EMC cohort study

31 evidence topics · 2 sources

Objective

Stated objective of the cohort study

“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.” (opens the source at this quote in a new tab)
“Also, it is relevant to determine whether the efficacy of a treatment demonstrated in a clinical trial (typically with a limited number of patients intrinsic to the low prevalence) is applicable in a real-life setting. Such long-term follow-up data of patients with MCT8 deficiency treated with Triac are currently lacking, particularly in young patients.” (opens the source at this quote in a new tab)
“In a joint international effort, we here retrospectively report long-term (up to 6 years) real-life follow-up data on children and adults with MCT8 deficiency treated with Triac.” (opens the source at this quote in a new tab)

Location and study date

Study sites and observation dates

“Between October 15, 2014, and January 1, 2020, 67 patients from 62 different families (with 46 different MCT8 mutations) had received Triac and were eligible for inclusion in this study.” (opens the source at this quote in a new tab)
“Patients were treated in 33 different sites in 18 countries: 19 sites were located in Europe, 4 in the Americas, 5 in Asia, 4 in Oceania and 1 in Africa (Supplementary Figure 2 (12)).” (opens the source at this quote in a new tab)
“Follow-up of the remaining patients continued to January 1, 2021.” (opens the source at this quote in a new tab)

Study design

Retrospective real-life cohort of off-label treatment

“In this international pragmatic real-life cohort, data were collected retrospectively in patients with MCT8 deficiency, within our consortium of 33 hospitals in 18 countries, who have been treated with the T3 analogue Triac on an off-label use basis.” (opens the source at this quote in a new tab)
“The cohort consisted of (1) patients who finished the Triac Trial I protocol and continued on Triac treatment on an off-label use basis; and (2) additional patients who were identified after the recruitment phase of Triac Trial I or could not be enrolled in the Triac Trial I due to the absence of study sites in their country. For patients who had been enrolled in the Triac Trial I, data from the assessments at baseline and after 1 year of Triac treatment have been re-utilized and extended by novel long-term follow-up data.” (opens the source at this quote in a new tab)

Consent and ethics review

“The parents or guardians of all patients provided consent for off-label use of Triac to their caregiving physician. Under off-label use and with retrospective collection of data that are part of routine clinical care from medical files, no institutional board approval was needed in the majority (30) of hub centers.” (opens the source at this quote in a new tab)

Eligibility criteria

Inclusion criteria

“Eligible subjects were those with MCT8 deficiency (confirmed by the presence of a pathogenic mutation in the SLC16A2 gene), irrespective of age or comorbidities, who were treated with Triac on an off-label use basis following our previously established dose escalation protocol (11), and had their biochemical parameters measured in the central laboratory of the Erasmus MC, The Netherlands. This approach allowed for a uniform strategy of Triac dosing and monitoring of effects.” (opens the source at this quote in a new tab)

Treatment

Washout, starting dose, and dose escalation

“All patients discontinued antithyroid drugs, levothyroxine, or other thyroid hormone analogs (if applicable, eg, diiodothyropropionic acid [DITPA]) before treatment with Triac was initiated. After a washout period of 2 weeks, baseline measurements were recorded.” (opens the source at this quote in a new tab)
“The daily starting dose was based on body weight (175 µg Triac < 10 kg; 350 µg Triac ≥ 10 kg). The daily dose was increased with increments of 175 µg or 350 µg with a goal of attaining serum total T3 concentrations within the target range of 1.4 to 2.5 nmol/L. Guided by the exploratory neurodevelopmental outcomes in Triac Trial I (11), serum T3 concentrations < 1.4 nmol/L were allowed in children under 2.5 years of age in the absence of dose-limiting toxicities, leaving the possibility to administer higher Triac dosages, possibly increasing the potential for neurocognitive benefits.” (opens the source at this quote in a new tab)

Time to maintenance dose and maintenance dose

“The mean time to reach the maintenance dose was 5.0 (SD 4.7) months, with a mean of 2.7 (SD 1.1) dose increments. The median maintenance dose was 38 µg/kg/day (interquartile range, 31-61 µg/kg/day; range, 15-105 µg/kg/day).” (opens the source at this quote in a new tab)

Treatment duration and exposure

“The median treatment duration was 2.2 years (range, 0.2-6.2 years). Twelve (18%) of the 67 patients were treated for a period of more than 5 years and 26 (39%) of 67 patients were treated for a period of 2 to 5 years. The treatment exposure in this cohort was 180.4 patient years (Supplementary Figure 3B (12)).” (opens the source at this quote in a new tab)

Study outcomes

Rationale for using serum t3 concentration as the primary endpoint

Primary and secondary endpoints

“The primary prespecified endpoint of this study was the change in serum T3 concentrations between baseline and last available measurement. The prespecified secondary endpoints were the change between baseline and last available body weight and body height (expressed as kg and cm, or weight-for-age and weight-for-height and height-for-age Z-scores, respectively, or as relative differences to the natural history reference; see Supplementary Methods (12)); heart rate (expressed as beats per minute, or heart-rate-for-age Z-score); serum thyroid-stimulating hormone (TSH; thyrotropin), free and total T4 concentrations; established biochemical markers that reflect thyroid hormone action in the liver (sex hormone-binding globulin [SHBG]), in the kidney (creatinine) and in muscle (creatine kinase [CK]); and Tanner stage of sexual maturation in patients who were aged between 8 and 18 years during treatment.” (opens the source at this quote in a new tab)
“The occurrence of (severe) adverse events related to Triac was actively monitored during treatment (see Supplementary Methods (12)).” (opens the source at this quote in a new tab)

Rationale stated by the investigators: peripheral thyrotoxicosis

“In MCT8-independent tissues, the elevated serum T3 concentrations cause chronic thyrotoxicosis with negative clinical sequelae that include being underweight and having cardiovascular dysfunction (8). Together, these disease characteristics result in substantial morbidity throughout life and predispose to high mortality in childhood (8).” (opens the source at this quote in a new tab)

German benefit assessment: clinical relevance of serum T3

“In the present therapeutic indication, the serum thyroid hormone T3 concentration is a clinically relevant laboratory parameter which is used for diagnosis and therapy management. Normalisation of serum values is an important therapeutic goal in peripheral thyrotoxicosis. No valid data could however be identified to show what effect a specific change in T3 concentration has on patient-individual symptomatology.” (opens the source at this quote in a new tab)

Statistical analysis description

Number of participants (Planned and analyzed)

Analysis populations

“All 67 participants received Triac and had at least 1 follow-up measurement of serum T3 concentrations and thus were included in the analysis of the primary endpoint. Of these 67 patients, 4 patients had not been treated longer than the mean time to optimal dose (5.0 months) and thus 63 participants were included in the analyses of the secondary endpoints. Of these 63 patients, 12 (19%) patients were treated for ≥ 5 years, 10 (16%) patients were treated for 3 to 5 years, 34 (53%) patients were treated for 1 to 3 years, and 7 (13%) patients were treated for < 1 year. Longitudinal within-subject analyses were performed in 38 patients with at least 2 years of follow-up.” (opens the source at this quote in a new tab)

Description of analysis sets

Full analysis set and secondary-outcome set

“Analysis on the primary outcome was based on the full analysis dataset, which included all patients who received at least 1 dose of Triac and who had at least 1 follow-up visit after the baseline assessment. Analyses on all prespecified secondary outcomes were done in all subjects who had a treatment duration that exceeded the mean time of dose escalation (defined as time from baseline measurement to the first follow-up visit on optimal dose), to ensure that treatment effects on secondary outcomes could be reliably assessed. Complementary analyses of secondary outcomes were performed on the full analysis dataset.” (opens the source at this quote in a new tab)

Statistical methods

“For all endpoints, P values and 95% CIs were calculated for the mean change between baseline and last available follow-up visit using paired t tests. Serum TSH and CK concentrations were first log-transformed to normalize the distribution. Complementary analyses after stratification by treatment duration (< 1 year, from 1 to 3 years, from 3 to 5 years and ≥ 5 years) were done using 1-way analysis of variance (ANOVA).” (opens the source at this quote in a new tab)
“In longitudinal within-subject analyses of the primary and secondary endpoints, performed in all subjects who were treated for at least 2 years, baseline data were compared with those obtained after 1 year (±4 months) of treatment and at the last available follow-up visit within the same subject, using repeated-measurement ANOVA.” (opens the source at this quote in a new tab)

