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

Stefan Groeneweg, Robin P. Peeters, Carla Moran, Mb Athanasia Stoupa, Francoise Auriol, Davide Tonduti, Alice Dica, Laura Paone, Klara Rozenkova, Jana Malikova, Adri van der Walt, Irenaeus F. M. de Coo, Anne McGowan, Greta Lyons, Rgn Feke K. Aarsen, PhD Diana Barca, Ingrid M. van Beynu, Marieke M. van der Knoop, Jurgen Jansen, Martien ManshandeRoelineke J. Lunsing, Stan Nowak, Corstiaan A. den Uil, M. Carola Zillikens, Frank E. Visser, Paul Vrijoeth, Marie Claire Y. de Wit, Nicole Wolf, Angelique Zandstra, Gauta Abegaonkar, Yogen Singh, Yolanda B. de Rijke, Marco Medici, Enrico S. Bertini, Sylvia Depoorter, Jan Lebl, Marco Cappa, Linda De Meirleir, Heiko Krude, Dana Craiu, Federica Zibordi, Isabelle Oliver Petit, Michel Polak, Krishna Chatterjee, Theo J. Visser, W. Edward Visser*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

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    Abstract

    Background Deficiency of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) causes severe intellectual and motor disability and high serum tri-iodothyronine (T-3) 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 T-3 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 mu g Triac, the daily dose was increased progressively in 350 mu g increments, with the goal of attaining serum total T-3 concentrations within the target range of 1.4-2.5 nmol/L We assessed changes in several dinical and biochemical signs of hyperthyroidism between baseline and 12 months of treatment. The prespecified primary endpoint was the change in serum T-3 concentrations from baseline to month 12. The co-primary endpoints were changes in concentrations of serum thyroid-stimulating hormone (TSH), free and total thyroxine (T-4), and total reverse T-3 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 mu g/kg of bodyweight (range 6.4-84.3) to attain T-3 concentrations within the target range. Serum T-3 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

    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. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

    Original languageEnglish
    Pages (from-to)695-706
    Number of pages12
    JournalLancet Diabetes & Endocrinology
    Volume7
    Issue number9
    DOIs
    Publication statusPublished - Sept-2019

    Keywords

    • ACID TREATMENT
    • HEART-RATE
    • TRANSPORTER
    • MUTATIONS
    • WORD

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