Clinical Trials Register

Summary
EudraCT Number:	2013-003817-16
Sponsor's Protocol Code Number:	EMR200061-005
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:	2014-02-27
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

2013-003817-16

A.3

Full title of the trial

A phase III, randomized, controlled, single-blind,
multicentre, parallel arm trial to assess the
efficacy and safety of Pergoveris® (follitropin alfa
and lutropin alfa) and GONAL-f® (follitropin
alfa) for multifollicular development as part of an
assisted reproductive technology treatment cycle
in poor ovarian responders, as defined by the
European Society of Human Reproduction and
Embryology criteria

Ensayo de fase III, aleatorizado, controlado, simple ciego, multicéntrico, de grupos paralelos para evaluar la eficacia y la seguridad de Pergoveris® (folitropina alfa y lutropina alfa) y GONAL-f® (folitropina alfa) para el desarrollo multifolicular como parte de un ciclo de tratamiento con tecnología de reproducción asistida en pacientes con respuesta ovárica deficiente, según su definición conforme a los criterios de la Sociedad Europea de Reproducción Humana y Embriología

A.3.1

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

A study to compare Pergoveris and GONAL-f in women who have responded poorly to previous infertiliy treatment cycles

Estudio para comparar Pergoveris y GONAL-f en mujeres con respuesta deficiente a ciclos de tratamiento de infertilidad previos

A.3.2

Name or abbreviated title of the trial where available

Pergoveris? in ART

Pergoveris? en TRA

A.4.1

Sponsor's protocol code number

EMR200061-005

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	Merck KGaA
B.1.3.4	Country	Germany
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	Merck KGaA, Darmstadt
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Merck KGaA
B.5.2	Functional name of contact point	Communication Centre Merck KGaA
B.5.3	Address:
B.5.3.1	Street Address	Frankfurter Strasse 250
B.5.3.2	Town/ city	Darmstadt
B.5.3.3	Post code	64293
B.5.3.4	Country	Germany
B.5.4	Telephone number	496151725200
B.5.5	Fax number	00000000
B.5.6	E-mail	service@merckgroup.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	Pergoveris 150 IU-75 IU Powder and solvent for solution for injection
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Serono Europe Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Powder and solvent for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Follitropin alfa
D.3.9.1	CAS number	56832-30-5
D.3.9.3	Other descriptive name	FOLLITROPIN ALFA
D.3.9.4	EV Substance Code	SUB12426MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Lutropin alfa
D.3.9.1	CAS number	152923-57-4
D.3.9.3	Other descriptive name	LUTROPIN ALFA
D.3.9.4	EV Substance Code	SUB12524MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	75
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Comparator
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	GONAL-f 450 IU/0.75 ml (33 micrograms/0.75 ml) powder and solvent for solution for injection
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Serono Europe Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Powder and solvent for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Follitropin alfa
D.3.9.1	CAS number	56832-30-5
D.3.9.3	Other descriptive name	FOLLITROPIN ALFA
D.3.9.4	EV Substance Code	SUB12426MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	600
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Poor Ovarian Response i.e. a failure to respond adequately to standard ART (assisted reproductive technologies) protocols and to recruit adequate follicles

Respuesta ovárica pobre, es decir, la falta de respuesta adecuada a los protocolos de TRA (tecnología de reproducción asistida) y reclutar los folículos adecuados

E.1.1.1

Medical condition in easily understood language

Poor Ovarian Response describes a less than expected response to standard treatments for infertility due to reduced production of eggs in the ovaries

La respuesta ovárica pobre describe una respuesta menor de lo esperado a los tratamientos habituales para la infertilidad debido a la menor producción de óvulos en los ovarios

E.1.1.2

Therapeutic area

Body processes [G] - Reproductive physiologi cal processes [G08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10033140
E.1.2	Term	Ovarian disorder NOS
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

The primary objective of the trial is to demonstrate superiority of Pergoveris® versus GONAL-f® in poor ovarian response (POR) patients.

El objetivo primario del estudio es demostrar la superioridad de Pergoveris® versus GONAL-f® en pacientes con respuesta ovárica deficiente

E.2.2

Secondary objectives of the trial

Key secondary objectives will include assessment of other clinical variables that reflect the efficacy of ovarian stimulation and safety assessment of combination treatment with recombinant human follicle-stimulating hormone (r-hFSH) and recombinant human luteinizing r-hLH (Pergoveris®) as compared to r-hFSH (GONAL-f®)-only treatment.

Objetivos secundarios clave incluirán la evaluación de otras variables clínicas que reflejan la eficacia de la evaluación de la estimulación ovárica y la seguridad del tratamiento combinado con la hormona estimulante del folículo recombinante humana (r-hFSH) y luteinizante humana recombinante r-hLH (Pergoveris ®) en comparación con r -hFSH (Gonal-f ®)-único tratamiento.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

The current trial will enroll poor ovarian responders according to specific criteria that are aligned with the POR criteria defined by ESHRE.
At least 2 of the following 3 features must be present:
- Advanced maternal age (? 40 years)
- A previous POR (? 3 oocytes with a conventional stimulation protocol)
- An abnormal ovarian reserve test (ORT) (ie, anti-mullerian hormone [AMH] < 0.5 - 1.1 ng mL)
Additional inclusion criteria are:
1. Female subjects, 18 to < 41 years of age (according to date of birth at time of informed consent) who are eligible for ovarian stimulation and ART treatment, including ICSI
2. Absence of anatomical abnormalities of the reproductive tract that would interfere with implantation or pregnancy
3. Absence of any medical condition in which pregnancy is contraindicated
4. Body mass index 18 to 30 kg/m2, inclusive
5. Motile, ejaculatory sperm must be available (donated and/or cryopreserved sperm is allowed). Intracytoplasmic sperm injection will be allowed during this trial.
6. Minimum of 1 month without treatment with either clomiphene citrate or gonadotrophins prior to screening

