Clinical trial NCT02967510
Conditions: Vaginal Atrophy
Sponsor: ITF Research Pharma, S.L.U.
Start date: 2016-10-01; Completion date: 2018-05-01
Enrollment: 283 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 2, Dose-ranging, 12-week Randomized, Double-blind, Placebo controlled, Parallel-group Study Evaluating the Efficacy and Safety of Three Formulations of Ultra-low Dose Estriol Vaginal Gel (0.005% Estriol Vaginal Gel, 0.002% Estriol Vaginal Gel, 0.0008% Estriol Vaginal Gel) for the Treatment of Vaginal Dryness in Postmenopausal Women with Vulvovaginal Atrophy.

Vulvovaginal atrophy is a natural consequence of the progressive estrogen deficiency that occurs in menopause. Epidemiological data have indicated that about 50% of otherwise healthy women over 60 years of age experience symptoms related to urogenital atrophy such as vaginal dryness, dyspareunia, burning, itching, as well as urinary complaints or infections of the lower urinary tract. As these alterations frequently affect the quality of life of postmenopausal women, it is important for doctors to detect their presence and offer treatment options. Estrogen therapy is the most effective treatment of moderate to severe symptoms of vulvar and vaginal atrophy. One advantage of local treatment with estrogen is avoidance of first-pass liver metabolism, making it possible to use lower doses of estrogen compared with oral therapy; the local route also minimize systemic adverse effects. The search for therapeutic alternatives which may present improvements in relation to the current products has been encouraged.

Detailed description:

Arms: arm 1: Vaginal. Administration by an applicator inserted deep inside the vagina Dose: 1 g of gel, containing 50 Mcg of estriol Dosage schedule: Weeks 1-3: single daily application Weeks 4-12: twice weekly administration arm 2: Vaginal. Administration by an applicator inserted deep inside the vagina Dose: 1 g of gel, containing 50 Mcg of estriol Dosage schedule: Weeks 1-3: single daily application Weeks 4-12: twice weekly administration arm 3: Vaginal. Administration by an applicator inserted deep inside the vagina Dose: 1 g of gel, containing 50 Mcg of estriol Dosage schedule: Weeks 1-3: single daily application Weeks 4-12: twice weekly administration arm 4: Vaginal. Administration by an applicator inserted deep inside the vagina Dose: 1 g of gel, containing 50 Mcg of estriol Dosage schedule: Weeks 1-3: single daily application Weeks 4-12: twice weekly administration
Interventions: intervention 1: Estriol intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_001.pdf: 
    CLINICAL STUDY PROTOCOL 
IND NUMBER 104785/EUDRACT NUMBER 2015-005787-42 
 
A Phase 2, Dose-ranging, 12-week Randomized, Double-blind, 
Placebo-controlled, Parallel-group Study Evaluating the Efficacy and 
Safety of Three Formulations of Ultra-low Dose Estriol Vaginal Gel 
(0.005% Estriol Vaginal Gel, 0.002% Estriol Vaginal Gel, 0.0008% Estriol 
Vaginal Gel) for the Treatment of Vaginal Dryness in Postmenopausal 
Women with Vulvovaginal Atrophy 
 
Protocol No. ITFE-2092-C1 
 
Sponsor: 
ITF Research Pharma SLU 
c/ San Rafael 3 
28108 Madrid, Spain 
Sponsor Contact: 
 
 
 
Version of Protocol:  
Final 5.0 
Date of Protocol:  
07 June 2017 
 
 
 
 
CONFIDENTIAL 
All financial and nonfinancial support for this study will be provided by ITF Research 
Pharma SLU. The concepts and information contained in this document or generated during 
the study are considered proprietary and may not be disclosed in whole or in part without the 
expressed, written consent of ITF Research Pharma SLU. 
The study will be conducted according to the International Conference on Harmonisation 
Harmonised Tripartite Guideline E6 (R1/R2): Good Clinical Practice. 


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Table of Contents 
Table of Contents ....................................................................................................................... 4 
List of Tables .............................................................................................................................. 7 
List of Figures ............................................................................................................................ 7 
Protocol Synopsis....................................................................................................................... 8 
List of Abbreviations................................................................................................................ 14 
1 
Introduction ...................................................................................................................... 15 
2 
Study Objectives............................................................................................................... 18 
2.1 
Primary Objective ................................................................................................... 18 
2.2 
Secondary Objectives.............................................................................................. 18 
2.3 
Exploratory Objectives ........................................................................................... 18 
3 
Investigational Plan .......................................................................................................... 19 
3.1 
Study Design ........................................................................................................... 19 
3.1.1 
Rationale of Study Design ....................................................................... 22 
4 
Subject Selection and Withdrawal Criteria ...................................................................... 23 
4.1 
Selection of Study Population ................................................................................. 23 
4.1.1 
Inclusion Criteria ..................................................................................... 23 
4.1.2 
Exclusion Criteria .................................................................................... 23 
4.2 
Withdrawal of Subjects from the Study .................................................................. 26 
4.2.1 
Reasons for Withdrawal/Discontinuation ................................................ 26 
4.2.2 
Handling of Withdrawals ......................................................................... 27 
4.2.3 
Re-screenings and Replacements............................................................. 27 
5 
Study Treatments .............................................................................................................. 29 
5.1 
Method of Assigning Subjects to Treatment Groups .............................................. 29 
5.2 
Treatments Administered ........................................................................................ 29 
5.3 
Identity of Investigational Product.......................................................................... 30 
5.4 
Management of Clinical Supplies ........................................................................... 31 
5.4.1 
Study Drug Packaging and Storage ......................................................... 31 
5.4.2 
Test Article Accountability ...................................................................... 32 
5.5 
Overdose Management ........................................................................................... 32 
5.5.1 
Treatment of Overdose ............................................................................ 33 
5.5.2 
Medication Errors .................................................................................... 33 


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5.6 
Misuse for Illegal Purposes ..................................................................................... 33 
5.7 
Blinding................................................................................................................... 33 
5.7.1 
Breaking the Blind ................................................................................... 34 
5.8 
Treatment Compliance ............................................................................................ 34 
5.9 
Prior and Concomitant Therapy .............................................................................. 35 
6 
Study Assessments and Procedures .................................................................................. 36 
6.1 
Study Visits ............................................................................................................. 36 
6.1.1 
Screening Visit ......................................................................................... 36 
6.1.2 
Baseline Visit ........................................................................................... 38 
6.1.3 
Week 3 Visit ............................................................................................. 38 
6.1.4 
Week 8 Visit ............................................................................................. 39 
6.1.5 
Week 12 Visit/Early Termination Visit .................................................... 39 
6.1.6 
Week 16 – End-of-Study Phone Call ....................................................... 40 
6.2 
Efficacy Assessments .............................................................................................. 40 
6.2.1. Vaginal Cytology .......................................................................................... 41 
6.2.2 Vaginal pH Determination ............................................................................. 41 
6.2.3 Evaluation of Vaginal Symptoms and Signs .................................................. 42 
6.2.3.1 Evaluation of Symptoms ............................................................................. 42 
6.2.3.3 Evaluation of Global Symptom Score ........................................................ 43 
6.2.4 Evaluation of Global Efficacy ....................................................................... 43 
6.3 
Safety Assessments ................................................................................................. 44 
6.3.1 
Clinical Laboratory Assessments ............................................................. 44 
6.3.2 
Transvaginal Ultrasound .......................................................................... 44 
6.3.3 
Endometrial Biopsy ................................................................................. 45 
6.3.4 
Adverse Events ........................................................................................ 46 
6.3.4.1 
Definitions of Adverse Events ................................................................. 46 
6.3.4.2 
Eliciting and Documenting Adverse Events ............................................ 50 
6.3.4.3 
Reporting Adverse Events ....................................................................... 52 
6.3.4.4 
Assessment of Severity ............................................................................ 52 
6.3.4.5 
Assessment of Causality .......................................................................... 53 
6.3.4.6 
Follow-Up of Subjects Reporting Adverse Events .................................. 53 
6.4 
Evaluation of Acceptability..................................................................................... 53 
6.5 
Laboratory Analyses ............................................................................................... 53 
6.6 
Sample Collections ................................................................................................. 54 
7 
Statistical and Analytical Plan .......................................................................................... 55 


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7.1 
Primary Efficacy Endpoints .................................................................................... 55 
7.2 
Secondary Efficacy Endpoints ................................................................................ 55 
7.3 
Exploratory Efficacy Endpoints .............................................................................. 56 
7.4 
Safety Endpoints ..................................................................................................... 56 
7.5 
Sample Size Calculations ........................................................................................ 57 
7.6 
Analysis Sets ........................................................................................................... 58 
7.7 
Description of Subgroups to be analyzed ............................................................... 59 
7.8 
Statistical Analysis Methodology ........................................................................... 59 
7.8.1 
Analysis of Primary Efficacy Endpoints ................................................. 59 
7.8.1.1 
Gatekeeping Procedure ............................................................................ 60 
7.8.2 
Analysis of Secondary Efficacy Endpoints ............................................. 61 
7.8.3 
Analyses of Exploratory Efficacy Endpoint ............................................ 61 
7.8.4 
Safety Analyses ........................................................................................ 62 
7.8.4.1 
Pooling of Study Sites.............................................................................. 62 
7.8.5 
Interim Analyses ...................................................................................... 62 
7.9 
Data Quality Assurance........................................................................................... 62 
7.9.1 
Data Management .................................................................................... 63 
8 
Ethics ................................................................................................................................ 64 
8.1 
Independent Ethics Committee or Institutional Review Board .............................. 64 
8.2 
Ethical Conduct of the Study .................................................................................. 64 
8.3 
Subject Information and Consent............................................................................ 64 
9 
Investigator’s Obligations ................................................................................................ 66 
9.1 
Confidentiality ........................................................................................................ 66 
9.2 
Financial Disclosure and Obligations ..................................................................... 66 
9.3 
Investigator Documentation .................................................................................... 67 
9.4 
Study Conduct ......................................................................................................... 67 
9.5 
Adherence to Protocol............................................................................................. 67 
9.6 
Adverse Events and Study Report Requirements ................................................... 68 
9.7 
Investigator’s Final Report ..................................................................................... 68 
9.8 
Records Retention ................................................................................................... 68 
9.9 
Publications ............................................................................................................. 68 
10 Study Management ........................................................................................................... 69 
10.1 Monitoring .............................................................................................................. 69 


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10.1.1 
Inspection of Records .............................................................................. 69 
10.2 Management of Protocol Amendments and Deviations.......................................... 69 
10.2.1 
Modification of the Protocol .................................................................... 69 
10.2.2 
Protocol Deviations.................................................................................. 70 
10.3 Study Termination ................................................................................................... 70 
10.4 Final Report ............................................................................................................ 71 
11 Reference List................................................................................................................... 72 
12 Appendices ....................................................................................................................... 74 
12.1 WMA Declaration of Helsinki ................................................................................ 75 
12.2 Investigator’s Statement and Agreement ................................................................ 82 
12.3 Screening Criteria – Allowed Pre-study Therapies ................................................. 83 
12.4 Screening Criteria - Excluded Medications ............................................................ 84 
 
List of Tables 
Table 1: Schedule of Events .................................................................................................... 20 
Table 2 Assumed Proportions for Wilcoxon Rank Sum Test of Vaginal Dryness .................. 57 
Table 3: Gatekeeping Procedure for Efficacy Analyses .......................................................... 60 
 
List of Figures 
Figure 1: Estriol Structural Formula ....................................................................................... 30 


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Protocol: ITFE-2092-C1, v5.0 
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Protocol Synopsis 
 
Protocol Number: 
ITFE-2092-C1 
Title: 
A Phase 2, Dose-ranging, 12-week, Randomized, Double-blind, 
Placebo-controlled, Parallel-group Study Evaluating the Efficacy 
and Safety of Three Formulations of Ultra-low Dose Estriol 
Vaginal Gel (0.005% Estriol Vaginal Gel, 0.002% Estriol 
Vaginal Gel, 0.0008% Estriol Vaginal Gel) for the Treatment of 
Vaginal Dryness in Postmenopausal Women with Vulvovaginal 
Atrophy 
Sponsor: 
ITF Research Pharma SLU 
San Rafael 3 
28108 Madrid, Spain 
Study Phase: 
Phase 2 
Study Sites: 
Approximately 25, in 5 European countries (Spain, Italy, 
Sweden, Hungary, Czech Republic). 
Indication: 
Treatment of vaginal dryness in postmenopausal women with 
vulvovaginal atrophy 
Rationale: 
Local estrogen therapy is the recommended approach to treat 
symptoms related to postmenopausal vulvovaginal atrophy. An 
estriol-based formulation allowing a lower dose per application 
provides reduced estrogen exposure while maintaining efficacy, 
resulting in fewer systemic effects and a more favorable risk-
benefit ratio for the patient. 
Objectives: 
Primary objective:  
Evaluate the efficacy of 0.005%, 0.002%, and 0.0008% estriol 
vaginal gel and determine the minimal effective dose for the 
treatment of postmenopausal vaginal atrophy in women who 
report moderate to severe vaginal dryness as the most 
bothersome symptom. 
Secondary objectives: 
Evaluate the efficacy of the three formulations of estriol vaginal 
gel in the improvement of other symptoms and signs of 
vulvovaginal atrophy. 
Evaluate the safety and tolerability of the three formulations of 
estriol vaginal gel. 
Exploratory objectives: 
Evaluate the final subjective global perception of efficacy of the 
three formulations of estriol vaginal gel. 
Evaluate the subject`s acceptability of the three formulations. 


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Subject Population: 
Inclusion criteria: 
1. Capable of understanding the written informed consent, 
provides signed and witnessed written informed consent, 
and agrees  to comply with the protocol procedures and 
assessments  
2. Age >40 and <80 years 
3. Postmenopausal (≥12 months since last spontaneous 
menstrual period, or having 6 months of spontaneous 
amenorrhea with serum FSH levels >40 IU/L, or ≥6 
weeks since bilateral oophorectomy with or without 
hysterectomy) 
4. BMI 36 kg/m2 
5. Vaginal Maturation Index ≤ 5% superficial cells on a 
vaginal smear 
6. Vaginal pH >5 
7. Moderate to severe vaginal dryness currently reported as 
the most bothersome symptom of vaginal atrophy. 
8. Negative mammogram at screening or documented 
negative mammogram within 9 months prior to 
randomization, with normal breast examination at 
screening. 
9. Negative Papanicolau test at screening (in women with 
cervix). 
Exclusion criteria: 
1. Subjects with contraindications for hormone therapy 
with estrogens such as those diagnosed or history of: 
malignant and premalignant lesions of the breast and/or 
endometrium, malignancy of the colon, malignant 
melanoma, hepatic tumor, venous thromboembolic 
conditions (including deep vein thrombosis or pulmonary 
embolism), 
arterial 
thromboembolic 
conditions 
(including angina pectoris, myocardial infarction, or 
cerebrovascular 
accident), 
coagulopathies, 
vaginal 
bleeding of unknown etiology, acute liver disease or a 
history of liver disease as long as liver function tests 
have failed to return to normal, or porphyria. 
2. Subjects who have abnormal laboratory values at 
screening that the investigator considers clinically 
relevant for the purposes of the study. 
3. Subjects with any medical-surgical pathology which is 
not controlled at the time of inclusion in the study. 


