Clinical Trials Register

Summary
EudraCT Number:	2015-005787-42
Sponsor's Protocol Code Number:	ITFE-2092-C1
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-08-05
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2015-005787-42

A.3

Full title of the trial

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.

Ensayo clínico de fase II, dosis-respuesta, aleatorizado, doble ciego y controlado con placebo, de grupos paralelos y 12 semanas para evaluar la eficacia y seguridad de tres formulaciones de gel vaginal con dosis ultra-bajas de estriol (gel vaginal de estriol al 0,005%, gel vaginal de estriol al 0,002%, gel vaginal de estriol al 0,0008%) en el tratamiento de la sequedad vaginal en mujeres postmenopáusicas con atrofia vaginal.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A Phase 2 Clinical Study Evaluating the Efficacy and Safety of Three Formulations of Ultra-low Dose Estriol Vaginal Gel for the Treatment of Vaginal Dryness in Postmenopausal Women with Vulvovaginal Atrophy

Ensayo clínico de fase II evaluando la eficacia y seguridad de tres formulaciones de gel vaginal con dosis ultra-bajas en el tratamiento de la sequedad vaginal en mujeres postmenopáusicas con atrofia vaginal.

A.4.1

Sponsor's protocol code number

ITFE-2092-C1

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	ITF Research Pharma SLU
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	ITF Research Pharma SLU
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ITF Research Pharma SLU
B.5.2	Functional name of contact point	Javier Suárez Almarza
B.5.3	Address:
B.5.3.1	Street Address	c/ San Rafael 3
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28108
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34916572323
B.5.6	E-mail	jsuarez@itfsp.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Blissel
D.2.1.1.2	Name of the Marketing Authorisation holder	Italfarmaco S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Blissel
D.3.4	Pharmaceutical form	Vaginal gel
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Vaginal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ESTRIOL
D.3.9.2	Current sponsor code	ITFE-2092
D.3.9.3	Other descriptive name	Estriol Vaginal Gel
D.3.9.4	EV Substance Code	SUB01971MIG
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.005
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Yes
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Estriol Vaginal Gel
D.3.2	Product code	ITFE-2092
D.3.4	Pharmaceutical form	Vaginal gel
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Vaginal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ESTRIOL
D.3.9.2	Current sponsor code	ITFE-2092
D.3.9.3	Other descriptive name	Estriol vaginal Gel
D.3.9.4	EV Substance Code	SUB01971MIG
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.002
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Yes
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Estriol Vaginal Gel
D.3.2	Product code	ITFE-2092
D.3.4	Pharmaceutical form	Vaginal gel
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Vaginal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ESTRIOL
D.3.9.2	Current sponsor code	ITFE-2092
D.3.9.3	Other descriptive name	Estriol vaginal gel
D.3.9.4	EV Substance Code	SUB01971MIG
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.0008
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Yes
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Vaginal gel
D.8.4	Route of administration of the placebo	Vaginal use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Vulvovaginal atrophy in postmenopausal women

sequedad vaginal en mujeres posmenopáusicas con atrofia vulvovaginal

E.1.1.1

Medical condition in easily understood language

The combination of symptoms such as vaginal dryness, dyspareunia, burning, itching, as well as urinary complaints or infections of the lower urinary tract presented during menopause

La combinación de síntomas tales como sequedad vaginal, dispareunia, ardor, picazón, así como problemas urinarios o infecciones del tracto urinario inferior presentado durante la menopausia

E.1.1.2

Therapeutic area

Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10047782
E.1.2	Term	Vulvovaginal atrophy
E.1.2	System Organ Class	100000004872

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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

Objetivo principal:
Evaluar la eficacia del gel vaginal de estriol al 0,005%, al 0,002% y al 0,0008% y determinar la dosis mínima eficaz para el tratamiento de la atrofia vaginal posmenopáusica en mujeres que describen como síntoma más molesto una sequedad vaginal de moderada a grave.

E.2.2

Secondary objectives of the trial

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.

