Clinical Trials Register

Summary
EudraCT Number:	2015-003412-20
Sponsor's Protocol Code Number:	DV-MV-MO
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2016-01-13
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

2015-003412-20

A.3

Full title of the trial

Efficacy and safety of hourly titrated misoprostol versus vaginal dinoprostone and misoprostol for cervical ripening and labor induction: randomized clinical trial.

Eficacia y seguridad de la administración de misoprostol por via oral en dosis tituladas frente a misoprostol y dinoprostona por via vaginal para la maduración cervical e inducción del parto: ensayo clínico aleatorio.

A.3.1

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

Efficacy and safety of hourly titrated misoprostol versus vaginal dinoprostone and misoprostol for and labor induction: randomized clinical trial.

Eficacia y seguridad de la administración de misoprostol por via oral en dosis tituladas frente a misoprostol y dinoprostona por via vaginal para l inducción del parto: ensayo clínico aleatorio.

A.3.2

Name or abbreviated title of the trial where available

DV-MV-MO

A.4.1

Sponsor's protocol code number

DV-MV-MO

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	Basque Health System
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	Basque Health System
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	Basque Health System
B.5.2	Functional name of contact point	Oihane Lapuente Ocamica
B.5.3	Address:
B.5.3.1	Street Address	Jose Atxotegui s/n
B.5.3.2	Town/ city	Vitoria-Gasteiz
B.5.3.3	Post code	01009
B.5.3.4	Country	Spain
B.5.4	Telephone number	34945007204
B.5.5	Fax number	34945007204
B.5.6	E-mail	OIHANE.LAPUENTEOCAMICA@osakidetza.eus

D. IMP Identification
D.IMP: 1
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	Misofar
D.2.1.1.2	Name of the Marketing Authorisation holder	Bial Industrial Farmaceutica, 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 tablet
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	Misoprostol
D.3.9.1	CAS number	59122-46-2
D.3.9.2	Current sponsor code	Misoprostol
D.3.9.3	Other descriptive name	MISOPROSTOL
D.3.9.4	EV Substance Code	SUB08998MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	25 to 150
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	Propess
D.2.1.1.2	Name of the Marketing Authorisation holder	Ferring S.A.U.
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 delivery system
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	Dinoprostone
D.3.9.1	CAS number	363-24-6
D.3.9.2	Current sponsor code	Misofar
D.3.9.3	Other descriptive name	DINOPROSTONE
D.3.9.4	EV Substance Code	SUB07195MIG
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: 3
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	oral misoprostol
D.3.2	Product code	oral misoprostol
D.3.4	Pharmaceutical form	Vaginal tablet
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	misoprostol oral
D.3.9.1	CAS number	59122-46-2
D.3.9.3	Other descriptive name	MISOPROSTOL
D.3.9.4	EV Substance Code	SUB08998MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(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.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

labor induction

Inducción del parto

E.1.1.1

Medical condition in easily understood language

labor induction

Inducción del parto

E.1.1.2

Therapeutic area

Body processes [G] - Physiological processes [G07]

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

Compare the percentage of women in each group who achieved vaginal delivery within 24 hours after the beginning of the administration in each group (oral misoprostol, vaginal misoprostol and intravaginal dinoprostone).

Comparar el porcentaje de mujeres en cada grupo que logra un parto vaginal a las 24 horas tras el inicio de la administración en cada grupo (misoprostol oral, misoprostol vaginal y dinoprostona intravaginal).

E.2.2

Secondary objectives of the trial

-Determinate the number of women who manage cervical favorable conditions at 12 and 24 hours after the beginning of the administration
-Analyze the percentage of women in each group who achieve vaginal delivery at 12 and 24 hours after the beginning of the administration in each group.
-Compare the number of women who achieve a vaginal delivery
-Analyze the number of caesarean sections
-Compare the percentage of women requiring oxytocin and mg
-Compare labor duration of in the 3 groups the length of the latent and active phase
-Compare the percentage of failed induction
-Determinate the percentage of women in each group having tachysystole and/or uterine hypertnya
-Compare the percentage of women who suffered from -severe postpartum hemorrhage
-Analyze the values of pH and Apgar at minute 1 and 5 on all children born alive
Compare the percentage of children with neonatal complications.
-Compare fetal or neonatal mortality
Estimate neonatal morbidity

-Determinar el número de mujeres que logran condiciones favorables cervical a las 12 y 24 horas después del inicio de la administración
-Analizar el porcentaje de mujeres en cada grupo que lograr el parto vaginal a las 12 y 24 horas después del inicio de la administración en cada grupo.
-Comparar el número de mujeres que lograr un parto vaginal
-Analizar el número de cesáreas
-Comparar el porcentaje de mujeres que requieren la oxitocina y mg
-Comparar la duracion del parto, de la fase latente y activa en cada grupo
-Comparar el porcentaje de inducciones fallida
-Determinar el porcentaje de mujeres en cada grupo que tiene taquisistolia y / o uterino hipertonia
-Comparar el porcentaje de mujeres que sufría de hemorragia posparto severa
-Analizar los valores de pH y de Apgar al minuto 1 y el 5 de todos los niños nacidos vivos
-Comparar el porcentaje de niños con complicaciones neonatales .
-La mortalidad fetal o neonatal -compare
.-Estimar la morbilidad neonatal

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

? Women over 18
? single pregnancy
? cephalic presentation
? intact membranes
? unfavorable cervix ( less than 6 Bishop )
? CTGR not reactive decelerative
? Signed informed consent by the patient.