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Subject Population: 
Exclusion criteria (continued): 
4. Subjects with any acute or chronic condition whose 
management or progression may interfere with the 
subject´s participation in the study. 
5. Subject with uncontrolled hypertension (>140 mmHg 
systolic blood pressure and/or ≥90 mmHg diastolic blood 
pressure). 
6. Subjects with Grade II or higher utero-vaginal prolapse. 
7. Subjects with uterine polyps. 
8. Subjects with symptomatic and/or large uterine fibroids 
(>3 cm) and/or palpable fibroids at gynecological 
examination.  
9. Subjects who have had urogenital surgery within 3 
months of baseline visit. 
10. Subjects with signs and symptoms suggestive of 
infection of the genital or urinary tract requiring 
treatment at the start of the study. 
11. In women who have a uterus, evidence of hyperplasia, 
cancer or other endometrial pathology in endometrial 
biopsy. 
12. Subjects who have received the following treatments 
within the specified time periods prior to screening 
procedures: any type of non-hormonal vulvovaginal 
treatment in the 7 days (including cosmetics expected to 
have an impact on vaginal pH such as special feminine 
wash gels); phytoestrogens by any route within 1 month; 
vaginal hormone therapy within 1 month; hormone 
therapy 
(estrogen 
alone, 
progestin 
alone 
or 
estrogen/progestin combination) by oral,  intrauterine or 
transdermal route within 2 months; progestational 
implants, estrogen, or estrogen/progestational injectable 
within 3 months; estrogen pellet therapy or progestin 
injectable drug therapy within 6 months; percutaneous 
estrogen lotions or gels within 1 month; testosterone or 
testosterone derivatives, DHEA, tibolone, or SERMs by 
any route within 2 months;  
13. Subjects receiving antiepileptic drugs (barbiturates, 
hydantoins, carbamazepine), certain antibiotics and other 
antiinfective 
medicinal 
products; 
phenylbutazone; 
preparations based on medicinal plants that contain St. 
John’s Wort. 
 


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Subject Population: 
Exclusion criteria (continued): 
14. Subjects who are allergic to any of the components of the 
medication under study.  
15. Subjects who are currently participating or have 
participated in the experimental evaluation of any 
product within 8 weeks of the start of the study. 
Study Design: 
 
Dose-ranging, 12-week, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study. 
Estimated Study 
Duration: 
Study duration will be approximately 20 weeks from the 
Screening Visit to End-of-Study phone call. Subject exposure to 
study drug will last 12 weeks, with a total of up to 6 study visits 
(including one telephone call visit). 
Efficacy Assessments: 
The co-primary efficacy variables in this study are:  
 Mean change from Baseline to Week 12 in the proportion 
of superficial and parabasal cells of the vaginal 
epithelium on vaginal smear;  
 Mean change from Baseline to Week 12 in vaginal pH;  
 Mean change from Baseline to Week 12 in the severity of 
vaginal dryness 
The secondary efficacy variables: 
 Mean change from Baseline to Week 3 in the proportion 
of superficial and parabasal cells of the vaginal 
epithelium;  
 Mean change from Baseline to Week 3 in vaginal pH;  
 Mean change from Baseline to Week 3 in the severity of 
vaginal dryness 
 Mean change of other individual vaginal symptoms 
(dyspareunia, pruritus, burning and dysuria) and signs 
(pallor, friability, thinning or flattening of folds, 
petechiae, and dry mucosa) of vaginal atrophy from 
Baseline to Week 3 and from Baseline to Week 12 
 Mean change in the Global Symptom Score from 
Baseline to Week 3 and from Baseline to Week 12 
The exploratory efficacy variables: 
 Evaluation of the final subjective global perception of 
efficacy by subjects at Week 12. 
 Evaluation of the acceptability of the therapy at Week 12. 


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Estriol Vaginal Gel 
Protocol: ITFE-2092-C1, v5.0 
07Jun2017 
 
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Safety Assessments: 
 
The safety variables in this study are:  
 Evaluation of adverse events 
 Histological 
evaluation 
of 
the 
endometrium 
by 
endometrial biopsy  
 Evaluation of the endometrium by ultrasonography 
 Change in hormone levels 
 Change in clinical safety laboratory parameters 
 Safety assessments of lipids and of carbohydrate and 
coagulation parameters (antithrombin III, factor V 
Leiden, protein-C and protein-S) 
Study Drug, Dosage, 
and Route of 
Administration: 
0.005% estriol vaginal gel, 1 g (50 µg estriol/intravaginal 
application dose), 0.002% estriol vaginal gel, 1 g (20 µg 
estriol/intravaginal application dose), 0.0008% estriol vaginal 
gel, 1 g (8 µg estriol/intravaginal application dose), placebo 
vaginal gel, 1 g (intravaginal administration) 
Sample Size: 
A total of 280 subjects randomly assigned equally to 0.005% 
estriol vaginal gel, 0.002% estriol vaginal gel, 0.0008% estriol 
vaginal gel, or placebo. 


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Statistical Methods: 
The Intent-to-Treat (ITT) Population, the Per Protocol (PP) 
Population, and the Safety Population will be used to present the 
results.  
Changes from Baseline to Week 12 in vaginal dryness will be 
analyzed using a Wilcoxon Rank Sum test, controlled for 
country, to obtain the p-values. The changes from Baseline to 
Week 12 in vaginal pH and the changes in proportions of 
parabasal and superficial cells will be analyzed using a 
parametric ANCOVA. The model will include fixed effects of 
treatment and country, and the baseline value will be used as a 
covariate. Model assumptions will be examined and, if required, 
a Wilcoxon Rank Sum test as described for vaginal dryness will 
be used. Missing values will be estimated using last observation 
carried forward (LOCF). Only post-Baseline values will be 
carried forward. 
For the co-primary endpoints (change from Baseline to Week 12 
in proportion of superficial and parabasal cells of the vaginal 
epithelium, pH, vaginal dryness), a gatekeeping procedure will 
be employed. 0.005% dose will be compared to placebo, and if 
this is significant at a one-sided alpha level of 0.025 then the 
other doses versus placebo can be considered in order of strength 
(strongest first); if all four co-primary endpoints are significant 
at the one-sided 2.5% level, then the next lowest dose can be 
presented; this approach will avoid any issues of multiple testing 
with four co-primary endpoints and three comparisons. 
The change from Baseline to Week 12 in the severity of 
individual vaginal symptoms (dyspareunia, dryness, pruritus, 
burning and dysuria) and signs (pallor, friability, thinning, 
petechiae, flattening of folds and dry mucosa) will be assessed 
using the same Wilcoxon Rank Sum test as for the co-primary 
endpoint of vaginal dryness at Week 12. The change from 
Baseline to Week 12 in the global symptom score will be 
assessed using the same parametric ANCOVA as for the co-
primary endpoints of vaginal pH and proportions of parabasal 
and superficial cells at Week 12.  The Week 3 efficacy endpoints 
will be assessed using similar methodology as Week 12. 
Endpoints of acceptability of therapy, final subjective global 
perception, and safety analyses will be summarized by treatment 
group. 
Date of Protocol: 
07 June 2017 


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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ANCOVA 
analysis of covariance 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CRO 
contract research organization 
CSA 
clinical study agreement 
E1 
estrone 
E2 
17-estradiol 
E3 
estriol 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ER 
estrogen receptor 
FDA 
US Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IRB 
institutional review board 
ITT 
intention to treat 
IWRS 
LH 
Interactive Web Response System 
luteinizing hormone 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
OTC 
over-the-counter 
PP 
per protocol 
PV 
pharmacovigilance 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SERM 
selective estrogen receptor modulator 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
TVU 
transvaginal ultrasound 


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1 Introduction 
Vulvovaginal atrophy is a natural consequence of the progressive estrogen deficiency that 
occurs in menopause. Epidemiological data have indicated that about 50% of otherwise 
healthy women over 60 years of age experience symptoms related to urogenital atrophy such 
as vaginal dryness, dyspareunia, burning, itching, as well as urinary complaints or infections 
of the lower urinary tract. As these alterations frequently affect the quality of life of 
postmenopausal women, it is important for doctors to detect their presence and offer 
treatment options. 
Estrogen therapy is the most effective treatment of moderate to severe symptoms of vulvar 
and vaginal atrophy. Scientific societies agree that when estrogen therapy is considered for 
treatment of vaginal atrophy, local treatment is advised (The 2007 Hormone Therapy Position 
Statement of the North American Menopause Society, 2007). One advantage of local 
treatment with estrogen is avoidance of first-pass liver metabolism, making it possible to use 
lower doses of estrogen compared with oral therapy; the local route also minimize systemic 
adverse effects. 
The primary risks of taking an estrogen product after menopause is that it can cause or 
exacerbate certain types of tumors, such as breast or endometrium. Taking low dose 
estrogens vaginally decreases the risk of the occurrence of these tumors, as a consequence of 
the very low doses employed that permit a local vaginal effect while the potential of 
absorption is minimized. It has been shown that lower doses of vaginal estrogen therapy than 
previously used, even with less frequent administration, often yield satisfactory results. The 
lowest effective dose of estrogen consistent with treatment goals, benefits, and risks for the 
individual woman should be the therapeutic goal (The 2012 Hormone Therapy Position 
Statement of the North American Menopause Society, 2012). 
Estriol (E3) is one of the most important estrogens produced in the human body, along with 
17β-estradiol (E2) and estrone (E1). Estriol is normally produced in the liver by irreversible 
transformation of estradiol and estrone. This process is considered to be a metabolic 
detoxification mechanism, by which potent estrogens are transformed into less active 
metabolites such as estriol. Also, estriol is produced in significant amounts 
during pregnancy as it is synthesized by the placenta. In all instances, there is no conversion 
from estriol to estradiol or estrone. 


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The physiological effect of estrogens is complex: they exert their action through the 
activation of specific nuclear receptors, and different estrogens bind with different affinities 
to their receptors. Two subtypes of estrogen receptors (ERs) have been identified; these 
subtypes are ERα and ERß, with different tissue distributions, although there is some overlap 
in their expression, as ERα is most abundantly expressed in the endometrium, breast, and 
ovarian stroma. The relative binding affinities of different estrogens for their receptors has 
been investigated in different models against 17ß-estradiol, the most potent natural estrogen. 
In this sense, the binding affinities of estriol to ERα and ERß have been shown to be 14% 
and 21% of those of estradiol, respectively (Gruber CJ, 2002). Also, the differential 
expression of receptors in tissues results in topological (tissue) differences in the affinities of 
the various estrogens. Compared to estradiol, estriol shows a relatively high affinity for the 
receptors in bladder and vaginal tissue, but relatively low affinity for receptors in the uterine 
and breast tissue (Bergink EW, 1984). The lower affinity in the uterus results in minimal or 
no uterotropic influence with estriol exposure (Takahi K, 2000) (Raz R, 1993) (Padwick ML, 
1986) (Reynolds TM, 1993). The non-uterotrophic effect is also attributed, in part, to its 
relatively short duration of nuclear receptor binding and rapid plasma clearance (Cardozo L, 
1998) (van Haaften M, 1997). 
Other claimed advantages of estriol over other natural estrogens include a protective effect 
against development of breast cancer, minimal mitogenic activity, less effect on plasma lipids 
and coagulation factors/platelets, and an ability to reduce/block the uterotrophic activity of 
other estrogens (competition with receptor binding) (Takahi K, 2000) (Padwick ML, 1986) 
(Hayashi T, 2000) (Nakayama H, 1999). 
Estriol formulations have been marketed since 1958 for the treatment of vulvovaginal 
atrophy in more than 50 countries worldwide, including all European countries, but not the 
United States. Topical (vaginal) formulations are currently available as creams (containing 
1 mg estriol/1 g cream) or as ovules (containing 0.5 mg estriol). Local vaginal estrogen 
therapy can also be administered in the form of estradiol vaginal tablets or vaginal creams, 
estradiol-releasing vaginal rings and conjugated estrogen-based vaginal creams. 
The search for therapeutic alternatives which may present improvements in relation to the 
current products has been encouraged. I
 -
 
 
 
 
 


ITF Research Pharma SLU 
 
Estriol Vaginal Gel 
Protocol: ITFE-2092-C1, v5.0 
07Jun2017 
 
Page 17 
 
 
 
 
 -
 
 
 
 
 
Clinical research to develop this product was performed in European populations under 
European guidelines. 
 
  
 
 
 
 
 
 -
 -
 
 


ITF Research Pharma SLU 
 
Estriol Vaginal Gel 
Protocol: ITFE-2092-C1, v5.0 
07Jun2017 
 
Page 18 
2 Study Objectives 
2.1 Primary Objective 
The primary objective of this study is to evaluate the efficacy of 0.005%, 0.002%, and 
0.0008% estriol vaginal gel and to determine the minimal effective dose for the treatment of 
postmenopausal vaginal atrophy in women that refer moderate to severe vaginal dryness as 
the most bothersome symptom. 
2.2 Secondary Objectives 
The secondary objectives of this study are to: 
 
Evaluate the efficacy of the three formulations of estriol vaginal gel in the 
improvement of other symptoms and signs of vulvovaginal atrophy. 
 
Evaluate the safety and tolerability of the three formulations of estriol vaginal gel. 
2.3 Exploratory Objectives 
The exploratory objectives of this study are to:  
• 
Evaluate the final subjective global perception of efficacy of the three formulations of 
estriol vaginal gel. 
• 
Evaluate the subject`s acceptability of the three formulations of estriol vaginal gel. 


ITF Research Pharma SLU 
 
Estriol Vaginal Gel 
Protocol: ITFE-2092-C1, v5.0 
07Jun2017 
 
Page 19 
3 Investigational Plan 
3.1 Study Design 
This study is a double-blind, randomized, dose-ranging, placebo-controlled multicenter study 
with four parallel groups. Approximately 25 sites in Europe will be included in the study. The 
study setting will include academic hospitals and gynecological clinics. The study population 
is postmenopausal women who report moderate to severe vaginal dryness as their most 
bothersome symptom in addition to other symptoms and/or signs of postmenopausal 
vulvovaginal atrophy. 
After providing informed consent, potential subjects will be evaluated during the screening 
period to determine if they are eligible to participate in the study. A screening identification 
number will be assigned to each eligible subject according to their order of arrival into the 
study at screening visit. Subjects who meet all of the inclusion criteria (see Section 4.1.1) and 
none of the exclusion criteria (see Section 4.1.2) will be randomized into the study. A total of 
280 subjects will be enrolled and randomly allocated to one of the four treatment groups 
(0.005%, 0.002%, or 0.0008% estriol vaginal gel or placebo vaginal gel); the allocation to 
treatment group will be 1:1:1:1. A blocked randomization across the entire study (i.e. all sites 
as a whole) will be used. Subjects will be assigned a randomization code according to their 
order of arrival into the study at the Baseline Visit. Initial treatment consists of daily vaginal 
administration of 1 gram of randomly-assigned estriol gel or placebo gel using the supplied 
applicator. After 21 days of daily administration, treatment will continue with twice-weekly 
administration up to Week 12 (i.e., Mondays and Thursdays). 
The duration of trial participation for each woman is expected to be approximately 20 weeks 
(from Screening to End-of-Study phone call) although the time on study drug will be 
approximately 12 weeks. Subject completion is defined as the completion of all phases of the 
study, including the End-of-Study phone call to be performed for safety purposes at Week 16. 
An overview of the study visit procedures is given in the Schedule of Events (Table 1). 
Details 
of 
specific 
procedures 
and 
testing 
are 
provided 
in 
Section 
6.


