While many people may consider this disorder to be perti-
nent only during reproductive years, it is very common in the menopausal women population, 
affecting 57% of women in menopause [5]. In 2014, Nappi et al published a review of data that 
shows the importance of discussing sexual function and vaginal atrophy with postmenopausal 
women. 1 in 5 women over the age of 70 still engage in intercourse. Moreover, 71% of women 
agree that, “it was important to them to maintain an active sex life.” The article also adds that 
only 3% of women will seek advice about sexual function if not prompted. Many who do bring 
this problem to their provider’s attention feel as though it is dismissed. Meanwhile, providers 
tended not to proactively address sexual health for middle and later life-aged women, because 
of time constraints, inadequate training, personal attitudes and beliefs that sex is not a priority 
for older patients [29]. 
 
What is Vulvovaginal Atrophy? 
 
There is significant overlap between FSD and VVA. Women with FSD are almost 4 times as 
likely to have VVA [29]. Once a woman reaches menopause, her ovarian production of estrogen 
decreases dramatically. The vagina and vulva are two organs that are affected by the lack of es-
tradiol in the body. Without estrogen, the vagina epithelial cells decline in maturation, and there 
is also an increase in the vaginal pH. These changes lead to the common symptoms of painful 
intercourse, vaginal dryness, pain, and itching. They also put the vaginal epithelium at risk for 
infection and inflammation. Further, the increase in pH is associated with an increased rate of 
recurrent urinary tract infections in postmenopausal women [13]. In the US, approximately 60% 
of women report symptoms related to vulvovaginal atrophy [4].  
 
There are a few effective treatment options for VVA. The most commonly used treatment is vag-
inal estrogen. This is prescribed in various forms, including a vaginal cream (Estrace, Premarin, 
compounded), a vaginal tablet (Vagifem), and a vaginal ring (Estring). Aside from the ring, the 
medication dosing typically involves nightly dosing for two weeks, followed by dosing twice per 
week. Estrogen functions by improving the percentage of vaginal superficial cells, while de-
creasing the pH, and improving symptom scores in participants [14,5]. Studies have also shown 
that the serum estradiol levels remained below 20mcg/mL, which is the typical maximum opti-
mum estradiol level in PMP women [15]. Other related estrogens, particularly estrone and es-
trone sulfate, also remained within postmenopausal levels [14]. With these findings, many clini-
cians feel comfortable recommending vaginal estrogen to patients who suffer from symptomatic 
vaginal atrophy. However, estrogen’s causal relationship with breast cancer and endometrial 
cancer causes many women to avoid using vaginal estrogen [16]. Hence, treatment options that 
do not involve the introduction of estrogen into the bloodstream are likely to be well sought after.  
 
Ospemifene 
 
Ospemifene is a selective estrogen receptor modulator (SERM), and it is the only SERM ap-
proved in the United States to treat moderate to severe dyspareunia associated with VVA [6,17]. 
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It is an oral medication that is taken as a 60mg tablet once daily. Food intake increases its ab-
sorption by 2 to 3-fold, and this is not impacted by the fat or calorie content of the food. It is me-
tabolized primarily in the liver, and is excreted in feces [4]. SERMs are estrogen receptor (ER) 
agonist/antagonists that typically induce the desirable effects of estrogen while avoiding estro-
gen-related adverse effects. Ospemifene is unique within this class because in addition to its 
protective activity in bone and breast tissue, it has a significant beneficial influence in the vagina 
without a carcinogenic effect on the endometrium. Initially, the drug was developed because of 
its bone-sparing reduction of bone resorption in OVX rats. However, its performance in other 
hormone-sensitive tissue led to further investigation [17].  
 
In its clinical development, ospemifene was singled out because unlike tamoxifen and raloxi-
fene, ospemifene significantly improves vaginal maturation. As a non-estrogen substance, its 
mechanism involves activation of estrogen receptors in the vagina, which leads to an increased 
thickness, mucification, and vacuolization of vaginal epithelium [18]. Several RCTs have shown 
an improvement in VVA with the use of ospemifene compared to placebo [6]. Importantly, the 
serum estradiol levels have been documented as unchanged in patients that use the medication 
for 12 weeks [19].  
 
Equally important is the activity of ospemifene in mammary tissue. In ER+ human breast cancer 
cells, ospemifene has either had no impact, or has had a dose-dependent growth inhibitory ef-
fect [20,21]. This implies its dependence on ER-alpha expression in this tissue. Two studies ex-
amined ospemifene’s ability to prevent dimethylbenzanthracene (DMBA)-induced breast cancer 
in mice. For up to 52 weeks of drug exposure, ospemifene prevented breast tumor formation 
similarly to tamoxifen [22]. Moreover, in normal human breast tissue, ospemifene also has simi-
lar antiestrogenic inhibitory effects as tamoxifen [23].  
 
