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    Clinical Trial Results:
    Phase III, Open-label, Uncontrolled, Multicenter Study to Assess Efficacy, Pharmacokinetics and Safety of IMMUNORHO in the Prevention of RhD Isoimmunization in Rh(D) negative Women Pregnant with Rh(D) positive Foetuses

    Summary
    EudraCT number
    		 2020-003570-49
    Trial protocol
    		 HU   CZ   PL   IT  
    Global end of trial date
    23 Mar 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Mar 2025
    First version publication date
    26 Mar 2025
    Other versions
    Summary report(s)
    		 Pharmacokinetics (PK) Results

    Trial information

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    Trial identification
    Sponsor protocol code
    KB065
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Kedrion S.p.A.
    Sponsor organisation address
    Loc. Ai Conti, Castelvecchio Pascoli, Barga (LU), Italy, 55051
    Public contact
    Clinical Trial Manager, Kedrion S.p.A., +39 0538767324, a.lotti@kedrion.com
    Scientific contact
    Clinical Trial Manager, Kedrion S.p.A., +39 0538767324, a.lotti@kedrion.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Jun 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Mar 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Efficacy objective: To assess the efficacy of IMMUNORHO in the prevention of Rh(D) isoimmunization in Rh(D) negative women pregnant with a Rh(D) positive foetus (including D, Dweak and Dpartial ), as measured by the incidence rate of anti-D antibodies at 24 weeks (corresponding to the 6 months timepoint in the EMA guideline) after last treatment administered. Safety objective: To assess the safety of IMMUNORHO in the prevention of Rh(D) isoimmunization in Rh(D) negative women pregnant with a Rh(D) positive foetus (including D, Dweak and Dpartial) from baseline visit to 24 weeks (corresponding to 6 months) after last treatment administered. Pharmacokinetic objective: To characterize the pharmacokinetics (PK) of anti-D immunoglobulins after IMMUNORHO administration in Rh(D) negative pregnant women.
    Protection of trial subjects
    This study was conducted in accordance with the protocol and consensus ethical principles derived from international guidelines including the Declaration of Helsinki, Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines, applicable International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines, and other applicable laws and regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Mar 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 137
    Country: Number of subjects enrolled
    Czechia: 29
    Country: Number of subjects enrolled
    Hungary: 48
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    Russian Federation: 24
    Worldwide total number of subjects
    255
    EEA total number of subjects
    231
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    255
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted between 31-March-2021 (first subject first visit) to 23-March-2024 (last subject last visit) at 21 initiated study sites, of which 20 sites recruited subjects in Europe and Russia.

    Pre-assignment
    Screening details
    		 The screening visit was performed between Week 25 (day 0-6) up to Week 26 (day 0-6) of pregnancy. In total, 504 subjects were screened for the study. Out of this, 255 were enrolled and 249 were screen failed subjects. Subjects who met the inclusion criteria and none of the exclusion criteria were enrolled to the study.

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BMI Group 1
    Arm description
    		 Non-obese subjects (BMI < 30 kg/m²) received IMMUNORHO as an intramuscular injection both antenatal [at Week 28 (from day0 to day7) of pregnancy] and postnatal (within 72 hours after delivery).
    Arm type
    		 Experimental

    Investigational medicinal product name
    IMMUNORHO
    Investigational medicinal product code
    Other name
    Human Anti-D Immunoglobulin
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    IMMUNORHO was provided as a single dose (2 mL solution) pre-filled syringe for intramuscular injection administration both antenatal and postnatal.

    Arm title
    		 BMI Group 2
    Arm description
    		 Obese subjects (BMI ≥ 30 kg/m²) received IMMUNORHO as an intramuscular injection both antenatal [at Week 28 (from day0 to day7) of pregnancy] and postnatal (within 72 hours after delivery).
    Arm type
    		 Experimental

    Investigational medicinal product name
    IMMUNORHO
    Investigational medicinal product code
    Other name
    Human Anti-D Immunoglobulin
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    IMMUNORHO was provided as a single dose (2 mL solution) pre-filled syringe for intramuscular injection administration both antenatal and postnatal.