ITF Research Pharma SLU 
Estriol Vaginal Gel 
Protocol: ITFE-2092-C1, v5.0 
07Jun 2017 
 
Page 20 
Table 1: Schedule of Events 
 
 
 
 
 
 
Procedure 
Screening 
Visit  
Baseline 
Week 3 
Week 8 
Week 12/ 
Early 
Termination 
Week 16/ 
End of Study 
Phone Call 
Visit Window (days) 
–30 to -1 
1 
21 3 
56  5 
84  5 
112  5 
Informed consent 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Medical history, medication history, and 
demographics 
X 
 
 
 
 
 
Physical examination a 
X 
 
 
 
X 
 
12 lead electrocardiogram b 
X 
 
 
 
X 
 
Gynecological examination c 
X 
 
 
 
X 
 
Transvaginal ultrasound (women who have a uterus) 
X 
 
 
 
X 
 
Mammogram (if no negative mammogram 
documented within 9 months prior to 
randomization)d 
X 
 
 
 
 
 
Clinical laboratory tests e 
X 
 
 
 
X 
 
Endometrial biopsy (women who have a uterus) 
X 
 
 
 
X 
 
Adverse event reporting f 
X 
X 
X 
X 
X 
X 
Concomitant medication reporting 
X 
X 
X 
X 
X 
X 
Evaluation of vaginal dryness g 
X 
 
X 
 
X 
 
Evaluation of symptoms and signs of vulvovaginal 
atrophy g, h 
 
X 
X 
 
X 
 
Vaginal pH 
X 
 
X 
 
X 
 
Vaginal smear for evaluation of vaginal cytology 
X 
 
X 
 
X 
 
Evaluation of global efficacy i 
 
 
 
 
X 
 
Evaluation of acceptability j 
 
 
 
 
X 
 
Administration of the first dose of the study 
medication k  
 
X 
 
 
 
 
Study drug and supply dispensing l 
 
X 
X 
X 
 
 
Reconciliation of returned study drug 
 
 
X 
X 
X 
 


ITF Research Pharma SLU 
Estriol Vaginal Gel 
Protocol: ITFE-2092-C1, v5.0 
07Jun 2017 
 
Page 21 
Table 1: Schedule of Events 
 
 
 
 
 
 
Procedure 
Screening 
Visit  
Baseline 
Week 3 
Week 8 
Week 12/ 
Early 
Termination 
Week 16/ 
End of Study 
Phone Call 
a 
Physical examination to include vital sign measurements (height [Screening visit only], weight, blood pressure, heart rate). 
b 
Two ECG exams will be performed in each of these two visits, about 5 minutes apart one from another.  
c              Gynecological examination to include visual inspection of external genitalia, speculum examination of vagina and cervix (if present), bimanual palpation 
of uterus and ovaries (if present), breast palpation. Papanicolau exam will be performed only at screening visit.  
d 
Neither mammograms performed as study specific procedure nor negative mammogram documented within 9 months prior to randomization will be 
recorded in the eCRF but archived in subject’s clinical records 
e              Laboratory testing performed under fasting conditions at Screening and Week 12 includes: standard hematology panel plus prothrombin time, activated 
thromboplastin partial time, fibrinogen, antithrombin III/protein C/protein S; standard chemistry panel (glucose, cholesterol, high-density lipoprotein, low-
density lipoprotein, triglycerides albumin, alanine aminotransferase, aspartate aminotransferase, creatine phosphokinase, bilirubin, creatinine, total 
protein, uric acid, blood urea nitrogen); hormones (estradiol, estriol, estrone, follicle-stimulating hormone, luteinizing hormone); and standard urinalysis 
with microbiology. Factor V Leiden testing will be performed only at screening visit (or Week 12/ET visit if not obtained at screening) 
f 
AEs and SAEs will be recorded from screening (post ICF signature) and subsequently at every study visit and up to 30 days post last study drug 
administration. Tolerability of study drug will be evaluated at weeks 3, 8, 12, and 16.  
g 
For the evaluation of symptoms and signs,  each symptom and each sign will be graded as:  0=absent; 1=mild; 2=moderate; 3=severe 
h 
Signs and symptoms other than vaginal dryness to be evaluated are the following:   
Symptoms: dyspareunia, pruritus or itching, burning, dysuria.    Signs: pallor, friability, thinning or flattening of folds, presence of petechiae, and dry 
mucosa 
i              Global efficacy will be assessed as: highly efficacious, efficacious, non-efficacious, detrimental 
j              Global acceptability will be assessed as: excellent, good, acceptable, unacceptable 
k             The investigator will administer the first study medication or will supervise the patient doing the administration 
l              Medication kits will be dispensed via IWRS 
 


ITF Research Pharma SLU 
Estriol Vaginal Gel 
Protocol: ITFE-2092-C1, v5.0 
07Jun2017 
 
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3.1.1 Rationale of Study Design 
 -
 
  
The study design is concordant with a dose response approach (three doses of estrogens 
will be tested and compared to placebo), as well as the indication and the estrogenic nature 
of the product, and thus follows the recommendations of the FDA in Draft Jan 2003 
Recommendations for Clinical Evaluation of Estrogen/Progestins to Treat Vulvovaginal 
Symptoms.  
A placebo arm has been included in the study as per the above referenced FDA 
recommendations, in which it is indicated to demonstrate a statistically significant 
improvement versus placebo in the primary efficacy analyses. By selecting placebo as 
comparator, all potential influences on the actual or apparent course of the disease other 
than those arising from the pharmacologic action of the test drug are controlled. Placebo- 
controlled trials measure the total pharmacologically mediated effect of treatment, and 
provide the maximum ability to distinguish adverse effects caused by a drug from those 
resulting from underlying disease or intercurrent illness.  (ICH Guideline E10)  


ITF Research Pharma SLU 
Estriol Vaginal Gel 
Protocol: ITFE-2092-C1, v5.0 
07Jun2017 
 
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4 Subject Selection and Withdrawal Criteria 
4.1 Selection of Study Population 
Approximately 280 subjects will be enrolled at approximately 25 sites in Europe. Subjects 
will be assigned to study drug only if they meet all of the inclusion criteria and none of the 
exclusion criteria. 
4.1.1 Inclusion Criteria 
Each subject must meet all of the following criteria to be enrolled in this study: 
1. Is capable of understanding the written informed consent, provides signed and 
witnessed written informed consent, and agrees to comply with protocol procedures 
and assessments. 
2. Is ≥40 and ≤80 years old. 
3. Is postmenopausal, defined as ≥12 months since last spontaneous menstrual period, 
or having 6 months of spontaneous amenorrhea with serum follicle-stimulating 
hormone (FSH) level  >40 IU/L, or ≥6 weeks since bilateral oophorectomy with or 
without hysterectomy. 
4. Has a body mass index (BMI) ≤36 kg/m2. 
5. Vaginal Maturation Index showed ≤5% superficial cells on a vaginal smear. 
6. Vaginal pH is >5. 
7. Moderate to severe vaginal dryness is currently reported as the most bothersome 
symptom of vaginal atrophy. 
8. Negative mammogram at screening or documented negative mammogram within 9 
months prior to randomization and normal breast examination at screening. 
9. Negative Papanicolau test at screening (in women with a cervix). 
4.1.2 Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Subjects with contraindication to hormone therapy with estrogens, such as those 
diagnosed with or having a history of: 
 Malignant and premalignant lesions of the breasts or endometrium 


ITF Research Pharma SLU 
Estriol Vaginal Gel 
Protocol: ITFE-2092-C1, v5.0 
07Jun2017 
 
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 Malignancy of the colon  
 Malignant melanoma 
 Hepatic tumor  
 Venous thromboembolic conditions (including deep vein thrombosis or 
pulmonary embolism)  
 arterial thromboembolic conditions (including angina pectoris, myocardial 
infarction, or cerebrovascular accident) 
 Coagulopathies 
 Vaginal bleeding of unknown etiology 
 Acute liver disease or a history of liver disease as long as liver function tests 
have failed to return to normal.  
 Porphyria 
2. Subjects with abnormal laboratory values at screening that the investigator considers 
clinically relevant for the purposes of the study. 
3. Subjects with any medical-surgical pathology which is not controlled at the time of 
study inclusion. 
4. Subjects with any acute or chronic condition whose management or progression 
may interfere with the subject’s participation in the study. 
5. Subjects with uncontrolled hypertension (≥140 mmHg systolic blood pressure 
and/or ≥90 mmHg diastolic blood pressure). 
6. Subjects with Grade II or higher uterovaginal prolapse. 
7. Subjects with uterine polyps. 
8. Subjects with symptomatic and/or large (>3 cm) uterine fibroids and/or palpable 
fibroids at gynecological examination. 
9. Subjects who have had urogenital surgery within 3 months of the Baseline Visit. 
10. Subjects with signs and symptoms suggestive of infection of the genital or urinary 
tract requiring treatment at the start of the study.  


ITF Research Pharma SLU 
Estriol Vaginal Gel 
Protocol: ITFE-2092-C1, v5.0 
07Jun2017 
 
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11.  In women who have a uterus, evidence of hyperplasia, cancer, or other endometrial 
pathology at endometrial biopsy. 
12. Subjects who have received the following treatments within the specified time 
period prior to screening: 
• 
Any type of non-hormonal vulvovaginal treatment within  7 days prior 
to screening (including cosmetics expected to have an impact on vaginal 
pH such as special feminine wash gels) 
• 
Phytoestrogens by any route in the period of 1 month prior to screening 
• 
Vaginal hormone therapy within 1 month prior to screening 
• 
Hormone therapy (estrogen alone, progestin alone, or estrogen/progestin 
combination) by oral, intrauterine, or transdermal route within 2 months 
prior to screening. 
• 
Progestational implants, estrogen, or estrogen/progestational injectable 
within 3 months prior to screening 
• 
Estrogen pellet therapy or progestin injectable drug therapy within 6 
months prior to screening 
• 
Percutaneous estrogen lotions/gels within 1 month prior to screening 
• 
Testosterone or testosterone derivatives, dehydroepiandrosterone, 
tibolone, or selective estrogen receptor modulators (SERMs) by any 
route within 2 months prior to screening. 
13. Subjects in treatment with antiepileptic drugs (e.g., barbiturates, hydantoins, 
carbamazepine), certain antibiotics and other anti-infective medicinal products (e.g. 
rifampicin, rifabutin, tetracyclines, ketoconazole, evirapine, efavirenz, ritonavir, 
nelfinavir); phenyobutazone, preparations based on medicinal plants that contain St. 
John’s Wort (Hypericum perforatum).  
14. Subjects who are allergic to any of the ingredients in the investigational medicinal 
product. 
15. Subjects who are currently participating or have participated in the experimental 
evaluation of any product within 8 weeks of the start of study. 


ITF Research Pharma SLU 
Estriol Vaginal Gel 
Protocol: ITFE-2092-C1, v5.0 
07Jun2017 
 
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4.2 Withdrawal of Subjects from the Study 
The duration of the study is defined for each subject as the date signed written informed 
consent is provided through the last follow-up phone call at Week 16. 
Participation in this study is strictly voluntary. A subject has the right to withdraw from the 
study at any time and for any reason. If she chooses to withdraw, the investigator must be 
informed immediately. 
4.2.1 Reasons for Withdrawal/Discontinuation 
Subjects may withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the investigator or at the study site. Every effort should be 
made to keep subjects in the study. The reasons for subjects not completing the study will 
be recorded. A subject may be withdrawn from the study for any of the following reasons: 
1. Does not meet the protocol inclusion or exclusion criteria. 
2. Noncompliance with the protocol and/or treatment schedule. 
3. An adverse event (AE) that in the investigator’s opinion may be possibly related to 
the study drug or examinations requires withdrawal from the study. 
4. The subject presents with jaundice or deterioration in liver function 
5. The subject presents with significant increase in blood pressure 
6. The subject presents with new onset of migraine-type headache 
7. The subject withdraws consent or the investigator or Sponsor decides to discontinue 
the subject’s participation in the study. 
8. The investigator may also terminate a subject`s study participation if considered it is 
in her best interest. 
The investigator will also withdraw a subject if ITF Research Pharma SLU terminates the 
study. Upon occurrence of a serious or intolerable AE, the investigator will confer with the 
Sponsor. If a subject is discontinued because of an AE, the event will be followed until it is 
resolved. Any subject may withdraw his or her consent at any time. 


ITF Research Pharma SLU 
Estriol Vaginal Gel 
Protocol: ITFE-2092-C1, v5.0 
07Jun2017 
 
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4.2.2 Handling of Withdrawals 
Subjects are free to withdraw from the study or study drug at any time upon request. 
Subject participation in the study may be stopped at any time at the discretion of the 
investigator or at the request of the Sponsor. 
Subjects who discontinue study drug or active participation in the study will no longer 
receive study drug. When a subject withdraws from the study, the reason(s) for withdrawal 
shall be recorded by the investigator on the relevant page of the electronic case report form 
(eCRF). 
Any subject who prematurely terminates participation and who has received at least one 
dose of the test or reference product will undergo a final examination (see Section 6.1.5 for 
details). 
If study participation is terminated due to an AE possibly related to the study drug or study 
examinations, the subject must be followed-up by additional examinations according to the 
medical judgment of the investigator until the abnormal condition is resolved or the 
investigator deems further observations or examinations to be no longer medically 
indicated. Subjects who fail to return for final assessments will be contacted by the site 
(via two telephone calls and then a registered letter) in an attempt to have them comply 
with the protocol. 
It is vital to obtain follow-up data on any subject withdrawn because of an AE or serious 
AE (SAE). In every case, efforts must be made to undertake protocol-specified, safety, 
follow-up procedures. All subjects withdrawn from the study should be registered 
accordingly on the Interactive Web Response System (IWRS). 
4.2.3 Re-screenings and Replacements 
Screen failures (subjects not randomized into the study) may be re-screened in cases where 
the unmet selection criteria have been resolved. A new Informed Consent will be needed 
for re-screened subjects. Timelines permitted for re-screening will vary at the discretion of 
the investigator depending on the unmet criterium and the time needed to have it clinically 
resolved. Only invasive procedures biopsy and Factor V Leiden will not be repeated if 
subjects are rescreened within 1 month of previous failure. Data obtained from screening 
visit will be used again for the re-screened subject in her new screening visit under her new 


ITF Research Pharma SLU 
Estriol Vaginal Gel 
Protocol: ITFE-2092-C1, v5.0 
07Jun2017 
 
Page 28 
rescreening number. Randomized subjects prematurely withdrawn from the study will not 
be replaced. 


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Estriol Vaginal Gel 
Protocol: ITFE-2092-C1, v5.0 
07Jun2017 
 
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5 Study Treatments 
5.1 Method of Assigning Subjects to Treatment Groups 
Subjects will be randomly assigned to receive 0.005% estriol vaginal gel, 0.002% estriol 
vaginal gel, 0.0008% estriol vaginal gel, or placebo vaginal gel using a 1:1:1:1 allocation 
ratio. Subjects will be assigned a randomization code according to their order of arrival 
into the study at the Baseline Visit. 
The randomization schedule is prepared by the designated unblinded statistical 
programmer and reviewed and distributed by the designated unblinded statistician of 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 –-
 
  


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Estriol Vaginal Gel 
Protocol: ITFE-2092-C1, v5.0 
07Jun2017 
 
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All subjects will start treatment with a single daily application of 1 g of gel during the first 
3 weeks of study participation, and then twice weekly from Weeks 4 to 12. Study drug will 
be administered at bedtime, except the first dose, which will be administered by the 
investigator or by the subject in the presence of the investigator at the office at baseline 
visit. Twice weekly dosing during Weeks 4 through 12 is recommended to be preferably 
carried out on, for example, a Monday and Thursday schedule. 
5.3 Identity of Investigational Product 
Estriol is chemically described as 3,16α, 17β-trihydroxy-1,3,5(10)-estratriene. It has an 
empirical formula of C18H24O3, and the structural formula is shown in Figure 1. 
 
