Down SyndromePhase 3ACTHYFNCT01576705

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

A Phase 3 study testing thyroid hormone and folinic acid in people with Down Syndrome, run by Institut Jerome Lejeune at 1 site in France.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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… Read more about this study

Who is it for?: Ages 6 to 18 months
Conditions the study is for: Down Syndrome
What is being tested?: thyroid hormone and folinic acid
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 175 participants
Where: 1 siteFrance
Study dates: 2 Apr 2012to 14 Dec 2017
Phase: Phase 3
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 6 to 18 months
All sexes
No healthy volunteers
Child

Who may be able to join

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

Who cannot join

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)

Show all 10Show fewer

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)

Trial locations and contacts

1 site in 1 country.

France1 site

Institut Jerome Lejeune
Paris, 75015

Other trials in France

About this study

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
Being tested: thyroid hormone and folinic acid
Keywords: Down syndrome, Young children, Psychomotor development, Thyroid hormone, Folinic acid, Psychometric tests, GMDS, Griffiths, Genetic factors, Biochemical factors
Medical subject headings: Down Syndrome

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

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

Study groups in NCT01576705
Study group	Role	What they receive
Thyroxin + folinic acid	Experimental	Not described Receives: Drug: thyroid hormone and folinic acid
Thyroxin+folinic acid placebo	Active comparator	Not described Receives: Drug: thyroid hormone and folinic acid
Thyroxin placebo+ folinic acid	Active comparator	Not described Receives: Drug: thyroid hormone and folinic acid
Thyroxin placebo+ folinic acid placebo	Placebo comparator	Not described Receives: Drug: thyroid hormone and folinic acid

What is being measured

The primary outcome is the main question the study is designed to answer.

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
Measured: 12 months

Secondary outcomes (1)

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.
Measured: 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

2 Apr 201214 Dec 2017

First posted12 Apr 2012 (estimated)
Study start2 Apr 2012
Primary completion14 Dec 2017
Study completion14 Dec 2017

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (6)Papers the sponsor has linked to this study.
Other trials for Down SyndromeStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 175 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01576705
Sponsor's protocol ID: IJL-AFHT-TH10
Acronym: ACTHYF
Status last verified: Dec 2019
First submitted: 11 Apr 2012
Last updated: 13 May 2020
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

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.
PubMed 20084109
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.
PubMed 16889491
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.
PubMed 15755847
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.
PubMed 18296460
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.
PubMed 34863019
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.
PubMed 31281181

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 13 May 2020. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Efficacy Assessment of Systematic Treatment With Folinic Acid and Thyroid Hormone on Psychomotor Development of Down Syndrome Young Children
ClinicalTrials.gov ID: NCT01576705
Acronym / sponsor ID: ACTHYF / IJL-AFHT-TH10
Conditions: Down Syndrome
Keywords: Down syndrome, Young children, Psychomotor development, Thyroid hormone, Folinic acid, Psychometric tests, GMDS, Griffiths
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 175 participants (actual)
Lead sponsor: Institut Jerome LejeuneUniversity, hospital or other
Collaborators: Hôpital Cochin, Central Hospital, Nancy, France
Study start: 2 Apr 2012 (actual)
Primary completion: 14 Dec 2017 (actual)
Study completion: 14 Dec 2017 (actual)
First posted: 12 Apr 2012 (estimated)
Results: Posted 13 May 2020

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 4

Arm	Type	Receives
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

Who may qualify

Ages: 6 to 18 months
Sex: All
Healthy volunteers: Not accepted
Age groups: Child

Key inclusion criteria (3 listed)

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

Key exclusion criteria (10 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
thyroid hormone and folinic acidthyroid hormone 25microg or placebo in tablets folinic acid 5 mg or placebo in capsules	Drug	Thyroxin + folinic acid, Thyroxin placebo+ folinic acid, Thyroxin placebo+ folinic acid placebo, Thyroxin+folinic acid placebo

Primary outcome

GMDS (Griffiths Mental Development Scale)
Time frame: 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

1 secondary outcome

BL (Brunet Lezine Revised Scale)
Time frame: 12 months

Results and safety

Results posted to the registry on 13 May 2020, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Thyroxin + Folinic Acid	43	40
Thyroxin+Folinic Acid Placebo	45	37
Thyroxin Placebo+ Folinic Acid	43	38
Thyroxin Placebo+ Folinic Acid Placebo	44	41

Primary outcome: GMDS (Griffiths Mental Development Scale)

Time frame: 12 months. Mean (Standard Deviation). Unit: developpement quotient

Measure	Thyroxin + Folinic Acid n = 38	Thyroxin+Folinic Acid Placebo n = 35	Thyroxin Placebo+ Folinic Acid n = 30	Thyroxin Placebo+ Folinic Acid Placebo n = 41
Value	51.96 (7.88)	51.27 (6.48)	51.66 (6.37)	51.67 (8.29)

Population analysed: 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.

1 secondary outcome is reported in the full results.

Adverse events

Time frame: 12 months. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Thyroxin+Folinic Acid Placebo	9 of 44 (20.5%)	0 of 44 (0%)	0 of 44
Thyroxin + Folinic Acid	8 of 43 (18.6%)	0 of 43 (0%)	1 of 43
Thyroxin Placebo+ Folinic Acid	8 of 43 (18.6%)	7 of 43 (16.3%)	0 of 43
Thyroxin Placebo+ Folinic Acid Placebo	5 of 44 (11.4%)	0 of 44 (0%)	0 of 44

Limitations and caveats (from the sponsor): 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.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 13 May 2020.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 20084109Blehaut 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.
Background: PubMed 16889491van 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.
Background: PubMed 15755847van 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.
Background: PubMed 18296460Ellis 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.
Derived from this study: PubMed 34863019Sacco 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.
Derived from this study: PubMed 31281181Mircher 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.
Institut Jerome LejeuneLink provided by the sponsor.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Clotilde MIRCHER, MD principal investigator

Institut Jerome Lejeune, Paris, France

Franck STURTZ, MD, PhD study chair

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

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing thyroid hormone and folinic acid in people with Down Syndrome, run by Institut Jerome Lejeune at 1 site in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 13 May 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 13 May 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

GMDS (Griffiths Mental Development Scale) (time frame: 12 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01576705, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 May 2020; AzTrials last refreshed its copy on 8 Nov 2026.