Clinical trial NCT01923298
Conditions: Estrogen Levels Among Breast Cancer Patients
Sponsor: University of Arizona
Start date: 2013-08-09; Completion date: 2019-04-24
Enrollment: 14 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Estrogen receptor positive breast cancer is the most common type of breast cancer and anti-estrogen therapy has been shown to be very effective in preventing recurrence. Side effects of anti-estrogens are due to estrogen deprivation and include hot flashes, mood changes and vaginal dryness/pain. Vaginal symptoms including pain, dryness, itching, bleeding after intercourse and frequent urinary tract infections have been reported to cause significant morbidity in postmenopausal women and higher in breast cancer survivors on anti-estrogen therapy. Treatment options include vaginal lubricants, Replens etc but unfortunately many women continue to have persistent symptoms. Local estrogen has been shown to be effective in post menopausal women (Estring or Vagifem) for their vaginal symptoms. There is a concern of using this in women with breast cancer given it may increase their blood estrogen levels. Studies done so far show have shown controversial results but majority of them report that blood estrogen levels do not change significantly. The major drawback of the studies was the sample size and inadequate accrual. The most recent trial reported showed no significant change in blood estrogen levels in women with breast cancer treated with aromatase inhibitors (anti-estrogen therapy) and were on vagifem for their vaginal symptoms. The authors reported results in 26 patients and reported no significant change in blood estrogen level. We propose to study the change in blood estrogen level when postmenopausal women with breast cancer who are currently on aromatase inhibitors are treated with Estring for their vaginal symptoms.

Detailed description:

Arms: arm 1: ESTRING® (estradiol vaginal ring) is a slightly opaque ring with a whitish core containing a drug reservoir of 2 mg estradiol. Estradiol, silicone polymers and barium sulfate are combined to form the ring. When placed in the vagina, ESTRING releases estradiol, approximately 7.5 mcg per 24 hours, in a consistent stable manner over 90 days.
Interventions: intervention 1: Estradiol
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
Revision 3, May 14, 2018 
 
 
1 
 
The University of Arizona Cancer Center 
Hematology Oncology Section 
Breast Cancer Program 
 
 
 
 
A Single-arm Phase II Trial to Evaluate Serum Estradiol Levels in Patients with 
Breast Cancer Treated with Vaginal Estrogen, Estring 
 
Original Protocol Date:  April 23, 2013 
Revision 1 Date:  July 5, 2013 
Revision 2 Date:  July 15, 2013 
Revision 3 data: May 14, 2018 
 
Study Coordinator and Principal investigator: 
 
Pavani Chalasani, M.D, MPH 
Assistant Professor Medicine 
The University of Arizona Cancer Center 
1515 N. Campbell Avenue, PO Box 245024 
Tucson, AZ 85724-5024 
P- (520) 626-0191 
F- (520) 626-2225 
pchalasani@uacc.arizona.edu 
 
 
Sponsor: University of Arizona Cancer Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Revision 3, May 14, 2018 
 
 
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CLINICAL PROTOCOL SYNOPSIS 
 
Title of Study: A Single-arm Phase II Trial to Evaluate Serum Estradiol Levels in Patients with 
Breast Cancer Treated with Vaginal Estrogen, Estring 
 
Principal Investigator:  
Pavani Chalasani MD, MPH (PI) 
 
Biostatistics:  
Haiyun Cui, PhD 
 
Study Center:  University of Arizona Cancer Center 
 
Primary Objective: To evaluate if there is a significant change in serum estradiol levels in 
patients with breast cancer when treated with vaginal estrogen preparation, Estring 
 
Secondary Objective:  
1. To assess if there is improvement in vaginal symptoms on treatment with Estring 
 
Primary Endpoint: To measure changes in serum estradiol level compared to their baseline in 
patients with breast cancer when treated with vaginal estrogen preparation, Estring 
 
Secondary Endpoint:  
1. To measure changes in vaginal dryness symptom questionnaire compared to their 
baseline while on treatment with Estring 
 
Study Design: This study is a prospective single arm Phase II trial to evaluate changes in 
serum estradiol levels in patients with breast cancer when treated with vaginal estrogen 
preparation, Estring. We will also collect data from a chart review of patients who were 
treatment in a similar manner as a part of their routine standard of care. 
 
Number of Patients: We plan to consent 14-20 patients, with the goal of accruing a total of 14 
patients to receive treatment on this prospective single arm, Phase II trial. 
 
Main Criteria for Inclusion/Exclusion:  
 
To be eligible for inclusion, each patient must have: 
- 
Diagnosis of estrogen receptor positive breast cancer as defined by FDA guidelines 
- 
Attained menopause as defined by World Health Organization 
- 
On adjuvant hormonal therapy with aromatase inhibitors, Anastrozole or Letrozole or 
Exemestane 
- 
Be informed of the nature of this study and provide written informed consent in 
accordance with institutional and federal guidelines prior to any study specific 
procedures 
- 
Be willing and able to comply with the treatment plan, scheduled clinic visits, laboratory 
tests and other study procedures 
- 
Greater than 18 years of age 
 


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3 
 
To be included each patient must not have: 
 
- 
Metastatic disease 
Intervention: Patients with breast cancer treated at the University of Arizona Cancer Center will 
be enrolled in this trial. Patients who are currently being treated with adjuvant aromatase 
inhibitors (anastrozole, letrozole or exemestane) will be screened by their physicians for 
genitourinary symptoms. Once identified, they will be consented to this study and be treated 
with Estring for their symptoms.  
 
Duration of Intervention: Patients will get a baseline serum estradiol level measured prior to 
receiving Estring. We will repeat serum estradiol levels at 4 weeks, 12 weeks and 16 weeks. 
Estring will be stopped if there is evidence of continued rise in serum estradiol. Also, it will be 
discontinued if there is development of persistent ≥ grade 3 vaginal discomfort or bleeding or if 
the patient chooses. 
 
Statistical Methods: This study is a prospective single arm Phase II trial to assess changes in 
serum estradiol levels when treated with vaginal estrogen preparation, Estring. We plan to enroll 
14 patients into this study. 
 
Analytic plan for primary objective:  
There is no statistical significant difference in the serum estradiol levels at week 16 compared to 
baseline. 
 