Figure 1: Estriol Structural Formula 
The molecular weight of estriol is 288.38. 
The drug product is a homogeneous colorless, odorless clear-to-slightly-translucent gel 
containing 0.05 mg/g of estriol. It contains, as excipients, AA-1 polycarbophil 
 
 Carbopol® 971P 
 
 
glycerol, 
sodium 
methyl 
parahydroxybenzoate, 
sodium 
propyl 
parahydroxybenzoate, hydrochloric acid, sodium hydroxide, and water. 
Formulations of 0.005%, 0.002%, and 0.0008% estriol vaginal gel are to be used in this 
study. The estriol vaginal gel formulations will be manufactured and released by 
 under the supervision of ITF Research Pharma SLU. 
The composition of the placebo gel is the same as the active with the exception of estriol. 
The placebo vaginal gel will be identical in appearance, texture, and odor to the estriol 
vaginal gel products. Placebo vaginal gel will be manufactured by 
 under 
the supervision of ITF Research Pharma SLU. 


ITF Research Pharma SLU 
Estriol Vaginal Gel 
Protocol: ITFE-2092-C1, v5.0 
07Jun2017 
 
Page 31 
ITF Research Pharma SLU will provide the Storage Site 
 with adequate supplies 
of estriol gel to be sent to the study sites. The following drug supplies will be used in the 
study:  estriol vaginal gel and placebo vaginal gel, both supplied as 10 g packaged in 
aluminum tubes with polyethylene screw caps. 
5.4 Management of Clinical Supplies 
5.4.1 Study Drug Packaging and Storage 
Estriol vaginal gel and matching placebo will be prepared in aluminum tubes (with internal 
lacquer) closed with a polyethylene screw cap, containing 10 g of drug product, packaged 
and shipped by 
 to the designated packaging/labeling vendor (
 
The designated packaging/labeling vendor (
 will then ship the experimental 
product to the study sites. The investigational product is packaged as a kit containing a 
tube of vaginal gel and ten 1-g capacity single-use vaginal applicators.  
The studies of stability with the investigational product packaged in 10-g tube indicate that 
the product should be stored under conditions not to exceed +25ºC.  
Packaging and labelling of the medicinal products will be performed in accordance with 
GMP and national regulatory requirements.   
Each study participant will be provided with an adequate number of 10-g tubes and 
1-g capacity vaginal applicators to fulfill the dosing regimen requirements. Study drug 
provided to each subject at the Baseline Visit will consist of three kits, each containing one 
10-g tube and 10 applicators (for 21 expected applications). At the Week 3 Visit, each 
subject will receive two kits of the study drug/applicators (for 10 expected applications), 
and at the Week 8 Visit, two additional kits of study drug/applicators (for 8 expected 
applications) will be provided. 
The Principal investigator or sub-investigator must explain to the subject how to 
administer the vaginal gel. The first application should be performed at site at baseline visit 
by the investigator or by the subject in the presence of the investigator. Subjects will be 
instructed to administer the rest of the treatment applications at bedtime to allow for 
maximum retention of the gel. 


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Estriol Vaginal Gel 
Protocol: ITFE-2092-C1, v5.0 
07Jun2017 
 
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5.4.2 Test Article Accountability 
The investigator will maintain accurate records of receipt of all medication kits, including 
dates of receipt. Reasons for departure from the expected dispensing regimen must also be 
recorded. 
Subjects must bring used and unused study drug containers as well as unused applicators 
with them to the Week 3, Week 8, and Week 12 study visits. Used applicators will be 
discarded by the subjects as normal household waste. All empty and partially empty 
containers of study drug will be stored at the site until the study closure visit has been 
performed.  
Drug accountability will be performed by the investigator on an ongoing basis. Final 
reconciliation of drug shipped, drug consumed and drug remaining will be performed at 
study closure. This reconciliation will be logged on the applicable forms, signed and dated. 
Any discrepancies noted will be investigated, resolved and documented prior to return or 
destruction.  
All unused and used supplies will be returned to the designated packaging/labeling vendor 
 for destruction. 
The Sponsor will be permitted access to the study supplies at any time within usual 
business hours and with appropriate notice during or after completion of the study to 
perform drug accountability reconciliation. 
5.5 Overdose Management 
Toxicity for estriol is very low. Overdose of 0.005%, 0.002%, and 0.0008% estriol vaginal 
gel with vaginal application is very unlikely. Symptoms that may occur in the case of a 
high dose being accidently ingested include nausea, vomiting, and vaginal bleeding (in 
women). 
An overdose of placebo vaginal gel is very unlikely. However, symptoms that may occur 
with accidental ingestion include nausea and vomiting.  
An overdose is any dose of study drug given to a subject or taken by a subject that exceeds 
the dose described in the protocol. Any overdose, with or without associated AEs, must be 


ITF Research Pharma SLU 
Estriol Vaginal Gel 
Protocol: ITFE-2092-C1, v5.0 
07Jun2017 
 
Page 33 
promptly documented in the eCRF. Overdoses without signs or symptoms need to be 
recorded as AEs; in case of any AEs associated with the overdose, these should be also 
reported on relevant AE/SAE sections in the eCRF. 
5.5.1 Treatment of Overdose 
There is no known specific antidote for an overdose of estriol gel or placebo gel. If 
necessary, symptomatic treatment should be instituted. 
5.5.2 Medication Errors 
Medication errors may result in this study from administration of study product outside the 
scheduled posology or use of incorrect amount of study product. Such medication errors 
occurring to a study subject are to be captured on the eCRF.  
Medication errors are reportable irrespective of the presence of an associated AE or SAE; 
these include medication errors involving subject exposure to the drug and potential 
medication errors or uses outside of what is foreseen in the protocol that do or do not 
involve the participating study subject. 
5.6 Misuse for Illegal Purposes 
Though the active ingredient of the estriol vaginal gel under investigation is a hormone, 
this is not likely to be an issue of concern in the study.  
If misuse of the study materials is identified by the investigator, immediate notification to 
the Sponsor is indicated.  
5.7 Blinding 
The study drug, 0.005% estriol vaginal gel, 0.002% estriol vaginal gel, 0.0008% estriol 
vaginal gel and the placebo vaginal gel will be of identical appearance, aroma, and texture 
in order to maintain the study blind. Treatments will be labelled undistinguishably. The 
Sponsor, the investigators, study site staff, and study subjects will be blinded to the identity 
of the study drugs used.  


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Protocol: ITFE-2092-C1, v5.0 
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5.7.1 Breaking the Blind 
Throughout the study, the medication with which the subject is being treated will be kept 
strictly confidential and only authorized persons will have access to this information, 
unless it is necessary to break the blind due to safety reasons. The unblinding must be done 
only by the site’s principal investigator or delegated authorized site staff, and only when 
the knowledge of the treatment assignment is deemed essential for the subject´s care. 
For emergency situations, an unblinding function will be available via the Interactive Web 
Response System.  
The investigator should immediately inform the study monitor that a treatment code has 
been opened. 
The blinding may be broken for expedited reporting purposes in the case of a Suspected 
Unexpected Serious Adverse Reaction (SUSAR). Expectedness will be determined by 
establishing whether the AE is among those identified in the ITFE-2092 Investigator’s 
Brochure 
The randomization codes will be unblinded and made available for the project statistician 
to perform the data analysis when the study has been finalized, the database has been 
verified, and all protocol violations have been determined. All personnel involved directly 
in the study shall be unaware of the treatment assigned to the subjects until the database 
has been closed. 
5.8 Treatment Compliance 
Subjects must bring unused study drug and applicators with them to the Week 3, Week 8, 
and Week 12 study visits. Used applicators will be discarded by the subjects as normal 
household waste. 
Treatment compliance will be evaluated by the investigator’s team at Weeks 3, 8, and 12 
by reviewing study drug and returned supplies (non-used applicators), supported by subject 
reporting. 


ITF Research Pharma SLU 
Estriol Vaginal Gel 
Protocol: ITFE-2092-C1, v5.0 
07Jun2017 
 
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5.9 Prior and Concomitant Therapy 
Use of all concomitant medications will be recorded in the subject’s eCRF. The minimum 
requirement is that the drug name and the dates of administration are to be recorded. This 
will include all prescription drugs, herbal products, and over-the-counter (OTC) 
medications from 28 days prior to the start of study drug and up to 30 days (±5 days) 
following the last dose of investigational product; the reason for the drug administration 
must be recorded in the eCRF. Any changes in concomitant medications also will be 
recorded in the subject’s eCRF. 
Record the name, start date (if known), indication for use, and whether ongoing or 
discontinued for all medications/treatments. 
The concomitant use of another drug with estrogens, progestins, androgen derivatives, 
SERMs, as well as phytoestrogen-based and cosmetics products expected to have an 
impact on vaginal pH such as special feminine wash gels is prohibited during the study. 
In vitro and in vivo studies have shown that estrogens are metabolized partially by 
cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect 
estrogen drug metabolism. Inducers of CYP3A4 such as St. John’s Wort preparations 
(Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma 
concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or 
changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, 
clarithromycin, ketoconazole, itraconazole, and ritonavir may increase plasma 
concentrations of estrogens and may result in side effects. As noted in Section 4.1.2, 
concomitant use of these medications is prohibited. 
Any concomitant medication deemed necessary for the welfare of the subject during the 
study may be given at the discretion of the investigator. However, it is the responsibility of 
the investigator to ensure that details regarding the medication are recorded in full in the 
eCRF. 


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Protocol: ITFE-2092-C1, v5.0 
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6 Study Assessments and Procedures 
Before performing any study procedures, all potential subjects will sign an informed 
consent form (ICF). Subjects will have the opportunity to have any questions answered 
before signing the ICF. The investigator must address all questions raised by the subject. 
The investigator will also sign the ICF. A subject number will be assigned to each subject.  
The following assessments and measurements will be carried out at the times specified in 
the study flow chart. A summary of the schedule of events is provided in Table 1.   
The time at which study procedures are conducted should follow the protocol timelines as 
closely as possible. However, it is recognized in a clinical setting that protocol-specified 
timings may not occur exactly as specified in the protocol. Provided that activities are 
carried out within the time windows outlined in the Schedule of Events (Table 1), it will 
not be necessary to file a protocol deviation for activities outside the nominal time defined 
in the protocol. 
6.1 Study Visits 
6.1.1 Screening Visit 
Screening is defined as the period prior to the administration of study drug. In this study, 
screening will cover a maximum period of 30 days before the baseline visit on the day of 
randomization. 
A subject will enter the screening period if basic study criteria are matched with the 
potential participant’s medical condition and profile. If the subject appears to meet these 
basic study criteria, they will be offered the opportunity to participate in the study. In case 
of agreement to participate, the subject will be requested to sign an ICF. A subject who 
agrees to participate and signs the ICF is to be given a copy of the fully signed consent 
signed by herself and the investigator or designee. 
During the Screening Visit, the investigator or designee will obtain/perform the following: 
 Investigator to register subject in IWRS and obtain the subject number. 
 Record demographic details (date of birth, race); 


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 Record recent (within the past year) and relevant gynecological, medical, and 
surgical history and any chronic or ongoing medical conditions for which the 
subject received or is receiving medical treatment; 
 Record use of prohibited medications during the periods defined in the exclusion 
criteria (see Appendix 12.3 and Appendix 12.4). 
 Record concomitant medications taken, including the 4 weeks prior to study entry. 
 Perform a general physical examination (height, weight) including seated for at 
least 5 minutes blood pressure, heart rate. Note any abnormal physical examination 
findings; 
 Perform 12-lead electrocardiogram (ECG). Two ECG exams will be performed, 
approximately 5 minutes apart one from the other.    
 Perform gynecological examination including a visual inspection of the external 
genitalia, speculum examination of the vagina and cervix, collection of a 
Papanicolau smear, as well as bimanual palpation of the uterus and ovaries (if 
present), and breast palpation. Any abnormalities that could interfere with study 
procedures or assessments should be recorded. At all post-screening visits, the 
investigator should report any clinically significant changes from baseline. 
 Perform mammogram if documented negative mammogram within 9 months prior 
to randomization is not available.  
 Record presence and intensity of the symptom vaginal dryness; obtain vaginal 
smear for evaluation of vaginal cytology; test vaginal pH; 
 If the woman has a uterus, perform transvaginal ultrasound to determine 
endometrial thickness and identify any gynecological abnormalities that would 
interfere with administration of the study drug, study procedures or results; 
 If the woman has an intact uterus, an endometrial biopsy will be performed; 
 Safety laboratory parameters (biochemistry and hematology, including coagulation 
and lipids, urinalysis) and serum hormone levels. These analysis should be 
performed under fasting conditions  
 Report adverse events 
The investigator or other qualified designee is to review information obtained to ensure 
subject meets all of the inclusion and none of the exclusion criteria for all measurements 
studied in the Screening Visit. 


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Before the Baseline Visit, the investigator will confirm that the subject meets all the 
inclusion and exclusion criteria, including the endometrial histological assessment.  
Subjects with signs and symptoms suggestive of infection of the genital or urinary tract 
requiring treatment at the start of the study will be excluded. However, once treated and 
symptoms have resolved (or there are negative microbiology findings), subjects can be re-
screened into the study.  Refer to section 4.2.3 for more details. 
6.1.2 Baseline Visit 
This visit will be performed on Day 1. The following procedures will be performed:  
 Randomization:  the investigator should randomize the subject through IWRS in 
which a randomization code and study drug kits will be allocated  
 Gynecological examination including evaluation of symptoms and signs of 
vulvovaginal atrophy other than vaginal dryness  
 Recording of adverse events since Screening Visit 
 Recording of concomitant medications 
 Administration of first dose of study drug by the investigator or by the subject in 
presence of the investigator Dispensing of dosing instructions and adequate 
medication supplies for 3 weeks (three medication kits) 
6.1.3 Week 3 Visit 
This visit will be scheduled on the day after having completed 21 days of treatment. For 
organizational reasons, a deviation of 3 days before or after the scheduled date is allowed, 
with the investigator attempting to schedule the visit as close as possible to the estimated 
ideal date. 
The following procedures will be performed: 
 Evaluation of symptoms and signs of vaginal atrophy, including vaginal dryness. 
 Determination of vaginal pH 
 Vaginal smear for evaluation of vaginal cytology 
 Recording of adverse events  
 Recording of concomitant medications 


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 Reconciliation of returned medication 
 Dispensing adequate medication supplies via IWRS through the Week 8 Visit (two 
medication kits) 
6.1.4 Week 8 Visit 
This visit will be scheduled on the day after having completed the end of 8 weeks of study 
participation. For organizational reasons, a deviation of 5 days before or after the 
scheduled visit date is allowed, with the investigator attempting to schedule the visit as 
close as possible to the estimated ideal date. 
The following procedures will be performed: 
 Recording of adverse events 
 Recording of concomitant medications 
 Reconciliation of returned medication  
 Dispensing adequate medication supplies via IWRS through the Week 12 Visit (two 
medication kits) 
6.1.5 Week 12 Visit/Early Termination Visit 
This visit will be scheduled on the day after having completed Week 12 of the study or if 
the subject terminates study participation before Week 12. For organizational reasons, a 
deviation of 5 days before or after the estimated ideal date is allowed, with the investigator 
attempting to schedule the visit as close as possible to the estimated ideal date.  
If a subject is discontinued/withdrawn the investigator should register the subject status as 
such in IWRS. 
The following procedures will be performed:   
 Evaluation of symptoms and signs of vaginal atrophy, including vaginal dryness 
 Determination of vaginal pH 
 Vaginal smear for evaluation of vaginal cytology 
 Evaluation of global efficacy 
 Evaluation of acceptability 
 Transvaginal ultrasound in women with a uterus 


