Clinical Trials Register

Summary
EudraCT Number:	2018-004212-21
Sponsor's Protocol Code Number:	AMAG-423-201
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2019-06-11
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

2018-004212-21

A.3

Full title of the trial

A Phase 2b/3a, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of the Efficacy and Safety of AMAG-423, a Digoxin Immune Fab, in Antepartum Subjects with Severe Preeclampsia

Estudio de fase IIb/IIIa, multicéntrico, aleatorizado, de grupos paralelos, con enmascaramiento doble y controlado con placebo para evaluar la eficacia y la seguridad de AMAG-423, un fragmento ab de anticuerpos antidigoxina, en pacientes embarazadas con preeclampsia grave

A.3.1

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

A research study to evaluate the experimental drug AMAG-423 to see how well it works and how safe it is in women who are near child birth who develop a condition called severe preeclampsia.

Estudio de investigación para evaluar el fármaco experimental AMAG-423 con el fin de determinar en qué medida funciona bien y resulta seguro en mujeres próximas al parto y que hayan desarrollado una enfermedad conocida como preeclampsia grave.

A.4.1

Sponsor's protocol code number

AMAG-423-201

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	AMAG Pharmaceuticals, Inc.
B.1.3.4	Country	United States
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	AMAG Pharmaceuticals, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AMAG Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Medical Information
B.5.3	Address:
B.5.3.1	Street Address	1100 Winter Street
B.5.3.2	Town/ city	Waltham
B.5.3.3	Post code	MA 02451
B.5.3.4	Country	United States
B.5.4	Telephone number	+1877411-2510
B.5.6	E-mail	amag@druginfo.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	DigiFab [Digoxine Immune Fab (Ovine)]
D.2.1.1.2	Name of the Marketing Authorisation holder	Protherics 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	AMAG-423
D.3.2	Product code	AMAG-423
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DIGOXIN IMMUNE FAB (OVINE)
D.3.9.3	Other descriptive name	DIGOXIN IMMUNE FAB (OVINE)
D.3.9.4	EV Substance Code	SUB129895
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	40
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)	Yes
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	Solvent for solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Severe Preeclampsia

Preeclampsia grave

E.1.1.1

Medical condition in easily understood language

Severe Preeclampsia

Preeclampsia grave

E.1.1.2

Therapeutic area

Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09]

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	10040444
E.1.2	Term	Severe pre-eclampsia
E.1.2	System Organ Class	100000004868

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine the efficacy of AMAG-423 for the prevention of intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), or death in the offspring of women with severe preeclampsia.

Determinar la eficacia de AMAG-423 para la prevención de la hemorragia intraventricular (HIV), la enterocolitis necrotizante (ECN) o la muerte en los bebés de mujeres con preeclampsia grave.

E.2.2

Secondary objectives of the trial

1. To determine the safety of AMAG-423 in women with severe preeclampsia.
2. To determine the safety of AMAG-423 in the offspring of women with severe preeclampsia.
3. To determine the pharmacokinetics (PK) of AMAG-423 in women with severe preeclampsia.

