Clinical Trials Register

Summary
EudraCT Number:	2015-005180-16
Sponsor's Protocol Code Number:	FFIS/2015/02/EV
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-01-17
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

Bulgarian Drug Agency

A.2

EudraCT number

2015-005180-16

A.3

Full title of the trial

Early vaginal progesterone for the prevention of spontaneous preterm birth in twins: A randomised, placebo controlled, double-blinded trial.

A.3.1

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

Prevention of preterm birth in twin pregnancies - “Randomised trial of progesterone versus placebo”

A.3.2

Name or abbreviated title of the trial where available

EVENTS

A.4.1

Sponsor's protocol code number

FFIS/2015/02/EV

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN66445401

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1175-4589

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	Fundación para la Formación e Investigación Sanitaria
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	Fetal Medicine Foundation
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	Laboratoires Besins International
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fetal Medicine Foundation
B.5.2	Functional name of contact point	Professor Kypros Nicolaides
B.5.3	Address:
B.5.3.1	Street Address	137 Harley Street
B.5.3.2	Town/ city	London
B.5.3.3	Post code	W1B 6BG
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	442032998256
B.5.6	E-mail	thanos@fetalmedicine.org

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	Utrogestan
D.3.4	Pharmaceutical form	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	Progesterone
D.3.9.1	CAS number	57-83-0
D.3.9.4	EV Substance Code	AS1
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	300
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	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

Spontaneous preterm birth in twin pregnancies.

E.1.1.1

Medical condition in easily understood language

Spontaneous preterm birth in twin pregnancies.

E.1.1.2

Therapeutic area

Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10023555
E.1.2	Term	Labour premature
E.1.2	System Organ Class	100000004868

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Does the use of high dose vaginal progesterone (Utrogestan) started in the first trimester reduce the chances of having a preterm birth before 34 weeks gestation in twin pregnancies?

E.2.2

Secondary objectives of the trial

Does the use of high dose vaginal progesterone from the first trimester of pregnancy reduce any of the following in twin pregnancies:
1. The rate of preterm delivery before 37 weeks,
2. The number of babies born that are low birthweight,
3. The number of stillborn babies or babies that die soon after birth,
4. The number of babies that are admitted to the neonatal intensive care unit or suffer from significant adverse outcomes that are associated with prematurity.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age > 18 years;
• DCDA or MCDA twin pregnancies;
• Live fetuses at 11-13 weeks of gestation;
• Fluent in local language (otherwise interpreters will be used);
• Informed and written consent.

E.4

Principal exclusion criteria

• Pregnancies complicated by major fetal abnormality or nuchal translucency thickness >3.5 mm identified at the 11-13 weeks’ scan;
• MCDA twin pregnancies in which there are early signs of twin-totwin
transfusion syndrome (TTTS), defined as 20% discordance in
crown-rump length (CRL) at the 11-13 weeks scan;
• Women who are unconscious or severely ill, those with learning
difficulties, or serious mental illness;
• Hypersensitivity to progesterone;
• Women taking progesterone at any time within the previous 7 days;
• Participation in another drug trial at any time within the previous 28
days;
• Severe hepatic dysfunction [AST or ALT >3 times the upper limit of
normal (ULN) or bilirubin >2 x ULN], mammary or genital tract
carcinoma, thrombophlebitis or thromboembolic disorders
• Porphyria
• Cerebral haemorrhage
• Allergy to sunflower oil, soy lethicin, gelatin, glycerol (E422),
titanium dioxide (E171)

E.5 End points

E.5.1

Primary end point(s)

Primary outcome: To determine the effect of progesterone on the incidence of spontaneous birth between 24+ 0 weeks (168 days) and 33+ 6weeks’s gestation inclusive (237 days).

E.5.1.1

Timepoint(s) of evaluation of this end point

Metric/method of measurement – Data on pregnancy outcome will be collected from hospital maternity records or general practitioners. The obstetric records of all participants delivered at <34 weeks (<238 days) will be examined to determine if the preterm birth is iatrogenic or spontaneous. The latter includes those with spontaneous onset of labour
and those with preterm pre-labour rupture of membranes.

E.5.2

Secondary end point(s)

• The incidence of spontaneous preterm birth between 24+0 (168 days) and 27+6 weeks’ gestation inclusive (195 days), 29+6 weeks (209 days), 31+6 weeks (223 days), 36+6 weeks (258 days);
• The incidence of total preterm birth between 24+0 (168 days) and 27+6 weeks’ gestation (195 days), 29+6 weeks (209 days), 31+6 weeks (223 days), 33+6 weeks (237 days), 36+6(258 days);
• Incidence of all births from randomization to <28, <30, <32 and <34 weeks’ gestation
• Incidence of birth between randomization and 23+6 weeks’ gestation
• Incidence of stillbirth or neonatal death due to any cause;
• Incidence of birth weight below the 3rd, 5th and 10th percentile;
• Neonatal morbidity
- Major adverse outcomes before discharge from the hospital
- Intraventricular haemorrhage (grade II or above),
- Respiratory distress syndrome (requiring ventilation and surfactant),
- Retinopathy of prematurity,
- Necrotizing entercolitis (requiring surgical intervention),
- Neonatal sepsis (confirmed by bacteraemia in cultures)
- Neonatal anaemia (low haemoglobin requiring blood transfusion)
- Composite of any of the above
• Neonatal therapy
- Admission to neonatal intensive care unit,
- Ventilation - defined as need of positive pressure (continuous positive airway pressure [CPAP] or nasal continuous positive airway pressure [NCPAP]) or intubation,
- Composite of any of the above

E.5.2.1

Timepoint(s) of evaluation of this end point

Data on pregnancy outcome will be collected from hospital maternity records or general practitioners. The obstetric records of all patients delivered at <34 weeks' (<238 days) will be examined to determine if the preterm birth is iatrogenic or spontaneous. The latter includes those with spontaneous onset of labour and those with preterm pre-labour rupture of membranes. In the event when the neonates are admitted to Special Care Baby Unit (SCBU)/Neonatal Intensive Care Unit (NICU), additional neonatal outcomes will be collected from the discharge summary of SCBU/NICU.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

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

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

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

Yes

E.8.4

The trial involves multiple sites in the 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

E.8.6.2

Trial being conducted completely outside of the EEA

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

The end of the study for individual participants will be defined as 30 days after the birth of the baby/end of the pregnancy. The end of the study as a whole will be defined as the last visit of the last participant with details of their complete pregnancy outcome. This will take approximately 18 months to complete.

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