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 Perform an endometrial biopsy in women with a uterus 
 Safety laboratory parameters (biochemistry and hematology, including coagulation 
and lipids, urinalysis) and serum hormone levels. These analyses should be 
performed under fasting conditions.  
 Recording of adverse events 
 Measurement of vital signs (blood pressure, heart rate, weight) 
 Perform physical examination  
 Perform 12-lead electrocardiogram. Two ECG exams will be performed, 
approximately 5 minutes apart one from the other.    
 Perform gynecological examination including a visual inspection of the external 
genitalia, speculum examination of the vagina and cervix, bimanual palpation of 
the uterus and ovaries (if present), and breast palpation. 
 Recording of concomitant medications 
 Reconciliation of returned medication 
6.1.6 Week 16 – End-of-Study Phone Call 
All subjects who completed the full 12 weeks of study drug will have a phone call 
scheduled for 4 weeks after last medication dose to record any AEs that may have appeared 
after treatment discontinuation, and to document changes in concomitant medication use. 
For organizational reasons, a deviation of 5 days before or after the estimated date will be 
allowed. 
When a subject has completed the study the investigator should register the subject 
completed in IWRS.  
6.2 Efficacy Assessments 
The main efficacy variables in this study are: change in the proportion of superficial and 
parabasal cells of the vaginal epithelium; change in vaginal pH; and change in the severity 
of vaginal dryness. 
Secondary efficacy variables are: change in the severity of individual vaginal symptoms 
and signs of vaginal atrophy (other than vaginal dryness); and change in the Global 
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The exploratory efficacy variables include evaluation of the final subjective global 
perception of efficacy by subjects at the end of study and evaluation of acceptability of the 
therapy at Week 12. 
The minimally effective dose of estriol vaginal gel will be determined based on using the 
gatekeeping procedure outlined in Section 7.8.1.1, the minimal effective dose will 
therefore be the lowest dose at which a significant difference is seen when compared with 
placebo.  
The gynecological procedures and evaluations to be performed for the assessment of the 
efficacy variables include the vaginal cytology, determination of the vaginal pH, evaluation 
of the different vaginal signs and symptoms, determination of the Global Symptom Score, 
and the evaluation of the global impression of efficacy. 
6.2.1. Vaginal Cytology 
Vaginal smears will be performed to evaluate the maturation index of the vaginal mucosa 
at Screening Visit and at the Week 3 and Week 12/Early Termination visits.  
Two vaginal smears should be collected per subject, from the bottom of the right and left 
vaginal walls respectively. The vaginal cytological samples will be fixed whilst they are 
still moist with a water-soluble fixation spray for cytodiagnosis. 
The vaginal cytological samples will be sent to the centralized laboratory for analysis. One 
sample is to be sent to the central laboratory for analysis, with the second sample retained 
at the site with no requirement of specific environmental storage conditions. Samples will 
be evaluated by two different cytopathologists who will be blinded as to subject treatment 
assignment. The back-up sample will be evaluated only in the event that the initial samples 
are invalid or have suffered any type of incident such as breakage or loss. 
For the cytologic evaluation, the number of parabasal, intermediate, and superficial cells 
will be calculated. The percentages of each type of cells will be calculated. 
6.2.2 Vaginal pH Determination 
For pH determination, a reactive pH strip will be used. On each occasion, the investigator 
will insert the strip into the vagina and moisten it as much as possible with the vaginal wall 


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secretions. Once adequate wetting has been achieved, the colors on the strip will be 
checked against a standard pH scale (provided by the manufacturer) to determine the pH 
value. The reading should be made while the strip is still moist. The strips will be 
discarded appropriately once the pH has been recorded. 
Vaginal pH determination will be performed at Screening Visit, at the Week 3 Visit, and at 
the Week 12/Early Termination Visit. 
6.2.3 Evaluation of Vaginal Symptoms and Signs 
6.2.3.1 Evaluation of Symptoms 
At study visits the investigators will interview the subjects on the presence and intensity of 
the symptoms of vulvovaginal atrophy they have. Study subjects will self-assess their 
symptoms and report their assessments  to the investigators to be 
recorded. . 
The symptoms evaluated in this study include vaginal dryness, pruritus or itching, burning, 
dyspareunia, and dysuria. 
Each symptom will be scored by the subject using a numeric scale from 0 to 3, as shown 
below: 
0 - Absent:      The symptom is not present. 
1 - Mild:  
The symptom is of mild intensity,  
2 - Moderate:   The symptom is of moderate intensity 
3 - Severe:      The symptom is severe in intensity. 
The presence and intensity of vaginal symptoms of vulvovaginal atrophy will be assessed 
at the following visits: Screening (vaginal dryness only); Baseline (pruritus or itching, 
burning, dyspareunia, and dysuria); Week 3 (all 5 symptoms: vaginal dryness, pruritus or 
itching, burning, dyspareunia, and dysuria); and Week 12/Early Termination (all 5 
symptoms: vaginal dryness, pruritus or itching, burning, dyspareunia, and dysuria). 
Specific to the evaluation of dyspareunia, women will be also asked if they have had 
sexual activity with penetration during the study period. 


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6.2.3.2 Evaluation of Signs 
The presence and severity of most typical signs of vulvovaginal atrophy will be recorded 
according to the visual inspection of the vagina as performed by the investigator. 
The signs evaluated in this study include vaginal mucosa with flattening of folds or 
thinning, dryness of the mucosa, pallor of the mucosa, friability of the mucosa, and 
presence of petechiae. 
Each one of these signs will be scored by the investigator on a numerical Liekert scale as 
follows: 
0 – Absent:     The sign is not present. 
1 – Mild:         The sign is present and is considered a mild alteration. 
2 – Moderate: The sign is present and is considered a moderate alteration. 
3 – Severe:      The sign is present and is considered a severe alteration. 
The presence and intensity of all these 5 signs of vulvovaginal atrophy will be assessed at 
the Baseline Visit, the Week 3 Visit, and at the Week 12/Early Termination Visit. 
6.2.3.3 Evaluation of Global Symptom Score 
A Global Symptom Score will be obtained by summing the numerical scores of all 
symptoms at different time points: Screening/Baseline, Week 3 and Week 12/Early 
termination visit. Thus, the Global Symptom Score will range at Screening/Baseline 
between 2 (at least moderate vaginal dryness as the only symptom) to 15 (all five studied 
symptoms severe in intensity). At Weeks 3 and Week 12/Early Termination visits the 
Global Symptom Score can range between 0 (no symptoms) and 15 (all symptoms severe 
in intensity). The Global Symptom Score will be evaluated when all 5 individual 
symptoms scores are available at a given time point. 
6.2.4 Evaluation of Global Efficacy 
At the Week 12/Early Withdrawal Visit, the subject will be interviewed by the investigator 
on her perception of the global efficacy of the therapy received over the completed study 
period. Global efficacy is defined as the subject’s perception of the effect of the treatment 
on her vaginal-related symptomatology. 


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The subject will be asked to rate the global efficacy of the treatment as:  highly efficacious, 
efficacious, non-efficacious, or detrimental.  
6.3 Safety Assessments 
6.3.1 Clinical Laboratory Assessments 
At the Screening and Week 12/Early Termination Visits, blood and urine specimens will be 
collected under fasting conditions for the following measurements:  
 Hematology: Standard hematology panel plus prothrombin time, activated 
thromboplastin partial time, fibrinogen, and antithrombin III/protein C/protein S. 
Factor V Leiden will be performed at either screening visit or week 12/ET visit if 
not previously obtained at screening. 
 Blood chemistry: Standard chemistry panel including albumin, alanine 
aminotransferase, aspartate aminotransferase, creatine phosphokinase, bilirubin, 
creatinine, total protein, uric acid, blood urea nitrogen, glucose, and lipids 
(cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides) 
 Hormones: Estradiol, estriol, estrone, follicle-stimulating hormone (FSH), and 
luteinizing hormone (LH) 
 Urinalysis: Standard urinalysis including testing for presence of blood, glucose, 
ketones, and protein, with microbiological analysis 
A laboratory manual will be provided to each site, detailing procedures for sample 
collection, storage, and shipment. Samples will be destroyed at the end of the study.  
6.3.2 Transvaginal Ultrasound 
Transvaginal ultrasound (TVU) will be performed by the investigator, sub-investigator or 
designated trained member of the staff at the Screening Visit to determine whether there 
are any abnormalities of the ovaries, whether the uterus and cervix are present, and 
whether there are any physical issues that would exclude the subject from participation in 
the study. In addition, TVU will be performed to measure endometrial thickness and to 
investigate the presence of any abnormal morphological findings. Follow-up TVU will be 


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conducted during the Week 12/Early Termination Visit, and any clinically significant 
changes from baseline will be noted.   
6.3.3 Endometrial Biopsy 
Endometrial biopsy will be performed per the provided standard collection method. 
Samples are to be fixed and stored using directions supplied by the centralized laboratory. 
The investigator shall do his/her best to obtain endometrial tissue for analysis. The 
Investigator must record whether tissue was obtained, and send the tissue obtained to the 
centralized laboratory to be processed.  
At the centralized laboratory, a single pathologist will assess the slides from the 
endometrial biopsies obtained at Screening (per the standardized criteria for determining 
hyperplasia, as detailed in Blaustein’s Pathology of the Female Genital Tract (Kurman 
RJ, 2011) as well as any biopsies obtained if a subject experiences vaginal bleeding while 
on study drug. Three independent pathologists (from different institutions with independent 
fiduciary and organizational reporting), blinded to subject’s treatment group and to each 
other’s readings, will assess the endometrial biopsies obtained at the Week 12/Early 
Termination Visit. The concurrence of two of the three pathologists will be accepted 
as the final diagnosis. If there is no agreement among the three pathologists, the most 
severe pathologic diagnosis (i.e., atypical hyperplasia > complex hyperplasia > simple 
hyperplasia > benign endometrium) would be used as the final diagnosis. If hyperplasia is 
diagnosed by the single safety reader for a subject who has bled while on study drug, this 
diagnosis be maintained for the efficacy evaluation and the slides become part of the slide 
set given to the two other pathologists for reading. 
Per the draft FDA guidance on estrogen and estrogen/progestin drug products to treat 
vasomotor symptoms and vulvar and vaginal atrophy symptoms (US Dept. Health and 
Human Services, 2003), the set of slides distributed to each of these pathologists for the 
end-of-study pathology review will incorporate control slides representing a randomly 
selected 10% of the screening normal slides and all slides from subjects excluded for the 
diagnosis of hyperplasia or cancer to insure quality control. 


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6.3.4 Adverse Events 
6.3.4.1 Definitions of Adverse Events 
The investigator is responsible for reporting all adverse events (AEs) that are observed or 
reported during the study, regardless of their relationship to study drug or their clinical 
significance. 
An AE is defined as any untoward medical occurrence in a subject enrolled into this study 
regardless of its causal relationship to study drug. An AE can, therefore, be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporarily associated with the use of a medicinal (investigational) 
product, whether or not considered related to the medicinal (investigational) product. 
Subjects will be instructed to contact the investigator at any time, after the subject gives 
informed consent until the end of study, if any symptoms develop. 
Note that, for the purpose of this protocol, the following circumstances – with or without 
associated adverse event/reaction - should be included the eCRF: 
 Overdose, abuse, misuse 
 Off-label use 
 Medication error 
A treatment-emergent AE (TEAE) is defined as any event not present before exposure to 
study drug or any event already present that worsens in either intensity or frequency after 
exposure to study drug. 
A serious AE (SAE) is defined as any event that: 
 Results in death; 
 Is immediately life-threatening; 
 Requires inpatient hospitalization or prolongation of existing hospitalization; 
 Results in persistent or significant disability/incapacity; or 
 Is a congenital anomaly/birth defect 


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 Is a medically significant event 
Medically significant events are defined as important medical events that may not result 
in death, be life-threatening, or require hospitalization but may be considered SAEs when, 
based upon appropriate medical judgment, they may jeopardize the subject or may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
Disability is defined as a substantial disruption of a person’s ability to conduct normal life 
functions. 
A life-threatening adverse event is one that places the subject, in the view of the 
investigator, at immediate risk of death from the event as it occurred. It does not include an 
event that, had it occurred in a more severe form, might have caused death. 
An unexpected adverse event is any adverse drug event, the nature, specificity or severity 
of which is not consistent with the applicable product information (e.g. Investigator’s 
brochure for an unauthorized investigational product or summary of product characteristics 
for an authorized product). 
Enter only one event as the reason for the SAE on the SAE form. Other non-serious events 
which did not directly result in the SAE should be detailed in the description section on the 
SAE form and listed separately as AEs if necessary. 
ANY SERIOUS ADVERSE EVENT MUST BE REPORTED IMMEDIATELY (WITHIN 
24 HOURS) BY THE STUDY SITE VIA EMAIL OR FAX TO 
 
 PHARMACOVIGILANCE GROUP USING THE SAE FORM PROVIDED. 
ENTER THE SUBJECT’S AVAILABLE INFORMATION INTO THE eCRF WITHIN 48 
HOURS. 
A SAE occurring during the study must be reported to the 
 
Pharmacovigilance Group.  Any such SAE due to any cause, whether or not related to the 
study drug, must be reported within 24 hours of occurrence or when the Investigator 
becomes aware of the event. SAEs occurring more than 4 weeks of stopping the treatment 


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and considered related to the study drug will be communicated. Notification can be made 
with the SAE reporting form by using the dedicated fax line or by scanning and emailing 
to the safety mailbox for the 
Pharmacovigilance Group: 
Pharmacovigilance Fax Number: 
 
Pharmacovigilance Email:  
 
The event must also be recorded on the standard AE eCRF.  Preliminary reports of SAEs 
must be followed by detailed descriptions later on, including clear and anonymized 
photocopies of hospital case reports, consultant reports, autopsy reports, and other 
documents when requested and applicable.  SAE reports must be made whether or not the 
Investigator considers the event to be related to the investigational drug. 
Appropriate remedial measures should be taken to treat the SAE, and the response should 
be recorded.  Clinical, laboratory, and diagnostic measures should be employed as needed 
in order to determine the etiology of the problem. The Investigator must report all 
additional follow-up SAE information to the 
 Pharmacovigilance 
Group within 24 hours of awareness of the information. All SAEs will be followed until 
the Investigator and Sponsor agree the event is satisfactorily resolved. 
Any SAE that is not resolved by the end of the study or upon discontinuation of the 
subject’s participation in the study is to be followed until it either resolves, stabilizes, 
returns to baseline values (if a baseline value is available), or is shown to not be 
attributable to the study drug or procedures. 
Reports relating to the subject’s subsequent medical course following a SAE must be 
submitted to 
until the event has subsided or, in case of permanent 
impairment, it stabilizes and the overall clinical outcome has been ascertained. 
All SAEs will be reported to the institutional review board (IRB)/independent ethics 
committee (IEC) periodically for SAEs that meet reporting guidelines or at a frequency 
determined by the IRB/IEC, at the end of the study, or per local institutional guidelines. 
All suspected unexpected serious adverse reactions (SUSARs) will be reported in an 
expedited manner to 
per the ICH Guideline for GCP and IRB/IEC 


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by the investigators and to all relevant regulatory authorities 
. A 
SUSAR is a SAE that is both related to the study drug (Relationship = Related) and 
unexpected (not previously described in the Investigator’s Brochure). Expectedness will be 
judged by the Sponsor’s medical monitor. It is therefore essential that all SAEs are 
reported within the 24-hour guideline so that the expectedness determination can be made. 
All SUSARs require immediate attention and expedited reporting to relevant regulatory 
authorities. 
is to ensure that all relevant information about fatal or life 
threatening SUSARs are appropriately recorded and reported to the concerned Regulatory 
Authority and to the concerned IRB(s)/IEC(s) within 7 calendar days of the date of first 
report 
 Follow-up information is to be subsequently 
communicated to the relevant Regulatory Authority within an additional 8 calendar days. 
All other SUSARs are to be reported to the Regulatory Authority and to the IRB(s)/IEC(s) 
concerned as soon as possible within a maximum of 15 calendar days of first knowledge 
by 
. 
The medical monitor/Sponsor or designee must also inform all investigators studying the 
investigational medicinal product about SUSARs and ensure that IRBs/IECs have been 
notified. 
For reported death of a subject, the investigator shall supply the Sponsor, 
 
nd/or the IRB(s)/IEC(s) with additional information requested on an expedited 
basis.   
The following events are not considered SAEs: 
 A visit to the emergency room or other hospital department lasting less than 
24 hours that does not result in admission (unless considered an “important medical 
event” or a life-threatening event). 
 Elective surgery planned before signing consent. 
 Hospitalization which is due solely to a planned study visit and without 
prolongation. 
 Routine health assessment requiring admission for baseline/trending health status 
(e.g., routine colonoscopy). 


