Trial document




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  DRKS00005036

Trial Description

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Title

The safety of anti-tumor necrosis factor-alpha (TNF-α) agents in pregnancy. An observational prospective multicenter study.

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Trial Acronym

TNF-α Blocker in Pregnancy

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URL of the Trial

[---]*

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Brief Summary in Lay Language

The safety in pregnancy of the five licensed TNF-α inhibitors adalimumab, certolizumab pegol, etanercept, golimumab and infliximab has been insufficiently examined. Part 1 of the study compares frequency and cluster of malformations and the risk of spontaneous abortion of exposed fetuses/children (during the first trimester or longer) with a suitable comparison group.

Part 2 focuses on infections, reactions to vaccines, allergies and the development of intrauterine exposed children during the first year of life. It is known that at least some of the TNF-alpha inhibitors have a high placental transfer beginning in week 20. It will be distinguished between early (<20 weeks of gestation) and late exposure (>20 weeks of gestation). All exposed children will also be compared to suitable control children.

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Brief Summary in Scientific Language

The five TNF-alpha inhibitors adalimumab, certolizumab pegol, etanercept, golimumab and infliximab are not labeled for use in pregnancy. However, inadvertent exposure occurs and in certain patients they might be the best treatment option. Existing experience during pregnancy does not suggest teratogenicity, but varies between the different substances and altogether is still limited. There are concerns against the use of TNF-α inhibitors in late pregnancy (> gestational week 20), because at least some of them exhibit an increasing placental transfer during the course of pregnancy. This results in therapeutic fetal/neonatal plasma concentrations. A case report of an infant raises concern. The mother was treated with infliximab throughout pregnancy. The 3-months old infant received BCG live-vaccination resulting in disseminated BCG infection and ultimately in the death of the child (Cheent 2010). Our prospective multicenter cohort study enrolls pregnant women who have spontaneously contacted a teratology information service (TIS) within the European Network (ENTIS). The sample of exposed includes women who have been treated with a TNF-alpha inhibitor during the first trimester (part 1). Part 2 consists of intrauterine exposed children (either till week 20 or longer than week 20) aged one year (part 2). The comparison groups consist of non-exposed women /children matched for year of enrollment and TIS. Cases exposed to major teratogens or fetotoxicants are excluded from all groups. The focus of part 1 lies on the risk of major malformations, spontaneous abortion, and low birth weight. Part 2 will evaluate potential impacts on the infant’s development and immune system. Infants of part 2 will be compared to non-exposed children and matched for sex, gestational week at birth, birth weight, and year of birth. Excluded are children born with major birth defects having an impact on infant development.

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Organizational Data

  •   DRKS00005036
  •   2013/05/31
  •   [---]*
  •   yes
  •   Approved
  •   EA4/013/13, Ethik-Kommission der Charité -Universitätsmedizin Berlin-
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Secondary IDs

  • [---]*
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Health Condition or Problem studied

  •   P04.1 -  Fetus and newborn affected by other maternal medication
  •   Malformation rate, rate of spontaneous abortion, both after first trimester exposure. Frequency and severity of infections, allergies, developmental delay, weight gain after exposure in late pregnancy.
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Interventions/Observational Groups

  •   Study part 1: maternal exposure to TNF-α blockers; prospectively ascertained; exposure time meets any time from last menstrual period (LMP) until week 12+0 after LMP. Exposure may have started earlier than LMP and can have continued beyond week 12.

    Study part 2: maternal exposure to TNF-α blockers; exposure time either took place before the 20th week of gestation or meets any time beyond week 20 after LMP. Exposure may have started earlier in pregnancy; at least one injection after week 20+0 and before delivery is obligatory. The pregnancy may have been included in the study part I, but need not and can be retrospectively ascertained shortly after birth as long as long-term follow-up up to at least 1 year of age is ascertained prospectively.
  •   Study part 1: prospectively ascertained pregnancies without TNF-alpha blocker therapy or other biologics; randomly chosen from the same data pool as the exposed.

    Study part 2: prospective long-term follow-up; noTNF-alpha blocker therapy or other biologics. Per exposed two control children matched for infant's sex, gestational week at birth, birth weight (+/-100g) and year of birth.
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Characteristics

  •   Non-interventional
  •   Observational study
  •   Non-randomized controlled trial
  •   Open (masking not used)
  •   [---]*
  •   Other
  •   Prognosis
  •   Parallel
  •   N/A
  •   Yes
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Primary Outcome

Part 1: Eight weeks after the estimated date of birth a structured questionnaire is sent to the mother /physician. Primary endpoints are delivery of the child with /without anomalies, spontaneous abortion, and elective termination of pregnancy.
Part 2: For children being one year or older, an extra questionnaire designed for this study, will be sent to the mothers dealing with infant development within the first year of life. Primary objectives are frequency and severity of infections, allergies and reactions to vaccines.

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Secondary Outcome

Part 1: prematurity, birth weight
Part 2: infant's weight gain, achievement of developmental milestones

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Countries of Recruitment

  •   Germany
  •   France
  •   Finland
  •   Italy
  •   Netherlands
  •   United Kingdom
  •   Switzerland
  •   Australia
  •   Turkey
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Locations of Recruitment

  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • other 
  • other 
  • University Medical Center 
  • Medical Center 
  • University Medical Center 
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Recruitment

  •   Actual
  •   2013/09/02
  •   1837
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   no minimum age
  •   no maximum age
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Additional Inclusion Criteria

Part 1: Prospectively ascertained pregnancies with first trimester exposure to adalimumab, certolizumab pegol, etanercept, golimumab or infliximab. Maternal therapy might have started earlier and can last longer. Comparison group: prospectively ascertained pregnancies without exposure to adalimumab, certolizumab pegol, etanercept, golimumab or infliximab (or other biologics).
Part 2: Prospective ascertainment of long-term follow-up of children being at least 1-year-old or older. They must have been exposed in utero to at least one maternal injection of the named TNF-alpha blockers. Comparison children: Prospective ascertainment of long-term follow-up of children being at least 1-year-old or older matched for sex, gestational week at birth, birth weight and year of birth. No TNF-alpha blockers (or other biologics) during pregnancy.

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Exclusion Criteria

Excluded from all cohorts are pregnancies with: major teratogens (acitretin, isotretinoin, mycophenolate, thalidomide, valproiic acid) or/and major fetotoxic agents (ACE-inhibitors or sartans when used in 2nd and/or 3rd trimester) or/and acute malignancies. For study part 2: Excluded are children with malformations having an impact on normal development and preterms born before week 34 0/7.

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Addresses

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Sources of Monetary or Material Support

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    • Bundesministerium für Gesundheit
    • 53123  Bonn
    • Germany
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    • Bundesinstitut für Arzneimittel und Medizinprodukte
    • Kurt-Georg-Kiesinger-Allee 3
    • 53175  Bonn
    • Germany
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Status

  •   Recruiting complete, follow-up continuing
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Trial Publications, Results and other Documents

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