1. Determinar la seguridad de AMAG-423 en mujeres con preeclampsia grave.
2. Determinar la seguridad de AMAG-423 en los bebés de mujeres con preeclampsia grave.
3. Determinar la farmacocinética (FC) de AMAG-423 en mujeres con preeclampsia grave.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Has a fetal gestational age of 23 0/7 to 31 6/7 weeks. Gestational age should be confirmed by best obstetrical estimate using one of the following three options:
• Confirmed last menstrual period (LMP) and confirmatory ultrasound
• Ultrasound alone when LMP is not known or reliable
• Known date of conception in instances of assisted reproductive technology
2. At least 18 years of age or older
3. Will be treated with expectant management
4. Singleton gestation
5. Meets modified ACOG (2013) criteria for either preeclampsia or chronic hypertension with superimposed preeclampsia, as specified below:
Preeclampsia as defined by:
a. Blood pressure greater than or equal to 140 mmHg systolic or greater than or equal to 90 mmHg diastolic on two occasions at least 4 hours apart after 20 weeks of gestation in a woman with a previously normal blood pressure; OR
b. Blood pressure greater than or equal to 160 mmHg systolic or greater than or equal to 110 mmHg diastolic, hypertension can be confirmed within a short interval (minutes) to facilitate timely antihypertensive therapy;
AND
I. Proteinuria:
1. Greater than or equal to 300 mg per 24-hour urine collection (or this amount extrapolated from a timed collection); OR
2. Protein/creatinine ratio greater than or equal to 0.3 (each measured as mg/dL)
3. Dipstick reading of 3+ (used only if more quantitative methods not available)
OR in the absence of proteinuria, hypertension with the new onset of any of the following:
ii. Thrombocytopenia – platelet count less than 100,000/microliter
iii. Renal insufficiency – serum creatinine concentrations greater than 1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease
iv. Impaired liver function as indicated by abnormally elevated blood concentrations of liver enzymes (two times upper limit of normal for local lab)
Chronic hypertension with superimposed preeclampsia as defined by:
a. A sudden increase in previously well controlled hypertension or escalation of antihypertensive medications; OR
b. New onset proteinuria or a sudden increase in proteinuria in a woman with known proteinuria before or early in pregnancy.
6. Meets modified ACOG (2013) criteria for either preeclampsia with severe features or chronic hypertension with superimposed preeclampsia with severe features, as specified below:
Preeclampsia with severe features as defined by at least one of the below:
a. Systolic blood pressure of 160 mmHg or higher, or diastolic blood pressure of 110 mmHg or higher on two occasions at least 4 hours apart (unless antihypertensive therapy is initiated before this time)
b. Thrombocytopenia – platelet count less than 100,000/microliter
c. Impaired liver function as indicated by abnormally elevated blood concentrations of liver enzymes (two times upper limit of normal for local lab)
d. Progressive renal insufficiency as defined by serum creatinine concentrations greater than 1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease
Chronic hypertension with superimposed preeclampsia with severe features as defined by at least one of the below:
a. Systolic blood pressure of 160 mmHg or higher, or diastolic blood pressure of 110 mmHg or higher despite escalation of antihypertensive therapy
b. Thrombocytopenia – platelet count less than 100,000/microliter
c. Impaired liver function as indicated by abnormally elevated blood concentrations of liver enzymes (two times upper limit of normal for local lab)
d. Progressive renal insufficiency as defined by serum creatinine concentrations greater than 1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease
7. Willing and able to provide written informed consent