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 Medical/surgical admission for purpose other than remedying ill health state that 
was planned before study entry. Appropriate documentation is required in these 
cases. 
 Admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (e.g., lack of housing, 
economic inadequacy, caregiver respite, family circumstances, administrative 
reasons). 
 An overnight stay in the hospital that is only due to transportation, organization, or 
accommodation problems and without medical background.  
 
These events will be reported in the eCRF and in the subject record. 
6.3.4.2 Eliciting and Documenting Adverse Events 
Adverse events will be assessed from the time the subject signs the informed consent form 
until exit from the study. 
Events that occur prior to signing the informed consent form will be entered as medical 
history; AEs that have an onset after signing the informed consent will be entered on the 
AE form. 
Subjects will be questioned and observed for evidence of AEs, whether or not related to 
study drug. For any pre-existing condition or abnormal laboratory finding that changes in 
severity after dosing, the change should be recorded as an AE. New abnormal laboratory 
findings that are considered clinically significant by the investigator are considered AEs. 
All AEs will be collected through the Follow-up Visit (i.e. the Week 16 phone call, 4 weeks 
after discontinuation of study drug). Adverse event details are to be documented, including 
start and stop dates, whether continuous or intermittent, severity, any intervention utilized 
to correct the event, outcome of the event, and the relationship to the study drug.   
All AEs determined by the investigator to be related to study drug must be followed until 
resolution, until they are considered stable, or for at least 30 days after discontinuation of 
study drug, whichever occurs first.   


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Adverse events should be classified following the Medical Dictionary for Regulatory 
Activities (MedDRA). Safety/PV will use the MedDRA medical dictionary to map the 
AE/SAE verbatim terms to specific system organ classes (SOC) and preferred terms. 
Note that, for the purpose of this protocol, the following circumstances (with or without 
associated adverse event/reaction) should be included in the data base and will be 
submitted to the Sponsor, being managed in the same way and time as adverse 
events/reactions:  any overdose (with or without associated AEs), abuse, misuse, off-label 
use, or medication error. 
The causal relation between the investigational product and the AE will be assessed by the 
investigator using the following assessment criteria:  
UNRELATED: This category applies to those AEs that are clearly and incontrovertibly due to extraneous 
causes (disease, environment, etc). 
UNLIKELY:    This category applies to those AEs that are judged to be unrelated to the study drug, but for 
which no extraneous cause may be found.  An AE may be considered unlikely to be related to study drug if 
or when it meets 2 of the following criteria:  (1) it does not follow a reasonable temporal sequence from 
administration of the study drug; (2) it could readily have been produced by the patient’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the patient; (3) it does not follow a 
known pattern of response to the study drug; or (4) it does not reappear or worsen when the drug is 
re-administered. 
POSSIBLY: This category applies to those AEs for which a connection with the study drug administration 
appears unlikely but cannot be ruled out with certainty.  An AE may be considered possibly related if or 
when it meets 2 of the following criteria: (1) it follows a reasonable temporal sequence from administration 
of the drug; (2) it could not readily have been produced by the patient’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient; or (3) it follows a known pattern of response to 
the study drug. 
PROBABLY: This category applies to those AEs that the investigator feels with a high degree of certainty 
are related to the study drug.  An AE may be considered probably related if or when it meets 3 of the 
following criteria: (1) it follows a reasonable temporal sequence from administration of the drug; (2) it could 
not be reasonably explained by the known characteristics of the patient’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the patient; (3) it disappears or decreases on 
cessation or reduction in dose (note that there are exceptions when an AE does not disappear upon 
discontinuation of the drug, yet drug-relatedness clearly exists; for example, as in bone marrow depression, 
fixed drug eruptions, or tardive dyskinesia); or (4) it follows a known pattern of response to the study drug. 
DEFINITELY: This category applies to those AEs that the investigator feels are incontrovertibly related to 
study drug.  An AE may be assigned an attribution of definitely related if or when it meets all of the 
following criteria: (1) it follows a reasonable temporal sequence from administration of the drug; (2) it could 
not be reasonably explained by the known characteristics of the patient’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the patient; (3) it disappears or decreases on 
cessation or reduction in dose and recurs with re-exposure to drug (if rechallenge occurs); and (4) it follows a 
known pattern of response to the study drug. 
 


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Possibly, probably and definitely will fit the characterization of “related AE.” Unlikely and 
unrelated will fit the characterization of “not related AE.”  
6.3.4.3 Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page in the 
eCRF. Information to be collected includes subject code, age, site, drug treatment and dose 
(if available), event term, time of onset, investigator-specified assessment of severity and 
relationship to study drug, time of resolution of the event, seriousness, any required 
treatment or evaluations, outcome, improvement of the AE after suspension/withdrawal of 
study drug, time of study (at screening, during treatment, or at follow-up) and action taken 
with the study drug. Adverse events resulting from concurrent illnesses, reactions to 
concurrent illnesses, reactions to concurrent medications, or progression of disease states 
must also be reported. All AEs will be followed to adequate resolution. MedDRA will be 
used to code all AEs.  
Any medical condition that is present at the time that the subject is screened but does not 
deteriorate should not be reported as an AE. However, if it deteriorates at any time during 
the study, it should be recorded as an AE. 
Any AE that meets SAE criteria (Section 6.3.4.1) must be reported to 
 
immediately (i.e., within 24 hours) after the time site personnel first learn about 
the event. The contact information in Section 6.3.4.1 is to be used for SAE reporting. 
6.3.4.4 Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the subject’s 
daily activities. The intensity of the AE will be rated as mild, moderate, or severe using the 
following criteria:  
MILD: An event that is easily tolerated by the patient, causing minimal discomfort and not interfering with 
everyday activities. 
MODERATE: An event that is sufficiently discomforting to interfere with normal everyday activities. 
SEVERE: An event that considerably restricts or prevents normal everyday activities. 
 
Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed. Adverse events 


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characterized as intermittent do not require documentation of onset and duration of each 
episode. 
6.3.4.5 Assessment of Causality 
The investigator’s assessment of an AE’s relationship to study drug is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the 
study. If there is any doubt as to whether a clinical observation is an AE, the event should 
be reported. The relationship or association of the test article in causing or contributing to 
the AE will be characterized using the following classification and criteria:  
Not Related AEs = those with no relationship with the study drug; other factor(s) 
(including subject’s clinical state or other therapy administered) may be causative.  
Related AEs = those with a reasonable possibility that the event was caused by the study 
drug (i.e. a time relationship exists, the AE is a known effect of the study drug or class of 
drugs, or the AE resolves/abates upon discontinuation of study drug), and other possible 
causative factor(s) may exist. 
6.3.4.6 Follow-Up of Subjects Reporting Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the investigator deems the event to be chronic or not clinically 
significant, or until the subject is considered to be stable. 
6.4  Evaluation of Acceptability 
At the Week 12/Early Termination Visit, the subject will be asked to rate the acceptability 
of the therapy received over the completed study period. The acceptability is defined as the 
subject`s perceptions of the ease in the method of administration and cleanliness of the 
product. The subject will be asked to rate the acceptability of the therapy as: excellent, 
good, acceptable, or unacceptable. 
6.5 Laboratory Analyses 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis, as 
described in Section 6.3.1), including those that worsen from baseline, felt to be clinically 


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significant in the medical and scientific judgment of the investigator are to be recorded as 
AEs or SAEs. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs. 
6.6 
Sample Collections 
Procedures for sample collection, storage, and shipping for analysis are provided in the 
study site laboratory manuals. 
Samples obtained for clinical laboratory assessments will be destroyed at the end of the 
study. The remaining biopsy and smear samples will be stored 
 
 
 
 
 
 


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7 Statistical and Analytical Plan 
A detailed statistical analysis plan will be prepared prior to completing the database and 
unblinding the study. Summaries for quantitative variables will include the mean, median, 
quartiles, standard deviation or standard error, minimum, and maximum. For qualitative 
variables, the summaries will include the number and percentage of subjects for each 
outcome. Statistical significance will be declared if the one-sided p-value is ≤ 0.025. All 
computations will be performed using SAS® 
 
The analysis of the 12-week double-blind study will be conducted when all data for all 
subjects have been entered, cleaned and locked. 
7.1 Primary Efficacy Endpoints 
The 4 co-primary efficacy endpoints in this study are:  
 change from Baseline to Week 12 in the severity of vaginal dryness;  
 change from Baseline to Week 12 in vaginal pH;  
 change from Baseline to Week 12 in the proportion of parabasal cells of the vaginal 
epithelium;  
 and change from Baseline to Week 12 in the proportion of superficial cells of the 
vaginal epithelium.  
7.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints in this study are:  
 change from Baseline to Week 12 in the severity of individual vaginal symptoms 
including dyspareunia, pruritus, burning and dysuria; 
 change from Baseline to Week 12 in the Global Symptom Score 
 change from Baseline to Week 12 in the severity of individual vaginal signs 
including pallor, friability, thinning or flattening of folds, petechiae and dry 
mucosa; 


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 change from Baseline to Week 3 in the proportion of superficial cells of the vaginal 
epithelium; 
 change from Baseline to Week 3 in the proportion of parabasal cells of the vaginal 
epithelium; 
 change from Baseline to Week 3 in the severity of vaginal dryness; 
 change from Baseline to Week 3 in vaginal pH; 
 change from Baseline to Week 3 in the severity of individual vaginal symptoms 
including dyspareunia, pruritus, burning and dysuria; 
 change from Baseline to Week 3 in the severity of individual vaginal signs 
including pallor, friability, thinning or flattening of folds, petechiae and dry 
mucosa; 
 change from Baseline to Week 3 in the Global Symptom Score. 
7.3 Exploratory Efficacy Endpoints 
The following exploratory endpoints will be analyzed: 
 evaluation of the final subjective global perception of efficacy at Week 12; 
 evaluation of the acceptability of the therapy at Week 12. 
7.4 Safety Endpoints 
The following safety variables will be analyzed: 
 laboratory parameters  
o biochemistry, hematology and urinalysis at Week 12;  
o serum lipids, and coagulation parameters at Week 12;  
o change from Baseline in hormone levels (estradiol, estrone, estriol, FSH, 
LH); 


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 change from Baseline in uterine evaluation by transvaginal ultrasound at Week 12 
for women with an intact uterus;  
 change from Baseline in endometrial histology at Week 12 for women with an 
intact uterus;  
 frequency and severity of AEs; 
 change from Baseline in ECG QTc 
7.5 Sample Size Calculations 
A total of 280 female subjects will be enrolled in the study. 
The estimates of treatment differences and variability were gained from the results of 
Study ITFE-2026-C2. 
A sample size of 57 in each group will have 90% power to detect a treatment difference for 
change in severity of vaginal dryness, assuming 5 categories with proportions in each 
treatment group as shown in the table below, using a Wilcoxon rank sum test with a 0.025 
one-sided significance level. 
Table 2 Assumed Proportions for Wilcoxon Rank Sum Test of Vaginal Dryness 
Change in Vaginal Dryness 
Severity 
Proportion in Estriol Vaginal 
Gel Group 
Proportion in Placebo Group 
-3 
0.189 
0.118 
-2 
0.423 
0.196 
-1 
0.270 
0.353 
0 
0.118 
0.333 
1 
0 
0 
 
A sample size of 48 in each group will have 90% power to detect a treatment difference of 
-0.89 for change in vaginal pH, assuming a common standard deviation of 1.33 using a 
two-group t-test with a 0.025 one-sided significance level. 


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A sample size of 24 in each group will have 90% power to detect a treatment difference of 
21 for change in proportion of superficial cells, assuming a standard deviation of 26.3 for 
0.005% estriol vaginal gel and 14.8 for placebo vaginal gel, using a two-group 
Satterthwaite t-test with a 0.025 one-sided significance level. 
A sample size of 9 in each group will have 90% power to detect a treatment difference of -
53 for change in proportion of parabasal cells, assuming a standard deviation of 37.9 for 
0.005% estriol vaginal gel and 19.6 for placebo vaginal gel, using a two-group 
Satterthwaite t-test with a 0.025 one-sided significance level. 
The largest sample size calculated for a single co-primary endpoint has been considered 
the sample size required for the whole study, thus, 57 subjects per group are estimated. 
Accounting for an 18% drop-out rate, and rounding numbers, approximately 70 
subjects/group have been finally estimated. 
7.6 Analysis Sets 
The following analysis sets will be used in the statistical analyses: 
 The Intent-to-Treat (ITT) population is defined as all randomized subjects.  The 
ITT population will be used to present all efficacy analyses, including the 4 co-
primary efficacy endpoints. Subjects will be summarized according to the treatment 
to which they were randomized. 
 Per Protocol (PP) population is defined as all randomized subjects who completed 
the study to Week 12 with no major protocol deviations impacting the co-primary 
efficacy analyses. The major deviations impacting the analysis will be defined in 
more detail in the statistical analysis plan (SAP). The PP population will be used 
for confirmation of efficacy analyses.  Subjects will be summarized according to 
the treatment to which they were randomized. 
 The Safety population includes all randomized subjects who administered at least 
one dose of study treatment. The Safety population will be used to present all safety 
analyses. Subjects will be summarized according to the actual treatment received. 


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7.7 Description of Subgroups to be analyzed 
No subgroup analyses are planned. 
7.8 Statistical Analysis Methodology 
All computations will be performed using SAS® (Version 9.3 or later). Continuous 
variables will be summarized using the mean, the standard deviation, median, minimum 
value, and maximum value. Categorical variables will be summarized using frequency 
counts and percentages. Data will be listed in data listings. 
Details of the statistical analyses, methods, and data conventions are described in the SAP. 
7.8.1 Analysis of Primary Efficacy Endpoints 
The changes from baseline to Week 12 in vaginal dryness will be analyzed using a 
Wilcoxon Rank Sum test, controlled for country, to obtain the p-values. The Hodges-
Lehmann estimate of median difference between treatment groups (0.005% versus placebo, 
0.002% versus placebo and 0.0008% versus placebo) will also be presented with 95% 
confidence intervals. It should be noted that, since the statistical tests are one-sided, only 
one limit of each confidence interval is of particular interest for analysis. Details of 
statistics to be presented will be described in the Statistical Analysis Plan.  Missing values 
at Week 12 will be estimated using the last observation carried forward (LOCF).  Only 
post-Baseline values will be carried forward. 
The changes from baseline to Week 12 in vaginal pH, and the changes in proportions of 
parabasal and superficial cells will be analyzed using a parametric ANCOVA model.  The 
model will include fixed effects of treatment and country, and the baseline value will be 
used as a covariate.  The adjusted (least-square) mean change from baseline to Week 12 
will be presented for each treatment, along with the corresponding standard error.  The 
difference in adjusted means between treatment groups (0.005% versus placebo, 0.002% 
versus placebo and 0.0008% versus placebo) will also be presented with 95% confidence 
intervals and p-values.  It should be noted that, since the statistical tests are one-sided, only 
one limit of each confidence interval is of particular interest for analysis. Model 
assumptions will be examined and, if required, a Wilcoxon Rank Sum test as described for 
vaginal dryness will be used. Missing values will be estimated using LOCF.  Only post-
Baseline values will be carried forward. 


