Triiodothyronine (T3) analog Triac significantly and safely alleviates certain features of peripheral thyrotoxicosis in patients with monocarboxylate transporter 8 (MCT8) deficiency, according to phase 2 study results published in The Lancet Diabetes & Endocrinology.

For patients with MCT8 deficiency, or Allan-Herndon-Dudley syndrome, exposure to elevated serum T3 concentrations leads to chronic thyrotoxicosis in peripheral tissues that rely on transporters other than MCT8. Researchers conducted this international open-label phase 2 trial of Triac (ClinicalTrials.gov Identifier: NCT02060474) to evaluate its effectiveness and safety in treating peripheral thyrotoxicosis in pediatric and adult patients with MCT8 deficiency. The study’s primary end points measured changes in serum thyroid hormone concentrations from baseline to 12-month follow-up. Secondary end points included change in body weight (expressed as weight-for-age z score) and measures of cardiac function.

Of the initial 50 patients, 46 were enrolled to receive Triac (median age, 7.1 years; range, 0.8-66.8 years), but 1 was withdrawn because of noncompliance with study procedures. Therefore, 45 received Triac allotted in escalating doses over the course of 12 months and completed ≥1 follow-up thyroid function measurement. All enrolled participants had severe motor and intellectual disability, and the majority were wheelchair-bound (n=41; 89%) and underweight (n=30; 65%). Of the 45 patients who received Triac, 2 withdrew, 1 was lost to follow-up, 1 developed Graves disease, and 1 died of pulmonary sepsis.

To attain T3 concentrations within the target range, patients required a mean daily Triac dose of 38.3 μg/kg of bodyweight. Overall, T3 concentration decreased from 4.97 nmol/L at baseline to 1.82 nmol/L at 12 months (mean decrease, 3.15 nmol/L; P <.0001). Serum thyroid-stimulating hormone concentrations decreased on average from 2.91 to 1.02 mU/L, free thyroxine concentrations decreased from 9.5 to 3.4 pmol/L, total thyroxine concentrations decreased from 56.0 to 24.4 nmol/L, and reverse T3 decreased by from 0.12 to 0.04 nmol/L (all P <.0001).

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Weight-for-age z score significantly increased during the study period, equating to a mean increase in body weight of 2.7 kg (P <.0001). Resting heart rate decreased by a mean 9 bpm (P =.010), and mean heart rate decreased by 5 bmp (P =.012). In addition, the proportion of participants with systolic hypertension decreased during the 12-month follow-up from 34% at baseline to 9% at month 12.

With regard to safety, 6 patients (13%) experienced a total of 7 treatment-related adverse events, the majority of which were related to mild hyperthyroidism (transient increase in perspiration or irritability). There were also 26 serious adverse events in 18 patients (39%), although these were all considered unrelated to treatment and were mostly intermittent infections.

Several limitations were noted for this study, including its heterogeneous population and small number of adult patients.

Summarizing their findings, the researchers said, “[s]evere underweight and cardiovascular dysfunction are important clinical sequelae of chronic peripheral thyrotoxicosis, causing significant morbidity and mortality in patients with MCT8 deficiency. The results of our study suggest that several key features related to the peripheral phenotype of MCT8 deficiency are alleviated under Triac treatment in paediatric and adult patients.”

Disclosure: Several study authors declared possible future affiliations with Rare Thyroid Therapeutics, the manufacturer of Triac. Please see the original reference for a full list of authors’ disclosures.

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Reference

Groeneweg S, Peeters RP, Moran C, et al. 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 [published online July 31, 2019]. Lancet Diabetes Endocrinol. doi:10.1016/S2213-8587(19)30155-X