An additional pilot study involving ospemifene administration to rhesus macaques suggest that it 
has a lower carcinogenic potential than tamoxifen, which is another SERM that is used in breast 
cancer treatment and prevention. In this study, there was no evidence of DNA adduct produc-
tion in the liver or the endometrium from daily ospemifene, while tamoxifen, the positive control, 
showed production of several DNA adducts in each organ [24]. Furthermore, clinical trials mir-
rored animal studies in that there was an increase in uterine weight and proliferative tissue, but 
there has never been any evidence of endometrial hyperplasia or bleeding with use of ospem-
ifene [25,26]. These findings have been strengthened by six RCTs, where no cases of endome-
trial hyperplasia or cancer has been identified [6]. 
 
Sexual Health 
 
As may be expected, VVA is four times more likely in patients who suffer from sexual dysfunc-
tion [14] . Ospemifene is FDA-approved specifically for dyspareunia in postmenopausal women 
with VVA. Studies show that it also improves the overall sexual health for women [12]. While es-
trogen has been shown to improve dyspareunia and lubrication, its impact on overall sexual 
health is not well-identified [27].  
 
In essence, Ospemifene seems to be a possible wonder drug for menopausal women. While it’s 
primary use if for VVA-associated dyspareunia, there is consistent evidence of protective activity 
in bone and breast tissue, while showing no evidence of carcinogenic potential in the endome-
trium, breast, or liver. Similar to vaginal estrogen, ospemifene has not been studied longer than 
12 months to determine long term risks of the medication [6]. Appendix 1 shows a summary of 
adverse events in various safety studies for vaginal estrogen and ospemifene. Research is 
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promising that Ospemifene may prove to be a safer and more beneficial choice for all postmen-
opausal women, regardless of their history of breast or endometrial cancer.   
 
Innovation 
 
Several studies have published data regarding the unique behavior of ospemifene in postmeno-
pausal women. Nonetheless, vaginal estrogen is still seen as the gold standard for the treat-
ment of VVA, regardless of the woman’s most bothersome symptom. To our knowledge, for the 
first time, this study will directly compare the efficacy of vaginal conjugated estrogens and 
ospemifene in improving sexual function in postmenopausal women who have vulvovaginal at-
rophy. By also directly comparing symptom improvement with VVA treatment, this study hopes 
to answer the question of whether or not clinicians should shift towards ospemifene as a first 
line treatment for sexual dysfunction in postmenopausal women with VVA.  
 
Approach 
 
Overview 
 
This study will be a prospective, randomized study that will compare efficacy and safety of 
ospemifene and vaginal estrogen. Because of the route of administration for each drug, it is not 
possible to blind the participants or clinicians to the treatment. However, we will be collecting 
objective data that cannot be misinterpreted by those collecting and analyzing the data. We 
hope to effectively inform clinicians who treat postmenopausal women that suffer from VVA 
about the efficacy of ospemifene as it compares to vaginal conjugated estrogens cream. As a 
specialty with a high population of patients who complain of VVA, we are very familiar with this 
patient population, as well as the use of vaginal estrogen in their treatment. This puts this re-
search team in an ideal position to properly execute the study and interpret the findings.  
 
Patient Groups 
 
All research activities will be performed after obtaining Institutional Review Board Approval from 
Emory University.  A consecutive sample of women will be recruited from the FPMRS and Men-
opause patients within The Emory clinics. Subjects are identified after their management plan has 
been established to include treatment of vulvar and/or vaginal atrophy.  Patients will be ap-
proached by the principal and/or co-investigators.  For women that agree to participate, written 
informed consent will be obtained.  All women who agree to participate in this study must meet 
inclusion criteria listed in Table 1. Once the exclusion criteria have been applied (Table 2), the 
qualifying subjects will be enrolled in the study. Once enrolled, each subject will complete the 
Female Sexual Function Index (FSFI) questionnaire and a symptom severity Likert scale. Finally, 
they will receive instructions on medication compliance, as well as potential adverse events for 
the designated medication. If we assume 50% of women offered enrollment in this study will agree 
and be eligible to participate, we expect to reach our target enrollment in seven to eight months.    
 