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No adjustment for multiplicity will be made, since statistical significance in all four co-
primary endpoints is required to declare efficacy. 
The robustness of the LOCF approach for missing data will be addressed by completing a 
sensitivity analysis. This will be an observed case analysis and will use no imputation 
methods in order to assess the robustness of the results. 
7.8.1.1 Gatekeeping Procedure 
For the co-primary endpoints a gatekeeping procedure will be employed. The 0.005% dose 
will be compared to placebo, and if this is significant at a one-sided alpha level of 0.025 
for all 4 co-primary endpoints, then the 0.002% dose versus placebo can be considered.  If 
this is also significant at a one-sided alpha level of 0.025 for all 4 co-primary endpoints, 
then the 0.0008% dose versus placebo can be considered. The following table (Table 3) 
outlines the approach to be taken.  
Table 3: Gatekeeping Procedure for Efficacy Analyses 
Test  
Endpoints  
All 
endpoints 
significant 
Result 
Next step 
0.005% versus 
placebo 
Vaginal dryness 
Vaginal pH 
Parabasal cells 
Superficial cells  
Yes 
If treatment 
difference exists at 
0.005% estriol gel, 
move to next dose 
Continue to test 
0.002% estriol 
gel versus 
placebo 
Vaginal dryness 
Vaginal pH 
Parabasal cells 
Superficial cells  
No 
Not enough 
evidence to 
conclude a 
difference exists 
with 0.005% estriol 
gel. 
Stop testing 
0.002% versus 
placebo 
Vaginal dryness 
Vaginal pH 
Parabasal cells 
Superficial cells  
Yes 
If treatment 
difference exists at 
0.002% estriol gel, 
move to next dose 
Continue to test 
0.0008% estriol 
gel versus 
placebo 
Vaginal dryness 
Vaginal pH 
Parabasal cells 
Superficial cells  
No 
Not enough 
evidence to 
conclude a 
difference exists at 
0.002% estriol gel 
Stop testing 
0.0008% versus 
placebo 
Vaginal dryness 
Vaginal pH 
Parabasal cells 
Superficial cells  
Yes 
Treatment 
difference exists at 
0.0008% estriol gel 
Stop testing 


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Test  
Endpoints  
All 
endpoints 
significant 
Result 
Next step 
Vaginal dryness 
Vaginal pH 
Parabasal cells 
Superficial cells  
No 
Not enough 
evidence to 
conclude a 
difference exists at 
0.0008% estriol gel 
Stop testing 
 
7.8.2 Analysis of Secondary Efficacy Endpoints 
The change from Baseline to Week 12 in the severity of individual vaginal symptoms 
(dyspareunia, pruritus, burning and dysuria) and signs (pallor, friability, thinning or 
flattening of folds, petechiae, and dry mucosa) will be assessed using the same Wilcoxon 
Rank Sum test as for the co-primary endpoint of vaginal dryness at Week 12.  Missing 
values will be estimated using LOCF. Only post-Baseline values will be carried forward. 
The change from Baseline to Week 12 in the Global Symptom Score will be assessed using 
the same parametric ANCOVA as for the co-primary endpoints of vaginal pH and 
proportions of parabasal and superficial cells at Week 12.  Missing values will be estimated 
using LOCF. Only post-Baseline values will be carried forward. 
The change from Baseline to Week 3 in the severity of individual vaginal symptoms 
(vaginal dryness, dyspareunia, pruritus, burning and mucosa) and signs (pallor, friability, 
thinning or flattening of folds, petechiae, and dry mucosa) will be assessed using the same 
Wilcoxon Rank Sum test as for the co-primary endpoint of vaginal dryness at Week 12.  
Missing data will not be imputed. 
The change from Baseline to Week 3 in the vaginal pH, the proportion of parabasal cells, 
the proportion of superficial cells, and the Global Symptom Score will be assessed using 
the same parametric ANCOVA as for the co-primary endpoints of vaginal pH and 
proportions of parabasal and superficial cells at Week 12.  Missing data will not be 
imputed. 
7.8.3 Analyses of Exploratory Efficacy Endpoint 
Endpoints of acceptability of therapy and final subjective global perception will be 
summarized by treatment group. 


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7.8.4 Safety Analyses 
The assessment of safety will be based on the incidence of AEs occurring during the 
12-weeks on study treatment, and changes from Baseline to Week 12 in laboratory values 
and ECG QTc determinations. Changes from Baseline to Week 12 in transvaginal 
ultrasound findings will be summarized for women with an intact uterus. Changes in 
endometrial histological evaluation at Week 12 will be summarized for women with an 
intact uterus.  
7.8.4.1 Pooling of Study Sites 
Sites will be pooled according to country for inclusion as an effect in the statistical models. 
It is recognized that the pooling of sites in this manner preserves the inclusion of all 
randomized subjects in the analysis. However, the result of pooling is a loss of the 
“individuality” of each site being pooled as well as the potential for the pooled site to be 
associated with an inflated sample size compared to sites that do not require pooling. The 
effect of this cannot be determined a priori but it is an acceptable approach for the retention 
of subjects in the analysis. 
7.8.5 Interim Analyses 
Interim analyses will not be performed. 
7.9 Data Quality Assurance 
Suitably qualified and trained clinical research personnel of the Sponsor or designee will 
visit the trial site at regular intervals during the trial for monitoring purposes and to assist 
the research staff with any queries. The eCRFs and source documentation will be available 
for review during monitoring visits to the trial site. The function of this monitoring is to 
ensure compliance with the protocol, adherence to regulatory and GCP obligations, proper 
maintenance of records including study drug accountability records, correct administration 
of study drug including storage conditions and accurate reporting of AEs. 
After data from the eCRFs have been entered onto the database, they will be reviewed and 
the data verified against the subject’s source data. Any discrepancies will be tracked by 
paper or electronically with an electronic audit trail. 


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The Sponsor or designee has an obligation to audit a proportion of study sites. A 
department other than the clinical department will undertake this obligation. Therefore the 
Sponsor, an independent auditor, or a regulatory authority may audit the trial site and trial 
documentation. These audits may take place while the trial is being conducted or up to 
several years later. 
7.9.1 Data Management 
As part of the responsibilities assumed by participating in the study, the investigator agrees 
to maintain adequate case histories for the subjects treated as part of the research under this 
protocol. The investigator agrees to maintain accurate eCRFs and source documentation as 
part of the case histories. These source documents may include laboratory reports, 
histology reports, and ultrasound findings. 
Investigative site personnel will enter subject data into Medidata Rave (eCRF). The 
analysis data sets will be a combination of these data and data from other sources (eg, 
laboratory data). 
Clinical data management will be performed in accordance with applicable 
 
standards and data cleaning procedures to ensure the integrity of the data, eg, 
removing errors and inconsistencies in the data. Adverse events and concomitant 
medication terms will be coded using the MedDRA. 


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8 Ethics 
8.1 Independent Ethics Committee or Institutional Review Board 
Federal regulations and the International Conference on Harmonisation (ICH) guidelines 
require that approval be obtained from an IRB/IEC before participation of human subjects 
in research studies. Before study onset, the protocol, informed consent, advertisements to 
be used for the recruitment of study subjects, and any other written information regarding 
this study to be provided to the subject or the subject’s legal guardian must be approved by 
the IRB/IEC. Documentation of all IRB/IEC approvals and of the IRB/IEC compliance 
with ICH Harmonised Tripartite Guideline E6 (R1/R2): Good Clinical Practice (GCP) will 
be maintained by the site and will be available for review by the Sponsor or its designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must 
identify the IRB/IEC name and address, the clinical protocol by title or protocol number or 
both, and the date approval or a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status 
of the study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The 
investigator must promptly supply the Sponsor or its designee, the IRB/IEC, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to subjects. 
8.2 Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin 
in the Declaration of Helsinki (Section 12.1), ICH Guideline for GCP E6 (R1/R2), and all 
applicable regulations. 
8.3 Subject Information and Consent 
A written informed consent in compliance with ICH Guideline for GCP E6 (R1/R2) and 
US Title 21 Code of Federal Regulations (CFR) Part 50 shall be obtained from each 
subject before entering the study or performing any unusual or non-routine procedure that 
involves risk to the subject. An informed consent template may be provided by the Sponsor 
to investigative sites. If any institution-specific modifications to study-related procedures 
are proposed or made by the site, the consent should be reviewed by the Sponsor or its 


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designee or both before IRB/IEC submission. Once reviewed, the consent will be 
submitted by the investigator to his or her IRB/IEC for review and approval before the start 
of the study. If the ICF is revised during the course of the study, all active participating 
subjects must sign the revised form. Reconsent will be needed before rescreening a patient.  
Before recruitment and enrollment, each prospective subject or his or her legal guardian 
will be given a full explanation of the study and be allowed to read the approved ICF. Once 
the investigator is assured that the subject/legal guardian understands the implications of 
participating in the study, the subject/legal guardian will be asked to give consent to 
participate in the study by signing the ICF. 
The investigator shall retain the signed original ICF and give a copy of the signed original 
form to the subject or legal guardian. 


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9 Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of 
the study but may be subject to change based on industry and government standard 
operating procedures, working practice documents, or guidelines. Changes will be reported 
to the IRB/IEC but will not result in protocol amendments. 
9.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in 
a manner designed to maintain subject confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the 
written permission of the subject (or the subject’s legal guardian), except as necessary for 
monitoring and auditing by the Sponsor, its designee, the IRB/IEC, or the US FDA. 
The investigator and all employees and coworkers involved with this study may not 
disclose or use for any purpose other than performance of the study any data, record, or 
other unpublished, confidential information disclosed to those individuals for the purpose 
of the study. Prior written agreement from the Sponsor or its designee must be obtained for 
the disclosure of any said confidential information to other parties. 
9.2 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the Sponsor 
to submit the complete and accurate certification or disclosure statements required under 
FDA 21 CFR 54 (even though the study is being conducted in the European Union). In 
addition, the investigator must provide to the Sponsor a commitment to promptly update 
this information if any relevant changes occur during the course of the investigation and 
for 1 year following the completion of the study. 
The Sponsor is not financially responsible for further testing or treatment of any medical 
condition that may be detected during the screening process. In addition, in the absence of 
specific arrangements, the Sponsor is not financially responsible for further treatment of 
the subject’s disease. 


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9.3 Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH GCP E6 
(R1/R2) 8.2 by providing the following essential documents, including but not limited to: 
 IRB/IEC approval 
 Original investigator-signed investigator agreement page of the protocol 
 Curriculum vitae for the investigator and each sub-investigator participating in the 
study 
 Financial disclosure information to allow the Sponsor or designee to submit 
complete and accurate certification or disclosure statements required under ICH 
GCP E6 (R1/R2). In addition, the investigators must provide to the Sponsor a 
commitment to promptly update this information if any relevant changes occur 
during the course of the investigation and for 1 year after the completion of the 
study. 
 IRB/IEC-approved informed consent, samples of site advertisements for 
recruitment for this study, and any other written information regarding this study 
that is to be provided to the subject or legal guardian, and 
 Laboratory certifications and normal ranges for any local laboratories used by the 
site, in accordance with GCP 
9.4 Study Conduct 
The investigator agrees that the study will be conducted according to the principles of ICH 
Guidelines for GCP E6 (R1/R2). The investigator will conduct all aspects of this study in 
accordance with all national, state, and local laws or regulations. Study information from 
this protocol will be posted on publicly available clinical trial registers before enrollment 
of subjects begins. 
9.5 Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH Guidelines for GCP E6 (R1/R2) and all applicable guidelines and regulations. 


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9.6 Adverse Events and Study Report Requirements 
By participating in this study the investigator agrees to submit reports of SAEs according 
to the time line and method outlined in the protocol. In addition, the investigator agrees to 
submit annual reports to the study site IRB/IEC as appropriate. 
9.7 Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB/IEC with a summary of the 
study’s outcome and the Sponsor and regulatory authority(ies) with any reports required. 
9.8 Records Retention 
Following completion of the study, the investigator will retain copies of the approved study 
protocol, ICF, relevant source documents, and all other supporting documentation related 
to the study according to the ICH guidelines, according to local regulations, or as  specified 
in the Clinical Study Agreement (CSA), whichever is longer. 
An investigator shall retain records required to be maintained under this part for a period of 
2 years following the date a marketing application is approved for the drug for the 
indication for which it is being investigated; or, if no application is to be filed or if the 
application is not approved for such indication, until 2 years after the investigation is 
discontinued and FDA is notified. The documentation should be retained for longer if 
required by regulatory requirements or by agreement with the sponsor. 
If the investigator can no longer maintain the archive of study records (e.g., due to 
retirement or relocation), the sponsor must be informed in writing about any change in 
responsibility for record retention, including the name of the new responsible party, contact 
information, and location of the study records. Records may not be destroyed without prior 
written consent from the sponsor. 
9.9 Publications 
The investigator will not be allowed to publish findings from study participation without 
prior written consent of the Sponsor. 


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10 Study Management 
10.1 Monitoring 
The clinical monitor, as a representative of the Sponsor, has the obligation to follow the 
study closely. In doing so, the monitor will visit the investigator and study site at periodic 
intervals, in addition to maintaining necessary telephone and letter contact. The monitor 
will maintain current personal knowledge of the study through observation, review of 
study records and source documentation, and discussion of the conduct of the study with 
the investigator and personnel. 
All aspects of the study will be carefully monitored, by the Sponsor or its designee, for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. 
10.1.1 Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB/IEC review, and regulatory inspections by providing direct access to all study 
records. In the event of an audit, the investigator agrees to allow the Sponsor, 
representatives of the Sponsor, or a regulatory agency (e.g., FDA or other regulatory 
agency) access to all study records. 
The investigator should promptly notify the Sponsor of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the 
Sponsor. 
10.2 Management of Protocol Amendments and Deviations 
10.2.1 Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the subject, must be reviewed and approved by the Sponsor. 
Amendments to the protocol must be submitted in writing to the investigator’s IRB/IEC for 
approval before subjects can be enrolled into an amended protocol. Amendments to the 
protocol may require changes to the informed consent document and must then be 
reviewed and approved by the investigator’s IRB/IEC before subjects can be enrolled into 
the amended protocol (see Section 8.3). 


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10.2.2 Protocol Deviations 
The investigator or designee must document and explain in the subject’s source 
documentation any deviation from the approved protocol. The investigator may implement 
a deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
subjects without prior IRB/IEC approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol 
amendments should be submitted to the IRB/IEC for review and approval, to the Sponsor 
for agreement, and to the regulatory authorities, as applicable. 
A significant deviation from the protocol is an unintended or unanticipated departure from 
the procedures or processes approved by the Sponsor and the IRB/IEC and agreed to by the 
investigator. A significant deviation occurs when there is non-adherence to the protocol by 
the subject or investigator that results in a significant, additional risk to the subject. 
Significant deviations can include non-adherence to inclusion or exclusion criteria, or non-
adherence to ICH GCP guidelines or FDA regulations, and will lead to the subject being 
withdrawn from the study (Section 4.2). 
Protocol deviations will be documented by the study site staff, the investigator, and the 
clinical monitor throughout the course of the study. Principal investigators will be notified 
in writing by the monitor of deviations. The IRB/IEC should be notified of all protocol 
deviations in a timely manner, as applicable. 
10.3 Study Termination 
The Sponsor reserves the right to modify or terminate the study at any time. Possible 
reasons for termination are unsatisfactory enrollment of subjects, new scientific knowledge 
becomes known that makes the objectives of the study no longer feasible, or safety reasons 
such as if the incidence of AEs in this study or other study using the same investigational 
drug indicates there is a potential health risk for subjects.  
The Sponsor will provide a written statement to the IRB/IEC and the relevant regulatory 
authority with the reasons for modification or termination of the study. This termination 
will be conducted within 15 days of the decision to terminate the study. If the study is 
terminated, a close out visit will be performed at each active site and applicable procedures 
will be carried out to close the trial site(s). Although the Sponsor has every intention of 


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completing the study, ITF Research Pharma SLU reserves the right to discontinue the study 
at any time for clinical or administrative reasons. 
The end of the study is defined as the date on which the last subject completes the last visit 
(includes Follow-up Visit). 
10.4 Final Report 
Whether the study is completed or prematurely terminated, the Sponsor will ensure that the 
clinical study reports are prepared and provided to the regulatory agency(ies) as required 
by the applicable regulatory requirement(s). The Sponsor will also ensure that the clinical 
study reports in marketing applications meet the standards of the ICH Harmonised 
Tripartite Guideline E3: Structure and content of clinical study reports. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results. 
Upon completion of the clinical study report, the Sponsor will provide the Investigator 
with the full summary of the study results. The investigator is encouraged to share the 
summary results with the study subjects, as appropriate. The study results will be posted in 
publicly available clinical trial registers. 


