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    Clinical Trial Results:
    A Multicenter Postmarketing Study to Evaluate the Placental Transfer of Certolizumab Pegol in Pregnant Women Receiving Treatment with Cimzia® (Certolizumab Pegol)

    Summary
    EudraCT number
    2013-003812-30
    Trial protocol
    NL  
    Global end of trial date
    21 Nov 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    07 Dec 2017
    First version publication date
    07 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UP0017
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02019602
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB BIOSCIENCES Inc.
    Sponsor organisation address
    8010 Arco Corporate Drive, Raleigh, United States, 27617
    Public contact
    Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
    Scientific contact
    Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.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
    13 Dec 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess whether there was transfer of Certolizumab Pegol (CZP) across the placenta to infants from mothers by evaluating the concentration of CZP in the plasma of infants at birth.
    Protection of trial subjects
    During the conduct of the study all mothers and infants were closely monitored. Additionally, for the comfort and convenience of the mother and her baby, the study allowed home healthcare nurses to perform study procedures in the mothers’ homes.
    Background therapy
    Background therapy was permitted as defined in the study protocol.
    Evidence for comparator
    Not applicable.
    Actual start date of recruitment
    09 Jan 2014
    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
    France: 7
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Switzerland: 12
    Country: Number of subjects enrolled
    United States: 16
    Worldwide total number of subjects
    37
    EEA total number of subjects
    9
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    16
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    21
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study started to enroll patients in January 2014 and concluded in November 2016.

    Pre-assignment
    Screening details
    The Participant Flow refers to the Safety Set for Mothers [SS-M] and the Safety Set for Infants [SS-I]. For mothers, Baseline is defined as their screening visit. Since babies are regarded as study participants once they are born, baseline for the infants is considered to be the day of their birth.

    Period 1
    Period 1 title
    Screening Period
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    SS-M
    Arm description
    This arm consisted of all participating mothers who entered the screening period and received at least 1 dose of Certolizumab Pegol (CZP) less than or equal to 35 days prior to delivery.
    Arm type
    Experimental

    Investigational medicinal product name
    Cimzia
    Investigational medicinal product code
    CZP
    Other name
    Certolizumab pegol
    Pharmaceutical forms
    Lyophilisate for solution for injection, Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    This study only included pregnant women who started or decided to continue treatment with CZP for an approved indication in accordance with their treating physician prior to participating in the study. The CZP was not provided by the Sponsor. The CZP dose and administration schedule were per the physician’s instructions.

    Arm title
    SS-I
    Arm description
    This arm consisted of all infants born to mothers in the SS-M group.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    SS-M SS-I
    Started
    21
    16
    Completed
    16
    16
    Not completed
    5
    0
         Ineligibility
             4
             -
         Adverse event, non-fatal
             1
             -
    Period 2
    Period 2 title
    Sampling Period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    SS-M
    Arm description
    This arm consisted of all participating mothers who entered the screening period and received at least 1 dose of Certolizumab Pegol (CZP) less than or equal to 35 days prior to delivery.
    Arm type
    Experimental

    Investigational medicinal product name
    Cimzia
    Investigational medicinal product code
    CZP
    Other name
    Certolizumab pegol
    Pharmaceutical forms
    Solution for injection in pre-filled syringe, Lyophilisate for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    This study only included pregnant women who started or decided to continue treatment with CZP for an approved indication in accordance with their treating physician prior to participating in the study. The CZP was not provided by the Sponsor. The CZP dose and administration schedule were per the physician’s instructions.

    Arm title
    SS-I
    Arm description
    This arm consisted of all infants born to mothers in the SS-M group.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    SS-M SS-I
    Started
    16
    16
    Completed
    16
    16

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SS-M
    Reporting group description
    This arm consisted of all participating mothers who entered the screening period and received at least 1 dose of Certolizumab Pegol (CZP) less than or equal to 35 days prior to delivery.

    Reporting group title
    SS-I
    Reporting group description
    This arm consisted of all infants born to mothers in the SS-M group.