Analytic plan for secondary objective:  
Vaginal dryness questionnaire will be completed and scores will be compared between baseline 
and 16 weeks. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4 
 
 
 
 
 
 
Schema 
 
14 patients with breast cancer on treatment with adjuvant hormonal therapy will be 
enrolled 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
                                                                                                                                                          
Page 
Protocol Synopsis 
 
2 
1. Introduction 
1.1. 
Breast Cancer 
1.2. 
Background 
1.3. 
Study Population 
 
8 
2. Trial Objectives 
 
9 
3. Trial Design 
3.1. 
Study Endpoints 
3.2. 
Study Design 
3.3. 
Study Duration and Follow up 
 
9 
4. Selection and Withdrawal of Patients 
4.1. 
Inclusion Criteria 
4.2. 
Exclusion Criteria 
4.3. 
Study Exit 
4.4. 
Study Patient Identification 
 
11 
5. Study Procedures 
5.1. 
Pretreatment 
5.2. 
Patient Registration 
5.3. 
Treatment Phase 
5.4. 
Follow Up 
 
12 
6. Criteria for Evaluation 
6.1. 
Evaluation Criteria Definitions 
 
13 
7. Drug Information 
 
13 
8. Study Statistics 
8.1. 
Analytic Plan for Primary Objective 
8.2. 
Analytic Plan for Secondary Objective 
 
14 
9. Data and Safety Monitoring Plan 
 
15 
10.  Discipline Review 
  
18 
11.  Data Submission Schedule 
 
18 


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12. Special Instructions 
 
18 
13. Ethics 
 
18 
14. Bibliography 
 
19 
15. Appendices 
 
22 
 
List of Appendices 
 
Appendix 1 
Investigator Statement 
Appendix 2 
Vaginal dryness symptom Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. Introduction 
 
1.1. Breast Cancer    
 
Breast cancer is the most common life threatening malignancy in women, with over 
200,000 new cases diagnosed in the United States annually.1 With early detection and 
novel treatment strategies survival has increased, increasing the number of survivors 
experiencing the short- and long-term consequences of estrogen deficiency. 
 
1.2. Background  
 
Majority of these cancers express estrogen receptors (75%) and/or progesterone 
receptors making endocrine manipulation a very effective therapeutic option. Several 
endocrine options with proven efficacy are currently available for treatment. Factors 
guiding the oncologist’s decision on the type and duration of endocrine therapy include 
the patient’s menopausal status, response to prior trials of endocrine treatment, and 
consideration of side-effect profiles. Tamoxifen, a selective ER modifier, may be used in 
pre-, peri-, and postmenopausal women.2,3 Alternative options for premenopausal and 
perimenopausal women who have contraindications to tamoxifen use include ovarian 
suppression and ablation.4 In postmenopausal women, where the majority of estrogen 
is derived from the peripheral conversion of androgens to estrogen, the incorporation of 
aromatase inhibitors (AIs) into treatment regimens has shown benefits in the early5-8 
and advanced settings.9,10 Aromatase inhibitors or selective estrogen receptor 
modulators are the standard adjuvant treatment for hormone receptor positive breast 
cancer in post-menopausal women. The aromatase inhibitors work by decreasing 
systemic estrogen production leading to lower circulating estrogen levels. 
 
Effects of normal menopause on the urogenital system 
 
Estrogen is fundamental for the normal development of multiple organ systems 
including the reproductive tract, mammary glands, bone, and blood vessels. To date, 
two ERs have been isolated, ER-α and ER-β, with a varied proportion of each type of 
receptor in various tissues.11 In general, the activation of these receptors at the nuclear 
level by estrogen and/or other cofactors is needed to induce cell growth and 
differentiation. ERs are heavily concentrated in the vulva, vagina, pelvic floor 
musculature, endopelvic fascia, bladder, and urethra.12,13 As a result, the urogenital 
system is exquisitely sensitive to estrogen deprivation. A decline in estradiol 
concentrations results in a reduction in squamous epithelial cells in the vulvovaginal 
area and uroepithelial lining with a predominance of basal cells.14 Moreover, collagen, 
glycogen, mucopolysaccharides, and hyaluronic acid significantly decline in 
hypoestrogenemic urogenital epithelium. The vaginal walls therefore become thin, 
friable, pale, and hyposecretory, and lose their elasticity with progressive stenosis, while 
the urethra develops increased atrophy and laxity.14 The uterus, ovaries, vagina,and 
vulva also shrink in size.15 Symptoms of estrogen deprivation include: vaginal dryness, 


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itchiness, discharge, incontinence, burning, and pain during sexual intercourse. 
Concomitant with these changes is a reduction in the vaginal Lactobacillus population, 
which in turn leads to greater vaginal alkalinity (pH >5) and further contributes to the 
greater risk for urinary tract infections.16 
 
Prevalence of genitourinary symptoms in breast cancer patients 
 
The prevalence and severity of genitourinary symptoms among women with a prior 
history of breast cancer have been reported using a variety of quality of life scales, 
making an overview analysis challenging. Nonetheless, the literature has demonstrated 
a clear increase in the incidence and progression of gynecologic symptoms following 
chemotherapy and/or endocrine therapy. Ganz et al. reported that up to 50%–75% of 
breast cancer survivors experience one or more urogenital symptoms.17 Treatment with 
both chemotherapy and tamoxifen seems to compound the severity of symptoms 
versus treatment with either agent alone.18 Vulvovaginal atrophy in turn contributes to 
increasing sexual dysfunction, reported as dyspareunia, diminished libido, and 
decreased sexual satisfaction.19,20 In a separate study, the severity of sexual symptoms 
and vaginal dryness negatively correlated with self-perceived quality of life, and 
perception of partner quality of life [32].21In recent years, multiple endocrine therapy 
trials have prospectively evaluated the prevalence of gynecologic symptoms in studies 
comparing tamoxifen with AIs. Reported results of urogenital side effects from AIs 
suggest less tolerable vulvovaginal symptoms in comparison with those observed with 
tamoxifen. Morales et al. found an increase in severe or intolerable dyspareunia among 
women started on nonsteroidal AIs, from 11% at baseline to 25% after 3 months of 
treatment, which was significantly associated with vaginal dryness.22 Similarly, a cohort 
of women in the Arimidex, Tamoxifen, Alone or in Combination trial after 5 years of 
treatment with anastrozole reported rates of dyspareunia, diminished libido and 
decreased sexual satisfaction, and vaginal dryness of 17.3%, 34.0%, and 18.5%, 
respectively.23 In comparison, among patients taking tamoxifen, reported side effects for 
dyspareunia, diminished libido and decreased sexual satisfaction, and vaginal dryness 
were significantly lower at 8.1%, 26.1%, and 9.1%, respectively (p< .05).23 The 
incidence of urinary tract infections among menopausal women varies depending on the 
presence of risk factors such as diabetes24 or the presence of urinary prolapse25, with 
reported incidences in the range of 5%–8%.25,26 Similar cystitis rates have been 
reported among women on estrogen deprivation therapy. Rates of urinary tract 
infections among women taking the AI anastrozole have ranged between 3.5% [38] and 
8%, while the incidence of urinary tract infections among women taking tamoxifen has 
been reported to be as high as 10%.27 
 