    Number of subjects in period 1 [1]
    		BMI Group 1 BMI Group 2
    Started
    206
    48
    Completed
    164
    40
    Not completed
    42
    8
         Consent withdrawn by subject
    11
    2
         Other
    8
    -
         Use of another Anti-D immunoglobulin
    18
    4
         Lost to follow-up
    5
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One treated subject did not have a baseline height reported, therefore, the BMI of that subject could not be calculated. That subject was not assigned to either BMI group but was included in the Overall Treatment population.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BMI Group 1
    Reporting group description
    		 Non-obese subjects (BMI < 30 kg/m²) received IMMUNORHO as an intramuscular injection both antenatal [at Week 28 (from day0 to day7) of pregnancy] and postnatal (within 72 hours after delivery).

    Reporting group title
    BMI Group 2
    Reporting group description
    		 Obese subjects (BMI ≥ 30 kg/m²) received IMMUNORHO as an intramuscular injection both antenatal [at Week 28 (from day0 to day7) of pregnancy] and postnatal (within 72 hours after delivery).

    Reporting group values
    		 BMI Group 1 BMI Group 2 Total
    Number of subjects
    		 206 48 254
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 206 48 254
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 32.2 ( 4.71 ) 33.1 ( 5.43 ) -
    Gender categorical
    Units: Subjects
        Female
    		 206 48 254
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    BMI Group 1
    Reporting group description
    		 Non-obese subjects (BMI < 30 kg/m²) received IMMUNORHO as an intramuscular injection both antenatal [at Week 28 (from day0 to day7) of pregnancy] and postnatal (within 72 hours after delivery).

    Reporting group title
    BMI Group 2
    Reporting group description
    		 Obese subjects (BMI ≥ 30 kg/m²) received IMMUNORHO as an intramuscular injection both antenatal [at Week 28 (from day0 to day7) of pregnancy] and postnatal (within 72 hours after delivery).

    Primary: Incidence rate of anti-D antibodies at 24 weeks after treatment

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    End point title
    		 Incidence rate of anti-D antibodies at 24 weeks after treatment [1]
    End point description
    Prevention of Isoimmunization at 24 weeks (Corresponding to 6 months timepoint in EMA Guideline) was measured by the “Incidence of Anti-D Antibodies using the Indirect Antiglobulin (Coombs) Test. The full analysis set (FAS) comprised all subjects that successfully met the Inclusion/Exclusion Criteria and were cleared for treatment by the investigator. The FAS was based upon the Intention-to-Treat principle. Based on the observed data, of 201 subjects with Coombs test results, there were 0 active immunizations due to anti-D antibodies. There were 7 passive immunizations (including one with missing data at 24 weeks where results were imputed from the 12-week results); these were weak detectable anti-D antibodies reported with an anti-D antibody titration value of <2. Due to no alloimmunization events, incidence rate of alloimmunization and its associated 95% CI were not analysed.
    End point type
    Primary
    End point timeframe
    At 24 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There were no events of alloimmunisation identified, therefore the incidence rate of alloimmunisation and its associated 95% CI were not analysed. Hence, no statistical analysis was performed for this endpoint.
    End point values
    		 BMI Group 1 BMI Group 2
    Number of subjects analysed
    161
    40
    Units: Subjects
        Actively Immunized
    0
    0
        Passively Immunized
    6
    0
        Not Applicable
    155
    40
        Missing
    1
    0
    No statistical analyses for this end point