    Reporting group values
    SS-M SS-I Total
    Number of subjects
    21 16 37
    Age Categorical
    Units: Subjects
        <=18 years
    0 16 16
        Between 18 and 65 years
    21 0 21
        >=65 years
    0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    31.4 ± 5.0 0 ± 0 -
    Gender Categorical
    Units: Subjects
        Male
    0 6 6
        Female
    21 10 31

    End points

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    End points reporting groups
    Reporting group title
    SS-M
    Reporting group description
    This arm consisted of all participating mothers who entered the screening period and received at least 1 dose of Certolizumab Pegol (CZP) less than or equal to 35 days prior to delivery.

    Reporting group title
    SS-I
    Reporting group description
    This arm consisted of all infants born to mothers in the SS-M group.
    Reporting group title
    SS-M
    Reporting group description
    This arm consisted of all participating mothers who entered the screening period and received at least 1 dose of Certolizumab Pegol (CZP) less than or equal to 35 days prior to delivery.

    Reporting group title
    SS-I
    Reporting group description
    This arm consisted of all infants born to mothers in the SS-M group.

    Subject analysis set title
    PKS-M
    Subject analysis set type
    Full analysis
    Subject analysis set description
    This arm consisted of all mothers from the SS-M analysis set who provided the CZP concentration sample at delivery.

    Subject analysis set title
    PKS-U
    Subject analysis set type
    Full analysis
    Subject analysis set description
    This arm consisted of all umbilical cords of infants from the SS-I analysis set from which a CZP concentration sample was obtained at birth.

    Subject analysis set title
    PK-PPS-I
    Subject analysis set type
    Per protocol
    Subject analysis set description
    This arm consisted of all infants from the SS-I analysis set who provided a CZP concentration sample at birth and had no important protocol deviations that would have impacted the primary PK analysis.

    Primary: The plasma concentration of Certolizumab Pegol (CZP) in the Infant(s) at birth

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    End point title
    The plasma concentration of Certolizumab Pegol (CZP) in the Infant(s) at birth [1]
    End point description
    Blood samples will be taken within 24 hours after birth from the infant(s). -999 = below limit of quantification.
    End point type
    Primary
    End point timeframe
    Day 0
    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: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.
    End point values
    PK-PPS-I
    Number of subjects analysed
    14
    Units: µg/mL
    median (full range (min-max))
        median (full range)
    -999 (-999 to 0.0422)
    No statistical analyses for this end point

    Secondary: The plasma concentration of Certolizumab Pegol (CZP) in the mother at delivery

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    End point title
    The plasma concentration of Certolizumab Pegol (CZP) in the mother at delivery
    End point description
    Blood samples will be taken within 24 hours before/after delivery from the mothers.
    End point type
    Secondary
    End point timeframe
    Day 0
    End point values
    PKS-M
    Number of subjects analysed
    16
    Units: µg/mL
    median (full range (min-max))
        median (full range)
    24.40 (4.96 to 49.4)
    No statistical analyses for this end point

    Secondary: The ratio of plasma concentration of Certolizumab Pegol (CZP) between the infant(s) and mother at delivery/birth

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    End point title
    The ratio of plasma concentration of Certolizumab Pegol (CZP) between the infant(s) and mother at delivery/birth
    End point description
    Blood samples will be taken within 24 hours before/after delivery from the mothers and within 24 hours after birth from the infant(s). Values below limit of quantification (BLQ) are replaced by values of lower limit of quantification/2=0.016 in calculations of ratios, however if both concentrations for a subject are BLQ then the ratio for that subject will not be calculated.
    End point type
    Secondary
    End point timeframe
    Day 0
    End point values
    PK-PPS-I
    Number of subjects analysed
    14
    Units: ratio
    median (full range (min-max))
        median (full range)
    0.0007634 (0.000403 to 0.00323)
    No statistical analyses for this end point

    Secondary: The plasma concentration of Certolizumab Pegol (CZP) in the umbilical cord at birth

