Clinical Trials Register

Summary
EudraCT Number:	2014-004517-84
Sponsor's Protocol Code Number:	ITFE-2026-C10
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:	2015-01-02
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

2014-004517-84

A.3

Full title of the trial

A PHASE II PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED AND MULTI-CENTRE CLINICAL TRIAL TO ASSESS THE SAFETY OF 0.005 % ESTRIOL VAGINAL GEL IN HORMONE RECEPTOR-POSITIVE POSTMENOPAUSAL WOMEN WITH EARLY STAGE BREAST CANCER IN TREATMENT WITH AROMATASE INHIBITOR IN THE ADJUVANT SETTING.?BLISSAFE Study?

Ensayo clínico fase II, prospectivo, multicéntrico, aleatorizado, doble ciego y controlado con placebo para evaluar la seguridad del gel vaginal de estriol al 0.005% en mujeres postmenopáusicas con cáncer de mama en estadio precoz y receptores hormonales positivos en tratamiento adyuvante con inhibidores de aromatasa.

A.3.1

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

Clinical trial to evaluate the safety of a vaginal gel containing 0.005% of estriol, in hormone receptor-positive women in menopause with early stage breast cancer in treatment with aromatase inhibitor

Ensayo clínico para evaluar al seguridad de un gel vaginal que contiene estriol 0.005%, en mujeres menopáusicas, con cáncer de mama en estadio precoz en tratamiento con inhibidores de aromatasa y receptores hormonales positivos

A.3.2

Name or abbreviated title of the trial where available

BLISSAFE

A.4.1

Sponsor's protocol code number

ITFE-2026-C10

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 S.L.U
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 S.L.U.
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	GEICAM Spanish Breast Cancer Group
B.5.2	Functional name of contact point	GEICAM
B.5.3	Address:
B.5.3.1	Street Address	Av de los Pirineos 7, 1ª Planta ? Oficina 1-3
B.5.3.2	Town/ city	San Sebastián de los Reyes (Madrid)
B.5.3.3	Post code	28703
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34916592870
B.5.5	Fax number	+34916510406
B.5.6	E-mail	geicam@geicam.org

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.3.4	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	ESTRIOL
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.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

In postmenopausal hormone receptor positive breast cancer, treatment with aromatase inhibitors is the most effective and well-studied therapy. Lack of adherence is common due to the side-effects; vaginal dryness and vaginal atrophy. The study will explore the safety of 0.005% estriol vaginal gel in the oncological context, to demostrate that the gel is a safe option to treat the vaginal atrophy caused by AIs, without a significant decline in gonadotropin or increase in systemic estrogen levels

En mujeres postmenopáusicas con cáncer de mama y receptores hormonales positivos , el tratamiento con inhibidores de la aromatasa es la terapia más eficaz pero produce efectos secundarios; sequedad y atrofia vaginal. El estudio explorará la seguridad del gel vaginal de estriol 0,005% en el contexto oncológico, para demostrar que es un tratamiento seguro para la atrofia vaginal causada por IAS, sin disminución significativa de gonadotropinas o aumento en los niveles sistémicos de estrógenos

E.1.1.1

Medical condition in easily understood language

Postmenopausal woman with breast cancer are treated with aromatase inhibitors. The problem is that causes many vaginal adverse events that may be treated safely with 0.005% estriol vaginal gel

Mujeres postmenopáusicas con cáncer de mama se tratan con inhibidores de aromatasa, pero tienen efectos secundarios vaginales que podrías tratarse de manera segura con el gel vaginal de estriol 0,005%

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the levels of FSH after treatment with 0.005% estriol vaginal gel in hormone receptor-positive postmenopausal women with early stage breast cancer in treatment with NSAIs in the adjuvant setting and symptoms of vaginal atrophy

Evaluar los niveles de FSH tras el tratamiento de los síntomas de la atrofia vaginal con el gel vaginal de estriol 0,005% en mujeres postmenopáusicas con cáncer de mama en estadio precoz y receptores hormonales positivos en tratamiento adyuvante con inhibidores de aromatasa.

E.2.2

Secondary objectives of the trial

To evaluate the levels of estriol, estradiol, estrone, FSH and LH after treatment with 0.005% estriol vaginal gel in hormone receptor-positive postmenopausal women with early stage breast cancer in treatment with NSAIs in the adjuvant setting and symptoms of vaginal atrophy.
To assess the safety and tolerability of 0.005% estriol vaginal gel in hormone receptor-positive postmenopausal women with early stage breast cancer in treatment with NSAIs in the adjuvant setting and symptoms of vaginal atrophy.
To assess the efficacy of 0.005% estriol vaginal gel in the treatment of symptoms and signs of vaginal atrophy in hormone receptor-positive postmenopausal women with early stage breast cancer in treatment with NSAIs and symptoms of vaginal atrophy.
To measure the impact of treatment with 0.005% estriol vaginal gel in sexual function of hormone receptor-positive postmenopausal women with early stage breast cancer in treatment with NSAIs and symptoms of vaginal atrophy

