Clinical Trials Register

Summary
EudraCT Number:	2017-004298-15
Sponsor's Protocol Code Number:	1601-ALC-002-MM
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Restarted
Date on which this record was first entered in the EudraCT database:	2018-08-14
Trial 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

2017-004298-15

A.3

Full title of the trial

A Phase III multicentre, randomized, unblinded clinical trial to test the effect
of treatment with recombinant LH prior to controlled ovarian stimulation in
poor ovarian responder women with an advanced maternal age

Ensayo clínico fase III multicéntrico, aleatorizado y abierto para comprobar
el efecto del tratamiento con LH recombinante previo a la estimulación
ovárica controlada en pacientes de edad materna avanzada con baja
respuesta ovárica

A.3.1

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

Recombinant LH prior to ovarian stimulation in poor ovarian responders (PRE-LH).

Tratamiento con LHr previo a la estimulación ovárica en pacientes con baja respuesta ovárica (PRE-LH)

A.4.1

Sponsor's protocol code number

1601-ALC-002-MM

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	IVI Alicante
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	IVI Alicante
B.4.2	Country	Spain
B.4.1	Name of organisation providing support	Merck 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	IVI Alicante
B.5.2	Functional name of contact point	Dr. Manuel Muñoz
B.5.3	Address:
B.5.3.1	Street Address	Avda. de Denia 111
B.5.3.2	Town/ city	Alicante
B.5.3.3	Post code	03015
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34966 01 24 90
B.5.5	Fax number	+34966 01 25 09
B.5.6	E-mail	Manuel.munoz@ivi.es

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	LUVERIS 75 UI, POLVO Y DISOLVENTE PARA SOLUCION INYECTABLE
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 solution 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	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	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

ovarian stimulation in poor ovarian responders

estimulación ovárica en baja respuesta ovárica

E.1.1.1

Medical condition in easily understood language

ovarian stimulation for assisted reproduction

estumulación de los ovarios para la reproducción asistida

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10071130
E.1.2	Term	Controlled ovarian stimulation
E.1.2	System Organ Class	100000004865

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 number of oocytes retrieved in poor ovarian responders with
advanced maternal age treated with rLH prior to the controlled ovarian stimulation protocol.

Evaluar el número de ovocitos recuperados en mujeres de edad materna
avanzada con baja respuesta tratadas con LHr previo al protocolo de estimulación ovárica controlada.

E.2.2

Secondary objectives of the trial

- Comparative analysis of the stimulation cycle
- Comparative analysis of oocyte quality parameters
- Comparative analysis of embryonic quality parameters
- Comparative analysis of clinical results in terms of reproductive success
- Assessment and recording of adverse events

- Análisis comparativo del ciclo de estimulación
- Análisis comparativo de los parámetros de calidad ovocitaria
- Análisis comparativo de los parámetros de calidad embrionaria
- Análisis comparativo de los resultados clínicos en términos de éxito reproductivo
- Evaluación y registro de los efectos adversos secundarios

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.- The current trial will include patients with POR according to specific criteria that are in line with the criteria defined by the ESHRE (Bologna Criteria), according to which a patient is classified as a poor ovarian responder when she meets two of the three of the following criteria:
I.- Previous episode of POR (> or = 3 oocytes) with conventional stimulation protocol.
II.- Abnormal ovarian reserve test with an antral follicle count (AFC) <5-7 and/or anti-mullerian
hormone values (AMH) <0.5-1.1 ng/mL.
III.- Women > or = 40 years old* and/or who have any other risk factor for POR.
In addition, two episodes of POR after maximal stimulation are sufficient to define a patient as poor
responder in the absence of advanced maternal age or abnormal ovarian reserve test.
2. Women > or = 35 to < or = 43 years for COS and assisted reproduction techniques (ART).
3.- Couple or single woman, accepting preimplantation genetic diagnosis (PGS) after blastocyst biopsy
and delayed transfer for selection of euploid embryos.
4.- Body Mass Index (BMI) between18 and 30 kg/m 2 , inclusive.
5.- Ejaculatory sperm with concentration > or = 5 mill spermatozoa/mL and > or = 5 mill total spermatozoa progressive motility. Bank and cryopreserved semen allowed.
6.- Informed consent completed, signed and dated.