Treatment options for genitourinary symptoms 
 
Non-hormonal vaginal moisturizers and lubricants are the recommended first line 
treatment for postmenopausal vaginal symptoms however results on their efficacy have 
been inconsistent. They adhere to the vaginal epithelium creating a moisture barrier but 
do not reverse the atrophic changes, which are the root cause of the symptoms 
moreover; they have minimal effect on urinary symptoms.28 Their efficacy in relief of 
genitourinary symptoms in breast cancer patients receiving aromatase inhibitors has not 
been studied.  
 


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Vaginal estrogen has been used effectively to treat postmenopausal genitourinary 
symptoms. Estrogen can be delivered locally as vaginal cream (Estrace and Premarin), 
ring (Estring and Femring) or tablet (Vagifem). The optimal treatment regimen, minimum 
effective dose and duration have not been established. A Cochrane review of 16 clinical 
trials conducted on 2,129 postmenopausal women concluded all formulations of local 
estrogen therapy had efficacy in relieving subjective genitourinary symptoms.29 There 
was also an improvement in vaginal elasticity, fluid volume and moisture unlike vaginal 
moisturizers which provide only symptomatic relief but do not alter objective atrophic 
findings. North American Menopause Society (NAMS) published a position statement in 
2007 on the role of local vaginal estrogen for treatment of vaginal atrophy in 
postmenopausal women.30 NAMS systematically reviewed all relevant medical literature 
and concluded that postmenopausal women with moderate to severe vaginal atrophy 
symptoms who have failed the first line therapy with non-hormonal vaginal moisturizers 
may be candidates for local estrogen treatment. However the main concern in using 
vaginal estrogen in breast cancer patients is related to their absorption and systemic 
levels of estrogen (estradiol, E2) and the theoretical concern that these levels could 
stimulate breast cancer growth.   
 
Clinical Studies using topical estrogen preparations in breast cancer patients 
 
A drop in serum estradiol levels following consistent use with either Estring or Vagifem 
has also been well documented among menopausal women without a prior history of 
breast cancer [51, 64].31,32 This fall in serum estradiol levels is likely a reflection of 
vaginal epithelial maturation, which further inhibits systemic absorption of estrogen. Of 
concern is whether even minor changes in serum estradiol levels from vaginal 
absorption of topical estrogen replacement agents increase breast cancer recurrence. 
Among postmenopausal women, the Endogenous Hormones and Breast Cancer 
Collaborative Group found an association between high levels of endogenous estrogen 
and higher breast cancer risk. However, this overview found a large range of median 
estrogen values of 21.7–101 pmol/l among the control group resulting from variations in 
laboratory analyses.33 Given the variation in results, a threshold estradiol level that was 
clearly associated with elevated breast cancer risk could not be established. Further 
highlighting the need for a sensitive estradiol assay for women taking AIs was a small 
study of 10 patients before and after AI use who had up to a 70% difference in estradiol 
levels when measured by direct assay versus being measured after pre-extraction with 
an organic solvent.34 Retrieval and storage of serum may also impact estradiol levels; 
delaying blood sample processing by 1 day has been shown to spuriously increase 
estrogen levels by 7.1% (95% CI, 3.2%–11.3%).35  
 
Few studies have investigated the impact of local vaginal estrogen preparations for the 
treatment of gynecologic symptoms with regard to breast cancer recurrence and 
mortality. A small cohort study of 69 women, some of whom were taking tamoxifen, 
suggested that vaginal estrogen cream or tablets did not increase the risk for recurrent 
breast cancer and resulted in a hazard ratio for disease recurrence of 0.57 (95% CI, 
0.20 –1.58; p = .28).36 A separate study of seven women taking AIs with subsequent 
intolerable urogenital side effects documented serum estradiol levels after treatment 
with Vagifem 25 µg. Estradiol levels rose from a mean baseline level of < 5 pmol/l to a 
mean of 72 pmol/l at 2 weeks, and then declined at 4 weeks to a median of 16 pmol/l. 
Two women had high estradiol levels after 7 weeks of treatment.37 In contrast, Santen 
et al have reported that at 12 weeks, serum estradiol levels were within 


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postmenopausal range of 3-10 pg/ml when treated with vaginal estradiol at a dose of 
10µg.38 Recently, data presented on 26 breast cancer patients at San Antonio Breast 
Cancer conference, showed no significant rise in serum estradiol level in breast cancer 
patients on aromatase inhibitors being treated by Vagifem 10µg tablets at week 12 
compared to baseline.39 There have been no prospective studies reporting serum 
estradiol levels in breast cancer patients being treated with aromatase inhibitors and 
concurrent use of Estring. We propose an investigator-initiated clinical trial at the 
university of Arizona cancer center to evaluate changes in serum estradiol level in 
patients with breast cancer treated with vaginal estrogen, Estring for their genitourinary 
symptoms. 
 
1.3. Study Population 
 
This study will enroll patients with stage I-III estrogen receptor positive breast cancer 
who are on adjuvant hormonal treatment with aromatase inhibitors. They will be 
screened for genitourinary symptoms and will be offered to participate in this study. 
Enrolled patients will be treated with vaginal estrogen preparation, Estring, for their 
symptoms. 
 
2. Trial Objectives 
 
Primary Objective: To evaluate if there is a significant change in serum estradiol levels in 
patients with breast cancer when treated with vaginal estrogen preparation, Estring 
 
Secondary Objective:  
1. To assess if there is improvement in vaginal symptoms on treatment with Estring 
 
3. Trial Design 
 
3.1. Study Endpoints 
 
Primary Endpoint: To measure changes in serum estradiol level compared to their 
baseline in patients with breast cancer when treated with vaginal estrogen preparation, 
Estring 
 
Secondary Endpoint:  
1. To measure changes in vaginal dryness symptom questionnaire compared to their 
baseline while on treatment with Estring 
 
3.2. Study Design This study is a prospective single arm Phase II trial to changes in serum 
estradiol levels in patients with breast cancer treated with aromatase inhibitors when 
treated with vaginal estrogen preparation, Estring. We will also collect data from a 
chart review of patients who were treatment in a similar manner as a part of their 
routine standard of care. 
 
