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Effects of a Multiple Sclerosis Relapse Therapy on Offspring Neurocognitive Development and Behaviour (MS-Children)

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ClinicalTrials.gov Identifier: NCT04832269
Recruitment Status : Recruiting
First Posted : April 5, 2021
Last Update Posted : August 9, 2022
Sponsor:
Collaborators:
Ruhr University of Bochum
Interdisciplinary Center of Clinical Research of the Medical Faculty Jena
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Information provided by (Responsible Party):
Florian Rakers, Jena University Hospital

Brief Summary:
Introduction: Fetal exposure to glucocorticoids (GCs) used to induce fetal lung maturation in women threatened by premature labour is known to induce aberrations in brain development and stress sensitivity, cognitive dysfunction and neuro-psychiatric disorders in later life which all predict early brain ageing. Another common source of fetal GC exposure is the treatment of relapses in multiple sclerosis (MS), the most common neurological disease in young women. Despite the lack of studies, the 300-fold higher dosage of GCs for MS relapse treatment compared to obstetric indications is considered harmless for the fetus . Objectives: To examine the effects of GCs for MS relapse treatment during pregnancy on offspring structural and functional brain development, stress sensitivity, and cognitive and behavioural performance. Methods: Epidemiological multi-centre cohort study in 80 children and adolescents aged 8 to 18 years whose mothers received GCs to treat a MS relapse during pregnancy compared to unexposed participants. Expected Impact: Creating a guideline-changing evidence-based risk-benefit assessment regarding benefits of the MS relapse therapy for the mother and potential harm to the child.

Condition or disease Intervention/treatment
Multiple Sclerosis Other: Exposure to methylprednisolone during pregnancy

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Study Type : Observational
Estimated Enrollment : 80 participants
Observational Model: Other
Time Perspective: Retrospective
Official Title: Effects of a Multiple Sclerosis Relapse Therapy With Methylprednisolone (MP) During Pregnancy on Offspring Cognitive Function, Stress Sensitivity, Behaviour and Functional and Structural Brain Development
Actual Study Start Date : October 19, 2020
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2022


Group/Cohort Intervention/treatment
MP exposed group
children and adolescents (aged 8 to 18 years) of mothers with prenatal exposition to MP in the context of an MS relapse therapy
Other: Exposure to methylprednisolone during pregnancy
Exposure to methylprednisolone during pregnancy in the context of an MS relapse therapy

MP non-exposed group/control group
children and adolescents of mothers suffering from MS aged 8 to 18 years



Primary Outcome Measures :
  1. General cognitive ability - Reynolds Intellectual Assessment Scales and Screening (RIAS) [ Time Frame: approx. 30 - 40 min. ]
    Intelligence quotient as measured by RIAS, higher scores denote better outcome.


Secondary Outcome Measures :
  1. Structural brain development - BrainAge score [ Time Frame: approx. 20 min. ]
    Volumetric cranial MRI change in standard T1 sequences (Developmental biomarker)

  2. Salivary cortisol decay curve [ Time Frame: approx. 5 min. per swab ]
    Salivary cortisol concentration (nmol/l) before, during, and after Trier Social Stress Test

  3. Salivary alpha-amylase [ Time Frame: approx. 5 min. per swab ]
    Salivary alpha-amylase concentration (U/ml) before, during, and after Trier Social Stress Test

  4. Heart rate variability [ Time Frame: approx. 75 min. ]
    Heart rate variability (band power low frequency, high frequency, and ratio; msec^2/Hz) before, during, and after the Trier Social Stress Test

  5. Spectral edge frequency in the EEG [ Time Frame: approx. 75 min. ]
    Fast Fourier transformation to measure cerebral activity before, during, and after the Trier Social Stress Test

  6. External assessment sheet for attention deficit / hyperactivity disorder (FBB-ADHS, German Version) [ Time Frame: approx. 15 - 20 min. ]
    Questionnaire for parents assessing attention deficit hyperactivity disorder associated behaviour. Items based on symptoms of hyperkinetic disorder (International Classification of Diseases-10) and attention deficit hyperactivity disorder (Diagnostic and Statistical Manual of Mental Disorders-5). Higher scores denote worse outcome.

  7. Child Behavior Checklist (CBCL/6-18R) [ Time Frame: approx. 15 - 20 min. ]
    Questionnaire for parents assessing the child's behavioural symptoms on eight scales - (1) anxious/depressed, (2) withdrawn/depressed, (3) somatic complaints, (4) social problems, (5) thought, sleep, and repetitive behaviour problems, (6) attention problems, (7) rule-breaking behaviour, and (8) aggressive behaviour. Higher scores denote worse outcome.

  8. Strengths and Difficulties Questionnaire (SDQ-Deu-S) [ Time Frame: approx. 15 - 20 min. ]
    Brief screening questionnaire for parents assessing emotional and behavioural problems, hyperactivity and inattention, peer relationship problems, and prosocial behaviour. Higher score denote worse outcome.

  9. Continuous Performance Test (CPT) [ Time Frame: approx. 15 min. ]
    Computer-based test of selective attention, vigilance, and impulsivity, measured as reaction time, performance variability, and commission and omission errors. Higher scores denote poorer performance.

