Pharmacokinetics and Safety of Roledumab in RhD-negative Pregnant Women Carrying an RhD-positive Foetus

Pharmacokinetics and Safety of Roledumab, a Fully Human Recombinant Monoclonal Anti-RhD Antibody, in RhD-negative Pregnant Woman Carrying an RhD-positive Foetus: a Phase IIb, Multicenter, Open-label Study

The aim of this study is to assess the pharmacokinetic profile of Roledumab 300μg IM / IV in RhD-negative pregnant women carrying an RhD-positive foetus.

To assess the safety of Roledumab in RhD-negative pregnant women and in RhD-positive fetus and newborns.

In addition the efficacy of Roledumab 300μg IM and IV to prevent RhD alloimmunisation in RhD-negative pregnant women carrying an RhD-positive fetus and the immunogenicity of Roledumab will be assessed.

Study Overview

• Status: Completed
• Conditions: Rh Disease
• Intervention / Treatment: Drug: ROLEDUMAB

• Study Type: Interventional
• Enrollment (Actual): 62
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Lille, France, 59037
    • Jeanne de Flandre Hospital
  • Lyon, France, 69317
    • Croix-Rousse Maternity
  • Nantes, France, 44093
    • University Hospital Center
  • Paris, France, 75012
    • Armand-Trousseau Hospital
  • Paris, France, 75014
    • Port-Royal Maternity
  • Poissy, France, 78303
    • Poissy-Saint-Germain-en-Laye Hospital
  • Reims, France, 51092
    • MAISON BLANCHE Hospital
  • Toulouse, France, 31059
    • Paule de Viguier Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Signed and dated informed consent form provided by the subject prior to proceeding with any study-related procedure,
• At least 18 years old,
• Pregnancy between 12 and 27 weeks gestational age as confirmed by early ultrasound,
• Pregnant RhD-negative woman carrying an RhD-positive fetus confirmed by a non-invasive fetal RhD genotyping test,
• Negative serology: HIV (1 and 2), hepatitis C and hepatitis B, except for positive results due to vaccinations,
• Covered by healthcare insurance in accordance with local requirements.

Exclusion Criteria:

• RhD allo-immunized subject,
• Positive for ADA test,
• Multiple fetuses,
• Occurrence of a documented potential sensitizing event in this pregnancy before the antenatal IMP administration,
• Prior administration of anti-RhD immunoglobulin during the current pregnancy,
• Known clinically relevant maternal or fetal abnormality (e.g., as determined by ultrasound or genetic testing), such as placenta previa,
• History of anaphylactic or severe systemic reaction to immunoglobulin of any origin,
• Current diagnosis of an immune disease which by itself or its treatment could impair the safety and/or efficacy evaluation of Roledumab in this study. These diseases are: All immune deficiencies, particularly those requiring IV-Ig supplementation or other systemic treatment / connective tissue and autoimmune diseases (e.g., systemic lupus erythematosus, antiphospholipid syndrome, Sjögren's syndrome, rheumatoid arthritis, ankylosing spondylarthritis) requiring systemic immunosuppressive treatment / allergic and inflammatory diseases requiring systemic immunosuppressive treatment,
• Clinically significant medical history contraindicating the participation in the study according to the judgment of the Investigator or Sponsor,
• Clinically significant laboratory (hematology, blood chemistry, or urinalysis) parameters,
• For the IM arm only, subject with coagulation disorders contraindicating intramuscular injection (patient will still be considered for the IV arm),
• Transfusion of RhD-positive blood or blood derived products within the 6 months prior to enrolment,
• Anticipated poor compliance with the study procedures,
• Subject within exclusion period further to her participation in a clinical study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Roledumab Open-label IM; - Planned antenatal prophylaxis: A single dose of 300 µg IM of Roledumab at 28 or 29 weeks of gestation. - Antenatal prophylaxis following sensitizing events: One or more dose(s) of 300μg IM anti-RhD antibodies (Rhophylac or Roledumab) based on the Kleihauer-test as soon as possible and no later than 72 hours after event occurrence. - Postnatal prophylaxis: Roledumab should be administered to the mother as soon as possible within 72 hours of delivery of an RhD positive infant. The postnatal dose must still be given even when antenatal prophylaxis has been administered. Before Roledumab 300μg IM postnatal administration, a Kleihauer-Betke test will be performed on maternal blood sample taken no earlier than 30 min after delivery in order to determine the volume of foetomaternal hemorrhage (FMH).	Drug: ROLEDUMAB; See Arm description; Other Names: LFB-R593
Experimental: Roledumab Open-label IV; - Planned antenatal prophylaxis: A single dose of 300 µg IV of Roledumab at 28 or 29 weeks of gestation. - Antenatal prophylaxis following sensitizing events: One or more dose(s) of 300μg IV anti-RhD antibodies (Rhophylac or Roledumab) based on the Kleihauer-test as soon as possible and no later than 72 hours after event occurrence. - Postnatal prophylaxis: Roledumab should be administered to the mother as soon as possible within 72 hours of delivery of an RhD positive infant. The postnatal dose must still be given even when antenatal prophylaxis has been administered. Before Roledumab 300μg IV postnatal administration, a Kleihauer-Betke test will be performed on maternal blood sample taken no earlier than 30 min after delivery in order to determine the volume of foetomaternal hemorrhage (FMH).	Drug: ROLEDUMAB; See Arm description; Other Names: LFB-R593

