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, Athanasia Stoupa, Françoise Auriol, Davide Tonduti, Alice Dica, Laura Paone, Klara Rozenkova, Jana Malikova, Adri van der Walt, Irenaeus F M de Coo, Anne McGowan, Greta Lyons, Femke K Aarsen, Diana Barca, Ingrid M van Beynum, Marieke M van der Knoop, Jurgen Jansen, Martien ManshandeRoelineke J Lunsing, Stan Nowak, Corstiaan A den Uil, M Carola Zillikens, Frank E Visser, Paul Vrijmoeth, Marie Claire Y de Wit, Nicole I Wolf, Angelique Zandstra, Gautam Ambegaonkar, 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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)695-706
Number of pages12
JournalThe Lancet Diabetes and Endocrinology
Volume7
Issue number9
DOIs
Publication statusPublished - Sep 2019

Fingerprint

Safety
Thyrotoxicosis
Serum
Allan-Herndon-Dudley syndrome
3,3',5-triiodothyroacetic acid
Thyrotropin
Therapeutics
Sepsis
Pragmatic Clinical Trials
Pediatrics
Lost to Follow-Up
Graves Disease
National Institutes of Health (U.S.)
Hyperthyroidism
South Africa
Hypothyroidism
Thyroxine
Thyroid Hormones
Tachycardia
Intellectual Disability

Cite this

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

In: The Lancet Diabetes and Endocrinology, Vol. 7, No. 9, 09.2019, p. 695-706.

Research output: Contribution to journalArticle

Groeneweg, S, Peeters, RP, Moran, C, Stoupa, A, Auriol, F, Tonduti, D, Dica, A, Paone, L, Rozenkova, K, Malikova, J, van der Walt, A, de Coo, IFM, McGowan, A, Lyons, G, Aarsen, FK, Barca, D, van Beynum, IM, van der Knoop, MM, Jansen, J, Manshande, M, Lunsing, RJ, Nowak, S, den Uil, CA, Zillikens, MC, Visser, FE, Vrijmoeth, P, de Wit, MCY, Wolf, NI, Zandstra, A, Ambegaonkar, G, Singh, Y, de Rijke, YB, Medici, M, Bertini, ES, Depoorter, S, Lebl, J, Cappa, M, De Meirleir, L, Krude, H, Craiu, D, Zibordi, F, Oliver Petit, I, Polak, M, Chatterjee, K, Visser, TJ & Visser, WE 2019, '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', The Lancet Diabetes and Endocrinology, vol. 7, no. 9, pp. 695-706. https://doi.org/10.1016/S2213-8587(19)30155-X
Groeneweg, Stefan ; Peeters, Robin P ; Moran, Carla ; Stoupa, Athanasia ; Auriol, Françoise ; Tonduti, Davide ; Dica, Alice ; Paone, Laura ; Rozenkova, Klara ; Malikova, Jana ; van der Walt, Adri ; de Coo, Irenaeus F M ; McGowan, Anne ; Lyons, Greta ; Aarsen, Femke K ; Barca, Diana ; van Beynum, Ingrid M ; van der Knoop, Marieke M ; Jansen, Jurgen ; Manshande, Martien ; Lunsing, Roelineke J ; Nowak, Stan ; den Uil, Corstiaan A ; Zillikens, M Carola ; Visser, Frank E ; Vrijmoeth, Paul ; de Wit, Marie Claire Y ; Wolf, Nicole I ; Zandstra, Angelique ; Ambegaonkar, Gautam ; Singh, Yogen ; de Rijke, Yolanda B ; Medici, Marco ; Bertini, Enrico S ; Depoorter, Sylvia ; Lebl, Jan ; Cappa, Marco ; De Meirleir, Linda ; Krude, Heiko ; Craiu, Dana ; Zibordi, Federica ; Oliver Petit, Isabelle ; Polak, Michel ; Chatterjee, Krishna ; Visser, Theo J ; Visser, W Edward. / 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. In: The Lancet Diabetes and Endocrinology. 2019 ; Vol. 7, No. 9. pp. 695-706.
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title = "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",
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.",
author = "Stefan Groeneweg and Peeters, {Robin P} and Carla Moran and Athanasia Stoupa and Fran{\cc}oise Auriol and Davide Tonduti and Alice Dica and Laura Paone and Klara Rozenkova and Jana Malikova and {van der Walt}, Adri and {de Coo}, {Irenaeus F M} and Anne McGowan and Greta Lyons and Aarsen, {Femke K} and Diana Barca and {van Beynum}, {Ingrid M} and {van der Knoop}, {Marieke M} and Jurgen Jansen and Martien Manshande and Lunsing, {Roelineke J} and Stan Nowak and {den Uil}, {Corstiaan A} and Zillikens, {M Carola} and Visser, {Frank E} and Paul Vrijmoeth and {de Wit}, {Marie Claire Y} and Wolf, {Nicole I} and Angelique Zandstra and Gautam Ambegaonkar and Yogen Singh and {de Rijke}, {Yolanda B} and Marco Medici and Bertini, {Enrico S} and Sylvia Depoorter and Jan Lebl and Marco Cappa and {De Meirleir}, Linda and Heiko Krude and Dana Craiu and Federica Zibordi and {Oliver Petit}, Isabelle and Michel Polak and Krishna Chatterjee and Visser, {Theo J} and Visser, {W Edward}",
note = "Copyright {\circledC} 2019 Elsevier Ltd. All rights reserved.",
year = "2019",
month = "9",
doi = "10.1016/S2213-8587(19)30155-X",
language = "English",
volume = "7",
pages = "695--706",
journal = "The Lancet Diabetes and Endocrinology",
issn = "2213-8587",
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}

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, Athanasia

AU - Auriol, Françoise

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, Femke K

AU - Barca, Diana

AU - van Beynum, 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 - Vrijmoeth, Paul

AU - de Wit, Marie Claire Y

AU - Wolf, Nicole I

AU - Zandstra, Angelique

AU - Ambegaonkar, Gautam

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 - Oliver Petit, Isabelle

AU - Polak, Michel

AU - Chatterjee, Krishna

AU - Visser, Theo J

AU - Visser, W Edward

N1 - Copyright © 2019 Elsevier Ltd. All rights reserved.

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 (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.

AB - 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.

U2 - 10.1016/S2213-8587(19)30155-X

DO - 10.1016/S2213-8587(19)30155-X

M3 - Article

C2 - 31377265

VL - 7

SP - 695

EP - 706

JO - The Lancet Diabetes and Endocrinology

JF - The Lancet Diabetes and Endocrinology

SN - 2213-8587

IS - 9

ER -