Table 1. Inclusion Criteria 
Interested in resuming or continuing sexual activity 
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Table 1. Inclusion Criteria 
Greater than 12 months since last menstrual cycle or prior bilateral oophorectomy 
40yo or older 
Dyspareunia as a vulvovaginal atrophy symptom 
Normal mammogram within 12 months prior to entry into the study 
 
Table 2. Exclusion Criteria 
History or suspicion of breast carcinoma 
History of hormone-dependent tumor 
Genital bleeding of unknown cause 
Ongoing vaginal infection 
History of CVA, MI or heart disease, uncontrolled HTN over 160/100 
Serious disease or chronic condition that may prevent completion of study, BMI over 40 
Hypercoagulable state, or currently on anticoagulant therapy 
Use of any exogenous sex hormone within three months from study entry, or during the study 
Pelvic surgery within the last 12 months 
 
Randomization and Allocation Concealment 
 
Once a qualifying subject is identified, she will be randomized into a treatment group.  The partic-
ipant will be randomized to receive either a vaginal conjugated estrogens prescription or an 
ospemifene prescription. A computerized randomization program will be used to perform block 
randomization in random blocks of 4 and 10. Allocations envelopes containing the assignment 
will be used for the study. They will be sealed opaque envelopes with aluminum foil inside. They 
will also contain carbon-copy paper. The treatment number will be printed on the envelope. Once 
the participant has signed the informed consent form, her name will be printed on the envelope, 
which will transfer over to the carbon-copy paper, and the envelope will be opened.  
 
Study Plan  
 
The patient will be informed of her assigned medication, and she will receive a medication coupon 
to help offset the cost of the medication. Each medication is FDA-approved for long-term use of 
at least 52 weeks. For this study, a 12-week prescription for the medication will be sent electron-
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ically to the pharmacy of her choice. Treatment with estrogen will consist of 0.5 gram of conju-
gated estrogens placed vaginally for 12 weeks. Treatment with ospemifene will consist of a 60mg 
tablet that will be taken at the same time daily for 12 weeks. 
 
The patient will receive an intake packet that includes the following information:  
1. Copy of signed informed consent form 
2. Important contacts and instructions for emergency/adverse events 
3. Allocation card 
4. Medication’s FDA packet insert 
5. Instructions on dosing 
6. 12-week date to repeat questionnaires  
 
She will be called the following day to confirm her start date of the medication. They will return at 
12 weeks and complete the same FSFI and Likert Scale questionnaires regarding sexual function 
and VVA symptoms. The questionnaires may also be completed over the phone with the investi-
gator.  
 
Alternatively, if time during clinic is limited, the patient can be consented and allocated to a med-
ication in person, by a co-investigator. She will be called by a co-investigator on the same day to 
complete the enrollment and questionnaires. Below is a summary of the study plan.  
 
 
 
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Sample Size Analysis 
 
To our knowledge, there has been no prior study that reported the prevalence of female sexual 
dysfunction amongst women using vaginal conjugated estrogens, defined as having an FSFI 
score of 26.55 or less. With an FSD prevalence of 57%, we determine a 50% reduction in the 
prevalence to be clinically significant. Setting an alpha of 0.05, and a power of 0.80, and assum-
ing a minimum of 15% dropout rate, the sample size is set to 52 in each group. 
 
Specific Aims 
 
Specific Aim 1: To compare the efficacy of each drug in improving sexual function. 
a. Experimental Design: In this study, participants will be asked to complete the 19-ques-
tion female sexual function index (FSFI) questionnaire at the beginning of the study 
period and at 12 weeks. The results will be used to compare the effect of each medica-
tion on the various domains of sexual function. 
 
The mean total score in each treatment group at baseline will be compared using Stu-
dent’s t-test. Additionally, the score of the components of desire, arousal, lubrication, or-
gasm, satisfaction and pain will be similarly compared. Later, the change in these scores 
between the two treatment groups at 12 weeks will be compared using a paired t-test 
analysis. 
 
Anticipated Results and Interpretation: We expect to see similar results in this study, 
showing comparable improvements in vaginal lubrication and dyspareunia, while show-
ing greater improvement for overall sexual health in the ospemifene group. 
 
Potential Pitfalls, Alternative Approaches, and Future Directions: We do not anticipate 
any challenges with the administration and analysis of this questionnaire.  
 
 
Specific Aim 2: To compare each drug’s impact on VVA symptoms 
a. Experimental Design: Participants will complete a Likert scale of symptom severity at the be-
ginning and at the end of the study. The symptoms listed will include dyspareunia, vaginal 
dryness, vaginal pain, and vaginal itching. The survey will ask them to rate the severity of 
each VVA symptom on a scale of 0 to 3, with 0 being none, 1 being mild, 2 being moderate, 
and 3 being severe. It will also ask them to choose their most bothersome symptom (MBS).  
 