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    End point title
    The plasma concentration of Certolizumab Pegol (CZP) in the umbilical cord at birth
    End point description
    Blood samples will be taken directly after delivery (within <= 1 hour) from the umbilical cord. -999 = below limit of quantification.
    End point type
    Secondary
    End point timeframe
    Day 0
    End point values
    PKS-U
    Number of subjects analysed
    15
    Units: µg/mL
    median (full range (min-max))
        median (full range)
    -999 (-999 to 0.0477)
    No statistical analyses for this end point

    Secondary: The plasma concentration level of anti-CZP antibodies in the mother at delivery

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    End point title
    The plasma concentration level of anti-CZP antibodies in the mother at delivery
    End point description
    Blood samples will be taken within 24 hours before/after delivery from the mothers. -999 = below limit of quantification.
    End point type
    Secondary
    End point timeframe
    Day 0
    End point values
    PKS-M
    Number of subjects analysed
    16
    Units: units/mL
    median (full range (min-max))
        median (full range)
    -999 (-999 to -999)
    No statistical analyses for this end point

    Secondary: The plasma concentration level of anti-CZP antibodies in the umbilical cord(s) at birth

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    End point title
    The plasma concentration level of anti-CZP antibodies in the umbilical cord(s) at birth
    End point description
    Blood samples will be taken directly after delivery (within <= 1 hour) from the umbilical cord. -999 = below limit of quantification.
    End point type
    Secondary
    End point timeframe
    Day 0
    End point values
    PKS-U
    Number of subjects analysed
    15
    Units: units/mL
    median (full range (min-max))
        median (full range)
    -999 (-999 to -999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were collected during the whole study period (from Week 0 up to Week 25)
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    SS-I
    Reporting group description
    This arm consisted of all infants born to mothers in the SS-M group.

    Reporting group title
    SS-M
    Reporting group description
    This arm consisted of all participating mothers who entered the screening period and received at least 1 dose of Certolizumab Pegol (CZP) less than or equal to 35 days prior to delivery.

    Serious adverse events
    SS-I SS-M
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 16 (12.50%)
    7 / 21 (33.33%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Vaginal laceration
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 21 (4.76%)
         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
    Arrested labour
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 21 (9.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gestational diabetes
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 21 (4.76%)
         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 / 16 (0.00%)
    1 / 21 (4.76%)
         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 / 16 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Premature baby
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prolonged labour
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meconium in amniotic fluid
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Macrosomia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Perineal abscess
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    SS-I SS-M
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 16 (25.00%)
    3 / 21 (14.29%)
    Pregnancy, puerperium and perinatal conditions
    Umbilical cord around neck
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    Foetal hypokinesia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    3
    Infections and infestations
    Candida infection
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Nov 2014
    Protocol Amendment 1, approved on 04 Nov 2014, was a substantial amendment implemented to provide clarification to aid smooth running of the study, to address inconsistencies between this study and the closely related breast milk study, UP0016, and to address some operational challenges observed or presented to UCB as feedback from Independent Ethics Committees/Institutional Review Boards and partner operations personnel, as well as Investigators and study site personnel. The main changes included: •Update of the text regarding the approval status for CZP, per the latest Investigator’s brochure, to include additional indications for CZP treatment – psoriatic arthritis, ankylosing spondylitis, and axial spondyloarthritis. •Clarification of infant consent/assent. •Clarification of the requirements for blood sampling for the infant. •Clarification of the procedures for analysis of blood samples. •Clarification of the noninterventional design of the study as it related to CZP therapy. •Clarifications of tuberculosis (TB) testing requirements and procedures for subjects who developed latent TB or active TB. •Clarification of the definitions of the analysis sets. •Analysis of the ratios of CZP and polyethylene glycol concentrations in maternal and umbilical cord were added as exploratory pharmacokinetic variables. •Minor changes were made for consistency with updated Sponsor document templates. •Some changes were made based on feedback from the Swiss Ethics Committee on Protocol UP0016: addition of names and addresses of central and local laboratories, and clarification of data confidentiality regarding data anonymization and retraction of consent. •Some changes were made in the statistical analysis sections (safety analyses and handling of protocol deviations) based on discussions during preparation of the Statistical Analysis Plan for UP0016. •Correction of typographical errors, minor inconsistencies, and editorial updates to aid clarity.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/29030361
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