1.-En el ensayo en curso se incluirá a pacientes con baja respuesta ovárica conforme a criterios
específicos que están en línea con los criterios definidos por la ESHRE (Criterios Bolonia, 2011),
según los cuales se cataloga a una paciente como baja respondedora cuando cumple dos de los
tres criterios siguientes:
I.- Episodio previo de baja respuesta ovárica (≤ 3 ovocitos) con protocolo convencional de
estimulación.
II.- Reserva ovárica anormal con un recuento de folículos antrales (RFA) < 5-7 y/o valores de la
hormona antimuleriana (AMH) < 0,5-1,1 ng/mL. Para simplificar, en nuestro estudio
tomaremos de referencia RFA <7 y AMH <1.1 ng/ml.
III.- Mujeres ≥ 40 años* y/o que presenten cualquier otro factor de riesgo de baja respuesta.
En ausencia de edad materna avanzada o reserva ovárica anormal, dos episodios previos de
baja respuesta ovárica con dosis máxima de estimulación se consideran condición suficiente
para definir a la paciente como baja respondedora ( Ferraretti et al., 2011)
2.- Mujeres de > o = 35* y < o = 43 años aptas para la estimulación ovárica controlada (EOC) y las técnicas
de reproducción asistida (TRA).
3.- La mujer, y su pareja en caso de que la hubiera, deben aceptar el diagnóstico genético
preimplantacional (DGP) tras biopsia de blastocisto y transferencia diferida para selección de
embriones euploides.
4.- Índice de masa corporal (IMC) de 18 a 30 kg/m 2 inclusive.
5.-Esperma eyaculatorio con concentración espermática > o = 5 millones/ml y motilidad > o = 5
millones de espermatozoides móviles progresivos totales. Se permite semen de banco y
criopreservado.
6.- Consentimiento informado comprendido, firmado y fechado.

E.4

Principal exclusion criteria

1.- Cases of recurrent spontaneous miscarriage (≥2 clinical miscarriages) or implantation failure (after
transfer of 6 good D3 embryos or 4 good blastocysts) will be excluded
2.- Use of testicular or epididymal spermatozoa as well as ejaculate with concentration < 5 mill
spermatozoa/mL and < 5 mill total spermatozoa progressive motility
3.- Primary ovarian failure, PCOS (in accordance with the Rotterdam criteria) or ovary/s inaccessible
for oocyte retrieval.
4.– Anatomical uterine abnormalities and any endometrium or myometrium pathology (adenomyosis,
polyps, myoma, etc.) that may interfere with implantation or pregnancy. Patients with previous
polypectomy, myomectomy or surgery for septate/subseptate/arcuatus uterus should not be
excluded.
5.- Presence of unilateral or bilateral hydrosalpinx that has not been surgically removed or ligated.
6.- Presence of level III-IV endometriosis.
7.- History of tumours in the hypothalamus or pituitary gland, or ovarian, uterine or breast cancer.
8.- Abnormal bleeding of undetermined origin.
9.- Known infection with human immunodeficiency virus, active hepatitis B or C virus in the woman or
her partner.
10.- Known allergy or hypersensitivity to the drugs administered during the trial.
11.- Concurrent significant medical pathologies that would endanger the patient's safety
(uncontrolled thyroid or adrenal dysfunction, severe hepatic or renal impairment, etc.) or interfere
with the test evaluations or the clinical outcomes (i.e. confirmed thrombophilia).
12.- Use of concomitant medication or any other circumstances that, in the opinion of the
investigator, interferes with the development of the trial or does not ensure the safety and efficacy of
the data.
13.- Simultaneous participation in another clinical trial or previous participation in this study.
14.- Participation in another clinical study two months before inclusion in the present study that could affect its objectives