1. Edad gestacional fetal de 23 semanas a 31 semanas y 6 días. El obstetra debe usar su juicio clínico para confirmar la edad gestacional mediante cualquiera de las tres opciones siguientes:
• Última menstruación confirmada (UMC) y ecografía confirmatoria
• Ecografía solamente cuando se desconozca o no resulte fiable la fecha de la UMC
• Fecha de concepción conocida en caso de haberse utilizado tecnología de reproducción asistida
2. Edad mínima de 18 años
3. Mujeres que reciban tratamiento expectante
4. Embarazo único
5. Cumplir los criterios ACOG (2013) modificados de preeclampsia o de hipertensión crónica con preeclampsia superpuesta, tal y como se especifica a continuación:
La preeclampsia se define por:
a. Tensión arterial sistólica mayor o igual a 140 mmHg o diastólica mayor o igual a 90 mmHg en dos ocasiones con al menos 4 horas de diferencia tras 20 semanas de gestación en mujeres que previamente presentasen una tensión arterial normal; O BIEN
b. Tensión arterial sistólica mayor o igual a 160 mmHg o diastólica mayor o igual a 110 mmHg; la hipertensión se puede confirmar en un breve intervalo de tiempo (minutos) para facilitar la administración inmediata de un tratamiento antihipertensivo;
Y
I. Proteinuria:
1. Mayor o igual a 300 mg por cada recogida de orina durante 24 horas (o esta cantidad extrapolada a partir de una recogida durante un intervalo temporal); O BIEN
2. Ratio de proteínas/creatinina mayor o igual a 0,3 (ambos valores medidos en mg/dl)
3. Lectura con tira reactiva = 3 o más (se usará solamente si no se pueden usar métodos más cuantitativos)
O BIEN, en ausencia de proteinuria, hipertensión con manifestación nueva de cualquiera de las siguientes circunstancias:
II. Trombocitopenia: recuento de plaquetas menor de 100.000/µl
III. Insuficiencia renal: concentraciones de creatinina sérica mayores de 1,1 mg/dl o duplicación de la concentración de creatinina sérica en ausencia de otra nefropatía
IV. Alteración de la actividad hepática, indicada por una concentración sanguínea anormalmente alta de enzimas hepáticas (dos veces el límite superior de la normalidad para el laboratorio local)
Hipertensión crónica con preeclampsia superpuesta, definida como:
a. Aumento repentino de una hipertensión que previamente estuviera adecuadamente controlada o aumento de la dosis de medicamentos antihipertensivos; O BIEN
b. Proteinuria de nueva manifestación o aumento repentino de la proteinuria en mujeres con proteinuria conocida antes del embarazo o en las primeras fases de este.
6. Cumplimiento de los criterios ACOG (2013) modificados de preeclampsia con características de gravedad o hipertensión crónica con preeclampsia superpuesta y con características de gravedad, tal y como se especifica a continuación:
Preeclampsia con características de gravedad, definida como el cumplimiento de al menos una de las condiciones siguientes:
a. Tensión arterial sistólica de 160 mmHg o mayor o tensión arterial diastólica de 110 mmHg o mayor en dos ocasiones con una diferencia mínima de 4 horas (salvo que se inicie un tratamiento antihipertensivo antes de esta hora)
b. Trombocitopenia: recuento de plaquetas menor de 100.000/µl
c. Alteración de la actividad hepática, indicada por una concentración sanguínea anormalmente alta de enzimas hepáticas (dos veces el límite superior de la normalidad para el laboratorio local)
d. Insuficiencia renal progresiva, definida por concentraciones de creatinina sérica mayores de 1,1 mg/dl o duplicación de la concentración de creatinina sérica en ausencia de otra nefropatía
Hipertensión crónica con preeclampsia superpuesta y con características de gravedad, definida como el cumplimiento de al menos una de las condiciones siguientes:
a. Tensión arterial sistólica de 160 mmHg o mayor o tensión arterial diastólica de 110 mmHg o mayor pese al aumento de la dosis del tratamiento antihipertensivo
b. Trombocitopenia: recuento de plaquetas menor de 100.000/µl
c. Alteración de la actividad hepática, indicada por una concentración sanguínea anormalmente alta de enzimas hepáticas (dos veces el límite superior de la normalidad para el laboratorio local)
d. Insuficiencia renal progresiva, definida por concentraciones de creatinina sérica mayores de 1,1 mg/dl o duplicación de la concentración de creatinina sérica en ausencia de otra nefropatía
7. Pacientes que estén dispuestas y sean capaces de otorgar su consentimiento informado por escrito

E.4

Principal exclusion criteria

1. Prior to randomization, the decision to induce or deliver the subject within 24 hours has been made
2. Weight > 150 kg
3. Eclampsia
4. Significant antecedent obstetrical problems which may, in the opinion of the investigator, interfere with study assessments or safe participation in the study
5. Evidence of non-reassuring fetal well-being
6. Evidence of clinically significant fetal anomaly or known chromosomal abnormality
7. Chronic renal disease
8. Active hepatic disease, antiphospholipid antibody syndrome, or lupus
9. Medical or psychiatric disorder which is unstable or which might, in the opinion of the investigator, interfere with study assessments or safe participation in the study
10. Evidence on medical history/evaluation of use of or need for digitalis-like products currently or in the future (e.g., diagnosis of atrial fibrillation)
11. History of an anaphylactic allergic reaction to previous medication, atopy, or allergic reactions to pineapple enzyme bromelain, papain, chymopapain, or other papaya extracts. (Potential subjects with this history may be more susceptible to allergic reactions to DIF).
12. Prior use of antibodies/Fab fragments from sheep (e.g. Digibind®, DigiFab®, CroFab®)
13. Serum creatinine ≥ 2.0 mg/dL
14. Platelet count < 50,000/µL
15. Pulmonary edema requiring treatment with a diuretic
16. Estimated fetal weight < 5th percentile
17. Any investigational drug use within 30 days of screen
18. Planned interventional clinical study participation for infants
19. Current history of methamphetamine or cocaine abuse