Missing data

“Missing data can mainly be attributed to the poor clinical condition of patients (including restricted availability of serum); common manifestations of MCT8 deficiency, such as scoliosis and dystonic posturing that hamper investigations for which patients needed proper positioning; and patients receiving clinical care outside the designated hub centers. With the assumption that omission of data occurred randomly, and given the broad age range of the participants and small group size, pairwise deletion was used to adjust when the baseline data point was missing; for missing data that were captured throughout the treatment period, the last available measurement was used (if available).” (opens the source at this quote in a new tab)

Historical natural-history comparison for growth outcomes

“Deterioration of body weight and height with increasing age is part of the natural history of patients with MCT8 deficiency who are not treated with Triac (8). Therefore, the results of anthropometric parameters were expressed against the natural history of untreated patients.” (opens the source at this quote in a new tab)

Results

Participant disposition

Enrollment pathways and overlap with Triac Trial I

“Among them, 27 patients had been enrolled in Triac Trial I and continued Triac treatment on an off-label use basis after completion of the trial protocol. Another 40 patients had been identified after the recruitment phase of Triac Trial I (n = 28) or could not be enrolled in the Triac Trial I due to the absence of study sites in their country (n = 12) (Supplementary Figure 1 (12)).” (opens the source at this quote in a new tab)

Deaths and discontinuations during follow-up

“During the study period, 3 patients died and 10 other patients discontinued Triac therapy (in 4 cases the parents decided to discontinue due to a lack of perceived benefit; 2 patients discontinued due to financial constraints or unavailability of Triac, and 4 patients discontinued for unknown reasons).” (opens the source at this quote in a new tab)

Baseline characteristics

Baseline age

“At baseline, the median age was 4.6 years, with a range of 0.5 to 66 years. Of the 67 patients, 63 (94%) were younger than 18 years of age and 23 (34%) were younger than 2.5 years (Table 1 and Supplementary Figure 3A (12)).” (opens the source at this quote in a new tab)

Baseline cohort characteristics

Characteristic	Off-label use cohort, n = 67
Age, median (range), years	“4.6 (0.5-66.8)”
Age 2.5 years or younger, n (%)	“23 (34%)”
Age older than 2.5 to 5 years, n (%)	“13 (19%)”
Age older than 5 to 10 years, n (%)	“17 (25%)”
Age older than 10 to 18 years, n (%)	“10 (15%)”
Age older than 18 years, n (%)	“4 (6%)”
Male, n (%)	“67 (100%)”
Continent of origin: Europe, n (%)	“45 (67%)”
Continent of origin: Asia, n (%)	“10 (15%)”
Continent of origin: Oceania, n (%)	“5 (7%)”
Continent of origin: North America, n (%)	“4 (6%)”
Continent of origin: South America, n (%)	“2 (3%)”
Continent of origin: Africa, n (%)	“1 (1%)”
Continuation after Triac Trial I, n (%)	“27 (40%)”
Direct off-label use, n (%)	“40 (60%)”
Serum T3, mean (SD), nmol/L	“4.58 (1.11)”
Body-weight-for-age Z-score, mean (SD)	“-2.80 (1.91)”
Tachycardia, n (%)	“21 (35%)”

“Body weight-for-age data were available for 66 patients.” (opens the source at this quote in a new tab)
“Heart rate data were available for 60 patients (denominator for percentage calculation).” (opens the source at this quote in a new tab)

Efficacy results

Primary endpoint: serum T3 concentration at the last available visit

“In the 67 patients assessed for the primary endpoint, mean serum T3 concentration decreased from 4.58 (SD 1.11) to 1.66 (SD 0.69) nmol/L (mean difference 2.92 nmol/L; 95% CI, 2.61-3.23 nmol/L; P < 0.0001; Fig. 1A and Table 2). Sixty (90%) of 67 patients reached T3 concentrations below 2.5 nmol/L, the upper limit of the target range.” (opens the source at this quote in a new tab)
“In patients who were treated for more than 2 years, serum T3 concentrations after 1 year of treatment and at the last visit did not significantly differ but were significantly reduced compared with baseline, indicating a sustained treatment effect (Fig. 1D and Supplementary Table 2 (12)).” (opens the source at this quote in a new tab)

Changes from baseline to last visit in predefined outcomes

Outcome	Baseline, mean (SD)	Last visit, mean (SD)	Mean change (95% CI)	P value
T3, nmol/L (n = 67)	“4.58 (1.11)”	“1.66 (0.69)”	“−2.92 (−3.23 to −2.61)”	“<0.0001”
Weight-for-age Z-score (n = 58)	“−2.81 (1.94)”	“−2.64 (1.81)”	“0.17 (−0.18 to 0.53)”	“0.3263”
Weight-for-age Z-score minus predicted weight-for-age Z-score (n = 55)	“0.07 (1.83)”	“0.79 (1.92)”	“0.72 (0.36 to 1.09)”	“0.0002”
Height-for-age Z-score (n = 44)	“−1.84 (1.77)”	“−1.92 (1.51)”	“−0.09 (−0.50 to 0.32)”	“0.6705”
Height-for-age Z-score minus predicted height-for-age Z-score (n = 43)	“−0.44 (1.38)”	“0.14 (1.41)”	“0.58 (0.12 to 1.05)”	“0.0139”
Weight-for-height Z-score (n = 44)	“−2.02 (2.49)”	“−1.50 (2.44)”	“0.52 (−0.35 to 1.39)”	“0.2358”
Heart rate, bpm (n = 48)	“113 (21)”	“97 (20)”	“−17 (−24 to −10)”	“<0.0001”
Heart-rate-for-age Z-score (n = 48)	“1.59 (0.89)”	“0.96 (1.01)”	“−0.64 (− 0.98 to −0.29)”	“0.0005”
TSH, mU/L (n = 62)	“3.32 (2.30)”	“0.95 (0.73)”	“−2.38 (−2.98 to −1.77)”	“<0.0001”
Free T4, pmol/L (n = 64)	“9.5 (2.3)”	“3.4 (1.6)”	“−6.1 (−6.7 to −5.4)”	“<0.0001”
Total T4, nmol/L (n = 63)	“54.2 (11.8)”	“18.1 (9.8)”	“−36.1 (−39.5 to −32.7)”	“<0.0001”
Sex hormone-binding globulin, nmol/L (n = 48)	“245 (99)”	“209 (92)”	“−36 (−57 to −16)”	“0.0008”
Creatinine, µmol/L (n = 47)	“32 (11)”	“39 (13)”	“7 (6 to 9)”	“<0.0001”
Creatine kinase, U/L (n = 47)	“110 (87)”	“128 (80)”	“18 (−8 to 45)”	“0.2166”

Body weight relative to the healthy reference population and to untreated historical controls

“In the 63 patients analyzed for secondary endpoints, the mean body-weight-for-age Z-score increased, but not statistically significantly, from −2.81 SD (SD 1.94) at baseline to −2.64 SD (SD 1.81) at the last visit (mean difference 0.17 SD; 95% CI, −0.18 to 0.53; P = 0.3263), representing a mean increase of 5.7 kg (Table 2).” (opens the source at this quote in a new tab)
“The mean body weight-for-age Z-score at baseline was 0.07 SD-points above the natural history reference line and at last visit 0.79 SD-points above the natural history reference line, corresponding to a statistically significant mean increase of 0.72 SD-points (95% CI, 0.36-1.09; P = 0.0002, Table 2). Compared with the natural history of treatment-naïve patients with MCT8 deficiency, body weight-for-age improved (> 0.25 SD increase compared with the natural history reference) in 32 (57%) of 55 patients upon treatment and remained stable (−0.25 to 0.25 SD change compared with the natural history reference) in 11 (20%) of 55 patients (Fig. 1E).” (opens the source at this quote in a new tab)

Body height

“The mean body height-for-age increased from baseline to last visit by a mean of 15 cm, although the body height-for-age score did not significantly differ between baseline and last visit (mean difference −0.09 SD, 95% CI, −0.5 to 0.32; P = 0.6705) (Table 2). The mean body height-for-age Z-score at baseline was 0.44 SD-points under the natural history reference line and at last visit 0.14 SD-points above the natural history reference line, corresponding with a mean increase of 0.58 SD-points (95% CI, 0.12-1.05; P = 0.0139, Table 2).” (opens the source at this quote in a new tab)

Heart rate

“Mean heart-rate-for-age Z-score decreased significantly (mean difference −0.64 SD; 95% CI, −0.98 to −0.29; P = 0.0005; Fig. 1G and Table 2), improving (> 0.25 SD decrease) in 29 (60%) of 48 patients and remaining stable (−0.25 to 0.25 SD change) in 10 (21%) of 48 patients. The proportion of patients with tachycardia (heart rate above the 90th percentile for the corresponding age, with cutoffs described by Fleming and colleagues (13)) decreased from 18 (38%) of 48 patients at baseline to 11 (23%) of 48 patients at the last visit.” (opens the source at this quote in a new tab)