3.3. Study Duration and Follow up 
 
All patients will be treated with vaginal estrogen preparation, Estring for at least 4 mths. 
Patients will get baseline serum estradiol value measured. It will be repeated at week 4, 
week 12 and week 16 (calculated from day 1 which is the first day of Estring insertion). 


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Patients will also fill out a vaginal dryness symptom questionnaire at baseline and week 
16. 
 
4. Selection and Withdrawal of Patients 
 
4.1. Inclusion Criteria: To be eligible for inclusion, each patient must have: 
4.1.1 Stage I-III estrogen receptor positive breast cancer (positive for estrogen 
receptor (ER)) with positivity defined as immunohistochemical staining in 
≥ 10% of cells)  on adjuvant hormonal therapy with aromatase inhibitors 
(anastrozole, letrozole or exemestane) 
4.1.2 Adults over 18 years of age with a life expectancy of at least 3 months 
4.1.3 Attained menopause as defined by World Health Organization Criteria 
(defined as permanent cessation of menstruation resulting from the loss 
of ovarian follicular activity. This is recognized to occur after 12 
consecutive months of amenorrhea, for which there is no other obvious 
pathological or physiological cause.) 
4.1.4 Persistent genitourinary symptoms causing discomfort for more than 2 
weeks prior to the visit with the physician. 
4.1.5 Tried at least 1 prior pharmacological/ non-pharmacological treatment for 
their genitourinary symptoms 
4.1.6 Be informed of the investigational nature of this study and provide written 
informed consent in accordance with institutional and federal guidelines 
prior to any study specific procedures 
4.1.7 Be willing and able to comply with the treatment plan, scheduled clinic 
visits, laboratory tests and other study procedures 
 
4.2 Exclusion Criteria 
 
4.2.1 Patients with metastatic breast cancer 
4.2.2 Have a concurrent active non-breast malignancy except for non-
melanoma skin cancer 
4.2.3 Patients with vaginal stenosis  
4.2.4 Patients unable to apply Estring 
 
4.3 Study Exit 
 
Patients will continue with study visits until study exit. Patients will exit the study at 
16 weeks or withdrawal. Each patient has the right to withdraw from the study at any 
time without prejudice. Should a patient withdraw from the study prior to completion, 
the reason(s) must be stated in the chart and on the case report form. All procedures 
(laboratory evaluations, study questionnaires and adverse events reporting) should 
be performed at the study exit visit. If a patient stops Estring prior to the study 
completion then they will go off study at that time of discontinuation. 
If a patient is noted to have a serum estradiol level of >10pg/ml at week 16 then 
Estring will be discontinued.  
 
Patients may be withdrawn from the study early due to:  
a. Development of toxicity which in the Investigator’s judgment precludes 
further study participation  


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b. Significant protocol violations or noncompliance on the part of the patient 
or Investigator  
c. Discontinuation, in the judgment of the Investigator, is in the patient’s best 
interest  
d. The patient is beginning another treatment for breast cancer 
e. Refusal of the patient to continue treatment or follow-up  
f. Loss to follow-up  
 
4.4 Patient Registration 
 
Patients must be registered prior to initiation of treatment. Patients will be registered 
through a Breast Team Clinical Research Coordinator (CRC) from 8:00 a.m. to 5:00 
p.m., Mountain Standard Time, Monday through Friday, (excluding holidays) 
 
4.5 Study Patient Identification 
 
Patients who have been consented and are undergoing study screening will be 
identified on study-related documentation and forms by their initials (first/middle and 
last name initials). All patients registered on this trial will be identified by their study 
initials and a unique study identification number. A unique study number will only be 
assigned to patients who meet the eligibility requirements and have completed the 
screening visit. The unique number will begin with the following prefix: VE. The prefix 
will be followed by the patient identification number beginning with # 001. These 
numbers will be issued to patients sequentially and no patient identification numbers 
will be re-assigned in the event that the subject withdraws from the protocol. 
 
5. Study Procedures 
 
5.1. Pretreatment 
 
Patients will be consented and evaluated for participation based on the following 
procedures which will be performed within 28 days of study entry (time of consent) 
before being registered and starting treatment 
• Documentation that patient has genitourinary symptoms  
 
5.2.  Patient Registration 
 
Patients must be registered prior to initiation of treatment. Patients will be registered 
through a Breast Team Clinical Research Coordinator (CRC) from 8:00 a.m. to 5:00 
p.m., Mountain Standard Time, Monday through Friday, (excluding holidays) 
 
Registration Guidelines 
Before a subject participates in the trial, the investigator or delegate is responsible for 
obtaining written informed consent after adequate explanation of the aims, methods, 
anticipated benefits, subject responsibilities and potential hazards of the study and 
before any protocol-specific screening procedures or any study required medications 
are administered. All patients must meet the eligibility requirements and complete the 
screening visit prior to registration. Once registration is complete treatment may begin.  
 
5.3. Treatment Phase 


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The following tests and observations will be performed during the treatment phase of 
the study. For the intervals below day 1 is the first day of Estring 
 
Test                                                                                                               Interval 
Symptom questionnaire 
Baseline and week 16 (+/- 
7days) 
Serum Estradiol level 
Baseline, week 4, 12& 16 
(+/- 7 days) 
 
SAEs that would be considered/classified as possible, probably or definitely related to 
study procedures or study required medication only will be followed.  
 
5.4. Follow Up 
 
Patients who have experienced a serious adverse event that has been attributed as 
possibly, probably or definitely related to study procedures or study required medication 
will have a follow up visit or a phone call 30 days (+/-_ 7 days) calculated from the week 
16 visit. 
6. Criteria for Evaluation 
The primary endpoint is the change in serum estradiol level compared to baseline. Other 
efficacy measures are changes in vaginal dryness questionnaire.  The SAEs will be 
assessed at time of week 4, 12 and 16 (+/- 7 days) by visit with the health care provider or 
phone call by the research RN.   
Evaluation Criteria Definitions 
6.1. Treatment related toxicity is an adverse effect that is clearly related to Estring. 
 
