Clinical Trials Register

Summary
EudraCT Number:	2017-004958-42
Sponsor's Protocol Code Number:	MOM-M281-003
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:	2019-03-27
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

2017-004958-42

A.3

Full title of the trial

A Multicenter, Open-Label Study to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of M281 Administered to Pregnant Women at High Risk for Early Onset Severe Hemolytic Disease of the Fetus and Newborn (HDFN)

Un estudio multicéntrico, abierto para evaluar la seguridad, la farmacocinética y la farmacodinámica del M281 administrado a mujeres embarazadas con alto riesgo de aparición temprana de enfermedad hemolítica grave del feto y recién nacido (EHRN)

A.3.1

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

Open Label Study to Evaluate the Safety and Efficacy of M281 Given to Pregnant Women at High Risk for Early Severe Hemolytic Disease of the Fetus and Newborn (HDFN)

Un estudio abierto para evaluar la seguridad y eficacia del M281 administrado a mujeres embarazadas con alto riesgo de aparición temprana de enfermedad hemolítica grave del feto y recién nacido (EHRN)

A.4.1

Sponsor's protocol code number

MOM-M281-003

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	Momenta 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	Momenta 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	Momenta Pharmaceuticals Inc.
B.5.2	Functional name of contact point	Chelsea Toner
B.5.3	Address:
B.5.3.1	Street Address	301 Binney Street
B.5.3.2	Town/ city	Cambridge
B.5.3.3	Post code	MA 02142
B.5.3.4	Country	United States
B.5.6	E-mail	clinicaltrialinfo@momentapharma.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	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	M281
D.3.4	Pharmaceutical form	Concentrate 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	M281
D.3.9.1	CAS number	2211985-36-1
D.3.9.2	Current sponsor code	M281
D.3.9.4	EV Substance Code	SUB182674
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	30
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)	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	Yes
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

Early onset Severe Hemolytic Disease of the fetus and newborn (HDFN)

enfermedad hemolítica grave de aparición temprana del feto y recién nacido (EHRN)

E.1.1.1

Medical condition in easily understood language

Pregnant women that are at risk of developing early onset of severe hemolytic disease that affects the fetus and neonate

Mujeres embarazadas que están en riesgo de desarrollar una enfermedad hemolítica severa que afecta al feto y al neonato

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

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	10019512
E.1.2	Term	Hemolytic disease due to Rh isoimmunization of fetus or newborn
E.1.2	System Organ Class	100000004850

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 evaluate the safety in mother and neonate/infant of M281 administered to pregnant women at high risk for early onset severe HDFN (EOS-HDFN).
• To evaluate the efficacy of M281 as measured by proportion of patients with live birth at or after gestational age (GA) 32 weeks without intrauterine transfusion (IUT).

•Evaluar la seguridad del M281 en la madre y el neonato/lactante cuando se administra a mujeres embarazadas con alto riesgo de aparición temprana de EHRN grave (AT-EHRN).
•Evaluar la eficacia del M281 determinada mediante la proporción de pacientes con un nacimiento vivo en o después de la edad gestacional (EG) de 32 semanas sin transfusión intrauterina (TIU).

E.2.2

Secondary objectives of the trial

•To evaluate the efficacy of M281 on antenatal management and outcome as measured by GA at first fetal IUT and frequency of fetal IUT.
•To evaluate the efficacy of M281 on postnatal management and outcome as measured by severity of hyperbilirubinemia, phototherapy, exchange transfusions, and transfusions in the first 3 months of life.
•To evaluate the PD activity of M281 as measured by effects on maternal FcRn occupancy, and maternal and neonatal/infant levels of total IgG and alloantibodies.
•To evaluate the PK of M281.