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CL/F : Apparent Clearance	The parameter was estimated through a population pharmacokinetic model, during which concentration data (ante- and postnatal) obtained after single IM or IV route dose of roledumab. All samples (ante- and postnatal samples for IM and IV route) will be used for population PK modeling.	IM: Antenatal PK time points at T0, 48h, 120h, 9d, 29d,59d and Posnatal PK time points at TO, 3d,9d, 6 weeks IV: antenal PK time points at T0, 1h, 24h, 48h, 96-120h, 29d, 59d and Postnatal PK time points at T0, 3d, 9d, 6 weeks.
V2/F : Central Volume of Distribution	The parameter was estimated through a population pharmacokinetic model, during which concentration data (ante- and postnatal) obtained after single IM or IV route dose of roledumab. All samples (ante- and postnatal samples for IM and IV route) will be used for population PK modeling.	IM: Antenatal PK time points at T0, 48h, 120h, 9d, 29d,59d and Posnatal PK time points at TO, 3d,9d, 6 weeks IV: antenal PK time points at T0, 1h, 24h, 48h, 96-120h, 29d, 59d and Postnatal PK time points at T0, 3d, 9d, 6 weeks.
t 1/2 : Terminal Half-life	The parameter was estimated through a population pharmacokinetic model, during which concentration data (ante- and postnatal) obtained after single IM or IV route dose of roledumab. All samples (ante- and postnatal samples for IM and IV route) will be used for population PK modeling.	IM: Antenatal PK time points at T0, 48h, 120h, 9d, 29d,59d and Posnatal PK time points at TO, 3d,9d, 6 weeks IV: antenal PK time points at T0, 1h, 24h, 48h, 96-120h, 29d, 59d and Postnatal PK time points at T0, 3d, 9d, 6 weeks.
C Max	C max (maximum observed serum concentration) of Roledumab in all ITT subjects enrolled in the IM arm or the IV arm, who had at least one valid PK assessment after the first IMP administration, providing at least one evaluable PK parameter. Only samples post-first administration (antenatal samples) will be analyzed by NCA PK analysis for each study arm.	for IM:T0, 48h, 120h, 9 days, 29 days, 59 days and for IV T0, 1h, 24h, 48h, 96-120h, 29 days, 59 days
T Max	T max (time of the maximum observed plasma concentration) of Roledumab in all ITT subjects enrolled in the IM arm or the IV arm, who had at least one valid PK assessment after the first IMP administration, providing at least one evaluable PK parameter. Only samples post-first administration (antenatal samples) will be analyzed by NCA PK analysis for each study arm.	for IM:T0, 48h, 120h, 9 days, 29 days, 59 days and for IV T0, 1h, 24h, 48h, 96-120h, 29 days, 59 days
T 1/2	T 1/2 (apparent plasma terminal elimination half-life) of Roledumab in all ITT subjects enrolled in the IM arm or the IV arm, who had at least one valid PK assessment after the first IMP administration, providing at least one evaluable PK parameter. Only samples post-first administration (antenatal samples) will be analyzed by NCA PK analysis for each study arm.	for IM:T0, 48h, 120h, 9 days, 29 days, 59 days and for IV: T0, 1h, 24h, 48h, 96-120h, 29 days, 59 days
AUC 0-t	AUC 0-t (area under the concentration-time curve from time 0 to time Tlast) of Roledumab in all ITT subjects enrolled in the IM arm or the IV arm, who had at least one valid PK assessment after the first IMP administration, providing at least one evaluable PK parameter. Only samples post-first administration (antenatal samples) will be analyzed by NCA PK analysis for each study arm.	for IM: T0, 48h, 120h, 9 days, 29 days, 59 days and for IV T0, 1h, 24h, 48h, 96-120h, 29 days, 59 days

Collaborators and Investigators

• Sponsor: Laboratoire français de Fractionnement et de Biotechnologies
• Investigators: Principal Investigator: Norbert WINER, MD, CHU de Nantes

Study record dates

Study Major Dates

• Study Start: April 1, 2014
• Primary Completion (Actual): September 13, 2017
• Study Completion (Actual): September 13, 2017

Study Registration Dates

• First Submitted: October 28, 2014
• First Submitted That Met QC Criteria: November 6, 2014
• First Posted (Estimate): November 11, 2014

Study Record Updates

• Last Update Posted (Actual): July 13, 2020
• Last Update Submitted That Met QC Criteria: June 27, 2020
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: RhD-negative pregnant woman; anti-RhD antibody
• Other Study ID Numbers: ADNC-1301; 2013-000269-35 (EudraCT Number)