Clinical Trials Register

Summary
EudraCT Number:	2012-002215-26
Sponsor's Protocol Code Number:	M13-563
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:	2013-12-05
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

2012-002215-26

A.3

Full title of the trial

A Double-Blind, Double-Dummy, Randomized, Two-arm, Multicenter Study Comparing the Efficacy, Safety and Tolerability of Oral Dydrogesterone 30 mg daily versus Intravaginal Micronized Progesterone Capsules 600 mg daily for Luteal Support in In-Vitro Fertilization

Estudio multicéntrico, doble ciego, con doble simulación, aleatorizado, con dos grupos, para comparar la eficacia, seguridad y tolerabilidad de 30 mg diarios de didrogesterona oral frente a 600 mg diarios de progesterona micronizada intravaginal en cápsulas, como apoyo en la fase lútea de la fertilización in vitro (LOTUS I)

A.3.1

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

A study to compare if 30mg of oral Dydrogesterone is as good, tolerable and safe as 600mg of intravaginal capsules for luteal support in IVF pregnancies. This study will be conducted at several study sites and neither the patient or the doctor will know which of the two different treatments a patient will receive.

Un estudio para comparar si 30 mg de didrogesterona oral es tan bueno, tolerable y seguro como 600 mg de cápsulas intravaginales para el apoyo en la fase lútea de embarazos de fecundación in vitro . Este estudio se llevará a cabo en varios centros del estudio, y ni el paciente ni el médico sabrán cual de los dos tratamientos diferentes recibirá el paciente.

A.3.2

Name or abbreviated title of the trial where available

Lotus I

A.4.1

Sponsor's protocol code number

M13-563

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	Abbott Laboratories GmbH
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	Abbott Laboratories GmbH
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	Quintiles GmbH
B.5.2	Functional name of contact point	Simone Schicker
B.5.3	Address:
B.5.3.1	Street Address	Hugenottenallee 167
B.5.3.2	Town/ city	Neu-Isenburg
B.5.3.3	Post code	63263
B.5.3.4	Country	Germany
B.5.4	Telephone number	+496102 296 213
B.5.5	Fax number	+496102296296
B.5.6	E-mail	simone.schicker@quintiles.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	Duphaston 10 mg comprimés pelliculés
D.2.1.1.2	Name of the Marketing Authorisation holder	Abbott Products S.A.-N.V
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	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DYDROGESTERONE
D.3.9.1	CAS number	152-62-5
D.3.9.4	EV Substance Code	SUB06433MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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.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	Utrogestan 200mg capsules
D.2.1.1.2	Name of the Marketing Authorisation holder	Laboratoires BESINS INTERNATIONAL
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	Vaginal capsule, soft
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	micronised progesterone
D.3.9.1	CAS number	9002-68-0
D.3.9.3	Other descriptive name	PROGESTERONE, MICRONISED
D.3.9.4	EV Substance Code	SUB45084
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
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	Tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Vaginal capsule, soft
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

Female infertility

Infertillidad femenina

E.1.1.1

Medical condition in easily understood language

Female inability to conceive a child

Incapacidad femenina para concebir un hijo

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10003540
E.1.2	Term	Assisted fertilization
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

The primary objective is to demonstrate non-inferiority of oral dydrogesterone 10 mg TID versus micronized progesterone vaginal capsules 200 mg TID. The primary efficacy parameter is the presence of fetal heart beats at 12 weeks? gestation determined by transvaginal ultrasound.

El objetivo principal es demostrar la no inferioridad de la dosis de 10 mg de didrogesterona suministrados por vía oral tres veces al día en comparación con cápsulas de 200 mg de progesterona micronizada intravaginal suministrados tres veces al día. El parámetro de eficacia principal es la presencia de latido fetal a las 12 semanas de gestación apreciado mediante ultrasonido transvaginal.

E.2.2

Secondary objectives of the trial

The secondary objectives and parameters are a positive pregnancy test on Day 14 after embryo transfer, the incidence of live births and healthy newborns.
The safety objective is to obtain safety and tolerability data by means of documentation of treatment emergent adverse events (TEAE) during the entire study period. In addition, data on vital signs, physical examination findings, and routine laboratory values will be obtained. Furthermore, signs and symptoms of threatened abortion, the rate of hypospadias and the rate of masculinization in female babies will be recorded. The time of delivery (pregnancy week) and the following parameters of the newborn will be obtained at delivery: gender, APGAR Score, weight, height, head circumference, abnormal findings of physical examination and any malformations.

