Efficacy Assessment of Systematic Treatment With Folinic Acid and Thyroid Hormone on Psychomotor Development of Down Syndrome Young Children

NCT01576705 | Completed Phase 3 Results DMC

• 1 other identifier: IJL-AFHT-TH10
• Study Type: interventional
• Target: 175
• Locations: 1 country
• Sites: 1

Brief Summary

Evaluation of the following in very young children with Down syndrome:

• the efficacy of systematic treatment with L-thyroxine at controlled doses (clinically and by ultrasensitive thyreostimulating hormone (TSH) assay),
• the efficacy of systematic folinic acid treatment at a dose of 1 mg/kg/o.i.d,
• any interaction between these two treatments.

Conditions

Down Syndrome

Keywords

Down syndrome; Young children; Psychomotor development; Thyroid hormone; Folinic acid; Psychometric tests; GMDS; Griffiths; Genetic factors; Biochemical factors

Outcome Measures

Primary Outcomes (1)

• GMDS (Griffiths Mental Development Scale)

  GMDS for testing and estimate babies psychomotor development from birth to 2 years trough six subscales : Locomotor, Personal-social, Hearing and language, Eye-Hand coordination, Performance.Sub- and General Quotients (GDQ) standard score are based on a mean of 100 and a standard deviation of 16. For children with delayed development, which is the case for children with Down Syndrome, Quotient tables could be not used because sub- and General quotient floors at 50. For each subscale, a raw score was derived from the contributing items. Total raw score was obtained by adding subscale raw scores. Sum of all subscale raw scores was converted into a development age using correspondence table. Subscale and global development quotients were computed by dividing the development age by the chronological age multiplied by 100. For preterm infants, chronological age was corrected taking into account the gestational term. Higher QD's scores show a better psychomotor development outcome

  12 months

Secondary Outcomes (1)

• BL (Brunet Lezine Revised Scale)

  12 months

Study Arms (4)

Thyroxin + folinic acid

EXPERIMENTAL

Drug: thyroid hormone and folinic acid

Thyroxin+folinic acid placebo

ACTIVE COMPARATOR

Drug: thyroid hormone and folinic acid

Thyroxin placebo+ folinic acid

ACTIVE COMPARATOR

Drug: thyroid hormone and folinic acid

Thyroxin placebo+ folinic acid placebo

PLACEBO COMPARATOR

Drug: thyroid hormone and folinic acid

Interventions

thyroid hormone and folinic acid DRUG

thyroid hormone 25microg or placebo in tablets folinic acid 5 mg or placebo in capsules

Thyroxin + folinic acid; Thyroxin placebo+ folinic acid; Thyroxin placebo+ folinic acid placebo; Thyroxin+folinic acid placebo

Eligibility Criteria

• Age: 6 Months - 18 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• patient with a karyotype demonstrating homogeneous, free or Robertsonian translocation trisomy 21
• patient having undergone a cardiac ultrasound not demonstrating any severe heart disease

You may not qualify if:

• congenital hypothyroidism
• hypothyroidism demonstrated by laboratory tests (TSH \> 7mUI/l)
• presenting or having presented hyperthyroidism
• presenting or having presented leukaemia
• presenting or having presented West syndrome or any other form of epilepsy or unstable neurological disease
• presenting or having presented signs of central nervous system distress: stroke, postoperative hypoxia, meningitis)
• presenting severe heart disease on cardiac ultrasound, with haemodynamic effects
• presenting non-controlled cardiac arrhythmia
• Apgar \< 7 to 5 min at birth
• Gestational age \< 231 days (33 gestation weeks)

Sponsors & Collaborators

• Institut Jerome Lejeune: lead
• Hôpital Cochin: collaborator
• Central Hospital, Nancy, France: collaborator

Study Sites (1)

Institut Jerome Lejeune

Paris, 75015, France

Location

Related Publications (6)

• Blehaut H, Mircher C, Ravel A, Conte M, de Portzamparc V, Poret G, de Kermadec FH, Rethore MO, Sturtz FG. Effect of leucovorin (folinic acid) on the developmental quotient of children with Down's syndrome (trisomy 21) and influence of thyroid status. PLoS One. 2010 Jan 11;5(1):e8394. doi: 10.1371/journal.pone.0008394.