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11 Reference List 
The 2007 Hormone Therapy Position Statement of the North American Menopause Society 
(2007). Menopause, 14:357-369 . 
The 2012 Hormone Therapy Position Statement of the North American Menopause 
Society. (2012). Menopause, 19:257-271. 
Bergink EW, Kloosterboer HJ, van der Vies J (1984). Oestrogen binding proeins in the 
female genital tract. J Steroid Biochem, 20:1057-1060. 
Cano A, Estevez J, Usandiziga R, et al (2012). The therapeutic effect of a new ultra low 
concentration estriol gel formulation (0.005% estriol vaginal gel) on symptoms and 
signs of postmenopausal vaginal atrophy: results from a pivotal phase III study. 
Menopause, 19:1130-1139. 
Cardozo L, Bachmann G, McClish D, et al (1998). Meta-analysis of estrogen therapy in 
the management of urogenital atrophy in postmenopausal women: second report of 
the Hormones and Urogenital Therapy Committee. Obstet Gynecol, 92:722-727. 
Fleiss JL (1986). The Design and Analysis of Clinical Experiments. New York: John Wiley 
& Sons. 
Gruber CJ, Tschuqquel W, Schneeberger C, et al (2002). Production and actions of 
estrogens. N Engl J Med, 346:340-352. 
Hayashi T, Ito I, et al (2000). Estriol (E3) replacement improves endothelial function and 
bone mineral density in very elderly women. J Gerontol A Biol Sci Med Sci, 
55:B183-B190. 
ICH Expert Working Group. ICH Harmonised Tripartite Guideline, Choice of Control 
Group and Related Issues in Clinical Trials E10. 20 July 2010 
Fleiss JL (1986). The Design and Analysis of Clinical Experiments. New York: John Wiley 
& Sons. 
Karch FE, Lasagna L (1977). Towards the operational identification of adverse drug 
reactions. Clin Pharm Ther, 21:247-254. 


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Kurman RJ, Hedrick Ellenson L, Ronnett BM (eds) (2011). Blaustein's Pathology of the 
Female Genital Tract, 6th Edition. New York: Springer. 
Nakayama H, Yano T, Sagara Y, et al (1999). Estriol add-back therapy in the long-acting 
gonadotropin-releasing hormone agonist treatmetn of uterine leiomyomata. 
Gynecol Endocrinol, 13:382-389. 
Padwick ML, Siddle NC, Lane G, et al (1986). Oestriol with oestradiol versus oestradiol 
alone: a comparison of endometrial, symptomatic and psychological effects. . Br J 
Obstet Gynaecol, 93:606-612. 
Raz R, Stamm WE (1993). A controlled trial of intravaginal estriol in postmenopausal 
women with recurrent urinary tract infections. N Engl J Med, 329:753-756. 
Reynolds TM, Nix AB, Bunstan FD, et al (1993). Age-specific detection and false-positive 
rates: an aid to counselling in Down syndrome risk screening. Obstet Gynecol, 
81:447-450. 
Takahashi K, Manabe A, Okada M, et al (2000). Efficacy and safety of oral estriol for 
managing postmenopausal symptoms. Maturitas, 34:169-177. 
US Dept. Health and Human Services (2003). Guidance for Industry: Estrogen and 
estrogen/progestin drug products to treat vasomotor symptoms and vulvar and 
vaginal atrophy symptoms - Recommendations for Clinical Evaluation. Draft 
Guidance. Washington: U.S. Department of Health and Human Services. 
http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/WomensHealthRes
earch/UCM133343.pdf 
van Haaften M, Donker GH, Sie-Go DM, et al (1997). Biochemical and histological effects 
of vaginal estriol and estradiol applications on the endometrium, myometrium and 
vagina of postmenopausal women. Gynecol Endocrinol, 11:175-185. 
 


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12Appendices 
 
 


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12.1 WMA Declaration of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended 
by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 
added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
INTRODUCTION  
The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data.  
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should not be applied without consideration of all other relevant paragraphs. 
Although the Declaration is addressed primarily to physicians, the WMA encourages other 
participants in medical research involving human subjects to adopt these principles. 
It is the duty of the physician to promote and safeguard the health of patients, including 
those who are involved in medical research. The physician's knowledge and conscience are 
dedicated to the fulfillment of this duty. 
The Declaration of Geneva of the WMA binds the physician with the words, "The health of 
my patient will be my first consideration," and the International Code of Medical Ethics 


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declares that, "A physician shall act in the patient's best interest when providing medical 
care." 
Medical progress is based on research that ultimately must include studies involving 
human subjects. Populations that are underrepresented in medical research should be 
provided appropriate access to participation in research. 
In medical research involving human subjects, the well-being of the individual research 
subject must take precedence over all other interests. 
The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best current 
interventions must be evaluated continually through research for their safety, effectiveness, 
efficiency, accessibility and quality. 
In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research is subject to ethical standards that promote respect for all human subjects 
and protect their health and rights. Some research populations are particularly vulnerable 
and need special protection. These include those who cannot give or refuse consent for 
themselves and those who may be vulnerable to coercion or undue influence. 
Physicians should consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or regulatory 
requirement should reduce or eliminate any of the protections for research subjects set 
forth in this Declaration. 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH  
It is the duty of physicians who participate in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. 
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 


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sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected.  
Appropriate caution must be exercised in the conduct of medical research that may harm 
the environment. 
The design and performance of each research study involving human subjects must be 
clearly described in a research protocol. The protocol should contain a statement of the 
ethical considerations involved and should indicate how the principles in this Declaration 
have been addressed. The protocol should include information regarding funding, 
Sponsors, institutional affiliations, other potential conflicts of interest, incentives for 
subjects and provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study. The protocol should describe 
arrangements for post-study access by study subjects to interventions identified as 
beneficial in the study or access to other appropriate care or benefits. 
The research protocol must be submitted for consideration, comment, guidance and 
approval to a research ethics committee before the study begins. This committee must be 
independent of the researcher, the Sponsor and any other undue influence. It must take into 
consideration the laws and regulations of the country or countries in which the research is 
to be performed as well as applicable international norms and standards but these must not 
be allowed to reduce or eliminate any of the protections for research subjects set forth in 
this Declaration. The committee must have the right to monitor ongoing studies. The 
researcher must provide monitoring information to the committee, especially information 
about any serious adverse events. No change to the protocol may be made without 
consideration and approval by the committee. 
Medical research involving human subjects must be conducted only by individuals with 
the appropriate scientific training and qualifications. Research on patients or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician or 
other health care professional. The responsibility for the protection of research subjects 
must always rest with the physician or other health care professional and never the research 
subjects, even though they have given consent. 
Medical research involving a disadvantaged or vulnerable population or community is only 
justified if the research is responsive to the health needs and priorities of this population or 


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community and if there is a reasonable likelihood that this population or community stands 
to benefit from the results of the research. 
Every medical research study involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and communities involved in 
the research in comparison with foreseeable benefits to them and to other individuals or 
communities affected by the condition under investigation. 
Every clinical trial must be registered in a publicly accessible database before recruitment 
of the first subject. 
Physicians may not participate in a research study involving human subjects unless they 
are confident that the risks involved have been adequately assessed and can be 
satisfactorily managed. Physicians must immediately stop a study when the risks are found 
to outweigh the potential benefits or when there is conclusive proof of positive and 
beneficial results. 
Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the research subjects. 
Participation by competent individuals as subjects in medical research must be voluntary. 
Although it may be appropriate to consult family members or community leaders, no 
competent individual may be enrolled in a research study unless he or she freely agrees. 
Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information and to minimize the impact of the study on 
their physical, mental and social integrity. 
In medical research involving competent human subjects, each potential subject must be 
adequately informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and potential 
risks of the study and the discomfort it may entail, and any other relevant aspects of the 
study. The potential subject must be informed of the right to refuse to participate in the 
study or to withdraw consent to participate at any time without reprisal. Special attention 
should be given to the specific information needs of individual potential subjects as well as 
to the methods used to deliver the information. After ensuring that the potential subject has 


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understood the information, the physician or another appropriately qualified individual 
must then seek the potential subject's freely-given informed consent, preferably in writing. 
If the consent cannot be expressed in writing, the non-written consent must be formally 
documented and witnessed. 
For medical research using identifiable human material or data, physicians must normally 
seek consent for the collection, analysis, storage and/or reuse. There may be situations 
where consent would be impossible or impractical to obtain for such research or would 
pose a threat to the validity of the research. In such situations the research may be done 
only after consideration and approval of a research ethics committee. 
When seeking informed consent for participation in a research study the physician should 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent should be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
For a potential research subject who is incompetent, the physician must seek informed 
consent from the legally authorized representative. These individuals must not be included 
in a research study that has no likelihood of benefit for them unless it is intended to 
promote the health of the population represented by the potential subject, the research 
cannot instead be performed with competent persons, and the research entails only minimal 
risk and minimal burden. 
When a potential research subject who is deemed incompetent is able to give assent to 
decisions about participation in research, the physician must seek that assent in addition to 
the consent of the legally authorized representative. The potential subject's dissent should 
be respected. 
Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition 
that prevents giving informed consent is a necessary characteristic of the research 
population. In such circumstances the physician should seek informed consent from the 
legally authorized representative. If no such representative is available and if the research 
cannot be delayed, the study may proceed without informed consent provided that the 
specific reasons for involving subjects with a condition that renders them unable to give 


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informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research should be 
obtained as soon as possible from the subject or a legally authorized representative. 
Authors, editors and publishers all have ethical obligations with regard to the publication 
of the results of research. Authors have a duty to make publicly available the results of 
their research on human subjects and are accountable for the completeness and accuracy of 
their reports. They should adhere to accepted guidelines for ethical reporting. Negative and 
inconclusive as well as positive results should be published or otherwise made publicly 
available. Sources of funding, institutional affiliations and conflicts of interest should be 
declared in the publication. Reports of research not in accordance with the principles of 
this Declaration should not be accepted for publication. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
The physician may combine medical research with medical care only to the extent that the 
research is justified by its potential preventive, diagnostic or therapeutic value and if the 
physician has good reason to believe that participation in the research study will not 
adversely affect the health of the patients who serve as research subjects. 
The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best current proven intervention, except in the following circumstances: 
The use of placebo, or no treatment, is acceptable in studies where no current proven 
intervention exists; or  
Where for compelling and scientifically sound methodological reasons the use of placebo 
is necessary to determine the efficacy or safety of an intervention and the patients who 
receive placebo or no treatment will not be subject to any risk of serious or irreversible 
harm. Extreme care must be taken to avoid abuse of this option. 
At the conclusion of the study, patients entered into the study are entitled to be informed 
about the outcome of the study and to share any benefits that result from it, for example, 
access to interventions identified as beneficial in the study or to other appropriate care or 
benefits. 


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The physician must fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study or the patient's decision to 
withdraw from the study must never interfere with the patient-physician relationship. 
In the treatment of a patient, where proven interventions do not exist or have been 
ineffective, the physician, after seeking expert advice, with informed consent from the 
patient or a legally authorized representative, may use an unproven intervention if in the 
physician's judgment it offers hope of saving life, re-establishing health or alleviating 
suffering. Where possible, this intervention should be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information should be 
recorded and, where appropriate, made publicly available. 


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12.2 Investigator’s Statement and Agreement 
I (as Investigator) have read and understood all sections of the study protocol Version 5.0, 
dated 07 June 2017, and the accompanying Investigator’s Brochure, 
 
. 
I hereby agree to supervise all aspects of the protocol and to conduct the clinical 
investigation in accordance with the Final Protocol, the International Conference on 
Harmonisation Harmonised Tripartite Guideline E6 (R1/R2): Good Clinical Practice and 
all applicable government regulations.  
I will not make changes to the protocol before consulting with ITF Research Pharma SLU 
or implement protocol changes without independent ethics committee approval except to 
eliminate an immediate risk to subjects. I agree to administer study drug only to subjects 
under my personal supervision or the supervision of a sub-investigator. I will not supply 
the investigational drug to any person not authorized to receive it. Subject identity will not 
be disclosed to third parties or appear in any study reports or publications. 
It is further agreed that the details of this trial and all information provided to me by ITF 
Research Pharma SLU will be held in the strictest confidence and will not be revealed for 
any reason without written authorization from ITF Research Pharma SLU except to those 
who are to participate in the conduct of the trial. 
I agree that all data, the case report forms and all materials provided for the conduct of the 
trial are the property of ITF Research Pharma SLU unless specified otherwise in writing.  
It is understood that ITF Research Pharma SLU will utilize the information derived from 
this trial in various ways, such as for submission to government regulatory agencies, 
required internal reports and presentations without violating patient/ subject confidentiality 
in any way. 
I further agree that ITF Research Pharma SLU or its representatives will be permitted 
access in accordance with current Good Clinical Practice Guidelines, to all data generated 
by this trial and the source documents from which case report form data were generated. 
Principal Investigator Printed Name: 
Signature:                                     Date:                               Site Nº or Name:  


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12.3 Screening Criteria – Allowed Pre-study Therapies 
Medication/Therapy 
Route of Administration 
Discontinuation Prior to 
Screening 
Non-hormonal vulvovaginal 
treatment (including cosmetics 
expected to have an impact on 
vaginal pH such as special feminine 
wash gels) 
Topical 
7 days 
Phytoestrogens 
Any route 
1 month 
Hormone therapy  
Vaginal 
1 month 
Hormone therapy: 
  estrogen alone 
  progestin alone 
  estrogen/progestin combination 
Oral, vaginal, intrauterine, 
or transdermal 
2 months 
Progestational implants 
Subcutaneous 
3 months 
Estrogen 
Injectable 
3 months 
Estrogen/progestational products 
Injectable 
3 months 
Estrogen pellet therapy 
Subcutaneous 
6 months 
Progestin therapy 
Injectable 
6 months 
Estrogen lotions/gels 
Percutaneous 
1 month 
Testosterone or testosterone 
derivatives 
Any route 
2 months 
Dehydroepiandrosterone 
Any route 
2 months 
Tibolone 
Any route 
2 months 
Selective estrogen receptor 
modulators 
Any route 
2 months 
 
 
 


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12.4  Screening Criteria - Excluded Medications 
Medication/Therapy 
Anti-epileptic drugs, including: 
   Barbiturates 
   Hydantoins 
   Carbamazepine 
Rifampicin 
Rifabutin 
Tetracyclines 
Ketoconazole 
Evirapine 
Efavirenz 
Ritonavir 
Nelfinavir 
Phenyobutazone 
Preparations based on medicinal plants that contain St. John’s Wort (Hypericum perforatum) 
 

SAP_000.pdf: