Clinical Trials Register

Summary
EudraCT Number:	2016-005206-19
Sponsor's Protocol Code Number:	FFIS/2016/02/ST
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:	2017-07-12
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2016-005206-19

A.3

Full title of the trial

Randomised Controlled Trial with Pravastatin versus Placebo for Prevention of Preeclampsia

Ensayo clinico randomizado controlado con Pravastatina para la prevención de preeclampsia.

A.3.1

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

Prevention of preeclampsia (high blood pressure): Randomised trial of Pravastatin versus placebo

Prevención de preeclampsia (alta presión sanguínea): Ensayo clínico randomizado de Pravastatina frente a placebo.

A.3.2

Name or abbreviated title of the trial where available

STATIN

A.4.1

Sponsor's protocol code number

FFIS/2016/02/ST

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 (FFIS)
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.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fundación para la formación sanitaria de la región de Murcia
B.5.2	Functional name of contact point	Lola Serna Guirao
B.5.3	Address:
B.5.3.1	Street Address	Sanitarias de la Región de Murcia, C/ Luis Fontes Pagán, 9, 1ª planta
B.5.3.2	Town/ city	Murcia
B.5.3.3	Post code	30003
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034968 359763
B.5.5	Fax number	0034968 359777
B.5.6	E-mail	lola.serna@carm.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	Pravastatina 20mg
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA UK LIMITED
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Pravastatin
D.3.4	Pharmaceutical form	Capsule
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	Pravastatin Sodium
D.3.9.1	CAS number	81093-37-0
D.3.9.3	Other descriptive name	Pravastatina
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	20
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
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Pre-eclampsia

E.1.1.1

Medical condition in easily understood language

Raised blood pressure in pregnancy as a result of abnormal function of the placenta

Tensión arterial elevada durante el embarazo como resultado de la función anormal de la placenta

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10036485
E.1.2	Term	Pre-eclampsia
E.1.2	System Organ Class	10036585 - Pregnancy, puerperium and perinatal conditions

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 examine if the use of Pravastatin starting at 35-36 weeks' gestation in women at increased risk of developing pre-eclampsia (high blood pressure in pregnancy) reduces the incidence and severity of this complication.

Examinar si el uso de pravastatina a partir de la gestación 35-36 semanas en mujeres con mayor riesgo de desarrollar preeclampsia (presión arterial alta durante el embarazo) reduce la incidencia y la gravedad de esta complicación.

E.2.2

Secondary objectives of the trial

To examine if the use of Pravastatin reduces the incidence of delivery due to complications from high blood pressure, fetal growth restriction, stillbirth or neonatal complications, rate of neonatal intensive care unit admission, and the incidence of placental abruption (separation). A safety assessment of pravastatin administration during pregnancy will also be undertaken.

Examinar si el uso de pravastatina reduce el impacto de parto debido a las complicaciones de la hipertensión arterial, la restricción del crecimiento fetal, muerte fetal o complicaciones neonatales, la tasa de admisión en la unidad de cuidados intensivos neonatal , y la incidencia de desprendimiento de la placenta (separación). Se realizará una evaluación de la seguridad de la administración de pravastatina durante el embarazo .

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

For the screening study:
• Singleton pregnancy;
• Live fetus at 35+0-36+6 weeks’ gestation;
• Informed and written consent.

For the randomised trial:
• Same as for screening
• High-risk for term-PE at screening by the algorithm combining maternal history and characteristics, MAP, PLGF and sFLT-1;
• Informed and written consent.

Para el estudio de cribado:
• embarazo simple;
• feto vivo de gestación 35 + 0-36 + 6 semanas;
• firma de Consentimiento informado.

Para el ensayo aleatorio:
• Lo mismo que para el cribado
• Alto riesgo de plazo-PE en el cribado por la historia materna algoritmo de la combinación y características, MAP, PIGF y sFlt-1;
• Firma de consentimiento informado.

E.4

Principal exclusion criteria

For the screening study:
• Age <18 years;
• Multiple pregnancy;
• Unconscious or very ill;
• Serious mental illness;
• Learning difficulties;
• Not fluent in local language and absence of interpreter.

For the randomised trial:
• Same as for screening, but in addition:
• Major fetal abnormality;
• Women with established PE;
• Statin use within 28 days prior to randomisation;
• Women with contraindications for statin therapy:
-Hypersensitivity to pravastatin or any component of the product;
-Lactose intolerance
-Current or previous cancer
-Previous solid organ transplant
-Active liver disease (acute hepatitis, chronic active hepatitis) in the past 6 months
-Chronic renal disease/insufficiency with baseline serum creatinine >1.5mg/dL
-History of myopathy or rhabdomyolysis;
-ALT and/or AST levels ≥ 2 x the upper limit of normal
-Creatine kinase levels ≥ 5 x the upper limit of normal
-Concurrent and chronic (>6 months) use of medications with potential drug interactions with statins, such as immunosuppressive drugs, fibrates, gemfibrozil, niacin, protease inhibitors, efavirenz (non-nucleoside reverse transcriptase inhibitor), erythromycin, clarithromycin, itraconazole, cholestyramine, digoxin, rifampicin (patients will not be excluded if the drug has been discontinued, or is prescribed for a short duration of time);
• Participating in another intervention study that influences the outcomes of this study.

Para el estudio de cribado:
• Edad <18 años;
• Embarazo múltiple;
• Estar inconsciente o muy enfermo;
• Enfermedad mental grave;
• Las dificultades de aprendizaje;
• No hablar el idioma local con fluidez y la falta de intérprete.

Para el ensayo aleatorio:
• Lo mismo que para la detección, el propósito, además:
• Anomalía fetal mayor ;
• Las mujeres con PE establecida;
• El uso de estatinas dentro de los 28 días antes de la aleatorización;
• Las mujeres con contraindicaciones para la terapia con estatinas: Hipersensibilidad a pravastatina y a cualquier componente del producto;
  - intolerancia a la lactosa
  - cáncer -actual o la anterior
  - trasplante de órgano sólido previo
  - enfermedad hepática activa (hepatitis aguda, hepatitis crónica activa) en los últimos 6 meses
  - Enfermedad renal crónica / insuficiencia renal con creatinina en suero > 1,5 mg / dl
  -Historia de miopatía o rabdomiólisis;
  -Niveles ALT y / o AST ≥ 2 x el límite superior normal
-Niveles de creatina quinasa ≥ 5 superior al limite superior normal
  -Uso crónico (> 6 meses) de medicamentos con potenciales interacciones medicamentosas con estatinas, tales como fármacos inmunosupresores, fibratos, gemfibrozil, niacina, inhibidores de proteasa, efavirenz (inhibidor de la transcriptasa inversa no nucleósido), eritromicina, claritromicina, itraconazol, colestiramina , digoxina, rifampicina (pacientes no será excluida si el medicamento ha sido descontinuado, o se prescribe por un corto período de tiempo);
• Estar participando en otro estudio que influya en los resultados de este estudio.

E.5 End points

E.5.1

Primary end point(s)

Incidence of PE after randomisation

Incidencia de preeclampsia después de la randomización

E.5.1.1

Timepoint(s) of evaluation of this end point

Once delivered, data on pregnancy outcome, including labour onset, gestational age at delivery, mode of delivery, development of hypertension in pregnancy, neonatal birth weight and gender, and other obstetrics complications, will be collected from the hospital maternity records or their general medical practitioners. In addition, the obstetric records of women with pre-existing or pregnancy associated hypertension will be examined to determine if the condition is pre-eclampsia requiring delivery after randomisation.

Tras el parto , los datos son el resultado del embarazo, incluyendo un comienzo de parto, la edad gestacional al momento del parto, método de administración, el desarrollo de la hipertensión en el embarazo, el peso al nacer neonatal y de género, y otras complicaciones obstétricas será Ficheros gestionan desde la maternidad de un hospital general médico Sus discos de oro Los practicantes. Además, los registros obstétricos de las mujeres con hipertensión preexistente o asociada al embarazo será examinada para determinar si la condición de la preeclampsia es el parto que requieren después de la aleatorización.