The mean score of the MBS in each treatment group at baseline will be compared using 
Student’s t-test. Later, the change in score of the MBS between the two treatment groups at 
four weeks and again at 12 weeks will be compared using a paired t-test analysis. 
 
Anticipated Results and Interpretation: Similar to objective findings, prior studies have 
shown significant improvement in VVA symptoms in patients using ospemifene or vaginal 
estrogen. We anticipate that the improvements seen with ospemifene will be comparable to 
those seen with vaginal estrogen. 
 
Potential Pitfalls, Alternative Approaches, and Future Directions: The Likert scale is com-
monly used to assess symptom improvement in VVA treatment studies. We do not antici-
pate any pitfalls in this specific aim.  
 
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Safety Monitoring 
 
Participants in the study will be provided with contact information to be used in the case of an 
adverse event related to the medication. For emergencies, they will be instructed to dial 911 
and/or seek immediate medical attention. They will be instructed to contact the study team at 
(404) 686-1000, to inform the team about any adverse event that may be related to the medica-
tion.  
 
All reports of injury will be logged in one password-protected electronic file, by members of the 
study team. Patient data, including adverse events will be reviewed every two weeks by the Dr. 
Gina Northington and Dr. Chidimma Eto. Appendix 1 shows adverse events that have been doc-
umented during prior clinical trials of the two medications. This data will be used to determine 
whether the study will be discontinued due to occurrence or frequency of any given adverse 
event.  
 
Individual Stopping Rules 
Any event that involves new onset of vaginal bleeding, cardiovascular event, venous thrombo-
embolism, or new diagnosis of cancer, will require the individual to discontinue the medication 
and withdraw from the study. 
 
 
Timeline 
 
Item 
Start 
Complete/Submit 
IRB application 
Started 
November 1, 2016 
Grant/Funding applications 
Started 
Februrary 2017 
Subject recruitment 
November 1, 2016 
August 1, 2017 
Data Analysis 
March 1, 2017 
August 30, 2017 
Thesis/Report 
November 15, 2017 
December 1, 2017 
 
 
Required Resources & Budget 
 
Resource 
Estimated Cost 
Personnel  
Consent forms, severity scale, questionnaire, other 
paper documents 
 
Counseling office  
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$10 gift cards for return visit, 104 subjects $1040.00 
 
 
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Appendix 1. TEAEs in Vaginal Conjugated Estrogens Cream and Ospemifene Trials 
 
Ospemifene 60mg 
x 12 weeks [17] 
Ospemifene 60mg 
x 52wks [7] 
Vaginal CE 
0.3mg x 12 
weeks [30] 
Vaginal CE 
0.3mg x 52 
weeks [30] 
% w/ 1 or more 
TEAE 
Not stated, 1892 
exposed patients 
total, 1000 patient 
years of exposure 
63.8% 
71.4% 
61.4% 
Headache 
2.4% 
 
18.6% 
14.4 
Muscle spasm 
3.2% 
 
 
 
Arthralgia 
 
 
 
9.1 
Vaginal discharge 
3.8% 
 
 
 
Vaginal candidia-
sis or mycotic in-
fection 
 
4.3% 
 
 
Vaginitis 
 
 
 
6.1% 
Hot flashes 
7.5% 
7.2% (1.6% dis-
continuation rate) 
 
 
UTI 
Similar to pla-
cebo 
8.7% (8.2% for 
placebo) 
 
 
Vaginal bleeding 
 
 
*1.4% of all 
groups 
*1% of all 
groups 
Proliferative endo-
metrium 
 
 
 
0.08% 
Hyperplasia or 
cancer 
0% 
0% 
 
0% 
Cardiovascular 
events/VTE 
0.3% 
0% 
 
 
URI/Nasopharyn-
gitis/Sinusitis 
 
5% or more 
 
 
Pharyngolaryn-
geal pain 
 
5% or more 
 
 
Hypercholesterol-
emia 
 
5% or more 
 
 
Serious/Severe 
TEAEs <5% 
0.13 per patient 
year (0.21 in pla-
cebo group) 
5 participants with 
7 TESAEs: breast 
prosthesis implan-
tation, encephali-
tis herpes, non-
cardiac chest 
pain, candida 
meningitis, gastri-
tis, chronic ob-
structive pulmo-
nary disease, and 
dehydration 
5 participants 
from all groups, 
considered unre-
lated to study 
6 participants 
from all groups, 
considered unre-
lated to study 
 
 
 
 
 
TEAE: treatment-emergent adverse event; CE: conjugated estrogens; VTE: venous thromboembolism; *: study does not distin-
guish between placebo and the two treatment arms.  
 
 
Updated 11/27/17 
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