Rh Disease
Conditions
Keywords
RhD-negative pregnant woman, anti-RhD antibody
Brief summary
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.
Interventions
DRUGROLEDUMAB
See Arm description
Sponsors
Laboratoire français de Fractionnement et de Biotechnologies
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CL/F : Apparent Clearance | 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. | 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. |
| V2/F : Central Volume of Distribution | 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. | 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. |
| t 1/2 : Terminal Half-life | 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. | 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. |
| C Max | for IM:T0, 48h, 120h, 9 days, 29 days, 59 days and for IV T0, 1h, 24h, 48h, 96-120h, 29 days, 59 days | 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. |
| T Max | 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 (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. |
| T 1/2 | 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 (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. |
| AUC 0-t | 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 (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. |
Countries
France
Participant flow
Pre-assignment details
100 subjects were pre-screened in the pre-assigment period, only 62 subjects were included in the study.
Participants by arm
| Arm | Count |
|---|---|
| IM Arm Roledumab Roledumab Open-label IM
Dosage and frequency of administration:
* 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 | 36 |
| IV Arm Roledumab Roledumab Open-label IV
Dosage and frequency of administration:
* 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. | 26 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Second Injection Visit | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Total | IM Arm Roledumab | IV Arm Roledumab |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 62 Participants | 36 Participants | 26 Participants |
| Age, Continuous | 31.0 years | 31.0 years | 31.5 years |
| Race and Ethnicity Not Collected | 0 Participants | — | — |
| Region of Enrollment France | 62 participants | 36 participants | 26 participants |
| Sex: Female, Male Female | 62 Participants | 36 Participants | 26 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 36 | 0 / 26 | 0 / 62 |
| other Total, other adverse events | 36 / 36 | 26 / 26 | 62 / 62 |
| serious Total, serious adverse events | 15 / 36 | 9 / 26 | 24 / 62 |
Outcome results
Primary
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.
Time frame: for IM: T0, 48h, 120h, 9 days, 29 days, 59 days and for IV T0, 1h, 24h, 48h, 96-120h, 29 days, 59 days
Population: In the IV arm, the number of participants analyzed was 25. Due to a sensitizing event at late stage of pregnancy in one woman and a premature delivery in another woman, the number of subjects in the analyzed population was 23.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Population PK (PKS1) | AUC 0-t | 16600 h*ng/mL |
| IV Arm Roledumab | AUC 0-t | 24900 h*ng/mL |
Primary
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Population PK (PKS1) | CL/F : Apparent Clearance | 0.0106 L/h | Standard Error 5.91 |
Primary
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.
Time frame: for IM:T0, 48h, 120h, 9 days, 29 days, 59 days and for IV T0, 1h, 24h, 48h, 96-120h, 29 days, 59 days
Population: In the IV arm (PKS3), the overall number of participants analyzed was 25. Due to a sensitizing event at late stage of pregnancy in one woman and a premature delivery in another woman, the number of subjects in the analyzed population was 23.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Population PK (PKS1) | C Max | 21.6 ng/mL |
| IV Arm Roledumab | C Max | 71.8 ng/mL |
Primary
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.
Time frame: for IM:T0, 48h, 120h, 9 days, 29 days, 59 days and for IV: T0, 1h, 24h, 48h, 96-120h, 29 days, 59 days
Population: In the IM arm, the number of participants analyzed was 34, but only 28 subjects with AUCextrap \<30% were eligible.~In the IV arm, the number of participants analyzed was 25. Due to a sensitizing event at late stage of pregnancy in one woman and a premature delivery in another woman, the number of subjects in the analyzed population was 23.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Population PK (PKS1) | T 1/2 | 462 hour |
| IV Arm Roledumab | T 1/2 | 412 hour |
Primary
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Population PK (PKS1) | t 1/2 : Terminal Half-life | 481.7 hour | Standard Error 0 |
Primary
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.
Time frame: for IM:T0, 48h, 120h, 9 days, 29 days, 59 days and for IV T0, 1h, 24h, 48h, 96-120h, 29 days, 59 days
Population: In the IV arm (PKS3), the overall number of participants analyzed was 25. Due to a sensitizing event at late stage of pregnancy in one woman and a premature delivery in another woman, the number of subjects in the analyzed population was 23.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Population PK (PKS1) | T Max | 167.21 hour |
| IV Arm Roledumab | T Max | 1.00 hour |
Primary
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Population PK (PKS1) | V2/F : Central Volume of Distribution | 4.02 L | Standard Error 4.98 |