 
7. 
Drug Information 
 
ESTRING® (estradiol vaginal ring) is a slightly opaque ring with a whitish core containing a drug 
reservoir of 2 mg estradiol. Estradiol, silicone polymers and barium sulfate are combined to form 
the ring. When placed in the vagina, ESTRING releases estradiol, approximately 7.5 mcg per 24 
hours, in a consistent stable manner over 90 days. 
Estradiol is chemically described as estra-1,3,5(10)-triene-3,17β-diol. The molecular formula of 
estradiol is C18H24O2 and the structural formula is:  
 
The molecular weight of estradiol is 272.39. 


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Pharmacokinetics  
A. Absorption  
Estrogens used in therapeutics are well absorbed through the skin, mucous membranes, and 
the gastrointestinal (GI) tract. The vaginal delivery of estrogens circumvents first-pass 
metabolism.  
In a Phase I study of 14 postmenopausal women, the insertion of ESTRING (estradiol vaginal 
ring) rapidly increased serum estradiol (E2) levels. The time to attain peak serum estradiol 
levels (Tmax) was 0.5 to 1 hour. Peak serum estradiol concentrations post-initial burst declined 
rapidly over the next 24 hours and were virtually indistinguishable from the baseline mean 
(range: 5 to 22 pg/mL). Serum levels of estradiol and estrone (E1) over the following 12 weeks 
during which the ring was maintained in the vaginal vault remained relatively unchanged (see 
Table 1).  
The initial estradiol peak post-application of the second ring in the same women resulted in ~38 
percent lower Cmax, apparently due to reduced systemic absorption via the treated vaginal 
epithelium. The relative systemic exposure from the initial peak of ESTRING accounted for 
approximately 4 percent of the total estradiol exposure over the 12-week period.  
The release of estradiol from ESTRING was demonstrated in a Phase II study of 222 
postmenopausal women who inserted up to four rings consecutively at three-month intervals. 
Systemic delivery of estradiol from ESTRING resulted in mean steady state serum estradiol 
estimates of 7.8, 7.0, 7.0, 8.1 pg/mL at weeks 12, 24, 36, and 48, respectively. Similar 
reproducibility is also seen in levels of estrone. The systemic exposure to estradiol and 
estrone was within the range observed in untreated women after the first eight hours.  
In postmenopausal women, mean dose of estradiol systemically absorbed unchanged from 
ESTRING is ~8 percent [95 percent CI: 2.8–12.8 percent] of the daily amount released locally. 
 
B. Distribution 
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens 
are widely distributed in the body and are generally found in higher concentrations in the sex 
hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding 
globulin (SHBG) and albumin.  
C. Metabolism 
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. 
Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These 
transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and 
both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo 
enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion 


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of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In 
postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate 
conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation 
of more active estrogens.  
D. Excretion  
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and 
sulfate conjugates.  
Mean percent dose excreted in the 24-hour urine as estradiol, 4 and 12 weeks post-application 
of ESTRING in a Phase I study was 5 percent and 8 percent, respectively, of the daily released 
amount.  
 
8. Study Statistics 
 
8.1. Analytic plan for primary objective: Patients will get a baseline serum estradiol level 
checked and at week 4, 12 and 16. Serum estradiol level of 10pg/ml is used as cut off 
point. All patients will have serum estradiol level ≤10pg/ml at baseline. At week 16, the 
proportion of patients with serum estradiol level >10pg/ml is used to assess the 
presence of an unacceptable increase change in serum estradiol level. With sample 
size of 14 patients, if none have serum estradiol level >10pg/ml at week 16, it will be 
concluded that the probability of serum estradiol level >10pg/ml at week 16 is less than 
10% (based on the upper limit of a one-sided 95% confidence interval). The proportion 
of patients with serum estradiol level >10pg/ml at week 16 and its one-sided 95% 
confidence interval will be estimated. The mean change in serum estradiol level 
between baseline and week 16 and its 95% confidence interval will be estimated.  In 
addition, to assess the presumed maximum change in serum estradiol level, the mean 
change in serum estradiol level between baseline and week 4 with its 95% confidence 
interval will be estimated.   
 
8.2. Analytic plan for secondary objective: The patients will complete the vaginal dryness 
symptoms questionnaire at baseline and week 16.   The mean (standard deviation) and 
median of scores at baseline and week 16 will be reported. The signed rank test will be 
used to evaluate if there is a significant change in the score between baseline and week 
16.   
 
 
9. Data and Safety Monitoring Plan 
 
Identification of the DSMB obligated for oversight responsibilities: 
The Arizona Cancer Center Data and Safety Monitoring Board (DSMB) will provide ongoing 
oversight for this trial. 
 
Identification of the entity obligated for routine monitoring duties: 
Routine monitoring will be provided by the Quality Assurance/Quality Control (QA/QC) 
Program to ensure that the investigation is conducted according to protocol design and 
regulatory requirements.  


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Monitoring progress and data review process: 
Routine monitoring of subject data will be conducted at least every six months.  
 
The first routine monitoring visit will include at a minimum: 
• Informed consent – 100% of cases enrolled;  
• Subject eligibility - 50% of cases, up to two subjects; 
• Data review - 50% of cases, up to two subjects. 
 
All subsequent monitoring visits will consist of randomly selected subject cases based on 
current enrollment and include continuing review of previously selected cases, as 
applicable. 
 
A monitoring visit report and follow-up letter will be completed within two weeks of the 
routine monitoring visit; a copy will be maintained in the study file. A query/finding form will 
also be completed by the monitor to request additional source documentation, clarification, 
information or corrections to the CRF and/or regulatory records. The Clinical Research 
Coordinator or other applicable staff responsible for the study will be given a copy of this 
form for resolution of queries/findings. The query/finding form will be maintained with a copy 
of the visit report for follow-up at the next monitoring visit.  
 
The Principal Investigator will ensure the accuracy, completeness, legibility and timeliness of 
the data reported in the Case Report Form (CRF). Source documentation supporting the 
CRF data will indicate the subject’s participation in the trial and will document the dates and 
details of study procedures, adverse events, and patient status.  
 
Case report forms, which include the inclusion/exclusion criteria form, adverse event forms 
and serious adverse event forms should be completed with a black ball-point pen or typed. 
Corrections to the forms should not obscure the original entry and should be made by 
striking the incorrect information with a single line. Each strike should be accompanied by 
the initials of the corrector and the correction date. All subject forms and study files will be 
stored in a secure area limited to authorized staff. 
 
