Clinical Trials Register

Summary
EudraCT Number:	2017-002906-10
Sponsor's Protocol Code Number:	BHR-700-301
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2017-11-07
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2017-002906-10

A.3

Full title of the trial

A Randomized, Double-blind, Placebo Controlled Trial of 4-Hydroxytamoxifen Gel for Reducing Breast Tissue Density in Women with BI-RADS Breast Density Categories C or D

Estudio aleatorio con doble ciego controlado con placebo del gel 4-hidroxitamoxifeno para reducir la densidad del tejido mamario en mujeres con categorías de densidad mamaria BI-RADS C o D

A.3.1

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

A Randomized, Double-blind, Placebo Controlled Trial of 4-Hydroxytamoxifen Gel for Reducing Breast Tissue Density in Women with BI-RADS Breast Density Categories C or D

Estudio aleatorio con doble ciego controlado con placebo del gel 4-hidroxitamoxifeno para reducir la densidad del tejido mamario en mujeres con categorías de densidad mamaria BI-RADS C o D

A.4.1

Sponsor's protocol code number

BHR-700-301

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	BHR Pharma, LLC
B.1.3.4	Country	United States
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	BHR Pharma, LLC
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	FGK Clinical Research GmbH
B.5.2	Functional name of contact point	Clinical Trials Information
B.5.3	Address:
B.5.3.1	Street Address	Heimeranstr. 35
B.5.3.2	Town/ city	München
B.5.3.3	Post code	80339
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49898931190
B.5.6	E-mail	ines.zapater@fgk-cro.de

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	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	BHR-700
D.3.2	Product code	FP-241
D.3.4	Pharmaceutical form	Gel
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Cutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Afimoxifene
D.3.9.1	CAS number	68392-35-8
D.3.9.2	Current sponsor code	BHR-700
D.3.9.3	Other descriptive name	FP-241
D.3.10	Strength
D.3.10.1	Concentration unit	mg/g milligram(s)/gram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2.28
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	No
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	Gel
D.8.4	Route of administration of the placebo	Cutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Breast tissue density in women with BI-RADS Breast Density Categories C to D

Densidad del tejido mamario en mujeres con categorías de densidad mamaria BI-RADS C o D

E.1.1.1

Medical condition in easily understood language

Breast tissue density in women identified as having dense breast tissue.

Densidad del tejido mamario en mujeres con tejido mamario denso.

E.1.1.2

Therapeutic area

Body processes [G] - Physiological processes [G07]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10065307
E.1.2	Term	Breast density increased
E.1.2	System Organ Class	100000004848

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 determine the efficacy of 8 mg/day (4 mg/breast) of BHR-700 gel compared to placebo for reducing breast tissue density in women identified as having dense breast tissue upon analysis of screening mammography using the Food and Drug Administration (FDA)-cleared Cumulus 2D software.

Determinar la eficacia de 8 mg/día (4 mg/mama) de gel BHR-700 en comparación con placebo para reducir la densidad de tejido mamario en mujeres a las que se les haya detectado tejido mamario denso tras un análisis de una mamografía de control mediante el programa informático Cumulus 2D aprobado por la Administración de Medicamentos y Alimentos de los EE.UU. (FDA).

E.2.2

Secondary objectives of the trial

Incidence and severity of adverse events (AEs) with special attention given to uterine abnormalities, cardiovascular events, thromboembolic events, and incidence of vasomotor symptoms (“hot flush”).

Change in serum concentration of sex hormone binding globulin (SHBG).

Change in serum concentration of: cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL).

Change in serum concentration of Protein C-activity, Protein Sactivity, Antithrombin 111 antigen, and Activated Protein C
resistance (APCR).

Change in serum concentration of select bone biomarkers CTx and BSAP.

Plasma concentrations of the E and Z isomers of 4-OHT.

Incidencia y gravedad de acontecimiento adverso (AA) con especial atención a anomalías uterinas, episodios cardiovasculares, episodios tromboembólicos y la incidencia de síntomas vasomotores («sofocos»).

Cambio en la concentración sérica de la globulina fijadora de hormonas sexuales (SHBG).

Cambio en la concentración sérica del colesterol, de los triglicéridos, de la lipoproteína de alta densidad (HDL) y de la lipoproteína de baja densidad (LDL).

Cambio en la concentración sérica de la proteína C, la proteína S, el antígeno 111 antitrombina y la resistencia a la proteína C activada (APCR).

Cambio en la concentración sérica de ciertos biomarcadores óseos específicos CTx y BSAP.

Concentraciones plasmáticas de los isómeros E y Z del 4-OHT.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Healthy women age 35 – 75 years with either heterogeneously dense (C) or extremely dense (D), breast tissue on 2D
mammography, based on American College of Radiology (ACR) Breast Imaging-Reporting and Data System (BI-RADS©) fifth edition classification) in either breast within 3 months prior to randomization. Mammogram with BI-RADS final assessment category 1 or 2 (negative or benign findings).
2. If the woman is of childbearing potential, she must have a documented negative urine pregnancy test at time of screening and randomization and no plans to become pregnant for the duration of study participation.
3. Ability to understand and the willingness to sign a written informed consent document.