  PMID: 20084109 BACKGROUND

• van Trotsenburg AS, Kempers MJ, Endert E, Tijssen JG, de Vijlder JJ, Vulsma T. Trisomy 21 causes persistent congenital hypothyroidism presumably of thyroidal origin. Thyroid. 2006 Jul;16(7):671-80. doi: 10.1089/thy.2006.16.671.

  PMID: 16889491 BACKGROUND

• van Trotsenburg AS, Vulsma T, van Rozenburg-Marres SL, van Baar AL, Ridder JC, Heymans HS, Tijssen JG, de Vijlder JJ. The effect of thyroxine treatment started in the neonatal period on development and growth of two-year-old Down syndrome children: a randomized clinical trial. J Clin Endocrinol Metab. 2005 Jun;90(6):3304-11. doi: 10.1210/jc.2005-0130. Epub 2005 Mar 8.

  PMID: 15755847 BACKGROUND

• Ellis JM, Tan HK, Gilbert RE, Muller DP, Henley W, Moy R, Pumphrey R, Ani C, Davies S, Edwards V, Green H, Salt A, Logan S. Supplementation with antioxidants and folinic acid for children with Down's syndrome: randomised controlled trial. BMJ. 2008 Mar 15;336(7644):594-7. doi: 10.1136/bmj.39465.544028.AE. Epub 2008 Feb 21.

  PMID: 18296460 BACKGROUND

• Sacco S, Bouis C, Gallard J, Pichot A, Blondiaux E, Marey I, Dorison N, Sturtz F, Cieuta-Walti C, Ravel A, Mircher C. Psychomotor development in infants and young children with Down syndrome-A prospective, repeated measure, post-hoc analysis. Am J Med Genet A. 2022 Mar;188(3):818-827. doi: 10.1002/ajmg.a.62587. Epub 2021 Dec 4.

  PMID: 34863019 DERIVED

• Mircher C, Sacco S, Bouis C, Gallard J, Pichot A, Le Galloudec E, Cieuta C, Marey I, Greiner-Mahler O, Dorison N, Gambarini A, Stora S, Durand S, Polak M, Baruchel A, Schlumberger E, Dewailly J, Azar-Kolakez A, Gueant-Rodriguez RM, Gueant JL, Borderie D, Bonnefont-Rousselot D, Blondiaux E, Ravel A, Sturtz FG. Thyroid hormone and folinic acid in young children with Down syndrome: the phase 3 ACTHYF trial. Genet Med. 2020 Jan;22(1):44-52. doi: 10.1038/s41436-019-0597-8. Epub 2019 Jul 8.

  PMID: 31281181 DERIVED

Related Links

• Institut Jerome Lejeune

MeSH Terms

Conditions

Down Syndrome

Interventions

Thyroid Hormones; Leucovorin

Condition Hierarchy (Ancestors)

Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Chromosome Disorders; Genetic Diseases, Inborn

Intervention Hierarchy (Ancestors)

Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Coenzymes; Enzymes and Coenzymes

Limitations and Caveats

The initial protocol planned for 256 patients, however due to difficulties in recruiting patients, the sample size was subsequently reduced to 175 patients, to obtain 140 evaluable patients.

Results Point of Contact

• Title: Dr Clotilde Mircher
• Organization: Institut Jérôme Lejeune

clotilde.mircher@institutlejeune.org

00 33 1 56 58 63 00

Study Officials

• Clotilde MIRCHER, MD

  Institut Jerome Lejeune, Paris, France

  PRINCIPAL INVESTIGATOR

• Franck STURTZ, MD, PhD

  Department of Biochemistry and Molecular Genetics, Limoges University, Limoges, France

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 11, 2012
• First Posted: April 12, 2012
• Study Start: April 2, 2012
• Primary Completion: December 14, 2017
• Study Completion: December 14, 2017
• Last Updated: May 13, 2020
• Results First Posted: May 13, 2020

Record last verified: 2019-12

Locations

FR (1)