Effectiveness and safety of the tri-iodothyronine analogue Triac in children and adults with MCT8 deficiency: an international, single-arm, open-label, phase 2 trial.
Adolescent
Child
Child, Preschool
Europe
Follow-Up Studies
Guidelines as Topic
Humans
Infant
Male
Membrane Transport Proteins
/ administration & dosage
Mental Retardation, X-Linked
/ drug therapy
Muscle Hypotonia
/ drug therapy
Muscular Atrophy
/ drug therapy
Patient Safety
South Africa
Triiodothyronine
/ administration & dosage
Young Adult
Journal
The lancet. Diabetes & endocrinology
ISSN: 2213-8595
Titre abrégé: Lancet Diabetes Endocrinol
Pays: England
ID NLM: 101618821
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
19
02
2019
revised:
18
04
2019
accepted:
18
04
2019
pubmed:
5
8
2019
medline:
27
5
2020
entrez:
5
8
2019
Statut:
ppublish
Résumé
Deficiency of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) causes severe intellectual and motor disability and high serum tri-iodothyronine (T In this investigator-initiated, multicentre, open-label, single-arm, phase 2, pragmatic trial, we investigated the effectiveness and safety of oral Triac in male paediatric and adult patients with MCT8 deficiency in eight countries in Europe and one site in South Africa. Triac was administered in a predefined escalating dose schedule-after the initial dose of once-daily 350 μg Triac, the daily dose was increased progressively in 350 μg increments, with the goal of attaining serum total T Between Oct 15, 2014, and June 1, 2017, we screened 50 patients, all of whom were eligible. Of these patients, four (8%) patients decided not to participate because of travel commitments. 46 (92%) patients were therefore enrolled in the trial to receive Triac (median age 7·1 years [range 0·8-66·8]). 45 (98%) participants received Triac and had at least one follow-up measurement of thyroid function and thus were included in the analyses of the primary endpoints. Of these 45 patients, five did not complete the trial (two patients withdrew [travel burden, severe pre-existing comorbidity], one was lost to follow-up, one developed of Graves disease, and one died of sepsis). Patients required a mean dose of 38.3 μg/kg of bodyweight (range 6·4-84·3) to attain T Key features of peripheral thyrotoxicosis were alleviated in paediatric and adult patients with MCT8 deficiency who were treated with Triac. Triac seems a reasonable treatment strategy to ameliorate the consequences of untreated peripheral thyrotoxicosis in patients with MCT8 deficiency. Dutch Scientific Organization, Sherman Foundation, NeMO Foundation, Wellcome Trust, UK National Institute for Health Research Cambridge Biomedical Centre, Toulouse University Hospital, and Una Vita Rara ONLUS.
Sections du résumé
BACKGROUND
Deficiency of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) causes severe intellectual and motor disability and high serum tri-iodothyronine (T
METHODS
In this investigator-initiated, multicentre, open-label, single-arm, phase 2, pragmatic trial, we investigated the effectiveness and safety of oral Triac in male paediatric and adult patients with MCT8 deficiency in eight countries in Europe and one site in South Africa. Triac was administered in a predefined escalating dose schedule-after the initial dose of once-daily 350 μg Triac, the daily dose was increased progressively in 350 μg increments, with the goal of attaining serum total T
FINDINGS
Between Oct 15, 2014, and June 1, 2017, we screened 50 patients, all of whom were eligible. Of these patients, four (8%) patients decided not to participate because of travel commitments. 46 (92%) patients were therefore enrolled in the trial to receive Triac (median age 7·1 years [range 0·8-66·8]). 45 (98%) participants received Triac and had at least one follow-up measurement of thyroid function and thus were included in the analyses of the primary endpoints. Of these 45 patients, five did not complete the trial (two patients withdrew [travel burden, severe pre-existing comorbidity], one was lost to follow-up, one developed of Graves disease, and one died of sepsis). Patients required a mean dose of 38.3 μg/kg of bodyweight (range 6·4-84·3) to attain T
INTERPRETATION
Key features of peripheral thyrotoxicosis were alleviated in paediatric and adult patients with MCT8 deficiency who were treated with Triac. Triac seems a reasonable treatment strategy to ameliorate the consequences of untreated peripheral thyrotoxicosis in patients with MCT8 deficiency.
