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| Name | Class |
|---|---|
| Hôpital Cochin | OTHER |
| Central Hospital, Nancy, France | OTHER |
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Evaluation of the following in very young children with Down syndrome:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Thyroxin + folinic acid | Experimental |
| |
| Thyroxin+folinic acid placebo | Active Comparator |
| |
| Thyroxin placebo+ folinic acid | Active Comparator |
| |
| Thyroxin placebo+ folinic acid placebo | Placebo Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| thyroid hormone and folinic acid | Drug | thyroid hormone 25microg or placebo in tablets folinic acid 5 mg or placebo in capsules |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| BL (Brunet Lezine Revised Scale) | BL includes 4 subscales : Locomotor, Coordination, Language, Sociability. Subscale and global developpemental quotients were computed by dividing the developpemental age by the chronological age multiplied by 100. This kind of formula do not give a min-max outcome. Higher QD's scores show a better psychomotor developpement outcome. | 12 months |
Not provided
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| 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 |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Institut Jerome Lejeune | Paris | 75015 | France |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20084109 | Background | 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. | |
| 16889491 |
| Label | URL |
|---|---|
| Institut Jerome Lejeune | View source |
Not provided
As recruitment was nationwide and patients were included at a single centre, screening and randomisation were performed on the same day to minimise visits to the centre. Eligibility of randomised patients for TSH levels per exclusion criterion #8 was thus confirmed retrospectively, and patients with high TSH levels were discontinued.
Recruitment period : 2012-2016 First inclusion : 02/04/2012 Last inclusion : 14/12/2016
Location : Institut Jérôme Lejeune
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| ID | Title | Description |
|---|---|---|
| FG000 | Thyroxin + Folinic Acid | thyroid hormone and folinic acid: thyroid hormone 25microg in tablets folinic acid 5 mg in capsules |
| FG001 | Thyroxin+Folinic Acid Placebo | thyroid hormone and folinic acid: thyroid hormone 25microg in tablets folinic acid placebo in capsules |
| FG002 | Thyroxin Placebo+ Folinic Acid | thyroid hormone and folinic acid: thyroid hormone placebo in tablets folinic acid 5 mg in capsules |
| FG003 | Thyroxin Placebo+ Folinic Acid Placebo | thyroid hormone and folinic acid: thyroid hormone placebo in tablets folinic acid placebo in capsules |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall 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)
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| ID | Title | Description |
|---|---|---|
| BG000 | Thyroxin + Folinic Acid | thyroid hormone and folinic acid: thyroid hormone 25microg or placebo in tablets folinic acid 5 mg or placebo in capsules |
| BG001 | Thyroxin+Folinic Acid Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Age at inclusion in months |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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 | The main analysis of the primary efficacy endpoint is the adjusted change from baseline in GDQ derived from the Griffith Mental Development Scales (GMDS) at 12 months analysed by ANCOVA adjusted for covariates. Expected Outcome : six points difference in GDQ between any of the three treatment group compared to placebo at 12 months from baseline. | Posted | Mean | Standard Deviation | developpement quotient | 12 months |
12 months
safety analysis were performed on all randomised patients receiving at least one dose of study treatment Safety population correspond to 174 subjects
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Thyroxin+Folinic Acid Placebo | thyroid hormone and folinic acid: thyroid hormone 25microg or placebo in tablets folinic acid 5 mg or placebo in capsules |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Infections and infestations | Infections and infestations | MedDRA version 20.1 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Endocrine disorders | Endocrine disorders | MedDRA version 20.1 | Systematic Assessment |
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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Clotilde Mircher | Institut Jérôme Lejeune | 00 33 1 56 58 63 00 | clotilde.mircher@institutlejeune.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 7, 2017 | Nov 5, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D004314 | Down Syndrome |
| ID | Term |
|---|---|
| D008607 | Intellectual Disability |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
Not provided
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| ID | Term |
