Stated aim of the trial

“We therefore aimed to evaluate the effectiveness and safety of Triac treatment for peripheral thyrotoxicosis in paediatric and adult patients with MCT8 deficiency. In view of the wide spectrum of patient age in our study, neurocognitive changes were assessed in an exploratory way only.” (opens the source at this quote in a new tab)

Study hypothesis

“Therefore, we hypothesised that Triac treatment could effectively reduce serum T3 concentrations, thereby improving the negative clinical sequelae of chronic tissue thyrotoxicosis in patients with MCT8 deficiency. Triac might also offer beneficial effects on neurodevelopment if treatment is commenced early in life.” (opens the source at this quote in a new tab)

Study sites

“We enrolled patients at 11 sites (ten hospitals and one outpatient facility) in eight countries in Europe (Belgium, Czech Republic, France, Germany, Italy, the Netherlands, Romania, and the UK) and one site in South Africa (appendix p 3).” (opens the source at this quote in a new tab)

Screening period

“Between Oct 15, 2014, and June 1, 2017, we screened 50 patients for eligibility for the trial, all of whom were eligible.” (opens the source at this quote in a new tab)

Investigator-initiated, open-label, single-arm, phase 2 design

“In this investigator-initiated, multicentre, open-label, single-arm, phase 2, pragmatic trial, we investigated the effectiveness and safety of Triac in male patients with MCT8 deficiency.” (opens the source at this quote in a new tab)
“All patients were assigned to receive Triac for 12 months. The trial was originally intended to be a national study in the Netherlands, but it was amended to allow additional enrolment of patients in other countries.” (opens the source at this quote in a new tab)
“An independent data safety monitoring board monitored patient safety.” (opens the source at this quote in a new tab)

Treatment extension period

“To ascertain long-term effectiveness and safety, the patients enrolled in the Netherlands could enter an open-label treatment extension period, the endpoint of which was defined as the completion date of the last patient in other countries.” (opens the source at this quote in a new tab)

Prescribing information: Study 2 design

“Study 2 (NCT02060474) was an open-label, single-arm, multicenter study of 12 months duration that enrolled 46 male patients with MCT8 deficiency” (opens the prescribing information at this quote)

German benefit assessment: study description

“The TRIAC I study is a single-arm, open-label, multicentre phase IIb study to evaluate the safety and efficacy of tiratricol in patients with MCT8 deficiency over 12 months.” (opens the source at this quote in a new tab)

Inclusion criteria

“Patients with MCT8 deficiency (confirmed by the presence of a mutation in the SLC16A2 gene) were eligible to participate, irrespective of their age and comorbidities. Patients were either known to the investigators through direct care or were enrolled in the trial after their doctors or parents became aware of the trial through its ClinicalTrials.gov registration.” (opens the source at this quote in a new tab)

Exclusion criteria

“Exclusion criteria were major illness or major surgery within the past 4 weeks, enrolment in other randomised controlled trials, allergy to components in Triac tablets, and the presence of any contraindications to Triac treatment (appendix p 13).” (opens the source at this quote in a new tab)

Withdrawal criteria

“Patients could be withdrawn from the trial at the request of the parents or guardians, if continued participation was considered to be harmful to participants’ health by the investigators because of dose-limiting toxicities, or because of non-adherence to the trial protocol, premature termination of the trial, or loss to follow-up (appendix p 13).” (opens the source at this quote in a new tab)

German benefit assessment: eligible sex, age, and genotype

“Male subjects of any age who had a clinically relevant mutation in the MCT8 gene (SLC16A2) at screening could participate in the study.” (opens the source at this quote in a new tab)

Washout of prior thyroid medication

“All participants discontinued treatment with antithyroid drugs, levothyroxine, or both (if applicable) before commencing treatment with the study drug. After a washout period of at least 4 weeks, baseline measurements were recorded.” (opens the source at this quote in a new tab)