Evaluar los niveles de estriol, estradiol, estrona, FSH y LH tras el tratamiento de los síntomas de la atrofia vaginal con el gel vaginal de estriol 0,005% en mujeres postmenopáusicas con cáncer de mama en estadio precoz y receptores hormonales positivos en tratamiento adyuvante con inhibidores de aromatasa
Evaluar la seguridad y tolerabilidad del gel vaginal de estriol 0,005%
Evaluar la eficacia del gel vaginal de estriol 0,005% en el tratamiento de los síntomas y signos de la atrofia vaginal
Medir el impacto del tratamiento con el gel vaginal de estriol 0,005% en la función sexual

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent prior to beginning specific protocol procedures.
2. Patients must have histological confirmation of breast adenocarcinoma with stage I-IIIA, documented at a local pathology department.
3. The breast tumors must be estrogen-receptor positive and/or progesterone receptor positive (?1% of stained tumor cells by IHC as determined by the local laboratory) with any HER2 status.
4. Postmenopausal status defined as: 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/ml or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.
5. Patient must be receiving the non-steroidal aromatase inhibitors anastrozole or letrozole as breast cancer treatment in the adjuvant setting for a minimum of 6 months.
6. Women suffering from moderate to severe vaginal dryness according to the FDA guidelines for drug development in postmenopausal women (Center for Drug Evaluation and Research, CDER Jan 2003). A moderate symptom will be considered if the symptom is present, bothersome and annoying, and a severe symptom will be considered if the symptom is present, bothersome and annoying, and interferes with the normal patient activity.
7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
8. Adequate bone marrow as defined by the following laboratory values:
a. Absolute Neutrophil Count (ANC) ? 1.5 x 109/L.
b. Platelets (plt) ? 100 x 109/L.
c. Hemoglobin (Hgb) ? 10 g/dl.
9. Patient has adequate organ function as defined by the following laboratory values:
d. Serum creatinine ? 1.5 x ULN.
e. Bilirubin ? 1.5 × ULN.
f. Alkaline phosphatase ? 2 × ULN.
g. AST and ALT ? 2 × ULN.
10. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.

consentimiento informado por escrito antes de iniciar procedimientos específicos del protocolo.
2. Los pacientes deben tener confirmación histológica de adenocarcinoma de mama en estadio I-IIIA, documentado en un departamento de patología local.
3. Los tumores de mama deben ser receptores de estrógenos positivos y / o receptor de progesterona positivo (?1% de las células tumorales teñidas por IHC según lo determinado por el laboratorio local) con cualquier estado de HER2.
4. Estado posmenopáusica defininido como: 12 meses de amenorrea espontánea o 6 meses de amenorrea espontánea con niveles séricos de FSH> 40 mUI / ml o 6 semanas ooforectomía bilateral postquirúrgica con o sin histerectomía.
5. La paciente debe estar recibiendo inhibidores de aromatasa no esteroideos anastrozol o letrozol como tratamiento para el cáncer de mama en el tratamiento adyuvante durante un mínimo de 6 meses.
6. Mujeres que sufren de sequedad vaginal moderada a severa según las directrices de la FDA para el desarrollo de fármacos en mujeres posmenopáusicas. Un síntoma es moderado si está presente y es molesto, y un síntoma grave será si está presente, es molesto, e interfiere con la actividad normal de la paciente.
7. Estado functional de 0 ó 1 según el Eastern Cooperative Oncology Group (PS ECOG).
8. Médula ósea en buen estado definido por los siguientes valores de laboratorio:
a. Recuento absoluto de neutrófilos (RAN) ? 1,5 x 109 / L.
b. Plaquetas (PLT) ? 100 x 109 / L.
c. Hemoglobina (Hgb) ? 10 g / dl.
9 Órganos en buen estado definido los siguientes valores de laboratorio:
d. Creatinina sérica ? 1,5 x LSN.
e. Bilirrubina ? 1,5 × LSN.
f. Fosfatasa alcalina ? 2 × LSN.
g. AST y ALT ? 2 × LSN.
10. Disposición y capacidad para cumplir con las visitas programadas, el plan de tratamiento, pruebas de laboratorio y otros procedimientos del estudio.