Objetivos secundarios:
Evaluar la eficacia de las tres formulaciones del gel vaginal de estriol en la mejoría de otros signos y síntomas de la atrofia vulvovaginal.
Evaluar la seguridad y la tolerabilidad de las tres formulaciones del gel vaginal de estriol.
Objetivos exploratorios:
Evaluar la percepción subjetiva global final de la eficacia de las tres formulaciones del gel vaginal de estriol.
Evaluar cuál es la aceptación que tiene la paciente de las tres formulaciones.

E.2.3

Trial contains a sub-study

E.3

Principal 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.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).

1 Persona capacitada para entender el consentimiento informado por escrito, otorgar y firmar un consentimiento
informado atestiguado y aceptar cumplir los procedimientos y evaluaciones del protocolo
2 Edad >40 y < 80 años
3 Mujer posmenopáusica (≥ 12 meses desde la última menstruación espontánea o amenorrea espontánea desde hace 6 meses, con concentraciones séricas de FSH > 40 UI/l, o ≥ 6 semanas desde una ooforectomía bilateral, con o sin histerectomía)
4. IMC ≤ 36 kg/m2
5. Índice de maduración vaginal ≤ 5% de células superficiales en un frotis vaginal
6. pH vaginal > 5
7. Sequedad vaginal de moderada a grave notificada como el síntoma más molesto de la atrofia vaginal.
8. Mamografía negativa documentada en los 9 meses anteriores a la aleatorización, con una exploración normal de las mamas en la selección.
9. Resultados negativos en la prueba de Papanicolau en la selección (en mujeres con cuello uterino).

E.4

Principal 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,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.
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 nonhormonal
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.
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.

Criterios de exclusión:
1. Pacientes con contraindicaciones para la hormonoterapia con estrógenos, como las mujeres con antecedentes o diagnóstico de lesiones premalignas o malignas de mama y/o endometrio, neoplasia maligna de colon, melanoma maligno, tumor hepático, trastornos tromboembólicos venosos (entre ellos trombosis venosa profunda o embolia pulmonar) trastornos tromboembólicos arteriales (entre ellos angina de pecho, infarto de miocardio o accidente cerebrovascular), coagulopatías o hemorragia vaginal de etiología desconocida, enfermedad hepática aguda o antecedentes de enfermedad hepática aguda siempre que los niveles de las pruebas de función hepática no hayan vuelto a la normalidad, o porfiria.
2. Pacientes con valores analíticos anómalos en la selección que el investigador considera clínicamente importantes para la finalidad del estudio.
3. Pacientes con cualquier patología médico-quirúrgica que no se encuentra controlada en el momento de la inclusión en el estudio.
4. Pacientes con cualquier trastorno agudo o crónico cuyo manejo o evolución puede interferir con su participación en el estudio.
5. Pacientes con hipertensión no controlada (presión arterial sistólica >140 mmHg o presión arterial diastólica ≥ 90 mmHg).
6. Pacientes con un prolapso del útero y de la vagina de grado II o mayor.
7. Pacientes con pólipos uterinos.
8. Pacientes con miomas uterinos sintomáticos o grandes (> 3 cm) y/o miomas palpables en la exploración ginecológica.
9. Pacientes sometidas a cirugía urogenital en los 3 meses anteriores a la visita basal.
10. Pacientes que al inicio del estudio tienen signos y síntomas sugerentes de infección genital o del tracto urinario con necesidad de tratamiento.
11. En mujeres con útero, evidencia de hiperplasia, cáncer u otra patología endometrial en la biopsia endometrial.
12. Pacientes que han recibido los siguientes tratamientos en los periodos de tiempo especificados antes de los procedimientos de selección: cualquier tipo de tratamiento vulvovaginal no hormonal en los 7 días anteriores (se incluyen los cosméticos que puedan tener un efecto en el pH vaginal, tales como los geles de higiene íntima femenina); fitoestrógenos por cualquier vía en el mes anterior; hormonoterapia vaginal en el mes anterior; hormonoterapia (estrógenos solos, gestágenos solos o combinación de estrógenos y gestágenos) por vía oral, intrauterina o transdérmica en los 2 meses anteriores; implantes de gestágenos, inyectables de estrógenos o de estrógenos y gestágenos en los 3 meses anteriores; tratamiento con microesferas (pellets) de estrógenos o gestágenos inyectables en los 6 meses anteriores; lociones percutáneas de estrógenos o geles en el mes anterior; testosterona o derivados de la testosterona, dehidroepiandrosterona (DHEA), tibolona, o los moduladores selectivos de los receptores estrogénicos (MSRE) por cualquier vía en los 2 meses anteriores;
13. Pacientes que reciben fármacos antiepilépticos (barbitúricos, hidantoínas, carbamazepina), ciertos antibióticos y otros agentes antiinfecciosos; fenilbutazona; preparados a base de plantas medicinales que contienen hierba de San Juan.
14. Pacientes alérgicas a cualquier componente de la medicación en estudio.
15. Pacientes que están participando o que han participado en una evaluación experimental de cualquier producto en las 8 semanas anteriores al inicio del estudio