• Evaluar la eficacia del M281 para el tratamiento prenatal y desenlace determinada mediante la EG en el momento de la primera TIU fetal y la frecuencia de TIU fetales.
• Evaluar la eficacia del M281 para el tratamiento posnatal y desenlace determinada mediante la gravedad de la hiperbilirrubinemia, la fototerapia, las transfusiones de intercambio y las transfusiones en los 3 primeros meses de vida.
• Evaluar la actividad FD del M281 determinada mediante los efectos sobre la ocupación del RFcn materna y los niveles de IgG total y aloanticuerpos maternos y del neonato/lactante.
• Evaluar la FC del M281.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Able to understand and voluntarily provide written informed consent to participate in the study.
2.Female and ≥18 years of age.
3.Pregnant with an estimated GA of 8 to 13 weeks.
4.A previous pregnancy with a gestation that included at least one of the following at ≤24 weeks gestation:
a.Severe fetal anemia, defined as hemoglobin ≤0.55 multiples of the median (MoM) for GA **refer to table on page 12 of the protocol.
b.Fetal hydrops (ascites) with an MCA-PSV MoM ≥1.5
c.Stillbirth with fetal or placental pathology indicative of HDFN
5.Maternal alloantibody titers for anti-D of ≥32, or anti-Kell titers ≥8.
6.Free fetal deoxyribonucleic acid (DNA) consistent with an antigen positive fetus (blood sample taken from mother).
7.Maternal evidence for immunity to measles mumps, rubella, and varicella, as documented by laboratory reports obtained from medical history or serologies performed during Screening.
8.Screening IgG and albumin levels within the laboratory normal range for gestational age of pregnancy.
9.Willing to receive standard of care with IUT if clinically indicated.
10.Agree to recommended vaccinations per local standard of care for both mother and child throughout the course of the study.
11.Willing to forego participation in another clinical trial of an investigational therapy for the duration of their participation in the current study.
12.Willing to consent to a 6 month safety follow-up period for the patient and a 24 month safety follow-up period for the neonate/infant.

1.Ser capaz de entender y otorgar voluntariamente un consentimiento informado por escrito para participar en el estudio.
2.Mujer ≥18 años de edad.
3.Mujer embarazada con una EG estimada de 8 a 13 semanas.
4.Existencia de un embarazo previo que incluyó al menos uno de los siguientes a las ≤24 semanas de gestación:
a.Anemia fetal grave, que se define como hemoglobina ≤0,55 múltiples de la mediana (MdM) para la EG (ver table pág 12 del Protocolo)
b.Edema fetal (ascitis) con una MdM de la VSM-ACM ≥1,5.
c.Mortinato con una patología fetal o placentaria indicativa de EHRN.
5.Valores de aloanticuerpos maternos anti-D ≥32 o valores de anti-Kell ≥8.
6.Ácido desoxirribonucleico (ADN) libre fetal indicativo de un feto con resultado positivo para el antígeno (muestra de sangre extraída de la madre).
7.Indicios de inmunidad materna al sarampión, parotiditis, rubéola y varicela, documentada mediante informes de análisis clínicos obtenidos del historial médico o mediante análisis de serología realizado durante la selección.
8.Niveles de IgG y albúmina dentro del intervalo analítico normal para la edad gestacional del embarazo en la selección.
9.Estar dispuesta a recibir tratamiento estándar con TIU si está clínicamente indicado.
10.Acceder a recibir las vacunas recomendadas conforme a la práctica clínica habitual local, tanto para la madre como para el hijo, durante el transcurso del estudio.
11.Estar dispuesta a renunciar a la participación en otro ensayo clínico con un tratamiento en investigación mientras participe en el estudio actual.
12.Estar dispuesta a otorgar el consentimiento para someterse a un periodo de seguimiento de la seguridad de 6 meses para la paciente y un periodo de seguimiento de la seguridad de 24 meses para el neonato/lactante.