Note: Routine monitoring of regulatory documents and test article will be conducted at least 
annually.  
 
Process to implement study closure when significant risks or benefits are identified:  
 
There is no planned interim analysis. Results will be analyzed after 14 patients are enrolled 
and data is collected for all of them. 
 
Description of adverse events and reporting procedures: 
 
Adverse Event 
 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and that does not necessarily 
have a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign, symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product.  


Revision 3, May 14, 2018 
 
 
17 
 
 
Any and all adverse events will be recorded on the UMC adverse events record form and 
reviewed by the Principal Investigator. 
 
All adverse events will be classified using either the MedDRA term or NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 and will address: 
• 
Grade 
• 
Relationship to study drug(not related, unlikely, possible, probable, definitely) 
• 
Causality other than study drug (disease related, concomitant medication related, 
intercurrent illness, other)   
• 
Date of onset, date of resolution 
• 
Frequency of event (single, intermittent, continuous) 
• 
Event outcome (resolved, ongoing, death) 
• 
Action taken (none, held, dose reduced, discontinued, medication given) 
 
Serious Adverse Events 
 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:  
• 
Results in death 
• 
Is life-threatening 
• 
Requires in-patient hospitalization or prolongation of an existing hospital stay 
• 
Results in disability persistent or significant disability/incapacity, or 
• 
Is a congenital anomaly/birth defect.  
 
Note: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention 
to prevent one of the outcomes listed above. 
 
All SAEs which meet the criteria for a reportable event will be reported to the University of 
Arizona Human Subjects Protection Program within 10 working days of the event date or 
receipt of notification of the event.  
 
Non-local Unanticipated Problem Involving Risks to Subjects or Others, which is any 
information that meets all three of the following criteria:  
i) Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent; and (b) the characteristics of the 
subject population being studied. A harm is “unexpected” when its specificity and 
severity are not accurately reflected in the consent document.  
ii) Related or possible related due to participation in this research (possible related means 
that the outcome may have been caused by the procedures involved in the 
research); and  
iii) Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. A harm is “at least probably related to the Human Research procedures” 
if in the opinion of the investigator, the research procedures more likely than not 
caused the harm.  
 
Plan for assuring data accuracy and protocol compliance: 


Revision 3, May 14, 2018 
 
 
18 
 
Routine study activity and safety information will be reported to the DSMB every six months, 
or more frequently if requested. These reports will include: 
• 
Study activity, cumulative and for the period under review; 
• 
Safety (narrative description on non-serious and serious adverse events); 
• 
Predetermined protocol early stopping rules for efficacy/futility;    
• 
Monitoring and protocol compliance; 
• 
Comments;  
• 
Attachments (AE data reviewed by the PI to compile the report, SAE letters and 
reports, results of any review(s), applicable correspondence with the IRB or other 
regulatory agencies.  
 
Data, safety and study progress will be reported to: 
• 
Human Subjects Protection Program (IRB) at least annually; 
• 
Sponsor (if applicable) at least every six months. 
 
Identification of the sponsor or funding agency, as applicable: 
The PI will immediately notify; in writing, the funding agency, if applicable, any action 
resulting in a temporary or permanent suspension of the study. 
10. Discipline Review  
There is no discipline review 
 
11. Data Submission  
 
Electronic case report forms will be completed in the OnCore system. 
 
12. Special instructions 
 
Serum Estradiol will be measured by tandem mass spectrometry and results will be reported 
in pg/ml. Estradiol assay used is a quantitative high performance liquid chromatography-
Tandem mass spectrometry which can report serum estradiol levels between 1pg/ml-
2000pg/ml. This is a send out lab and University Medical Center is contracted with ARUP 
laboratories for this. This test is also done by LabCorp and SonoraQuest diagnostics. We 
will send out the samples to appropriate laboratories based on patient’s insurance approval.  
 
13.  Ethics  
The trial will be conducted in accordance with the Declaration of Helsinki for biomedical 
research involving human subjects and local regulatory requirements.  
 
Ethical Principles  
This study will be conducted in accordance with Title 21 of the Code of Federal Regulations 
(CFR).  Specifically, this study is based on adequately performed laboratory and animal 
experimentation; the study will be conducted under a protocol reviewed by an Institutional 
Review Board; the study is to be conducted by scientifically and medically qualified persons; 
the benefits of the study are in proportion to the risks; the rights and welfare of the patients 
will be respected; the physicians conducting the study will ensure that the hazards do not 
outweigh the potential benefits; the results to be reported will be accurate; patients will give 


Revision 3, May 14, 2018 
 
 
19 
 
their informed consent and will be competent to do so and not under duress; and the study 
will comply with the ethical principles in Title 21 of the CFR.  
 
Informed Consent  
This study will be conducted in full compliance with the informed consent regulations in 21 
CFR 50. The Sponsor-Investigator is responsible for obtaining written consent from potential 
patients prior to performing any trial tests or assessments required by the protocol. 
A copy of the fully executed informed consent form (PHI authorization form and ancillary 
consent forms if applicable), is given to the subject. One copy is placed in the subject’s 
medical record, another copy is placed in the research chart, and the originals are filed by 
the protocol number in room 2111 at UACC North Campus. 
 
Institutional Review Board  
This study will be conducted in full compliance with the Institutional Review Board (IRB) 
regulations in 21 CFR 56, in accordance with the Declaration of Helsinki. This protocol will 
not be initiated unless it and the informed consent form have been reviewed and approved 
by, and remains open to continuing review by, an IRB meeting the requirements of 21 CFR 
56. The IRB shall review and have the authority to approve, require modification in (to 
secure approval), or disapprove the protocol. The IRB shall notify the Investigator and the 
institution in writing of its decision. The IRB shall require that the information given to 
patients as part of the informed consent is in accordance with 21 CFR 50.25. The IRB shall 
conduct continuing reviews of the protocol at intervals appropriate to the degree of risk, but 
not less than once per year. At the completion or early termination of the trial, a final report 
should be sent to the IRB by the Investigator. The Investigator is obligated to maintain an 
IRB correspondence file.  
 
Confidentiality of Patient Data 
The investigator must ensure that patient confidentiality will be maintained. Patients will be 
identified by initials and a protocol-assigned patient number as described in section 4.4. 
Permission for direct access to patient data will be sought in writing for the patient by the 
investigator as part of the informed consent procedure. The patient will be informed that all 
clinical information is confidential, but that the IRB, and regulatory authorities may inspect 
these records. 
 