    Secondary: Incidence rate of anti-D antibodies at 12 weeks after treatment

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    End point title
    		 Incidence rate of anti-D antibodies at 12 weeks after treatment
    End point description
    Prevention of Isoimmunization at 12 weeks (Corresponding to 3 months timepoint in EMA Guideline) was measured by the “Incidence of Anti-D Antibodies using the Indirect Antiglobulin (Coombs) Test. The FAS comprised all subjects that successfully met the Inclusion/Exclusion Criteria and were cleared for treatment by the investigator. The FAS was based upon the Intention-to-Treat principle. Based on observed data, of 185 subjects with Coombs test results, there were 0 active immunisations due to anti-D antibodies. There were 146 passive immunisations; these were weak detectable anti-D antibodies reported with an anti-D antibody titration value of <2. Due to no alloimmunisation events, incidence rate of alloimmunisation and its associated 95% CI were not analysed.
    End point type
    Secondary
    End point timeframe
    At 12 weeks
    End point values
    		 BMI Group 1 BMI Group 2
    Number of subjects analysed
    148
    36
    Units: Subjects
        Actively Immunized
    0
    0
        Passively Immunized
    124
    22
        Not Applicable
    24
    14
        Missing
    4
    1
    No statistical analyses for this end point

    Other pre-specified: Number of subjects with adverse events (AEs) and serious AEs

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    End point title
    		 Number of subjects with adverse events (AEs) and serious AEs
    End point description
    The safety analysis set (SAF) comprised all subjects who had received at least one dose of study medication. In this study, the SAF and FAS were coincident as no randomization occurred. The safety of IMMUNORHO in the prevention of Rh(D) isoimmunisation in Rh(D) negative women pregnant with a Rh(D) positive foetus (including D, Dweak and Dpartial) from Baseline visit to 24 weeks (corresponding to 6 months) after last treatment administered was assessed. A related TEAE was a TEAE with Related, Certainly Related, Probably Related, or Possibly Related as relationship to study drug.
    End point type
    Other pre-specified
    End point timeframe
    Baseline [(Week 28 (from day 0 to day 7) of pregnancy] to 24 weeks after last dose administered
    End point values
    		 BMI Group 1 BMI Group 2
    Number of subjects analysed
    206
    48
    Units: Subjects
        AE
    123
    33
        Treatment Emergent AE (TEAE)
    121
    32
        Treatment Related TEAE
    4
    0
        Study Procedure Related TEAE
    0
    0
        TEAE due to Potentially sensitising event (PSE)
    4
    0
        TEAE of Special Interest
    9
    2
        TEAE about Worsening from a Pre-existing Condition
    1
    2
        Serious AEs (SAEs)
    48
    16
        AE leading to Death
    0
    0
        AE Leading to Study Discontinuation
    1
    0
        AE Leading to Hospitalisation
    24
    6
        AE Leading to Study Drug Withdrawal
    1
    0
        AE Leading to Study Drug Dose Delayed
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline [(Week 28 (from day 0 to day 7) of pregnancy] to 24 weeks after last dose administered
    Adverse event reporting additional description
    The SAF comprised all subjects who had received at least one dose of study medication. In this study, the SAF and FAS were coincident as no randomization occurred.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    BMI Group 2
    Reporting group description
    		 Obese subjects received IMMUNORHO as an intramuscular injection both antenatal [at Week 28 (from day0 to day7) of pregnancy] and postnatal (within 72 hours after delivery).

    Reporting group title
    BMI Group 1
    Reporting group description
    		 Non-obese subjects received IMMUNORHO as an intramuscular injection both antenatal [at Week 28 (from day0 to day7) of pregnancy] and postnatal (within 72 hours after delivery).