  10. Emotional excitability scale from Personality questionnaire for children between 9 and 14 years (PFK 9-14, German Version) [ Time Frame: approx. 15 min. ]
    Computer-based personality assessment reported by the child; for ages 9 - 14

  11. Movement Assessment Battery for Children - Second Edition (M-ABC-2) [ Time Frame: approx. 20 - 30 min. ]
    Motor impairment assessment for ages 3 - 16

  12. Child anxiety test III (KAT-III, German version) [ Time Frame: approx. 5 min. each ]
    State and trait anxiety in children aged 6 - 18 years; before and after the Trier Social Stress Test; higher scores denotes higher subjective anxiety


Other Outcome Measures:
  1. Methylation of GR-receptor gene [ Time Frame: approx. 10 min. ]
    DNA methylation at GC receptor gene NR3C1 and at the H19 locus


Biospecimen Retention:   Samples With DNA
GC receptor sensitivity, methylation of the GR-receptor gene


Information from the National Library of Medicine

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Ages Eligible for Study:   8 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
The study population is composed of children aged 8 to 18 from mothers with multiple sclerosis who received methylprednisolone in pregnancy and children aged 8 to 18 from mothers with multiple sclerosis without methylprednisolone therapy during pregnancy
Criteria

Inclusion Criteria:

  • MS diagnosis was made based on the McDonald criteria valid at the time of diagnosis
  • Written consent by the legal guardians of the participating child following a detailed oral and written education
  • Exposed group (n=40): Children and adolescents (aged 8 to 18 years) of mothers with prenatal exposition to MP in the context of a MS relapse therapy
  • Non-exposed group (n=40): Children and adolescents of mothers suffering from MS without MP therapy during pregnancy (aged 8 to 18 years) matched for age, gender and social background

Exclusion Criteria:

  • Perinatal complications such as cerebral bleeding, neonatal intensive care with ventilation, prenatal therapy with glucocorticoids except for an MS relapse
  • Maternal abuse of noxious agents during pregnancy
  • Long-term glucocorticoid medication (e.g. asthma)
  • Preterm births (before 36 weeks of pregnancy)
  • Severe disease making an examination impossible (e.g. mental retardation)
  • disease-modifying therapy during pregnancy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04832269


Contacts
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Contact: Michelle Dreiling, Dr. +493641 9 32 35 93 michelle.dreiling@med.uni-jena.de
Contact: Florian Rakers, PD Dr. +493641 9 32 34 67 florian.rakers@med.uni-jena.de

Locations
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Germany
Ruhr University of Bochum Recruiting
Bochum, Germany, 44791
Contact: Michelle Dreiling    +4936419323593    michelle.dreiling@med.uni-jena.de   
University Hospital Jena Recruiting
Jena, Germany, 07747
Contact: Michelle Dreiling    +4936419323593    michelle.dreiling@med.uni-jena.de   
Contact: Florian Rakers    +4936419323467    florian.rakers@med.uni-jena.de   
Sponsors and Collaborators
Jena University Hospital
Ruhr University of Bochum
Interdisciplinary Center of Clinical Research of the Medical Faculty Jena
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Investigators
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Principal Investigator: Florian Rakers University Hospital Jena
Study Director: Matthias Schwab, Prof. Dr. University Hospital Jena
Additional Information:
Publications:
Schmidt K, Schwab M, Eiselt M, Kott M, Hoyer D, Zwiener U. Nonlinear modeling of different fetal and neo-natal behaviorial states. Pathophysiology. 1998;1001(5):257
Society GN. Guidline for the treatment of Multiple Sklerosis. https://www.dgn.org/images/red_leitlinien/LL_2012/pdf/030-050l_S2e_Multiple_Sklerose_Diagnostik_Therapie_Archiv-min.pdf. Published 2012
Hagmann-von Arx P, Grob A. RIAS-Reynolds intellectual assessment scales and screening: deutschspra-chige Adaptation der Reynolds Intellectual Assessment Scales (RIAS) & des Reynolds Intellectual Screening Test (RIST) von Cecil R. Reynolds und Randy W. Kamphaus: Manual. Hans Huber; 2014
Malik M. Heart rate variability: Standards of measurement, physiological interpretation, and clinical use: Task force of the European Society of Cardiology and the North American Society for Pacing and Electrophysi-ology. Annals of Noninvasive Electrocardiology. 1996;1(2):151-181

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Florian Rakers, Principal Investigator, Jena University Hospital
ClinicalTrials.gov Identifier: NCT04832269    
Other Study ID Numbers: ZKSJ0130
First Posted: April 5, 2021    Key Record Dates
Last Update Posted: August 9, 2022
Last Verified: August 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Florian Rakers, Jena University Hospital:
fetal programming
pregnancy
relapse therapy
Additional relevant MeSH terms:
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Multiple Sclerosis
Sclerosis
Recurrence
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Disease Attributes
Methylprednisolone
Methylprednisolone Acetate
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Neuroprotective Agents
Protective Agents
Antineoplastic Agents, Hormonal