1. Mujeres sanas entre 35 y 75 años con un tejido mamario heterogéneamente denso (C) o muy denso (D) en una mamografía bidimensional conforme a la clasificación de la quinta edición del sistema de información de radiografías de mamas Breast Imaging-Reporting and Data System (BI-RADS©) del Colegio Estadounidense de Radiología (ACR) en alguna de las mamas en un plazo de 3 meses anterior a la aleatorización. Mamografía con categoría de evaluación final de BI-RADS de 1 o 2 (negativa o resultados benignos).
2. Si la mujer tiene posibilidad de procrear, debe dejarse constancia de una prueba de embarazo en orina negativa en el momento de la selección y de la aleatorización, y no puede tener planes de quedarse embarazada durante su participación en el estudio.
3. La capacidad de comprender y la voluntad de firmar un documento de consentimiento informado por escrito.

E.4

Principal exclusion criteria

1. Participants may not be receiving treatment with any investigational drug or investigational biologic within 30 days of
randomization or at any time during the study.
2. Women with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to
Tamoxifen.
3. Pregnant women are excluded from this study because the effects of 4-OHT gel on the developing human fetus at the recommended dose and route are unknown.
4. Pregnancy (independent of outcome) and/or lactation within 1 year prior to the screening mammogram.
5. Women with previous history of cancer (including invasive or intra-ductal breast cancer) except for non-melanoma skin cancer.
6. Women who have had a prior mastectomy (unilateral or bilateral), segmental mastectomy, reduction mammoplasty or breast augmentation including implants.
7. Women with surgical breast biopsy(s) performed within 3 years or core biopsy(s) performed within 1 year prior to the screening mammogram.
8. Women with an abnormal mammogram (BI-RADS final assessment category 3-probably benign, 4-suspicious, or 5-
malignant findings). Women with BI-RADS 0 assessment (needs additional imaging evaluation) that are subsequently found to have negative (BI-RADS 1) or benign findings (BI-RADS 2), are NOT excluded.
9. Women with only synthetic 2D mammograms generated from 3D (tomosynthesis) are excluded as breast density measurements are not yet validated for synthetic mammograms. Women with combination 2D+3D mammograms are not excluded.
10. Women with active liver disease or thromboembolic disorder.
11. Women with skin conditions such as psoriasis, fungal infections, keloids etc., or tattoos and/or piercings, which in the opinion of the Investigator, would interfere with absorption of the IP.
12. Women who have had an abnormal gynecology exam within the last three years with clinically significant findings, such as secondary dysmenorrhea, polyps, or atypia, which in the opinion of the Investigator would interfere with the study.
13. Women who have received treatment with Selective Estrogen Receptor Modulators (SERMs) (e.g. tamoxifen, raloxifen) or aromatase inhibitors.
14. Women taking estrogen containing contraceptives or Hormone Replacement Therapy (HRT) must discontinue the treatment a minimum of 6 months prior to the screening mammogram. Progestin only contraceptives are permitted.
15. Women with a concurrent illness, disease or condition that, in the opinion of the Investigator, would limit their compliance with study requirements or place them at additional risk.

1. Las participantes no pueden estar recibiendo otro tratamiento de estudio o otro tratamiento biológico de estudio entre 30 días antes de la aleatorización ni durante todo el ensayo.
2. Mujeres con un historial de reacciones alérgicas atribuidas a compuestos con una composición química o biológica similar al tamoxifeno.
3. Las embarazadas quedan excluidas del presente estudio porque se desconocen los efectos del gel 4-OHT con la dosis y ruta recomendadas en un feto humano en desarrollo.
4. Un embarazo (independientemente del resultado) y/o la lactancia durante un 1 año antes de la mamografía de control.
5. Mujeres con un historial previo de cáncer (incluido cáncer de mama invasivo o intraductal) excepto los cánceres de piel no melánicos.
6. Mujeres que se hayan sometido previamente a una mastectomía (unilateral o bilateral), una mastectomía segmentaria, mamoplastia de reducción o aumento de pecho, incluidos implantes.
7. Mujeres a las que se les haya realizado una o varias biopsias de mama quirúrgicas en un plazo de 3 años o biopsias centrales durante un periodo de 1 año antes de la mamografía de control.
8. Mujeres con una mamografía anormal (categoría de evaluación final BI-RADS 3-probablemente benigno, 4-sospechoso o 5-resultados malignos). NO quedan excluidas las mujeres con una evaluación 0 de BI-RADS (es necesaria una evaluación de diagnóstico por imagen adicional) que posteriormente sean negativos (BI-RADS 1) o resultados benignos (BI-RADS 2).
9. Quedan excluidas las mujeres con solo mamografías bidimensionales sintéticas generadas partir de una imagen tridimensional (tomosíntesis), puesto que las medidas de densidad mamaria todavía no han sido validadas para mamografías sintéticas. No quedan excluidas las mujeres con una combinación de mamografías bidimensionales y tridimensionales.
10. Mujeres con una enfermedad hepática o un trastorno tromboembólico.
11. Mujeres con enfermedades cutáneas como psoriasis, infecciones fúngicas, queloides, etc., o tatuajes y/o piercings, que, en opinión del Investigador, puedan interferir con la absorción del IP.
12. Mujeres que hayan obtenido resultados anormales en un examen ginecológico en los últimos tres años con resultados significativos clínicamente, como dismenorrea secundaria, pólipos o atipia, que, en opinión del Investigador, puedan interferir con el estudio.
13. Mujeres que hayan recibido tratamiento con moduladores receptivos de selectores de estrógeno (SERM) (p. ej. tamoxifeno, raloxifeno) o inhibidores de aromatasa.
14. Mujeres que tomen anticonceptivos que contengan estrógenos o tratamiento de sustitución hormonal (HRT) deben interrumpir el tratamiento como mínimo 6 meses antes de la mamografía de control. Están permitidos los anticonceptivos que únicamente contienen progestágenos.
15. Las mujeres con enfermedades, dolencias o trastornos concomitantes que, en opinión del Investigador, puedan limitar su cumplimiento de los requisitos del estudio o ponerlas en un riesgo adicional.

