Long-Term Efficacy of T3 Analogue Triac in Children and Adults With MCT8 Deficiency: A Real-Life Retrospective Cohort Study

Abstract

Context: Patients with mutations in thyroid hormone transporter MCT8 have developmental delay and chronic thyrotoxicosis associated with being underweight and having cardiovascular dysfunction.

Objective: Our previous trial showed improvement of key clinical and biochemical features during 1-year treatment with the T3 analogue Triac, but long-term follow-up data are needed.

Methods: In this real-life retrospective cohort study, we investigated the efficacy of Triac in MCT8-deficient patients in 33 sites. The primary endpoint was change in serum T3 concentrations from baseline to last available measurement. Secondary endpoints were changes in other thyroid parameters, anthropometric parameters, heart rate, and biochemical markers of thyroid hormone action.

Results: From October 15, 2014 to January 1, 2021, 67 patients (median baseline age 4.6 years; range, 0.5-66) were treated up to 6 years (median 2.2 years; range, 0.2-6.2). Mean T3 concentrations decreased from 4.58 (SD 1.11) to 1.66 (0.69) nmol/L (mean decrease 2.92 nmol/L; 95% CI, 2.61-3.23; P < 0.0001; target 1.4-2.5 nmol/L). Body-weight-for-age exceeded that of untreated historical controls (mean difference 0.72 SD; 95% CI, 0.36-1.09; P = 0.0002). Heart-rate-for-age decreased (mean difference 0.64 SD; 95% CI, 0.29-0.98; P = 0.0005). SHBG concentrations decreased from 245 (99) to 209 (92) nmol/L (mean decrease 36 nmol/L; 95% CI, 16-57; P = 0.0008). Mean creatinine concentrations increased from 32 (11) to 39 (13) µmol/L (mean increase 7 µmol/L; 95% CI, 6-9; P < 0.0001). Mean creatine kinase concentrations did not significantly change. No drug-related severe adverse events were reported.

Conclusions: Key features were sustainably alleviated in patients with MCT8 deficiency across all ages, highlighting the real-life potential of Triac for MCT8 deficiency.

Keywords: AHDS; Allan-Herndon-Dudley syndrome; MCT8 deficiency; T3 analogue; thyromimetic drug.

© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.

Figures

Figure 1.

Changes from baseline to interim evaluation and last visit in primary and secondary outcomes (anthropometric parameters). Data are changes in serum concentrations of T3 between baseline and last available follow-up visit on treatment with Triac: A, by patient; B, change in serum T3 between baseline and last available follow-up visit after stratification based on treatment duration; C, by patient, ordered by treatment duration). Panel D shows the change in serum T3 concentrations from baseline to 1 year and last available visit (longitudinal within-subject analyses; n = 36). Panel E shows change in body weight-for-age between baseline and last visit (blue dots and lines; n = 55); the natural history of untreated patients with MCT8 deficiency is depicted in grey dots with the historical reference line in red (with the 95% error band in dashed lines), based on a historical control cohort (8). Panel F shows the change in difference between the body weight-for-age Z-score and the expected Z-score based on the natural history data on the corresponding age from baseline to 1 year and last available visit (longitudinal within-subject analyses; n = 32). Panel G shows change in heart rate-for-age from baseline to last visit (n = 48). Panel H shows the change in heart rate-for-age from baseline to 1 year and last available visit (longitudinal within-subject analyses; n = 19). Median treatment duration was 2.2 years (interquartile range [IQR] 1.2–3.7 years) for analyses of the primary outcome (panels A, B, and C), 2.2 years (IQR 1.5–3.9 years) for analyses of secondary outcomes (panels E and G), and 3.6 years (IQR 2.5–5.2 years) for longitudinal within-subject analyses (panels D, F, and H). Red dots represent baseline measurement and blue arrows represent the last available measurement in panels A, C, and G. Grey dots represent measurements in the individual patients in panels B, D, F, and H; means and standard error of the mean (SEM) are displayed in blue. Black dashed lines represent the target range in panels A, C, and D. Of the patients with a decrease in body weight-for-age compared with the reference line, 7 (78%) of 9 patients were known to have feeding problems, and only 2 (22%) of 9 patients had a feeding tube in place (information not available for 4 patients), compared with 36% of patients in the rest of the group. Body weight-for-age Z scores were calculated using TNO growth calculator and heart rate-for-age Z scores were calculated using the Boston Z score calculator. Abbreviations: T3, triiodothyronine; T4=thyroxine.

Figure 2.

Changes from baseline to interim evaluation and last visit in secondary outcomes (peripheral markers). Panel A shows changes in serum concentrations of SHBG between baseline and last available follow-up visit on treatment with Triac (n = 47). Panel B shows the change in serum SHBG concentrations from baseline to 1 year and last available visit (longitudinal within-subject analyses; n = 22). Panel C shows changes in serum concentrations of creatinine between baseline and last available follow-up visit on treatment with Triac (n = 46). Panel D shows the change in serum creatinine concentrations from baseline to 1 year and last available visit (longitudinal within-subject analyses; n = 19). Panel E shows changes in serum concentrations of CK between baseline and last available follow-up visit on treatment with Triac (n = 46). Panel F shows the change in serum CK concentrations from baseline to 1 year and last available visit (longitudinal within-subject analyses; n = 19; for clarity, data are depicted as nontransformed in panels E and F). Median treatment duration was 2.2 years (interquartile range [IQR] 1.5–3.9 years) for analyses of secondary outcomes (panels A, C, and E) and 3.6 years (IQR 2.5–5.2 years) for longitudinal within-subject analyses (panels B, D, and F). Black dashed lines represent the reference intervals (for the median baseline age). Black dots represent baseline measurement and gray arrows represent the last available measurement in panels A, C, and E. Gray dots represent measurements in the individual patients in panels B, D, and F; means and standard error of the mean are displayed in blue. Abbreviations: CK, creatine kinase; SHBG, sex hormone-binding globulin.