1. Antes de la aleatorización, se ha tomado la decisión de inducir el parto o realizar una cesárea en un plazo de 24 horas
2. Peso > 150 kg
3. Eclampsia
4. Antecedentes de problemas obstétricos importantes que, en opinión del investigador, puedan interferir con las evaluaciones del estudio o con la participación segura en el estudio
5. Signos de inestabilidad en cuanto al bienestar fetal
6. Signos de anomalía clínicamente significativa o de anomalía cromosómica conocida del feto
7. Nefropatía crónica
8. Hepatopatía activa, síndrome de los anticuerpos antifosfolipídicos o lupus
9. Trastorno médico o psiquiátrico inestable que, en opinión del investigador, pueda interferir con las evaluaciones del estudio o con la participación segura en el estudio
10. Signos en la evaluación/historia clínica de uso o necesidad de usar productos de tipo digitálico, ya sea en la actualidad o en el futuro (p. ej., diagnóstico de fibrilación auricular)
11. Antecedentes de reacción alérgica anafiláctica a la medicación anterior, atopia o reacciones alérgicas a la enzima bromelaína de la piña, papaína, quimopapaína u otros extractos de la papaya. (Las candidatas con estos antecedentes podrían ser más susceptibles de sufrir reacciones alérgicas a los anticuerpos específicos antidigoxina).
12. Antecedentes de uso de anticuerpos/fragmentos Fab de oveja (p. ej., Digibind®, DigiFab® o CroFab®)
13. Creatinina sérica ≥ 2,0 mg/dl
14. Recuento de plaquetas < 50.000/µl
15. Edema pulmonar que requiera la administración de diuréticos
16. Peso fetal estimado < percentil 5
17. Uso de cualquier producto en investigación durante los 30 días previos a la selección
18. Participación prevista en estudio clínico intervencionista dirigido a lactantes
19. Antecedentes actuales de consumo de metanfetaminas o cocaína

E.5 End points

E.5.1

Primary end point(s)

Composite of the incidence of IVH (Grade ≥ 3) or NEC or death in infants from randomization to 36 weeks (± 1 week) corrected gestational age.

Valor compuesto de la incidencia de HIV (grado ≥ 3), ECN o la muerte en lactantes entre la aleatorización y las 36 semanas (± 1 semana) de edad gestacional corregida

E.5.1.1

Timepoint(s) of evaluation of this end point

Timepoint of primary end point evaluation is from time of randomization until max 37 weeks corrected gestational age for infants

El intervalo temporal para la evaluación del criterio de valoración principal será entre el momento de la aleatorización y, como máximo, las 37 semanas de edad gestacional corregida de los lactantes

E.5.2

Secondary end point(s)

• Change from baseline in serum creatinine.
• Incidence of pulmonary edema during the treatment period.

• Cambio en la creatinina sérica respecto al valor inicial.
• Incidencia de edema pulmonar durante el período de tratamiento.

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary end points:
1. 24 hours post-initiation of treatment
2.Treatment period is max 90 hours (~4 days)

Criterios de valoración secundarios:
1. 24 horas después del inicio del tratamiento
2. El período de tratamiento será de 90 horas (unos 4 días) como máximo

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

Yes

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)

Yes

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)

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

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

Australia

Colombia

Czech Republic

Hungary

Mexico

Poland

Puerto Rico

South Africa

Spain

Ukraine

United Kingdom

United States

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

LVLS

UVUP

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:

200

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

200

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

2019-08-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-08-05

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-07-02

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