E.5 End points

E.5.1

Primary end point(s)

The percentage reduction of mammographic breast tissue density on a follow-up mammogram compared to the baseline mammogram after 52 weeks of treatment.

La reducción porcentual de la densidad del tejido mamario mamográfico en una mamografía de seguimiento en comparación con la mamografía inicial tras 52 semanas de tratamiento.

E.5.1.1

Timepoint(s) of evaluation of this end point

52 weeks

52 semanas

E.5.2

Secondary end point(s)

#1 Incidence and severity of adverse events (AEs) with special attention given to uterine abnormalities, cardiovascular events, thromboembolic events, and incidence of vasomotor symptoms (“hot flush”).

#2 Change in serum concentration of sex hormone binding globulin (SHBG).

#3 Change in serum concentration of: cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL).

#4 Change in serum concentration of Protein C-activity, Protein Sactivity, Antithrombin 111 antigen, and Activated Protein C resistance (APCR).

#5 Change in serum concentration of select bone biomarkers CTx and BSAP.

#6 Plasma concentrations of the E and Z isomers of 4-OHT.

#1 Incidencia y gravedad de acontecimiento adverso (AA) con especial atención a anomalías uterinas, episodios cardiovasculares, episodios tromboembólicos y la incidencia de síntomas vasomotores («sofocos»).

#2 Cambio en la concentración sérica de la globulina fijadora de hormonas sexuales (SHBG).

#3 Cambio en la concentración sérica del colesterol, de los triglicéridos, de la lipoproteína de alta densidad (HDL) y de la lipoproteína de baja densidad (LDL).

#4 Cambio en la concentración sérica de la proteína C, la proteína S, el antígeno 111 antitrombina y la resistencia a la proteína C activada (APCR).

#5 Cambio en la concentración sérica de ciertos biomarcadores óseos específicos CTx y BSAP.

#6 Concentraciones plasmáticas de los isómeros E y Z del 4-OHT.

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary end point #1
Blinded Phase Week 13, Week 26, Week 39, Week 52
Open-Label Phase Week 13, Week 26, Week 39, Week 52

Secondary end point #2
Blinded Phase Week 52
Open-Label Phase Week 52

Secondary end point #3
Blinded Phase Week 26, Week 52
Open-Label Phase Week 26, Week 52

Secondary end point #4
Blinded Phase Week 26, Week 52
Open-Label Phase Week 26, Week 52

Secondary end point #5
Blinded Phase Week 52
Open-Label Phase Week 52

Secondary end point #6
Blinded Phase Week 13, Week 26, Week 52
Open-Label Phase Week 26, Week 52

Variable secundaria #1
Fase ciega Semana 13, Semana 26, Semana 39, Semana 52
Fase abierta Semana 13, Semana 26, Semana 39, Semana 52

Variable secundaria #2
Fase ciega Semana 52
Fase abierta Semana 52

Variable secundaria #3
Fase ciega Semana 26, Semana 52
Fase abierta Semana 26, Semana 52

Variable secundaria #4
Fase ciega Semana 26, Semana 52
Fase abierta Semana 26, Semana 52

Variable secundaria #5
Fase ciega Semana 52
Fase abierta Semana 52

Variable secundaria #6
Fase ciega Semana 13, Semana 26, Semana 52
Fase abierta Semana 26, Semana 52

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

Yes

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Open-label treatment phase (52 wks) after 52 wks randomized double-blind treatment phase (elective)

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Germany

Spain

United States

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

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:

280

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

Yes

F.3.2

Patients

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

330

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

2017-12-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-12-21

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2019-04-23

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials