Down Syndrome
Conditions
Keywords
Down syndrome, Young children, Psychomotor development, Thyroid hormone, Folinic acid, Psychometric tests, GMDS, Griffiths, Genetic factors, Biochemical factors
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.
Interventions
DRUGthyroid hormone and folinic acid
thyroid hormone 25microg or placebo in tablets folinic acid 5 mg or placebo in capsules
Sponsors
Hôpital Cochin
Central Hospital, Nancy, France
Institut Jerome Lejeune
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Months to 18 Months
Healthy volunteers
No
Inclusion criteria
* patient with a karyotype demonstrating homogeneous, free or Robertsonian translocation trisomy 21 * patient having undergone a cardiac ultrasound not demonstrating any severe heart disease * patient aged 6 to 18 months at inclusion
Exclusion criteria
* 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| GMDS (Griffiths Mental Development Scale) | 12 months | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| BL (Brunet Lezine Revised Scale) | 12 months | 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. |
Countries
France
Participant flow
Recruitment details
Recruitment period : 2012-2016 First inclusion : 02/04/2012 Last inclusion : 14/12/2016 Location : Institut Jérôme Lejeune
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Thyroxin + Folinic Acid thyroid hormone and folinic acid: thyroid hormone 25microg or placebo in tablets folinic acid 5 mg or placebo in capsules | 40 |
| Thyroxin+Folinic Acid Placebo thyroid hormone and folinic acid: thyroid hormone 25microg or placebo in tablets folinic acid 5 mg or placebo in capsules | 37 |
| Thyroxin Placebo+ Folinic Acid thyroid hormone and folinic acid: thyroid hormone 25microg or placebo in tablets folinic acid 5 mg or placebo in capsules | 38 |
| 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 | 41 |
| Total | 156 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | invalid ICF | 0 | 1 | 0 | 0 |
| Overall Study | TSH > 7 mIU/L at baseline | 3 | 7 | 5 | 3 |
Baseline characteristics
| Characteristic | Thyroxin + Folinic Acid | Thyroxin+Folinic Acid Placebo | Thyroxin Placebo+ Folinic Acid | Thyroxin Placebo+ Folinic Acid Placebo | Total |
|---|---|---|---|---|---|
| Age, Customized Age | 12.3 months STANDARD_DEVIATION 3.4 | 12.2 months STANDARD_DEVIATION 3.8 | 12.3 months STANDARD_DEVIATION 4 | 12.7 months STANDARD_DEVIATION 3.3 | 12.37 months STANDARD_DEVIATION 3.58 |
| Cardiac abnormalities Atrioventricular septal defect (AVSD) | 2 participants | 1 participants | 1 participants | 2 participants | 6 participants |
| Cardiac abnormalities Isolated hear murmur | 1 participants | 3 participants | 2 participants | 1 participants | 7 participants |
| Karyotype % Free trisomy 21 | 39 Participants | 37 Participants | 38 Participants | 40 Participants | 154 Participants |
| Karyotype % Robertsonian translocation | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Patient's head circumference at baseline | 43.5 cm STANDARD_DEVIATION 1.59 | 43.55 cm STANDARD_DEVIATION 1.64 | 43.63 cm STANDARD_DEVIATION 1.55 | 43.82 cm STANDARD_DEVIATION 1.68 | 43.63 cm STANDARD_DEVIATION 1.6 |
| Patient's height at baseline | 70.86 cm STANDARD_DEVIATION 3.88 | 71.14 cm STANDARD_DEVIATION 5.03 | 71.13 cm STANDARD_DEVIATION 4.15 | 71.68 cm STANDARD_DEVIATION 4.36 | 71.21 cm STANDARD_DEVIATION 4.33 |
| Patient's weight at baseline | 8.30 Kg STANDARD_DEVIATION 1.2 | 8.19 Kg STANDARD_DEVIATION 1.42 | 8.54 Kg STANDARD_DEVIATION 1.13 | 8.62 Kg STANDARD_DEVIATION 1.6 | 8.42 Kg STANDARD_DEVIATION 1.35 |
| Pregnancy term | 38.03 weeks of amenorrhea STANDARD_DEVIATION 1.37 | 38.14 weeks of amenorrhea STANDARD_DEVIATION 0.98 | 38.29 weeks of amenorrhea STANDARD_DEVIATION 1.33 | 37.85 weeks of amenorrhea STANDARD_DEVIATION 0.99 | 38.07 weeks of amenorrhea STANDARD_DEVIATION 1.18 |
| Race and Ethnicity Not Collected | — | — | — | — | 0 Participants |
| Region of Enrollment France | 40 Participants | 37 Participants | 38 Participants | 41 Participants | 156 Participants |
| Sex: Female, Male Female | 17 Participants | 16 Participants | 17 Participants | 17 Participants | 67 Participants |
| Sex: Female, Male Male | 23 Participants | 21 Participants | 21 Participants | 24 Participants | 89 Participants |
| TSH | 4.3 mIU/L STANDARD_DEVIATION 1.7 | 4.32 mIU/L STANDARD_DEVIATION 1.52 | 4.79 mIU/L STANDARD_DEVIATION 1.23 | 4.45 mIU/L STANDARD_DEVIATION 1.49 | 4.46 mIU/L STANDARD_DEVIATION 1.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 1 / 43 | 0 / 43 | 0 / 44 |
| other Total, other adverse events | 0 / 44 | 0 / 43 | 7 / 43 | 0 / 44 |
| serious Total, serious adverse events | 9 / 44 | 8 / 43 | 8 / 43 | 5 / 44 |
Outcome results
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
Time frame: 12 months
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Thyroxin + Folinic Acid | GMDS (Griffiths Mental Development Scale) | 51.96 developpement quotient | Standard Deviation 7.88 |
| Thyroxin+Folinic Acid Placebo | GMDS (Griffiths Mental Development Scale) | 51.27 developpement quotient | Standard Deviation 6.48 |
| Thyroxin Placebo+ Folinic Acid | GMDS (Griffiths Mental Development Scale) | 51.66 developpement quotient | Standard Deviation 6.37 |
| Thyroxin Placebo+ Folinic Acid Placebo | GMDS (Griffiths Mental Development Scale) | 51.67 developpement quotient | Standard Deviation 8.29 |
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.
Time frame: 12 months
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Thyroxin + Folinic Acid | BL (Brunet Lezine Revised Scale) | 51.18 developpement quotient | Standard Deviation 6.98 |
| Thyroxin+Folinic Acid Placebo | BL (Brunet Lezine Revised Scale) | 50.64 developpement quotient | Standard Deviation 7.25 |
| Thyroxin Placebo+ Folinic Acid | BL (Brunet Lezine Revised Scale) | 51.24 developpement quotient | Standard Deviation 6.46 |
| Thyroxin Placebo+ Folinic Acid Placebo | BL (Brunet Lezine Revised Scale) | 51.36 developpement quotient | Standard Deviation 8.27 |