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    Clinical Trial Results:
    Intravenous immunoglobulin and prednisolone to women with unexplained recurrent pregnancy loss after assisted reproductive technology treatment: a randomised, double-blind, placebo-controlled trial

    Summary
    EudraCT number
    		 2020-000256-35
    Trial protocol
    		 DK  
    Global end of trial date
    18 Apr 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Oct 2025
    First version publication date
    23 Oct 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CNPOBC2020
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04701034
    WHO universal trial number (UTN)
    		 U1111-1273-8585
    Sponsors
    Sponsor organisation name
    Aalborg University Hospital
    Sponsor organisation address
    Reberbansgade 15, Aalborg, Denmark, 9000
    Public contact
    Ole B. Christiansen, Aalborg University Hospital , +45 26821960, olbc@rn.dk
    Scientific contact
    Ole B. Christiansen, Aalborg University Hospital , +45 26821960, olbc@rn.dk
    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
    28 Jun 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Apr 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Apr 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    In a randomized, double-blinded placebo-controlled trial we aim to investigate whether treatment with prednisolone and IVIg before and in early pregnancy improves the chance of a live birth in women undergoing treatment with artificial reproductive technologies (ART) after previous recurrent pregnancy losses after ART.
    Protection of trial subjects
    The study has been conducted in accordance with ICH-GCP guideline
    Background therapy
    		 Intravenous immunoglobulin (Privigen 10%) 25-35g per infusion at the time of embryo transfer and maximum 3 times in early pregnancy or similar intravenous placebo (human Albumin 5%) given after same protocol in addition to 5-10 g prednisolone or similar placebo tablets given daily from start of ART cycle to gestational week 8 in participants who became pregnant
    Evidence for comparator
    		 The comparators (Human Albumin and oral placebo) had similar visual appearance as the active drugs (Privigen and prednisolone) and were given with same doses and frequency as the active drugs.
    Actual start date of recruitment
    28 Jan 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 80
    Worldwide total number of subjects
    80
    EEA total number of subjects
    80
    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)
    80
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients with ≥ 2 consecutive early pregnancy losses after ART treatment who were referred to the Centre for Recurrent Pregnancy Loss of Western Denmark between 28th January 2021 and 23rd February 2024

    Pre-assignment
    Screening details
    		 All patients were screened for uterine anomalies by hysteroscopy, water hysterosonography or 3D vaginal ultrasound and in addition they were screened for a series of antiphospholipid antibodies, thyroid dysfunction by TSH, ovarian insufficiency by anti-Müllerian hormone and total IgA was measured to detect possible IgA deficiency

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer
    Blinding implementation details
    The randomization list was only held at the Hospital Pharmacy of the North Denmark Region, Aalborg and at the Department of Clinical Immunology, Aalborg University Hospital, which were the two sites preparing the oral and intravenous trial drugs. The investigators, caretakers, monitors and patients had no access to the list, The active trial drugs and the placebos had complete similar appearances.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intravenous immunoglobulin and prednisolone
    Arm description
    		 A maximum of 4 Privigen infusions from time of embryo transfer and to gestational week 7 of pregnancy and prednisolone tablets from start of ART cycle to gestational week 8 in pregnant participants
    Arm type
    		 Experimental

    Investigational medicinal product name
    privigen
    Investigational medicinal product code
    J06BA02
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Information provided previously

    Investigational medicinal product name
    prednisolone
    Investigational medicinal product code
    H02AB06
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Information provided previously

    Arm title
    		 Intravenous (Human Albumin) and peroral placebo
    Arm description
    		 A maximum of 4 albumin infusions from time of embryo transfer and to gestational week 7 of pregnancy and placebo tablets from start of ART cycle to gestational week 8 in pregnant participants
    Arm type
    		 Placebo

    Investigational medicinal product name
    Albumin
    Investigational medicinal product code
    B05AA01
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Information provided previously

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0 mg coated tablet administered daily from the start of the ART cycle to gestational week 8.