    Serious adverse events
    		 BMI Group 2 BMI Group 1
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 48 (35.42%)
    51 / 206 (24.76%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Venous thrombosis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial rupture
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Meconium in amniotic fluid
         subjects affected / exposed
    1 / 48 (2.08%)
    5 / 206 (2.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Threatened labour
         subjects affected / exposed
    1 / 48 (2.08%)
    4 / 206 (1.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gestational hypertension
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gestational diabetes
         subjects affected / exposed
    3 / 48 (6.25%)
    6 / 206 (2.91%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oligohydramnios
         subjects affected / exposed
    0 / 48 (0.00%)
    3 / 206 (1.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Premature separation of placenta
         subjects affected / exposed
    0 / 48 (0.00%)
    3 / 206 (1.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervix dystocia
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foetal growth restriction
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    High risk pregnancy
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prolonged labour
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical cord around neck
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical cord compression
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine atony
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Premature rupture of membranes
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Premature labour
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Premature delivery
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyhydramnios
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Placental insufficiency
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Placenta accreta
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperemesis gravidarum
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foetal arm prolapse
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pre-eclampsia
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine hypotonus
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Neonatal asphyxia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Foetal monitoring abnormal
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foetal heart rate abnormal
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Uterine rupture
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electric shock
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulvovaginal injury
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Foetal heart rate deceleration abnormality
         subjects affected / exposed
    4 / 48 (8.33%)
    4 / 206 (1.94%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia foetal
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia foetal
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytosis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia of pregnancy
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness neurosensory
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal rigidity
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholestasis of pregnancy
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometritis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 BMI Group 2 BMI Group 1
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 48 (39.58%)
    55 / 206 (26.70%)
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    7 / 48 (14.58%)
    18 / 206 (8.74%)
         occurrences all number
    8
    21
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 48 (6.25%)
    18 / 206 (8.74%)
         occurrences all number
    3
    49
    Pregnancy, puerperium and perinatal conditions
    Gestational hypertension
         subjects affected / exposed
    4 / 48 (8.33%)
    0 / 206 (0.00%)
         occurrences all number
    4
    0
    Afterbirth pain
         subjects affected / exposed
    3 / 48 (6.25%)
    15 / 206 (7.28%)
         occurrences all number
    3
    15
    Blood and lymphatic system disorders
    Anaemia of pregnancy
         subjects affected / exposed
    4 / 48 (8.33%)
    17 / 206 (8.25%)
         occurrences all number
    4
    17
    Anaemia
         subjects affected / exposed
    3 / 48 (6.25%)
    5 / 206 (2.43%)
         occurrences all number
    3
    5
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    3 / 48 (6.25%)
    5 / 206 (2.43%)
         occurrences all number
    3
    6

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jun 2021
    o Clarifications added regarding standard of care procedures for PSEs and FMH across different countries/sites. o Added collection of subject's height and weight at baseline to calculate BMI, as requested by Russian Ministry of Health. o Specified that anti-D antibody testing includes indirect antiglobulin test, red blood cell alloantibodies identification, and anti-D titration/microtitration. o Added reporting of Coronavirus Disease 2019 (COVID-19) related AEs as an Adverse Event of Special Interest (AESI). o Added section on collecting AEs in neonates/breastfeeding infants exposed to the study drug. o Clarified definition of EOS as Last Patient Last Visit. o Added details on handling of PK samples and analysis. o Removed planned interim analysis. o Clarified that missing data will not be imputed for primary/secondary efficacy analyses. o Added analysis by BMI groups (obese vs non-obese) for efficacy endpoints. o Made minor wording changes and corrections throughout to improve clarity.
    13 May 2022
    o Enrolment period of the study was prolonged. o Number of subjects to be screened was increased due to the high screening failure rate. o Added the possibility to use the Home Health Care agency. o Some clarifying wording for visits description added.
    27 Jul 2022
    o Contact information: A new Sponsor's Medical Expert had been appointed for the study, and their contact details were added. o Blood typing correction: References to "ABO/RhD" have been changed to just "RhD" throughout the document (Tables 1-4, Sections 2.3, 7.2.3, 8.1, and 9.2). o Clarification in Section 7.2.3: A statement was added to clarify the exception of ABO/RhD blood group testing for mothers, fathers, and newborns.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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