Dose-escalation protocol and serum total T3 target

“We treated all patients with Triac (Téatrois tablets [350 µg], taken orally; Rare Thyroid Therapeutics, Stockholm, Sweden) with individualised dose-escalation that followed a predefined dose-escalation protocol: after the initial dose of 350 µg Triac (one tablet) once per day was given and no predefined dose-limiting toxic effects were identified, the daily dose was increased progressively in 350 µg increments (one tablet) with no maximum dose defined, with a goal of attaining serum total T3 concentrations within the target range of 1·4–2·5 nmol/L.” (opens the source at this quote in a new tab)
“The maintenance Triac dose was continued for the rest of the study period (appendix p 4), but it could be further adjusted according to the dose-escalation protocol if T3 concentrations were outside the target range during control visits (appendix p 4).” (opens the source at this quote in a new tab)

Dose required to reach the target range

“The median time to achieve serum T3 concentrations within the target range was 2·5 months (IQR 1·5–3·7), which required a mean daily Triac dose of 38·3 µg/kg of bodyweight (SD 15·3; range 6·4–84·3), administered as a median of three doses per day (IQR 2–3; appendix p 6).” (opens the source at this quote in a new tab)
“The median daily Triac dose remained stable after the dose-escalation phase, although seven (16%) of 45 patients required further dose adjustments to maintain T3 concentrations within the target range (appendix p 6). The median daily Triac dose during the final study visit, either at month 12 or at time of withdrawal, was 37·0 µg/kg bodyweight (IQR 28·9–47·2).” (opens the source at this quote in a new tab)

Prescribing information: Study 2 dose titration and maintenance dose

“The EMCITATE dose was titrated in 350 mcg daily (175 mcg daily for participants < 10 kg) increments every 2 weeks to achieve serum total T3 levels within the normal range for adults of 91 ng/dL to 163 ng/dL.” (opens the prescribing information at this quote)
“The mean maintenance dose of EMCITATE was 741 mcg.” (opens the prescribing information at this quote)

Primary and co-primary endpoints

“The prespecified main primary endpoint was the change in the serum T3 concentrations between baseline and month 12. The prespecified co-primary endpoints were the change in serum TSH, free and total T4, and total reverse T3 concentrations between baseline and month 12.” (opens the source at this quote in a new tab)

Rationale stated by the investigators: chronic tissue thyrotoxicosis

“The endocrine hallmark of MCT8 deficiency is increased serum T3 concentrations, reduced free T4, and normal thyroid-stimulating hormone (TSH) concentrations.” (opens the source at this quote in a new tab)
“This chronic tissue thyrotoxicosis in patients with MCT8 deficiency leads to tachycardia, muscle wasting, hypermetabolism, and progressive reduction in bodyweight for age, causing substantial morbidity and mortality” (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. The endpoint is therefore only considered in addition.” (opens the source at this quote in a new tab)

Secondary endpoints

“The prespecified secondary endpoints were the change between baseline and month 12 in bodyweight (expressed as bodyweight-for-age Z score, to account for natural development in children); mean heart rate, measured by 24 h ambulatory cardiac monitoring, and resting heart rate, measured by electrocardiography, both in bpm; blood pressure (in mm Hg and percentiles, based on reference ranges in healthy people;” (opens the source at this quote in a new tab)
“mean of two measurements); and established biochemical parameters that reflect thyroid hormone activity in the liver (sex hormone-binding globulin and total cholesterol) and muscle (creatine kinase). Bodyweight was assessed instead of BMI, because accurate height measurements can be hampered by scoliosis and contractures.” (opens the source at this quote in a new tab)

Safety assessments, post-hoc endpoints, and endpoints not reported

“The prespecified assessments were the documentation of adverse events; echocardiography and 24-h monitoring of heart rhythm; bone mineral density measurement; and biochemical evaluations, including renal and liver function tests and bone turnover markers (appendix).” (opens the source at this quote in a new tab)
“Post hoc, we also assessed the change in all available primary and secondary endpoints between baseline and the end of the treatment extension period in the participants treated for this time.” (opens the source at this quote in a new tab)
“Although the measurement of energy expenditure (secondary endpoint) and hair cortisol concentrations (exploratory endpoint) were prespecified endpoints, their acquisition was compromised by technical difficulties and are, therefore, not reported.” (opens the source at this quote in a new tab)