E.4

Principal exclusion criteria

1.Currently pregnant with multiples (twins or more).
2.Pre-eclampsia in current pregnancy or history of pre-eclampsia in a previous pregnancy.
3.History of severe or recurrent pyelonephritis, 4 or more lower urinary tract infections in the past year or in a previous pregnancy, or genital herpes.
4.Positive for human immunodeficiency virus (HIV), hepatitis B, or hepatitis C during Screening.
5.Active infection at Screening or Baseline with Coxsackie, syphilis, cytomegalovirus, toxoplasmosis or herpes simplex 1 or 2, as evidenced by clinical signs and symptoms (evidence for prior infection or exposure, but without clinical signs and symptoms of active infection is acceptable).
6.Active infection with tuberculosis as evidenced by positive QuantiFERON-TB testing.
7.Requires treatment with corticosteroids or immunosuppression for disorders unrelated to the pregnancy (use of low-potency topical corticosteroids or intra-articular corticosteroids is permitted).
8.History of drug allergy, hypersensitivity, or intolerance to any drug product that, in the opinion of the Investigator, would compromise the safety of the patient.
9.In the Investigator’s opinion, shows evidence of ongoing alcohol/substance abuse/dependence.
10.Smoking during pregnancy.
11.Received plasmapheresis and/or IVIG during the current pregnancy for treatment of HDFN.
12.Received an investigational drug and/or device within 30 days or 5 half-lives prior to receiving the first IV infusion of M281.
13.A history or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine/metabolic, immunologic, severe or recurrent infections (eg, frequent hospitalized pneumonia), dermatologic, neurologic, oncologic, or psychiatric disease, or any other condition or issue that, in the opinion of the Investigator, would jeopardize the safety of the patient or fetus/neonate/infant or the validity of the study results.

1.Embarazo múltiple actual (gemelos o más).
2.Preeclampsia en el embarazo actual o antecedentes de preeclampsia en un embarazo anterior.
3.Antecedentes de pielonefritis grave o recurrente, de 4 o más infecciones de las vías urinarias bajas en el año previo o en un embarazo anterior o de herpes genital.
4.Resultado positivo en la prueba de detección del virus de la inmunodeficiencia humana (VIH), hepatitis B o hepatitis C durante la selección.
5.Infección activa en la selección o al inicio por virus Coxsackie, sífilis, citomegalovirus, toxoplasmosis o herpes simple 1 o 2, que se demuestra por signos y síntomas clínicos (se aceptan aquellos casos en los que existan indicios de infección previa o de exposición, pero sin signos y síntomas clínicos de infección activa).
6.Infección activa de tuberculosis que se demuestra por un resultado positivo en la prueba QuantiFERON-TB.
7.Necesidad de tratamiento con corticoesteroides o inmunodepresión para trastornos no relacionados con el embarazo (se permite el uso de corticoesteroides tópicos de poca potencia o corticoesteroides intraarticulares).
8.Antecedentes de alergia farmacológica, hipersensibilidad o intolerancia a cualquier fármaco que, en opinión del investigador, pondría en riesgo la seguridad de la paciente.
9.Pacientes que, en opinión del investigador, muestren indicios de abuso o dependencia de alcohol o de sustancias en curso.
10.Tabaquismo durante el embarazo.
11.Pacientes que han recibido plasmaféresis o IgIV durante el embarazo actual para el tratamiento de EHRN.
12.Pacientes que han recibido un fármaco o dispositivo en investigación en los 30 días o 5 semividas anteriores a recibir la primera infusión i.v. del M281.
13.Antecedentes o presencia de infección cardiovascular, pulmonar, hepática, renal, hematológica, gastrointestinal, endocrina/metabólica o inmunológica, grave o recurrente, clínicamente significativa (p. ej., neumonía que requiere la hospitalización frecuente), de enfermedad dermatológica, neurológica, oncológica o psiquiátrica,o cualquier otra afección o problema que, en opinión del investigador, pueda poner en peligro la seguridad de la paciente, del feto/neonato/lactante o la validez de los resultados del estudio.

