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Lancet Diabetes Endocrinol. 2019 Sep;7(9):695-706. doi: 10.1016/S2213-8587(19)30155-X. Epub 2019 Jul 31.

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.

Author information

1
Academic Center for Thyroid Diseases, Erasmus Medical Centre, Rotterdam, Netherlands.
2
Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
3
Paediatric Endocrinology, Diabetology and Gynaecology Department, Necker Children's University Hospital, Imagine Institute, Paris, France.
4
Department of Paediatric Endocrinology and Genetics, Children's Hospital, Toulouse University Hospital, Toulouse, France.
5
Child Neurology Unit, Fondazione IRCCS, Istituto Neurologico Carlo Besta, Milan, Italy.
6
Paediatric Neurology Clinic, Alexandru Obregia Hospital, Bucharest, Romania.
7
Division of Endocrinology, Bambino Gesu' Children's Research Hospital IRCCS, Rome, Italy.
8
Department of Paediatrics, Second Faculty of Medicine, Charles University, University Hospital Motol, Prague, Czech Republic.
9
Panorama Medical Centre, Cape Town, South Africa.
10
Sophia Children's Hospital, Department of Paediatric Neurology, Erasmus Medical Centre, Rotterdam, Netherlands.
11
Paediatric Neurology Clinic, Alexandru Obregia Hospital, Bucharest, Romania; Department of Neurosciences, Paediatric Neurology Discipline II, Carol Davila University of Medicine, Bucharest, Romania.
12
Sophia Children's Hospital, Division of Paediatric Cardiology, Erasmus Medical Centre, Rotterdam, Netherlands.
13
Department of Paediatrics, Meander Medical Center, Amersfoort, Netherlands.
14
's Heeren Loo, Julianadorp, Netherlands.
15
Department of Child Neurology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
16
Department of Paediatrics, Refaja Hospital, Stadskanaal, Netherlands.
17
Department of Cardiology and Intensive Care Medicine, Erasmus Medical Centre, Rotterdam, Netherlands.
18
Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, Netherlands.
19
's Heeren Loo, Ermelo, Netherlands.
20
Baalderborg, Hardenberg, Netherlands.
21
Department of Child Neurology, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, Netherlands; Amsterdam Neuroscience, Amsterdam, Netherlands.
22
Latyrus, Dedemsvaart, Netherlands.
23
Department of Paediatric Neurology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
24
Department of Paediatric Cardiology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
25
Department of Clinical Chemistry, Erasmus Medical Centre, Rotterdam, Netherlands.
26
Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesu' Children's Research Hospital IRCCS, Rome, Italy.
27
Department of Paediatrics, Algemeen Ziekenhuis Sint-Jan, Bruges, Belgium.
28
Paediatric Neurology Unit, Department of Paediatrics, Universitair Ziekenhuis Brussel, Brussels, Belgium.
29
Department of Paediatric Endocrinology and Diabetology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
30
Academic Center for Thyroid Diseases, Erasmus Medical Centre, Rotterdam, Netherlands. Electronic address: w.e.visser@erasmusmc.nl.

Abstract

BACKGROUND:

Deficiency of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) causes severe intellectual and motor disability and high serum tri-iodothyronine (T3) concentrations (Allan-Herndon-Dudley syndrome). This chronic thyrotoxicosis leads to progressive deterioration in bodyweight, tachycardia, and muscle wasting, predisposing affected individuals to substantial morbidity and mortality. Treatment that safely alleviates peripheral thyrotoxicosis and reverses cerebral hypothyroidism is not yet available. We aimed to investigate the effects of treatment with the T3 analogue Triac (3,3',5-tri-iodothyroacetic acid, or tiratricol), in patients with MCT8 deficiency.

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 T3 concentrations within the target range of 1·4-2·5 nmol/L. We assessed changes in several clinical and biochemical signs of hyperthyroidism between baseline and 12 months of treatment. The prespecified primary endpoint was the change in serum T3 concentrations from baseline to month 12. The co-primary endpoints were changes in concentrations of serum thyroid-stimulating hormone (TSH), free and total thyroxine (T4), and total reverse T3 from baseline to month 12. These analyses were done in patients who received at least one dose of Triac and had at least one post-baseline evaluation of serum throid function. This trial is registered with ClinicalTrials.gov, number NCT02060474.

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 T3 concentrations within the target range. Serum T3 concentration decreased from 4·97 nmol/L (SD 1·55) at baseline to 1·82 nmol/L (0·69) at month 12 (mean decrease 3·15 nmol/L, 95% CI 2·68-3·62; p<0·0001), while serum TSH concentrations decreased from 2·91 mU/L (SD 1·68) to 1·02 mU/L (1·14; mean decrease 1·89 mU/L, 1·39-2·39; p<0·0001) and serum free T4 concentrations decreased from 9·5 pmol/L (SD 2·5) to 3·4 (1·6; mean decrease 6·1 pmol/L (5·4-6·8; p<0·0001). Additionally, serum total T4 concentrations decreased by 31·6 nmol/L (28·0-35·2; p<0·0001) and reverse T3 by 0·08 nmol/L (0·05-0·10; p<0·0001). Seven treatment-related adverse events (transiently increased perspiration or irritability) occurred in six (13%) patients. 26 serious adverse events that were considered unrelated to treatment occurred in 18 (39%) patients (mostly hospital admissions because of infections). One patient died from pulmonary sepsis leading to multi-organ failure, which was unrelated to Triac treatment.

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.

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