14. 
Bibliography 
 
1. 
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clinicians. Jan 2013;63(1):11-30. 
2. 
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3. 
Early Breast Cancer Trialists' Collaborative G, Davies C, Godwin J, et al. Relevance of 
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4. 
Ovarian ablation in early breast cancer: overview of the randomised trials. Early Breast 
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5. 
Baum M, Budzar AU, Cuzick J, et al. Anastrozole alone or in combination with 
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with early breast cancer: first results of the ATAC randomised trial. Lancet. Jun 22 
2002;359(9324):2131-2139. 
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Breast International Group 1-98 Collaborative G, Thurlimann B, Keshaviah A, et al. A 
comparison of letrozole and tamoxifen in postmenopausal women with early breast 
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7. 
Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to 
three years of tamoxifen therapy in postmenopausal women with primary breast cancer. 
The New England journal of medicine. Mar 11 2004;350(11):1081-1092. 
8. 
Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal 
women after five years of tamoxifen therapy for early-stage breast cancer. The New 
England journal of medicine. Nov 6 2003;349(19):1793-1802. 
9. 
Mouridsen H, Gershanovich M, Sun Y, et al. Phase III study of letrozole versus 
tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: 
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Oncology. Jun 1 2003;21(11):2101-2109. 
10. 
Nabholtz JM, Buzdar A, Pollak M, et al. Anastrozole is superior to tamoxifen as first-line 
therapy for advanced breast cancer in postmenopausal women: results of a North 
American multicenter randomized trial. Arimidex Study Group. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology. Nov 15 
2000;18(22):3758-3767. 
11. 
Nilsson S, Makela S, Treuter E, et al. Mechanisms of estrogen action. Physiological 
reviews. Oct 2001;81(4):1535-1565. 
12. 
Iosif CS, Batra S, Ek A, Astedt B. Estrogen receptors in the human female lower uninary 
tract. American journal of obstetrics and gynecology. Dec 1 1981;141(7):817-820. 
13. 
Elia G, Bergman A. Estrogen effects on the urethra: beneficial effects in women with 
genuine stress incontinence. Obstetrical & gynecological survey. Jul 1993;48(7):509-517. 
14. 
Castelo-Branco C, Cancelo MJ, Villero J, Nohales F, Julia MD. Management of post-
menopausal vaginal atrophy and atrophic vaginitis. Maturitas. Nov 15 2005;52 Suppl 
1:S46-52. 
15. 
Society of O, Gynaecologists of C. SOGC clinical practice guidelines. The detection and 
management of vaginal atrophy. Number 145, May 2004. International journal of 
gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and 
Obstetrics. Feb 2005;88(2):222-228. 
16. 
Bruno D, Feeney KJ. Management of postmenopausal symptoms in breast cancer 
survivors. Seminars in oncology. Dec 2006;33(6):696-707. 
17. 
Ganz PA, Rowland JH, Desmond K, Meyerowitz BE, Wyatt GE. Life after breast cancer: 
understanding women's health-related quality of life and sexual functioning. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology. Feb 
1998;16(2):501-514. 
18. 
Ganz PA, Rowland JH, Meyerowitz BE, Desmond KA. Impact of different adjuvant 
therapy strategies on quality of life in breast cancer survivors. Recent results in cancer 
research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer. 
1998;152:396-411. 
19. 
Mourits MJ, Bockermann I, de Vries EG, et al. Tamoxifen effects on subjective and 
psychosexual well-being, in a randomised breast cancer study comparing high-dose and 
standard-dose chemotherapy. British journal of cancer. May 20 2002;86(10):1546-1550. 


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20. 
Mortimer JE, Boucher L, Baty J, Knapp DL, Ryan E, Rowland JH. Effect of tamoxifen on 
sexual functioning in patients with breast cancer. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology. May 1999;17(5):1488-1492. 
21. 
Gupta P, Sturdee DW, Palin SL, et al. Menopausal symptoms in women treated for 
breast cancer: the prevalence and severity of symptoms and their perceived effects on 
quality of life. Climacteric : the journal of the International Menopause Society. Feb 
2006;9(1):49-58. 
22. 
Morales L, Neven P, Timmerman D, et al. Acute effects of tamoxifen and third-
generation aromatase inhibitors on menopausal symptoms of breast cancer patients. 
Anti-cancer drugs. Sep 2004;15(8):753-760. 
23. 
Cella D, Fallowfield L, Barker P, et al. Quality of life of postmenopausal women in the 
ATAC ("Arimidex", tamoxifen, alone or in combination) trial after completion of 5 years' 
adjuvant treatment for early breast cancer. Breast cancer research and treatment. Dec 
2006;100(3):273-284. 
24. 
Hu KK, Boyko EJ, Scholes D, et al. Risk factors for urinary tract infections in 
postmenopausal women. Archives of internal medicine. May 10 2004;164(9):989-993. 
25. 
Brown JS, Vittinghoff E, Kanaya AM, et al. Urinary tract infections in postmenopausal 
women: effect of hormone therapy and risk factors. Obstetrics and gynecology. Dec 
2001;98(6):1045-1052. 
26. 
Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women 
with recurrent urinary tract infections. The New England journal of medicine. Sep 9 
1993;329(11):753-756. 
27. 
Arimidex TAoiCTG, Buzdar A, Howell A, et al. Comprehensive side-effect profile of 
anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: long-term 
safety analysis of the ATAC trial. The lancet oncology. Aug 2006;7(8):633-643. 
28. 
Chalasani P DL. Menopausal symptoms: Alternatives to hormone replacement therapy. 
Arizona Geriatrics Society. 2008;13(1):9-13. 
29. 
Suckling J, Lethaby A, Kennedy R. Local oestrogen for vaginal atrophy in 
postmenopausal women. Cochrane database of systematic reviews. 2003(4):CD001500. 
30. 
North American Menopause S. The role of local vaginal estrogen for treatment of 
vaginal atrophy in postmenopausal women: 2007 position statement of The North 
American Menopause Society. Menopause. May-Jun 2007;14(3 Pt 1):355-369; quiz 370-351. 
31. 
Notelovitz M, Funk S, Nanavati N, Mazzeo M. Estradiol absorption from vaginal tablets 
in postmenopausal women. Obstetrics and gynecology. Apr 2002;99(4):556-562. 
32. 
Weisberg E, Ayton R, Darling G, et al. Endometrial and vaginal effects of low-dose 
estradiol delivered by vaginal ring or vaginal tablet. Climacteric : the journal of the 
International Menopause Society. Mar 2005;8(1):83-92. 
33. 
Key T, Appleby P, Barnes I, Reeves G, Endogenous H, Breast Cancer Collaborative G. 
Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of 
nine prospective studies. Journal of the National Cancer Institute. Apr 17 2002;94(8):606-
616. 
34. 
Dowsett M, Folkerd E. Deficits in plasma oestradiol measurement in studies and 
management of breast cancer. Breast Cancer Res. 2005;7(1):1-4. 
35. 
Jones ME, Folkerd EJ, Doody DA, et al. Effect of delays in processing blood samples on 
measured endogenous plasma sex hormone levels in women. Cancer epidemiology, 
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36. 
Dew JE, Wren BG, Eden JA. A cohort study of topical vaginal estrogen therapy in 
women previously treated for breast cancer. Climacteric : the journal of the International 
Menopause Society. Mar 2003;6(1):45-52. 
37. 
Kendall A, Dowsett M, Folkerd E, Smith I. Caution: Vaginal estradiol appears to be 
contraindicated in postmenopausal women on adjuvant aromatase inhibitors. Ann 
Oncol. Apr 2006;17(4):584-587. 
38. 
Santen RJ, Pinkerton JV, Conaway M, et al. Treatment of urogenital atrophy with low-
dose estradiol: preliminary results. Menopause. May-Jun 2002;9(3):179-187. 
39. 
Goldfarb SB DM, Dnistrian A et al. Limited absorption of low dose 10ug intrvaginal 17-b 
estradiol (vafifem) in postmenopausal women with breast cancer on aromatase 
inhibitors. Paper presented at: San Antonio Breast Cancer Symposium2012; San Antonio. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Revision 3, May 14, 2018 
 