Los parámetros y objetivos secundarios son una prueba de embarazo positiva el día 14 después de haberse realizado la transferencia de embriones y la incidencia de nacidos vivos y recién nacidos sanos.
El objetivo de seguridad es obtener datos sobre seguridad y tolerabilidad mediante la documentación de los acontecimientos adversos surgidos durante el tratamiento a lo largo de todo el período de estudio. Por otro lado, se obtendrán datos sobre las constantes vitales, los hallazgos realizados gracias a la exploración física y los valores rutinarios de laboratorio. Además, se registrarán los signos o síntomas en caso de amenaza de aborto, el índice de hipospadias y el índice de virilismo en bebés femeninos. La fecha del parto (semana de embarazo) y los siguientes parámetros del recién nacido se obtendrán en el parto: género, índice de Apgar, peso, altura, circunferencia de la cabeza, hallazgos inusuales durante la exploración física y cualquier malformación.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed informed consent;
2. Premenopausal females, age > 18 years < 42 years
3. Non-smokers. For females who were past smokers, they must have stopped tobacco usage for at least 3 months prior baseline visit
4. Early follicular phase (Day 2-4) FSH (Follicle stimulating hormone) less than or equal to 15 IU/L and estradiol (E2)within normal limits
5. LH (luteinizing hormone), PRL (prolactin), T (testosterone) and TSH (thyroid-stimulating hormone), within the normal limits for the clinical laboratory, or considered not clinically significant by the Investigator within 6 months prior to screening
6. Documented history of infertility (e.g., unable to conceive for at least one year or for 6 months for women ? 38 years of age or bilateral tubal occlusion or absence)
7. Normal transvaginal ultrasound at screening (or within 14 days of screening) without evidence of clinically significant abnormality consistent with finding adequate for ART with respect to uterus and adnexa (no hydrosalpinx or clinically relevant uterine fibroids)
8. Negative pregnancy test on the day of pituitary down regulation (prior to administration of GnRH agonist or GnRH antagonist)
9. Clinically indicated protocol for induction of IVF with a fresh embryo
10. Single or dual embryo transfer
11. BMI ? 18 and ? 30 kg/m2

1. Firma del consentimiento informado.
2. Mujeres premenopáusicas con edades comprendidas entre los 18 y los 42 años.
3. No fumadoras. Aquellas mujeres que hayan sido fumadoras anteriormente deben haber dejado de fumar al menos 3 meses antes de la visita inicial.
4. En la primera fase folicular (de los días 2 a 4) los niveles de hormona foliculoestimulante (FSH) deben ser menores o iguales a 15 UI/l y los niveles de estradiol (E2) deben estar dentro de los límites normales.
5. Los niveles de hormona luteinizante (luteinizing hormone, LH), prolactina (PRL), testosterona (T) y tirotropina (thyroid-stimulating hormone, TSH) durante los 6 meses anteriores a la selección deben estar dentro de los límites que el laboratorio clínico considere normales o que el investigador no considere clínicamente importantes.
6. Historial de infertilidad documentado (por ejemplo, casos de mujeres que no han podido concebir en el último año, o en los últimos 6 meses para mujeres de 38 años o más, o de mujeres con oclusión tubaria bilateral o ausencia de trompas).
7. Ultrasonido transvaginal normal en el momento de la selección (o dentro de los 14 días antes de la selección) sin que exista ninguna evidencia de anomalías clínicas importantes consistentes con hallazgo suficiente para someterse a la tecnología de reproducción asistida con respecto al útero u otros órganos anexos (ausencia de hidrosalpinges o de miomas uterinos clínicamente relevantes).
8. Prueba de embarazo negativa el día de la regulación descendente de la pituitaria (con anterioridad al suministro del fármaco agonista de GnRH y el antagonista de GnRH).
9. Protocolo clínico indicado para la inducción de la FIV con un embrión fresco.
10. Transferencia única o dual de embriones.
11. IMC mayor o igual a 18 y menor o igual a 30 kg/m2.

