TY - JOUR
T1 - Effectiveness and safety of the tri-iodothyronine analogue Triac in children and adults with MCT8 deficiency
T2 - an international, single-arm, open-label, phase 2 trial
AU - Groeneweg, Stefan
AU - Peeters, Robin P.
AU - Moran, Carla
AU - Stoupa, Mb Athanasia
AU - Auriol, Francoise
AU - Tonduti, Davide
AU - Dica, Alice
AU - Paone, Laura
AU - Rozenkova, Klara
AU - Malikova, Jana
AU - van der Walt, Adri
AU - de Coo, Irenaeus F. M.
AU - McGowan, Anne
AU - Lyons, Greta
AU - Aarsen, Rgn Feke K.
AU - Barca, PhD Diana
AU - van Beynu, Ingrid M.
AU - van der Knoop, Marieke M.
AU - Jansen, Jurgen
AU - Manshande, Martien
AU - Lunsing, Roelineke J.
AU - Nowak, Stan
AU - den Uil, Corstiaan A.
AU - Zillikens, M. Carola
AU - Visser, Frank E.
AU - Vrijoeth, Paul
AU - de Wit, Marie Claire Y.
AU - Wolf, Nicole
AU - Zandstra, Angelique
AU - Abegaonkar, Gauta
AU - Singh, Yogen
AU - de Rijke, Yolanda B.
AU - Medici, Marco
AU - Bertini, Enrico S.
AU - Depoorter, Sylvia
AU - Lebl, Jan
AU - Cappa, Marco
AU - De Meirleir, Linda
AU - Krude, Heiko
AU - Craiu, Dana
AU - Zibordi, Federica
AU - Petit, Isabelle Oliver
AU - Polak, Michel
AU - Chatterjee, Krishna
AU - Visser, Theo J.
AU - Visser, W. Edward
PY - 2019/9
Y1 - 2019/9
N2 - 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; pInterpretation 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.
AB - 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; pInterpretation 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.
KW - ACID TREATMENT
KW - HEART-RATE
KW - TRANSPORTER
KW - MUTATIONS
KW - WORD
U2 - 10.1016/S2213-8587(19)30155-X
DO - 10.1016/S2213-8587(19)30155-X
M3 - Article
SN - 2213-8587
VL - 7
SP - 695
EP - 706
JO - Lancet Diabetes & Endocrinology
JF - Lancet Diabetes & Endocrinology
IS - 9
ER -