E.5.2

Secondary end point(s)

• To determine the effect of pravastatin on adverse outcome of pregnancy at any gestation.
o PE, with delivery at any gestation
o GH, with delivery at any gestation
o SGA (<5th percentile), with delivery at any gestation
o Stillbirth at any gestation
o Placental abruption (clinically or on placental examination) at any gestation
o Composite of any of the above
• To determine the effect of pravastatin on adverse outcome of pregnancy at >37 weeks’ gestation.
o PE, with delivery at >37 weeks
o GH, with delivery at >37 weeks
o SGA (<5th percentile), with delivery at >37 weeks
o Stillbirth at >37 weeks
o Placental abruption (clinically or on placental examination) at >37 weeks
o Composite of any of the above
• To determine the effect of pravastatin on stillbirth or neonatal death
o Neonatal death
o Neonatal morbidity
o To determine the effect of pravastatin on neonatal morbidity Intraventricular haemorrhage,neonatal sepsis, neonatal anaemia, respiratory distress syndrome, necrotising enterocolitis
o Composite of any of the above
• To determine the effect of pravastatin on neonatal therapy
o Neonatal intensive care unit admission
o Ventilation - Defined as need of positive pressure (continuous positive airway pressure (CPAP) or nasal continuous positive airway pressure (NCPAP)) or intubation
o Composite of any of the above
• To determine the effect of pravastatin on the incidence of low birthweight below the 3rd, 5th and 10th centile.
o Birthweight will be recorded in the participants’ medical notes and birthweight percentile for gestational age at delivery is calculated using a normal range derived from our population.
• To determine the effect of pravastatin on sFLT-1 and PLGF value 1 and 3 weeks after the onset of treatment
• Pravastatin safety assessment during pregnancy

• Determinar el efecto de pravastatina resultado adverso del embarazo están en cualquier edad gestacional.
- PE, con parto en cualquier gestacion
- GH, con parto en cualquier gestacion
- SGA (<percentil 5), con parto en cualquier gestación
- La muerte fetal o en cualquier gestacion
- Desprendimiento de la placenta o (Clínica o en examen placentario) en cualquier gestación
- Composición de cualquiera de las anteriores
• Determinar el efecto de los resultados adversos del embarazo pravastatina está en gestación> 37 semanas.
- PE, con parto en> 37 semanas
- GH, con parto en> 37 semanas
- SGA (<percentil 5), con parto en> 37 semanas
- La muerte fetal o en> 37 semanas
- Desprendimiento de la placenta o (Clínica o en examen placentario) a> 37 semanas
- composición de las anteriores
• Determinar el efecto de la pravastatina es la muerte fetal o neonatal
- la muerte neonatal
- morbilidad neonatal
- Para determinar el efecto de pravastatina es neonatal hemorragia morbilidad intraventricular, sepsis neonatal, anemia neonatal, síndrome de dificultad respiratoria, enterocolitis necrotizante
- compuesto de cualquiera de las anteriores
• Determinar el efecto de la pravastatina es la terapia neonatal
- unidad de cuidados intensivos neonatales de admisión
- Ventilación - definida como la necesidad de presión positiva (presión positiva continua en vía aérea (CPAP) o presión positiva continua nasal (CPAP)) intubación
-composicion de cualquiera de las anteriores
• Determinar el efecto de pravastatina sobre la incidencia de bajo peso al nacer por debajo de la tercero, quinto y décimo percentil.
El peso al nacer se registrará en las notas médicas de los participantes y el percentil de peso al nacer para la edad gestacional al momento del parto se calcula utilizando una rangos normales derivadas de nuestra población.
• Para determinar el efecto de la pravastatina en sFlt-1 y PlGF valor de 1 y 3 semanas después del inicio del tratamiento

E.5.2.1

Timepoint(s) of evaluation of this end point

Once delivered, data on pregnancy outcome, including labour onset, gestational age at delivery, mode of delivery, development of hypertension in pregnancy, neonatal birth weight and gender, and other obstetrics complications, will be collected from the hospital maternity records or their general medical practitioners.
Neonatal outcomes will be collected from Special Care Baby Unit.

Una vez nazca el bebe, los datos son el resultado del embarazo, incluyendo un comienzo de trabajo de parto , la edad gestacional al momento del parto, método de parto, el desarrollo de la hipertensión en el embarazo, el peso al nacer neonatal y de género, y otras complicaciones obstétricas serán recogidas de los archivos del Hospital .
Los resultados neonatales serán recogidos de la unidad de cuidados especiales neonatales

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

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

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

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

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 6 weeks 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 patient (n=1,120) with details of their complete pregnancy outcome. This will take approximately 15 months to complete.

El final del estudio para los participantes individuales se definirá como socio de 6 semanas después del nacimiento del bebé / final del embarazo.

Al final del estudio en su conjunto se define como la última visita del último paciente (n = 1.120) con los detalles de su resultado total embarazo. Serán necesarios los 15 meses aproximadamente.

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