E.4

Principal exclusion criteria

1. Stage IIIB-IV breast cancer or bilateral breast cancer.
2. Treatment with any other current anti-tumoral therapy (chemotherapy, anti-Her2?etc) besides the NSAI. Pamidronate or Alendronate are permitted.
3. Prior history of other malignancy within 5 years of study entry, aside from non-melanoma skin cancer or carcinoma-in-situ of the uterine cervix adequately treated.
4. Postmenopausal uterine bleeding. Vaginal bleeding of unknown etiology.
5. Patients with endometrial thickness equal to or greater than 4 mm measured by transvaginal ultrasound.
6. Patients who have received any type of vulvovaginal treatment in the 15 days prior to the start of the study.
7. Use of any hormone, natural (phytoestrogens) or herbal products for the treatment of menopausal symptoms within the last 6 months.
8. Current or previous history of thromboembolic disease or coagulopathies.
9. Severe cardiovascular or respiratory diseases in the previous 6 months.
10. Renal Impairment.
11. Hepatitis B and/or hepatitis C carriers (unless with normal hepatic function).
12. Known human immunodeficiency virus infection.
13. Known hypersensitivity to NSAI.
14. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
15. Previous investigational treatment for any condition or participation in any clinical trial within 4 weeks of inclusion date.

Cáncer de mama estadio IIIB-IV o cáncer de mama bilateral.
2. Tratamiento con cualquier otra terapia anti-tumoral (quimioterapia, anti-Her2 ... etc) además de la IANS. Se permiten pamidronato o alendronato.
3. Antecedentes de otra enfermedad maligna en los 5 años previos al estudio, aparte de cáncer de piel no melanoma o carcinoma in situ del cuello uterino tratado adecuadamente.
4. Sangrado uterino posmenopáusico. Sangrado vaginal de etiología desconocida.
5. Pacientes con grosor endometrial igual o mayor a 4 mm medido por ecografía transvaginal.
6. Pacientes que hayan recibido algún tipo de tratamiento vulvovaginal en los 15 días anteriores al inicio del estudio.
7. Uso de cualquier hormona, natural (fitoestrógenos) o productos a base de hierbas para el tratamiento de los síntomas de la menopausia en los últimos 6 meses.
8. Historia actual o previa de enfermedad tromboembólica o coagulopatías.
9. Enfermedades cardiovasculares o respiratorias severas en los últimos 6 meses.
10. Insuficiencia renal.
11. Hepatitis B y / o portadores de hepatitis C (a no ser que tengan función hepática normal).
12. Infección por VIH.
13. Hipersensibilidad conocida a IANS.
14. Otra anomalía médica, aguda o crónica, grave o enfermedad psiquiátrica, o alteración de laboratorio que podría considerar, a juicio del investigador, un riesgo asociado la participación en el estudio o la administración de fármacos del estudio, o que, a juicio del investigador, considere la participación en estudio inapropiada para la paciente.
15. Tratamiento con fármaco en investigación para cualquier indicación o participación en un ensayo clínico dentro de las 4 semanas previas a la fecha de inclusión.

E.5 End points

E.5.1

Primary end point(s)

Variation in serum levels of FSH from baseline to 12 weeks of treatment.

Variación de los niveles séricos de FSH de Basal a 12 semanas de tratamiento.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 weeks of treatment

12 semanas de tratamiento

E.5.2

Secondary end point(s)

Variation in serum levels of FSH at different time points compared to baseline (weeks 1, 3 and 8).
Variation in serum levels of LH and plasma levels of estriol, estradiol and estrone, at different time points compared to baseline (weeks 1, 3, 8 and 12).
AEs according to the Medical Dictionary for Regulatory Activities (MedDRA)
Changes in vaginal dryness and other symptoms and signs of vaginal atrophy; changes in vaginal maturation value and changes in vaginal pH at week 3 and week 12 vs baseline.
Changes in sexual function measured by the Female Sexual Function Index (FSFI ) scale at week 3 and week 12 vs baseline.

Variación en los niveles séricos de FSH en diferentes tiempos (semana 1, 3 y 8) en comparación con la basal.
Variación en los niveles séricos de LH y de plasma de estriol, estradiol y estrona, en diferentes tiempos (semana 1, 3, 8 y 12) en comparación con la basal.
Acontecimientos Adversos de acuerdo con el Diccionario Médico para las actividades de regulación (MedDRA)
Cambios en la sequedad vaginal y otros síntomas y signos de atrofia vaginal; cambios en el valor de maduración vaginal y los cambios en el pH vaginal en la semana 3 y la semana 12 vs basal.
Los cambios en la función sexual medidos por el Índice de Función Sexual (FSFI) en la semana 3 y la semana 12 vs basal.

E.5.2.1

Timepoint(s) of evaluation of this end point

Weeks 1, 3, 8, 12 of treatment

Semanas 1, 3, 8 y 12 de tratamiento

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

Yes

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

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

Yes

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

Ultima visita de la última paciente

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 months

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:

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

F.4.2.2

In the whole clinical trial

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
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	GEICAM Spanish Breast Cancer Group
G.4.3.4	Network Country	Spain

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-02-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-02-05

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-02-10

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