E.4

Principal exclusion criteria

1. Evidence of cardiovascular, respiratory, urogenital, gastrointestinal/hepatic, hematologic/immunologic, HEENT (head, ears, eyes, nose, throat), dermatologic/connective tissue, musculoskeletal, metabolic/nutritional, endocrine, neurologic/psychiatric, allergy, recent major surgery (< 3 months), or other relevant diseases as revealed by history, physical examination and/or laboratory assessments which could limit participation in or completion of the study;
2. Acute urogenital disease
3. Known allergic reactions to progesterone products
4. Known allergic reactions to peanuts and peanut oil
5. Intake of experimental drug or participation in any other clinical trial within 30 days prior to study start
6. Mental disability or any other lack of fitness, in the Investigator's opinion, to preclude subjects to participate in or to complete the study
7. Current or recent substance abuse, including alcohol and tobacco (Note: Patients who stopped tobacco usage at least 3 months prior to screening visit would be allowed)
8. History of chemotherapy or radiotherapy
9. Patients with more than 3 unsuccessful IVF attempts
10. Contraindication for pregnancy
11. Refusal or inability to comply with the requirements of the study protocol for any reason, including scheduled clinic visits and laboratory tests
12. History of recurrent pregnancy loss defined as 3 or more spontaneous miscarriages

1. Prueba de existencia de afecciones cardiovasculares, respiratorias, genitourinarias, gastrointestinales/hepáticas, hematológicas/inmunológicas, que afecten a la cabeza, oídos, ojos, nariz o garganta, afecciones dermatológicas o del tejido conectivo, musculoesqueléticas, metabólicas o nutricionales, endocrinas, neurológicas o psiquiátricas, alergias o cirugía mayor reciente (menos de 3 meses), así como otras enfermedades relevantes que se encuentren incluidas en la historia clínica, que se hallen durante la exploración física o en las evaluaciones de laboratorio que puedan limitar la participación de la paciente o evitar que esta complete el estudio.
2. Enfermedad grave genitourinaria.
3. Reacciones alérgicas conocidas a productos con progesterona.
4. Reacciones alérgicas conocidas a cacahuetes o al aceite de cacahuete.
5. Que haya ingerido algún medicamento experimental o participado en algún otro estudio clínico 30 días antes del inicio del estudio.
6. Discapacidad mental o cualquier otro problema de salud, según la opinión del investigador, que impida la participación del sujeto o evitar que esta complete el estudio.
7. Cualquier caso reciente de abuso de sustancias, incluyendo el tabaco y el alcohol (Nota: Se permitirá la participación de pacientes que hayan dejado de fumar al menos tres meses antes de la visita de selección).
8. Pacientes que se hayan sometido a quimioterapia o radioterapia.
9. Pacientes que se hayan sometido a la FIV más de 3 veces sin éxito.
10. Pacientes a las que se haya contraindicado el embarazo.
11. Rechazo o incapacidad de cumplir los requisitos establecidos por el protocolo del estudio debido a cualquier razón, incluyéndose incompatibilidad con los horarios de las visitas a la clínica o con las pruebas de laboratorio.
12. Pacientes con historia de aborto recurrente, definido como 3 o más abortos espontáneos.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy parameter is the pregnancy rate defined as the presence of fetal heart beats at 12 weeks? gestation determined by transvaginal ultrasound.

El parámetro de eficacia principal es el embarazo definido por la presencia de latido fetal a las 12 semanas de gestación apreciado mediante ultrasonido transvaginal.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 weeks? gestation

12 semanas de gestación

E.5.2

Secondary end point(s)

The secondary parameters are a positive pregnancy test on Day 14 after embryo transfer, the incidence of live births and healthy newborns.
Further secondary parameters are gender and APGAR score as well as the height, weight and head circumference of the newborn (s).
In addition, a physical examination of the newborn will be performed and any malformations will be recorded.

Los parámetros y objetivos secundarios son una prueba de embarazo positiva el día 14 después de haberse realizado la transferencia de embriones y la incidencia de nacidos vivos y recién nacidos sanos.
Otros parámetros secundarios son el sexo y el índice de Apgar, así como la altura, el peso y el perímetro cefálico del recién nacido (s).
Además, se realizará un exploración físico del recién nacido y se grabará cualquier malformación.

E.5.2.1

Timepoint(s) of evaluation of this end point

Day 14 after embryo transfer and birth

Día 14 después de la transferencia de embriones y el nacimiento

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

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

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

India

Israel

Austria

Russian Federation

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

End of Study is defined as Last Subject Last Visit

Fin del estudio esta definido para la última visita del último sujeto

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:

1066

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

Yes

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

590

F.4.2

For a multinational trial

F.4.2.1

In the EEA

705

F.4.2.2

In the whole clinical trial

1066

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

2014-01-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-12-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-09-06

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