E.5 End points

E.5.1

Primary end point(s)

1) Incidence and severity of AEs, SAEs, and AESIs (i.e., infections requiring use of oral or intravenous anti-infectives in the patient; hypoalbuminemia ≥ Grade 3)

2)Proportion of patients with live birth at or after GA Week 32 without IUT

1. Incidencia y gravedad de los EA, los EASs y los EASIs (es decir, infecciones que requieren el uso de antiinfecciosos orales o intravenosos en el paciente; hipòalbuminemia>_ Grado 3)
2. Proporción de pacientes con nacidos vivos en o despue´s de GA semana 32 sin IUT

E.5.1.1

Timepoint(s) of evaluation of this end point

1) continuous throughout the whole trial

2)week 32

1. continuo durante todo el ensayo
2. semana 32

E.5.2

Secondary end point(s)

1) Desirability of Overall Clinical Outcome, as defined by ranking of the pregnancy outcome (live birth or fetal loss), neonate transfusion for anemia/hyperbilirubinemia, intervention for fetal anemia (timing and frequency of IUT).
2) Percentage of patients with live birth
3) Percentage of patients at GA Week 24 without an IUT
4) GA at first IUT
5) Number of IUTs required
6) GA at delivery
7) Percentage of patients with fetal hydrops
8) Percentage of neonates requiring phototherapy
9) Percentage of neonates requiring exchange transfusions
10) Number of days of phototherapy required by neonate
11) Percentage of neonates requiring simple transfusions in the first 3 months of life
12) Number of simple transfusions required by neonate in the first 3 months of life

1)Conveniencia del resultado clínico general, definida por la valoración del desenlace del embarazo (nacimiento vivo o pérdida del feto), transfusión del neonato debido a anemia/hiperbilirrubinemia, intervención debido a anemia fetal (puntos temporales y frecuencia de la TIU).
2)Porcentaje de pacientes con un nacimiento vivo.
3)Porcentaje de pacientes sin una TIU en la EG de 24 semanas.
4)Edad gestacional en el momento de la primera TIU.
5)Número de TIU necesarias.
6)Edad gestacional al parto
7)Porcentaje de pacientes con edema fetal.
8)Porcentaje de neonatos que requieren fototerapia.
9)Porcentaje de neonatos que requieren transfusiones de intercambio.
10)Número de días de fototerapia requeridos por el neonato.
11)Porcentaje de neonatos que requieren transfusiones simples en los 3 primeros meses de vida.
12)Número de transfusiones simples requeridas por el neonato en los 3 primeros meses de vida

E.5.2.1

Timepoint(s) of evaluation of this end point

1) at birth
2) at birth
3) at Week GA 24
4) at first IUT
5) at birth
6) after birth
7) within first 3 months of birth
8) within first 3 months of birth
9) within first 3 months of birth
10) within first 3 months of birth
11) within first 3 months of birth

1) al nacer
2) al nacer
3) en la EG semana 24
4) a la primera TIU
5) al nacer
6) despues de nacer
7) dentro de los primeros 3 mesees de nacimiento
8) dentro de los primeros 3 mesees de nacimiento
9) dentro de los primeros 3 mesees de nacimiento
10) dentro de los primeros 3 mesees de nacimiento
11) dentro de los primeros 3 mesees de 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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

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

Yes

E.6.13.1

Other scope of the trial description

Will assess immunogenicity of M281

Evaluará la inmunogenicidad de M281

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)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

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

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

Belgium

Canada

Germany

Israel

Netherlands

Spain

Sweden

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

End of trial is LVLS

El fin de Ensayo es la última visita del ultimo paciente

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

Yes

F.1.1.1.1

Number of subjects for this age range:

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:

F.1.3

Elderly (>=65 years)

F.1.3.1

Number of subjects for this age range:

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

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

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)

Standard of Care

Cuidado estandar

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

2019-03-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-02-18

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

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