    Number of subjects in period 1
    		Intravenous immunoglobulin and prednisolone Intravenous (Human Albumin) and peroral placebo
    Started
    40
    40
    Completed
    37
    37
    Not completed
    3
    3
         Protocol deviation
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 80 80
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 80 80
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 34.75 (30.5 to 37.25) -
    Gender categorical
    Units: Subjects
        Female
    		 80 80
        Male
    		 0 0
    Number of previous consecutive pregnancy losses
    Units: number
        median (inter-quartile range (Q1-Q3))
    		 -
    Subject analysis sets

    Subject analysis set title
    ARM 1 Experimental
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per protocol 1

    Subject analysis set title
    ARM 2 (Placebo)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per protocol 2

    Subject analysis sets values
    		 ARM 1 Experimental ARM 2 (Placebo)
    Number of subjects
    37
    37
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    37
    37
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    33.5 (30.0 to 37.0)
    35.0 (31.0 to 37.5)
    Gender categorical
    Units: Subjects
        Female
    40
    40
        Male
    0
    0
    Number of previous consecutive pregnancy losses
    Units: number
        median (inter-quartile range (Q1-Q3))
    3 (3 to 4)
    4 (3 to 4)

    End points

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    End points reporting groups
    Reporting group title
    Intravenous immunoglobulin and prednisolone
    Reporting group description
    		 A maximum of 4 Privigen infusions from time of embryo transfer and to gestational week 7 of pregnancy and prednisolone tablets from start of ART cycle to gestational week 8 in pregnant participants

    Reporting group title
    Intravenous (Human Albumin) and peroral placebo
    Reporting group description
    		 A maximum of 4 albumin infusions from time of embryo transfer and to gestational week 7 of pregnancy and placebo tablets from start of ART cycle to gestational week 8 in pregnant participants

    Subject analysis set title
    ARM 1 Experimental
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per protocol 1

    Subject analysis set title
    ARM 2 (Placebo)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per protocol 2

    Primary: Ongoing pregnancy rates in all participants and among those who conceived

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    End point title
    		 Ongoing pregnancy rates in all participants and among those who conceived
    End point description
    End point type
    Primary
    End point timeframe
    End of study
    End point values
    		 Intravenous immunoglobulin and prednisolone Intravenous (Human Albumin) and peroral placebo ARM 1 Experimental ARM 2 (Placebo)
    Number of subjects analysed
    40
    40
    40
    40
    Units: number
        Category 1: Number of ongoing pregnancies/all part
    10
    6
    10
    6
        Category 2: Number of ongoing pregnancies /partici
    10
    6
    10
    6
    Statistical analysis title
    		 Ongoing pregnancy rate in reporting group 1 vs rep
    Statistical analysis description
    Chi-square analysis
    Comparison groups
    ARM 1 Experimental v ARM 2 (Placebo)
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.26
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 4.15
    Variability estimate
    Standard deviation
    Statistical analysis title
    		 Ongoing pregnancy rate in reporting group 1 vs rep
    Comparison groups
    ARM 1 Experimental v ARM 2 (Placebo)
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.01
         upper limit
    		 3.75

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first day of taking study medicine until 6 months after last intravenous infusion in participants not achieving pregnancy or until the day of delivery in pregnant participants
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    28
    Reporting groups
    Reporting group title
    Reporting group 1
    Reporting group description
    		 Active treatment

    Reporting group title
    Reporting group 2
    Reporting group description
    		 Placebo treatment

    Serious adverse events
    		 Reporting group 1 Reporting group 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 37 (2.70%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Pregnancy, puerperium and perinatal conditions
    Vaginal haemorrhage in gestational week 11
    Additional description: The pregnancy continued
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postpartum chorioamnionitis in the mother and newborn child
    Additional description: Both recovered without sequelae
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postpartum seizures and signs of cerebral ischemia in the child
    Additional description: The child is one year old healthy without signs of brain damage
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Reporting group 1 Reporting group 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 37 (54.05%)
    16 / 37 (43.24%)
    Pregnancy, puerperium and perinatal conditions
    Potentially infusion-related
    Additional description: Headache, fatigue, nausea, skin rash, dizziness, flu-like symptoms, muscle/joint pain
         subjects affected / exposed
    20 / 37 (54.05%)
    16 / 37 (43.24%)
         occurrences all number
    20
    16
    Nervous system disorders
    Event term Potentially tablet-related
    Additional description: Insomnia, mood-swings
         subjects affected / exposed
    6 / 37 (16.22%)
    1 / 37 (2.70%)
         occurrences all number
    6
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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