Clotilde Mircher1, Silvia Sacco2, Charles Bouis2, Jennifer Gallard2, Aude Pichot2, Eric Le Galloudec2, Cécile Cieuta2, Isabelle Marey2, Oliver Greiner-Mahler2, Nathalie Dorison2, Alicia Gambarini2, Samantha Stora3, Sophie Durand2, Michel Polak4, André Baruchel5, Emilie Schlumberger6, Jean Dewailly7, Ahlam Azar-Kolakez8, Rosa-Maria Guéant-Rodriguez9,10, Jean-Louis Guéant9,10, Didier Borderie11, Dominique Bonnefont-Rousselot12,13, Elodie Blondiaux14, Aimé Ravel2, Franck G Sturtz2,15,16. 1. Institut Jérôme Lejeune, Paris, France. clotilde.mircher@institutlejeune.org. 2. Institut Jérôme Lejeune, Paris, France. 3. Institut Jérôme Lejeune Biobank BioJeL, Paris, France. 4. Endocrinologie gynécologie diabétologie pédiatriques, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, INSERM U1016, Institut IMAGINE, Paris, France. 5. Pediatric Hematology-Immunology Department, University Hospital Robert Debré, Assistance Publique-Hôpitaux de Paris. Paris Diderot University, EA 3518; Institute of Hematology, Sorbonne Paris-Cité, Paris, France. 6. Reference Center for Language and Learning Disorders, Raymond Poincaré Hospital, Assistance Publique-Hôpitaux de Paris, Garches, France. 7. Bluestat Statistical Company, Garches, France. 8. Endocrinology-Diabetology Department, Reference Center for Endocrine Growth and Developmental Disease, Robert Debré Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. 9. Research Unit (Inserm) UMRS 1256 N-GERE (Nutrition-Genetics-Environmental Risks), University de Lorraine, Faculty of Medicine, Nancy, France. 10. Department of Endocrinology, Diabetology and Nutrition, University Hospital of Nancy, Nancy, France. 11. Biochemistry and Molecular Biology Laboratory, Cochin University Hospital, Paris, France. 12. Metabolic Biochemistry Department, Pitié-Salpêtrière-Charles Foix University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. 13. Biochemistry Department, Faculty of Pharmacy, CNRS UMR 8258 - INSERM U1022, Paris Descartes University, Paris, France. 14. Department of Statistics, Effi-Stat, Paris, France. 15. Biochemistry and Molecular Biology Department, CHU Limoges, Limoges, France. 16. Univ. Limoges, EA 6309, Limoges, France.
Abstract
PURPOSE: To determine whether folinic acid (FA) and thyroxine, in combination or alone, benefit psychomotor development in young patients with Down syndrome (DS). METHODS: The Assessment of Systematic Treatment With Folinic Acid and Thyroid Hormone on Psychomotor Development of Down Syndrome Young Children (ACTHYF) was a single-center, randomized, double-blind, placebo-controlled phase 3 trial in DS infants aged 6-18 months. Patients were randomly assigned to one of four treatments: placebo, folinic acid (FA), L-thyroxine, or FA+L-thyroxine, administered for 12 months. Randomization was done by age and sex. The primary endpoint was adjusted change from baseline in Griffiths Mental Development Scale global development quotient (GDQ) after 12 months. RESULTS: Of 175 patients randomized, 143 completed the study. The modified intention-to-treat (mITT) population included all randomized patients who did not prematurely discontinue due to elevated baseline thyroid stimulating hormone (TSH). Baseline characteristics in the mITT were well balanced between groups, with reliable developmental assessment outcomes. Adjusted mean change in GDQ in the mITT showed similar decreases in all groups (placebo: -5.10 [95% confidence interval (CI) -7.84 to -2.37]; FA: -4.69 [95% CI -7.73 to -1.64]; L-thyroxine: -3.89 [95% CI -6.94 to -0.83]; FA+L-thyroxine: -3.86 [95% CI -6.67 to -1.06]), with no significant difference for any active treatment group versus placebo. CONCLUSION: This trial does not support the hypotheses that thyroxine and/or folinic acid improve development of young children with DS or are synergistic. This trial is registered with ClinicalTrials.gov number, NCT01576705.
PURPOSE: To determine whether folinic acid (FA) and thyroxine, in combination or alone, benefit psychomotor development in young patients with Down syndrome (DS). METHODS: The Assessment of Systematic Treatment With Folinic Acid and Thyroid Hormone on Psychomotor Development of Down Syndrome Young Children (ACTHYF) was a single-center, randomized, double-blind, placebo-controlled phase 3 trial in DS infants aged 6-18 months. Patients were randomly assigned to one of four treatments: placebo, folinic acid (FA), L-thyroxine, or FA+L-thyroxine, administered for 12 months. Randomization was done by age and sex. The primary endpoint was adjusted change from baseline in Griffiths Mental Development Scale global development quotient (GDQ) after 12 months. RESULTS: Of 175 patients randomized, 143 completed the study. The modified intention-to-treat (mITT) population included all randomized patients who did not prematurely discontinue due to elevated baseline thyroid stimulating hormone (TSH). Baseline characteristics in the mITT were well balanced between groups, with reliable developmental assessment outcomes. Adjusted mean change in GDQ in the mITT showed similar decreases in all groups (placebo: -5.10 [95% confidence interval (CI) -7.84 to -2.37]; FA: -4.69 [95% CI -7.73 to -1.64]; L-thyroxine: -3.89 [95% CI -6.94 to -0.83]; FA+L-thyroxine: -3.86 [95% CI -6.67 to -1.06]), with no significant difference for any active treatment group versus placebo. CONCLUSION: This trial does not support the hypotheses that thyroxine and/or folinic acid improve development of young children with DS or are synergistic. This trial is registered with ClinicalTrials.gov number, NCT01576705.
Entities:
Keywords:
Down syndrome, pediatrics; clinical trial; folate; thyroid hormone