En el ensayo en curso se inscribirá a pacientes con respuesta ovárica deficiente conforme a los criterios específicos que están en línea con los criterios POR ajustados definidos por la ESHRE.
Al menos dos de las tres siguientes caracteristicas deben estar presentes:
- La edad materna avanzada (? 40 años)
- A POR anterior (? 3 ovocitos con un protocolo de estimulación convencional)
- Una prueba de reserva ovárica anormal (ORT) (es decir, [HAM] <0,5 a 1,1 ng ml)
Los criterios adicionales de inclusión serán:
1.Pacientes de sexo femenino, de 18 < 41 años de edad (según la fecha de nacimiento en el momento del consentimiento informado) que sean aptas para el tratamiento de estimulación ovárica y TRA, incluida la IICE
2.Ausencia de anomalías anatómicas del aparato reproductor que pudieran interferir con la implantación o con el embarazo
3.Ausencia de cualquier patología médica en la que el embarazo estuviera contraindicado
4.Índice de masa corporal de 18 a 30 kg/m2, inclusive
5.Se debe disponer de esperma eyaculatorio con motilidad (se permite que sean espermatozoides donados y/o criopreservados). La inyección intracitoplasmática de espermatozoides estará permitida durante este ensayo.
6.Un mínimo de 1 mes sin tratamiento ya sea con citrato de clomifeno o gonadotropinas antes de la selección

E.4

Principal exclusion criteria

1. Two episodes of POR after maximal stimulation
2. History or presence of tumors of the hypothalamus or pituitary gland
3. History or presence of ovarian enlargement or cyst of unknown etiology, or presence of an ovarian cyst > 25 mm on the day of randomization
4. Presence of endometriosis grade III ? IV, confirmed or suspected
5. Presence of uni- or bilateral hydrosalpinx
6. Abnormal gynecological bleeding of undetermined origin
7. Contraindication to being pregnant and/or carrying a pregnancy to term
8. History or presence of ovarian, uterine or mammary cancer
9. Use of testicular or epididymal sperm

2.Dos episodios de POR después de estimulación máxima
3.Historial de presencia de tumores del hipotálamo o de la glándula pituitaria
4.Historial de presencia de ensanchamiento en el ovario o quiste de etiología desconocida, o de presencia de un quiste ovárico > 25 mm el día de la aleatorización
5.Presencia de endometriosis de grado III - IV, confirmada o sospechada
6.Presencia de hidrosálpinx unilateral o bilateral
7.Hemorragia ginecológica anómala de origen no determinado
8.Contraindicación para quedarse embarazada o llevar un embarazo a término
9.Patología médica significativa clínicamente concurrente (por ejemplo, diabetes) que pondría en peligro la seguridad de la paciente o interferiría con las evaluaciones del ensayo
10.Infección conocida con virus de inmunodeficiencia humana, virus activo de la hepatitis B o C en la mujer o en su pareja
11.Historial de presencia de cáncer de ovario, útero o mama

E.5 End points

E.5.1

Primary end point(s)

Total number of retrieved oocytes.

Número total de oocitos recuperados

E.5.1.1

Timepoint(s) of evaluation of this end point

On/before day 113 (Visit 12)

En/antes del día 113 (visita 12)

E.5.2

Secondary end point(s)

? Ongoing pregnancy rate (assessed on/before day 185 -Visit 16).
? Live birth rate (assessed on/before day 365 - Visit 17).
? Embryo implantation rate (determined on/before day 154 - Visit 15).
? Clinical pregnancy rate (determined on/before day 154 - Visit 15).
? Biochemical pregnancy rate (determined on/before day 132 - Visit 14).

? La tasa de embarazo en curso (evaluada en / antes del día 185-Visita 16).
? Tasa de nacimientos vivos (evaluada en / antes del día 365 - Visita 17).
? La tasa de implantación embrionaria (determinado en / antes del día 154 - Visita 15).
? Tasa de embarazo clínico (determinado en / antes del día 154 - Visita 15).
? Tasa de embarazo bioquímico (determinado en / antes del día 132 - Visita 14).

E.5.2.1

Timepoint(s) of evaluation of this end point

Visits 14 to 17 as described above

Visitas 14 a 17 como se describe más arriba

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

Yes

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)

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

Yes

E.8.1.4

Double blind

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)

Yes

E.8.2.2

Placebo

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

Belgium

Denmark

France

Italy

Netherlands

Sweden

Czech Republic

Estonia

Finland

Germany

Hungary

Latvia

Spain

Poland

Russian Federation

Turkey

United Kingdom

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

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:

946

F.1.3

Elderly (>=65 years)

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

Yes

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

862

F.4.2.2

In the whole clinical trial

946

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)

After a subject has completed the trial or has withdrawn early, usual treatment will be administered, if required, in accordance with the trial site?s standard of care and generally accepted medical practice and depending on the subject?s individual medical needs.

Después de un sujeto ha concluido ensayo o ha sido discontinuado, se administrará tratamiento habitual, si se requiere, de acuerdo con el estándar del centro de ensayo y generalmente se acepta la práctica médica y en función de las necesidades médicas individuales del sujeto.

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

2014-02-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-01-27

P. End of Trial
P.	End of Trial Status	Completed

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