FUNDING
Dutch Scientific Organization, Sherman Foundation, NeMO Foundation, Wellcome Trust, UK National Institute for Health Research Cambridge Biomedical Centre, Toulouse University Hospital, and Una Vita Rara ONLUS.
Identifiants
pubmed: 31377265
pii: S2213-8587(19)30155-X
doi: 10.1016/S2213-8587(19)30155-X
pmc: PMC7611958
mid: EMS137437
pii:
doi:
Substances chimiques
Membrane Transport Proteins
0
Triiodothyronine
06LU7C9H1V
3,3',5-triiodothyroacetic acid
29OQ9EU4R1
Banques de données
ClinicalTrials.gov
['NCT02060474']
Types de publication
Clinical Trial, Phase II
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
695-706Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 210755
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0502115
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.
Références
Thyroid. 2016 May;26(5):615-7
pubmed: 27042766
Obes Rev. 2009 May;10(3):280-9
pubmed: 19243518
Nat Rev Endocrinol. 2015 Jul;11(7):406-17
pubmed: 25942657
Dev Med Child Neurol. 1989 Jun;31(3):341-52
pubmed: 2753238
Am Heart J. 2009 Oct;158(4):622-8
pubmed: 19781423
Br Heart J. 1980 Sep;44(3):304-8
pubmed: 7426187
J Clin Endocrinol Metab. 1997 Jul;82(7):2153-8
pubmed: 9215287
Mol Cell Endocrinol. 2000 Jul 25;165(1-2):57-66
pubmed: 10940484
Thyroid. 2016 Oct;26(10):1343-1421
pubmed: 27521067
Best Pract Res Clin Endocrinol Metab. 2017 Mar;31(2):241-253
pubmed: 28648511
Clin Endocrinol (Oxf). 1991 Aug;35(2):123-8
pubmed: 1934526
N Engl J Med. 2009 Apr 9;360(15):1574-5
pubmed: 19357418
J Clin Endocrinol Metab. 2003 Nov;88(11):5287-92
pubmed: 14602763
Circulation. 2010 May 4;121(17):1904-11
pubmed: 20404258
Dis Model Mech. 2016 Nov 1;9(11):1339-1348
pubmed: 27664134
Am J Cardiol. 1989 Apr 15;63(13):930-3
pubmed: 2929466
Pediatrics. 2017 Sep;140(3):
pubmed: 28827377
Lancet. 2011 Mar 19;377(9770):1011-8
pubmed: 21411136
J Biol Chem. 2003 Oct 10;278(41):40128-35
pubmed: 12871948
Mol Endocrinol. 2014 Dec;28(12):1961-70
pubmed: 25389909
Clin Endocrinol (Oxf). 2013 Feb;78(2):310-5
pubmed: 22924588
Acta Endocrinol (Copenh). 1979 Nov;92(3):455-67
pubmed: 117664
J Clin Endocrinol Metab. 2012 Dec;97(12):4515-23
pubmed: 22993035
N Engl J Med. 2012 Jan 12;366(2):120-9
pubmed: 22236222
J Clin Endocrinol Metab. 1993 Jul;77(1):221-8
pubmed: 8325946
Lancet. 2004 Oct 16-22;364(9443):1435-7
pubmed: 15488219
Am J Hum Genet. 2004 Jan;74(1):168-75
pubmed: 14661163
J Endocrinol. 2017 Aug;234(2):R99-R121
pubmed: 28576869
Hypertension. 2018 Jun;71(6):1269-1324
pubmed: 29133354
Thyroid. 2016 May;26(5):618-26
pubmed: 26701289