? Mujeres mayores de 18 años
? Gestación única
? Presentación cefálica
? Membranas intactas
? Valore de cérvix desfavorables (Bishop inferior a 6)
? RCTG reactivo no decelerativo
? Consentimiento informado firmado por el paciente.

E.4

Principal exclusion criteria

? prior Cesarean section or previous uterine surgery .
? Allergy or intolerance to any of the study drugs
? stillbirth
? uterine growth restricted fetuses
? contraindication for vaginal delivery
? Anterior placenta
? Multiparity
? moderate to severe heart disease
? hypertensive disorders of pregnancy
? Suspected chorioamnionitis

? Dinámica uterina presente.
? Cesárea previa o cirugía uterina previa.
? Alergia o intolerancia a cualquier de los fármacos a estudio
? Feto muerto
? Fetos con crecimiento uterino restringido (CIR)
? Contraindicación para parto vaginal
? Placenta previa o vasa previ
? Multiparidad
? Cardiopatía moderada-grave
? Trastornos hipertensivos del embarazo
? Sospecha de corioamnionitos

E.5 End points

E.5.1

Primary end point(s)

Vaginal delivery within 24 hours after the begining of administration.

Parto vaginal en las primeras 24 horas tras el inicio de la administración

E.5.1.1

Timepoint(s) of evaluation of this end point

24 hours

24 horas

E.5.2

Secondary end point(s)

-Favorable cervix: This criterion is determined at 12 and 24 hours after initiation of drug administration . It is considered a favorable cervix should submit a Bishop equal to or greater than 6 .-This criterion is determined at 12 and 48 hours after the begining of drug administration.
-vaginal delivery: Eutocic and instrumental labor will be taken into account.
- number of cesarean sections
-oxitocin administration and dose(mg)
-labor duration (hour)
-active and latent phases duration (hours)
-Induction failure: Induction failure will be considered in case of incapacity of the patient into active labor after oxytocin for 12 ± 3 hours after the rupture of membranes.
-Taquisistolia:It will be considered when uterine activity occurs with 6 or more contractions in 10 min for at least 30 minutes.
-Hipertonía: It will be considered when uterine contraction maintained longer than 2 minutes produced complete relaxation occurs .
- Severe postpartum hemorrhage: All those postpartum hemorrhage requiring blood transfusion , positioning of intrauterine balloon , carrying uterine compression suture (B- Lynch) , radiological embolization , performing vascular ligatures, hysterectomy, ICU admission or death
-pH value and Apgar (1 and 5 minutes)
-neonatal morbidity: For the purposes of this study are considered fetal morbidity Apgar at 5 minutes less than 4, neonatal trauma , seizuresi in the first 24 hours of life, tracheal ventilation over 24 hours and / or hospitalization in neonatal unit of length equal to or greater than 5 days.

Cérvix favorable: Este criterio se determina a las 12 y 24 horas después del inicio de la administración del fármaco. Se considera un cuello uterino favorable debería presentar un Bishpo igual o superior a 6.
-Este Criterio se determina a las 12 y 48 horas después de que el comienzo de la administración del fármaco.
- Parto vaginal: Eutócico y mano de obra instrumentales se tendrán en cuenta.
- Número de cesáreas
- administración de oxitocina y la dosis (mg)
- Duración del parto (horas)
- Duración fases activa y latente(horas)
- Fracaso de la inducción: será considerada en caso de incapacidad del paciente de iniciar el trabajo de parto activo después de la adminsitración de oxitocina durante 12 ± 3 horas después de la rotura de membranas.
-Taquisistolia: Se considerará cuando la actividad uterina se produce con 6 o más contracciones en 10 minutos por lo menos durante 30 minutos.
-Hipertonía: Se considerará que la contracción uterina de más de 2 minutos sin producirse relajación completa.
- Hemorragia postparto severa: Todos aquella hemorragia posparto que requiere transfusión de sangre, la colocacion del balón intrauterino, realización de sutura de compresión uterina (B- Lynch), la embolización radiológica, la realización de ligaduras vasculares, histerectomía, ingreso en la UCI o la muerte
-pH valor de Apgar (1 y 5 minutos)
morbilidad -neonatal: A los efectos de este estudio se consideró la morbilidad fetal Apgar a los 5 minutos de menos de 4, trauma neonatal, crisis epilectica en las primeras 24 horas de vida, ventilación traqueal de más de 24 horas y / o la hospitalización en la unidad neonatal de duración igual a o mayor que 5 días.

E.5.2.1

Timepoint(s) of evaluation of this end point

between 12 hours and 3 days

entre 12 horas y 3 dias

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)

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

vaginal misoprostol and vaginal dinoprostona

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

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

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:

372

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

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

372

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

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

2016-08-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-07-17

P. End of Trial
P.	End of Trial Status	Ongoing

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