E.5 End points

E.5.1

Primary end point(s)

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.

Variables de eficacia coprimarias:
- Media del cambio en la proporción de células superficiales y parabasales del epitelio vaginal en un frotis vaginal desde el inicio hasta la semana 12;
- Media del cambio en el pH vaginal desde el inicio hasta la semana 12;
- Media del cambio en la intensidad de la sequedad vaginal desde el inicio hasta la semana 12

E.5.1.1

Timepoint(s) of evaluation of this end point

at week 12

Semana 12

E.5.2

Secondary end point(s)

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;
- 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.

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.

Safety Endpoints
The following safety variables will be analyzed:
- laboratory parameters
- biochemistry, hematology and urinalysis at Week 12;
- serum lipids, and coagulation parameters at Week 12;
- change from Baseline in hormone levels (estradiol, estrone, estriol, FSH, LH);
- 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.

Variables secundarias de eficacia:
- Media del cambio en la proporción de células superficiales y parabasales del epitelio vaginal desde el inicio hasta la semana 3;
- Media del cambio en el pH vaginal desde el inicio hasta la semana 3;
- Media del cambio en la intensidad de la sequedad vaginal desde el inicio hasta la semana 3.
- Media del cambio de otros síntomas vaginales individuales de atrofia vaginal (dispareunia, prurito, escozor y disuria) y signos (palidez, friabilidad, engrosamiento o adelgazamiento de los pliegues, petequias y sequedad de la mucosa) desde el inicio hasta la semana 3 y desde el inicio hasta la semana 12.
- Media del cambio en la puntuación sintomática global desde el inicio hasta la semana 3 y desde el inicio hasta la semana 12.
Variables exploratorias de la eficacia:
- Evaluación de la percepción subjetiva global final de la eficacia de las pacientes en la semana 12.
- Evaluación de la aceptación del tratamiento en la semana 12.

Variables de seguridad:
- Evaluación de los acontecimientos adversos
- Evaluación histológica del endometrio mediante biopsia endometrial
- Evaluación del endometrio mediante ecografía
- Cambio en las concentraciones hormonales
- Cambio en los parámetros analíticos de seguridad, entre ellos las evaluaciones de seguridad de los lípidos y carbohidratos y los parámetros de coagulación (antitrombina III, factor V de Leiden, proteína C y proteína S).

E.5.2.1

Timepoint(s) of evaluation of this end point

please refer to the timepoint specified in each variable

Refiéranse a cada punto temporal para cada variable.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS (including End of Study phone call at week 16)

Última Visita del Último Paciente (incluyendo la llamada del fina de ensayo en la semana 16).

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

200

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

280

F.4.2.2

In the whole clinical trial

280

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

Ninguno

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-08-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-07-13

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-05-10

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Orphan Designation Number:
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