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.

's Heeren Loo Ermelo Netherlands

's Heeren Loo Julianadorp Netherlands

Academic Center for Thyroid Diseases Erasmus Medical Centre Rotterdam Netherlands

Baalderborg Hardenberg Netherlands

Child Neurology Unit Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy

Department of Cardiology and Intensive Care Medicine Erasmus Medical Centre Rotterdam Netherlands

Department of Child Neurology Emma Children's Hospital Amsterdam University Medical Centers Vrije Universiteit Amsterdam Amsterdam Netherlands; Amsterdam Neuroscience Amsterdam Netherlands

Department of Child Neurology University Medical Center Groningen University of Groningen Groningen Netherlands

Department of Clinical Chemistry Erasmus Medical Centre Rotterdam Netherlands

Department of Internal Medicine Erasmus Medical Centre Rotterdam Netherlands

Department of Paediatric Cardiology Addenbrooke's Hospital Cambridge University Hospitals NHS Foundation Trust Cambridge UK

Department of Paediatric Endocrinology and Diabetology Charité Universitätsmedizin Berlin Berlin Germany

Department of Paediatric Endocrinology and Genetics Children's Hospital Toulouse University Hospital Toulouse France

Department of Paediatric Neurology Addenbrooke's Hospital Cambridge University Hospitals NHS Foundation Trust Cambridge UK

Department of Paediatrics 2nd Faculty of Medicine Charles University University Hospital Motol Prague Czech Republic

Department of Paediatrics Algemeen Ziekenhuis Sint Jan Bruges Belgium

Department of Paediatrics Meander Medical Center Amersfoort Netherlands

Department of Paediatrics Refaja Hospital Stadskanaal Netherlands

Division of Endocrinology Bambino Gesu' Children's Research Hospital IRCCS Rome Italy

Latyrus Dedemsvaart Netherlands

Paediatric Endocrinology Diabetology and Gynaecology Department Necker Children's University Hospital Imagine Institute Paris France

Paediatric Neurology Clinic Alexandru Obregia Hospital Bucharest Romania

Paediatric Neurology Clinic Alexandru Obregia Hospital Bucharest Romania; Department of Neurosciences Paediatric Neurology Discipline 2 Carol Davila University of Medicine Bucharest Romania

Paediatric Neurology Unit Department of Paediatrics Universitair Ziekenhuis Brussel Brussels Belgium

Panorama Medical Centre Cape Town South Africa

Sophia Children's Hospital Department of Paediatric Neurology Erasmus Medical Centre Rotterdam Netherlands

Sophia Children's Hospital Division of Paediatric Cardiology Erasmus Medical Centre Rotterdam Netherlands

Unit of Neuromuscular and Neurodegenerative Disorders Bambino Gesu' Children's Research Hospital IRCCS Rome Italy

Wellcome Trust Medical Research Council Institute of Metabolic Science University of Cambridge Cambridge UK

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ClinicalTrials.gov
NCT02060474