Thyroid function and tissue markers of thyroid hormone action

“Mean serum TSH, free T4, and total T4 concentrations significantly declined upon Triac treatment (Table 2).” (opens the source at this quote in a new tab)
“Mean SHBG concentration, reflecting the liver-specific status of thyroid hormone action, decreased from 245 (SD 99) to 209 (SD 92) nmol/L (mean difference 36 nmol/L; 95% CI, 16-57; P = 0.0008) (Fig. 2A and Table 2).” (opens the source at this quote in a new tab)
“Creatinine, reflecting renal thyroid hormone activity, increased from 32 (SD 11) to 39 (SD 13) µmol/L (mean difference 7 µmol/L; 95% CI, 6-9; P < 0.0001) (Fig. 2C and Table 2).” (opens the source at this quote in a new tab)
“In contrast, CK, a marker of thyroid hormone activity in skeletal muscle, showed no statistically significant changes on Triac treatment [110 (SD 87) to 128 (SD 80) U/L; mean increase 18 U/L; 95% CI, −8 to 45; P = 0.2166; Fig. 2E and 2F and Table 2].” (opens the source at this quote in a new tab)

Sexual maturation

“Available Tanner stage at the last visit of patients aged from 8 to 18 years during treatment showed delayed sexual maturation in 5 (29%) out of 17 patients (Supplementary Figure 7 (12)), similar to untreated patients with MCT8 deficiency (8). No effects of Triac treatment on sexual maturation were reported in these patients.” (opens the source at this quote in a new tab)

Health-related quality of life and patient-reported outcomes

No evidence found.

Safety results

Adverse events and hospitalizations related to tiratricol

“No severe adverse events related to Triac were reported during follow-up. Transient signs of increased thyrotoxicosis (increased irritability and anxiety, reduced sleep, increase in blood pressure, and tachycardia) were reported in a small subset of patients (5 of 67 patients; Supplementary Table 4). No hospitalizations related to Triac were reported.” (opens the source at this quote in a new tab)

Deaths during follow-up

“During the total treatment period, 3 patients died: a 13-year-old patient died due to sudden death, a 71-year-old patient died after aspiration and a 14-year-old patient died of unknown cause. This is in line with commonly observed causes of death in MCT8 deficiency, with cause of death also often being unknown (8). Postmortem examination was performed in none of the cases. At the time of death, all patients had been on a stable dose of Triac for > 1.5 years, > 4 years, and >2.5 years, respectively.” (opens the source at this quote in a new tab)

Study limitations

Summary

This retrospective cohort included 67 participants treated off-label at 33 sites, of whom 27 (40%) had completed Triac Trial I; the baseline and 1-year data of those 27 participants are counted in both studies. Treatment duration ranged from 0.2 to 6.2 years, 4 participants were excluded from the secondary-outcome analyses, and missing measurements were handled by pairwise deletion and last available measurement. The change in body-weight-for-age Z-score relative to the healthy reference population was 0.17 SD (P = 0.3263), and the 0.72 SD increase was measured against a historical natural-history reference. The investigators state that the cohort may not represent all patients with MCT8 deficiency, that the real-life setting impeded optimal collection of efficacy and safety data, that care outside the designated centers could hamper adverse event reporting, and that neurodevelopmental outcomes were not collected uniformly. No concurrent comparator was included.

Limitations stated by the investigators

“This study has several limitations. First, it is unknown whether this cohort is fully representative for the entire population of patients with MCT8 deficiency. This cohort, however, represents a significant proportion of known patients (67 patients out of approximately 225 patients known in literature (8)). Second, this observational study collecting data on off-label use of Triac treatment in patients with MCT8 deficiency in a real-life treatment setting provides a less-controlled environment compared with a clinical trial, impeding optimal collection of efficacy and safety data. Patients have potentially also received care outside of their designated center, which could hamper reporting of adverse events.” (opens the source at this quote in a new tab)
“Third, this study precludes determining the optimal Triac dose for MCT8 deficiency for both the peripheral and neurocognitive phenotype as data on neurodevelopmental outcomes had not been uniformly collected.” (opens the source at this quote in a new tab)