|---|---|
| D013963 | Thyroid Hormones |
| D002955 | Leucovorin |
| ID | Term |
|---|---|
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D005575 | Formyltetrahydrofolates |
| D013763 | Tetrahydrofolates |
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| 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. |
| 15755847 | 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. |
| 18296460 | 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. |
| 34863019 | Derived | 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. |
| 31281181 | 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. |
| invalid ICF |
|
thyroid hormone and folinic acid: thyroid hormone 25microg or placebo in tablets folinic acid 5 mg or placebo in capsules
| BG002 | Thyroxin Placebo+ Folinic Acid | thyroid hormone and folinic acid: thyroid hormone 25microg or placebo in tablets folinic acid 5 mg or placebo in capsules |
| BG003 | Thyroxin Placebo+ Folinic Acid Placebo | thyroid hormone and folinic acid: thyroid hormone 25microg or placebo in tablets folinic acid 5 mg or placebo in capsules |
| BG004 | Total | Total of all reporting groups |
| Mean |
| Standard Deviation |
| months |
|
| Sex: Female, Male | Male or Female | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Patient's height at baseline | Height measured in cm | Mean | Standard Deviation | cm |
|
| Karyotype % | Count of Participants | Participants |
|
| Pregnancy term | Mean | Standard Deviation | weeks of amenorrhea |
|
| Cardiac abnormalities | Number | participants |
|
| TSH | Mean | Standard Deviation | mIU/L |
|
| Patient's weight at baseline | Weight measured in kg | Mean | Standard Deviation | Kg |
|
| Patient's head circumference at baseline | Head circumference measured in cm | Mean | Standard Deviation | cm |
|
|
|
|
| Secondary | BL (Brunet Lezine Revised Scale) | BL includes 4 subscales : Locomotor, Coordination, Language, Sociability. Subscale and global developpemental quotients were computed by dividing the developpemental age by the chronological age multiplied by 100. This kind of formula do not give a min-max outcome. Higher QD's scores show a better psychomotor developpement outcome. | The main analysis of the secondary efficacy endpoint of the adjusted change from baseline in the BL-R GDQ at 12 months, analysed by ANCOVA adjusted for covariates, is presented in the mITT population. | Posted | Mean | Standard Deviation | developpement quotient | 12 months |
|
|
|
| 0 |
| 44 |
| 9 |
| 44 |
| 0 |
| 44 |
| EG001 | Thyroxin + Folinic Acid | thyroid hormone and folinic acid: thyroid hormone 25microg or placebo in tablets folinic acid 5 mg or placebo in capsules | 1 | 43 | 8 | 43 | 0 | 43 |
| EG002 | Thyroxin Placebo+ Folinic Acid | thyroid hormone and folinic acid: thyroid hormone 25microg or placebo in tablets folinic acid 5 mg or placebo in capsules | 0 | 43 | 8 | 43 | 7 | 43 |
| EG003 | Thyroxin Placebo+ Folinic Acid Placebo | thyroid hormone and folinic acid: thyroid hormone 25microg or placebo in tablets folinic acid 5 mg or placebo in capsules | 0 | 44 | 5 | 44 | 0 | 44 |
| Respiratory, thoracic and mediastinal disorders | Respiratory, thoracic and mediastinal disorders | MedDRA version 20.1 | Systematic Assessment |
|
| General disorders and administration site conditions | General disorders | MedDRA version 20.1 | Systematic Assessment |
|
| Metabolism and nutrition disorders | Metabolism and nutrition disorders | MedDRA version 20.1 | Systematic Assessment |
|
| Surgical and medical procedures | Surgical and medical procedures | MedDRA version 20.1 | Systematic Assessment |
|
| Congenital, familial and genetic disorders | Congenital, familial and genetic disorders | MedDRA version 20.1 | Systematic Assessment |
|
| Injury, poisoning and procedural complications | Injury, poisoning and procedural complications | MedDRA version 20.1 | Systematic Assessment |
|
| Neoplasm begign, maligant and unspecified | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA version 20.1 | Systematic Assessment |
|
| Nervous system disorders | Nervous system disorders | MedDRA version 20.1 | Systematic Assessment |
|
| Skin and subcutnaeous tissue disorders | Skin and subcutaneous tissue disorders | MedDRA version 20.1 | Systematic Assessment |
|
| Neoplasms begnin, malignant and unspecified | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA version 20.1 | Systematic Assessment |
|
| Nervous system disorders | Nervous system disorders | MedDRA version 20.1 | Systematic Assessment |
|
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| D000015 | Abnormalities, Multiple |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D025063 | Chromosome Disorders |
| D030342 | Genetic Diseases, Inborn |
| D005492 | Folic Acid |
| D011622 | Pterins |
| D011621 | Pteridines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D003067 | Coenzymes |
| D045762 | Enzymes and Coenzymes |
| Male |
|
| Robertsonian translocation |
|
|