 
23 
 
 
 
 
 
 
 
 
 
 
APPENDIX 1 
  
Investigator Agreement  
 
Protocol No.  
 
Protocol Title: A Phase II Trial to Evaluate Serum Estradiol Levels in Patients with Breast 
Cancer Treated with Estring 
 
By signing below I agree:  
 
1) That my staff and I have read, understand and will adhere to the protocol as written, and that 
any changes to the protocol will be agreed to and approved by the Sponsor and the Institutional 
Review Board (IRB), except a change to eliminate an immediate hazard to study subjects, 
which may be implemented at once, with notice to the Principal Investigator and the IRB;  
 
2) To abide by all obligations stated on the FDA Form 1572 and other documents required by 
regulation;  
 
3) To conduct this study in accordance with the current International Conference on 
Harmonization (ICH) guidance, the Good Clinical Practices (GCP) guidance, the Declaration of 
Helsinki, US FDA regulations and local IRB and legal requirements;  
 
4) To obtain IRB approval of the protocol, any amendments to the protocol, and periodic re-
approval as required, and to keep the IRB informed of adverse events and periodically report 
the status of the study to them;  
 
5) To ensure that each individual enrolled into the trial, or legally authorized representative, has 
read, understands, and has signed the Informed Consent form;  
 
6) To ensure that I and all persons assisting me with the study are adequately informed and 
trained about the investigational drug and their study-related duties and functions as described 
in the protocol;  
 
7) To make prompt reports of SAEs and deaths to the FDA according to the regulations;  
 
8) To prepare and maintain adequate and accurate case histories to document all observations 
and other data pertinent to the study for each individual enrolled in the clinical trial.  
 
 
Investigator Signature Date  


Revision 3, May 14, 2018 
 
 
24 
 
 
 
Investigator Name (Print) 
 
 
 
 
 
 
 
APPENDIX 2 
 
VAGINAL DRYNESS SYMPTOM QUESTIONNAIRE 
 
EVERYDAY PROBLEMS DURING THE PAST 4 WEEKS 
 
We are interested in knowing how much you have been bothered by any of the following 
problems during the PAST 4 WEEKS. (Check one box on each line.  If you do not have the problem, 
check “not at all”.) 
 
During the past 4 weeks, how much were you bothered by: 
 
 
Not at 
all 
 
Slightly 
 
Moderately 
 
Quite a 
bit 
 
Extremely 
 
1.   Hot flashes 
 
 0 
 
1 
 
2 
 
3 
 
4 
2.   Nausea 
 
 0 
 
1 
 
2 
 
3 
 
4 
3.   Vomiting 
 
 0 
 
1 
 
2 
 
3 
 
4 
4.   Difficulty with bladder control 
when laughing or crying. 
 
 0 
 
1 
 
2 
 
3 
 
4 
5.   Difficulty with bladder control at 
other times 
 
 0 
 
1 
 
2 
 
3 
 
4 
6.  Vaginal dryness 
 
 0 
 
1 
 
2 
 
3 
 
4 
7.  Pain with intercourse 
 
 0 
 
1 
 
2 
 
3 
 
4 
8.  General aches and pains 
 
 0 
 
1 
 
2 
 
3 
 
4 


Revision 3, May 14, 2018 
 
 
25 
 
9.  Joint pains 
 
 0 
 
1 
 
2 
 
3 
 
4 
10.  Muscle stiffness 
 
 0 
 
1 
 
2 
 
3 
 
4 
11.  Weight gain 
 
 0 
 
1 
 
2 
 
3 
 
4 
12.  Unhappiness with the appearance 
of your body 
 
 0 
 
1 
 
2 
 
3 
 
4 
13.  Forgetfulness 
 
 0 
 
1 
 
2 
 
3 
 
4 
14.  Night sweats 
 
 0 
 
1 
 
2 
 
3 
 
4 
15.  Difficulty concentrating 
 
 0 
 
1 
 
2 
 
3 
 
4 
16.  Being easily distracted 
 
 0 
 
1 
 
2 
 
3 
 
4 
19.  Vaginal discharge 
 
 0 
 
1 
 
2 
 
3 
 
4 
20.  Vaginal bleeding or spotting 
 
 0 
 
1 
 
2 
 
3 
 
4 
21.  Genital itching/irritation 
 
 0 
 
1 
 
2 
 
3 
 
4 
22.  Lack of energy 
 
 0 
 
1 
 
2 
 
3 
 
4 
23. Tiredness 
 
 0 
 
1 
 
2 
 
3 
 
4 
24. Lack of interest in sex 
 
 0 
 
1 
 
2 
 
3 
 
4 
25. Low sexual enjoyment 
 
 0 
 
1 
 
2 
 
3 
 
4