1.- Se excluirán los casos de aborto de repetición (≥2 abortos clínicos) o fallo de implantación (tras
transferencia de 6 embriones D3 o de 4 blastocistos de buena calidad en ciclos previos).
2.- Uso de espermatozoides testiculares o epididimales, así como eyaculados con concentración
< 5 millones espermatozoides/mL (factor masculino grave) o < 5 millones de espermatozoides
móviles progresivos totales.
3.- Insuficiencia ovárica primaria, SOP (de acuerdo con los criterios Rotterdam) u ovario/s
inaccesibles para recuperación ovocitaria.
4.- Anomalías anatómicas uterinas u otras patologías endo/miometriales (adenomiosis, pólipos,
miomas, etc.) que pudieran interferir en los resultados del ciclo Se admiten pacientes con
polipectomía/miomectomía y metroplastia de útero septo/subsepto/arcuato previamente a la
inclusión en este estudio.
5.- Presencia de hidrosálpinx unilateral o bilateral, sin corrección quirúrgica previa a inclusión en
este estudio.
6.- Presencia de endometriosis de grado III-IV
7.- Historial de presencia de tumores de hipotálamo o de la glándula pituitaria, cáncer de ovario,
útero o mama.
8.- Hemorragia ginecológica anómala de origen desconocido.
9.- Infección conocida con virus de inmunodeficiencia humana, virus activo de la hepatitis B o C,
en la mujer o en su pareja si la hubiera.
10.- Alergia o hipersensibilidad conocida a los medicamentos administrados en el ensayo.
11.- Patologías médicas, significativas clínicamente, concurrentes que pondría en peligro la
seguridad de la paciente (disfunción tiroidea no corregida con tratamiento médico, disfunción
adrenal, insuficiencia hepática o renal severa, etc.) o que pueda interferir con las evaluaciones del
ensayo o los resultados clínicos (p.ej. trombofilia constatada y conocida previamente en la mujer).
12.- Uso de medicación concomitante y/o cualquier circunstancia que a criterio del investigador
no garantice la seguridad y eficacia de los datos del estudio, o interfiera con el desarrollo del
mismo.
13.- Participación simultánea en otro ensayo clínico o previa participación en este estudio.
14.- Participación en otro estudio clínico 2 meses antes de la inclusión en el presente estudio que
pudiera afectar a los objetivos del mismo.

E.5 End points

E.5.1

Primary end point(s)

number of oocytes retrieved

número de oocitos recuperados

E.5.1.1

Timepoint(s) of evaluation of this end point

Visit 6

E.5.2

Secondary end point(s)

Variables related to the stimulation cycle
Variables related to oocyte quality
Variables related to embryo quality
Variables of clinical success

Variables relacionadas con el ciclo de estimulación
Variables relacionadas con la calidad de los oocitos
variables relacionadas con la calidad de los embriones
variables relacionadas con el éxito clínico

E.5.2.1

Timepoint(s) of evaluation of this end point

- stimulation cycle: after the routine assisted reproduction procedures
- oocyte quality: after the routine assisted reproduction procedures performed in the IVF laboratory
- embryo quality: during the days of embryonic development in the IVF laboratory
- clincal success: after the routine assisted reproduction procedures

- ciclo de estimulación: tras los procedimientos rutinarios de reproducción asistida
- calidad de los oocito: tras los procedimientos rutinarios de reproducción asistida realizados en el laboratorio de fertilización in vitro
- calidad de los embriones: durante los días de desarrollo embrionario en el laboratorio de fertilización in vitro
- éxito clínico: tras los procedimientos rutinarios de reproducción asistida

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

E.6.5

Efficacy

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

Yes

E.6.13.1

Other scope of the trial description

assisted reproduction

reproducción asistida

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

Yes

E.8.1.3

Single blind

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Sin tratamiento

No treatment

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

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

Last Patient Last Visit

Última visita del último 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 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:

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

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.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)

Not applicable

No proced

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

2018-10-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-08-29

P. End of Trial
P.	End of Trial Status	Restarted

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