Sample size calculation

“We did a power calculation based on a one-sample t test to estimate the difference in serum T3 concentrations after 12 months of treatment, by use of a mean serum T3 concentration of 4·3 nmol/L (SD 1·2), which we derived from a historical group of 31 patients with MCT8 deficiency (unpublished data). With ten patients we would have 80% power (at a significance level of 0·05) to detect a mean decrease in serum T3 concentrations from 4·3 nmol/L to 3·3 nmol/L.” (opens the source at this quote in a new tab)
“After approval by all relevant ethical committees, we recruited additional patients to ascertain uniform documentation of the effects of Triac in this rare disorder and to provide more meaningful data on secondary outcomes and safety measures.” (opens the source at this quote in a new tab)

Screened, enrolled, and analyzed populations

Population	Participants
Screened and eligible	“50”
Declined participation	“four (8%)”
Enrolled	“46 (92%)”
Primary endpoint analysis	“45 (98%)”
Completed the 12-month intervention period; secondary and exploratory endpoint analyses	“40 (87%)”
Treatment extension period	“Ten (22%)”

Full analysis set, completer set, and safety population

“Analyses of the prespecified primary endpoints were based on the full analysis dataset, which included all patients who received at least one dose of Triac and who had at least one control visit after the baseline assessment (appendix p 4). As such, patients who withdrew were included in the analyses, with their last available measurement used. The main analyses of the prespecified secondary endpoints were done in all patients who completed 12 months of treatment.” (opens the source at this quote in a new tab)
“Analyses of safety endpoints were done in the safety population, which included all patients exposed to at least one dose of the study drug.” (opens the source at this quote in a new tab)

Statistical methods

“For all prespecified primary and secondary endpoints, p values and 95% CIs were calculated for the mean change between baseline and month 12 by use of paired Student’s t tests. Serum TSH and creatine kinase concentrations were first log-transformed to normalise the distribution. For all prespecified exploratory and safety measures, 95% CIs were calculated for the mean change between baseline and 12 months of Triac treatment.” (opens the source at this quote in a new tab)
“Two-sided p values of less than 0·05 were considered to denote statistical significance.” (opens the source at this quote in a new tab)
“CIs for exploratory measures have not been adjusted for multiplicity and these data should not be used to infer definitive treatment effects.” (opens the source at this quote in a new tab)

Missing data

“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 for missing data that were only captured at baseline and 12 months; for missing data that were captured throughout the study, the last available measurement was used.” (opens the source at this quote in a new tab)
“If 12-month measurements were not available, the last available observation in the same patient was used (<3% of included datapoints).” (opens the source at this quote in a new tab)

Caregiver-reported outcomes: post-hoc analysis methods

“To study the effect of Triac on patient-centered outcome measures in the Triac Trial I.” (opens the source at this quote in a new tab)
“We performed post-hoc analyses on caregiver-reported patient-centered outcome measures from the multicentre, phase 2, single-arm, open-label Triac Trial I. In this trial, 40 patients with MCT8 deficiency completed 1 year of Triac treatment. At baseline, during clinical visits and at the end of the study, semi-structured interviews were held with caregivers on complex needs and daily care challenges, including motor skills, sleep problems, seizure frequency and most prominent changes. Moreover, parents were asked to report perceived changes in (thyrotoxic) symptoms such as increased perspiration and hyposialia.” (opens the source at this quote in a new tab)

Enrollment and withdrawals

“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.” (opens the source at this quote in a new tab)
“Of these 50 patients, four declined to participate; 46 patients were therefore enrolled and assigned to receive Triac (appendix p 5), but one (2%) patient was withdrawn before the first control visit because of non-compliance to study procedures. This patient was included in safety analyses, but not primary efficacy analyses.” (opens the source at this quote in a new tab)
“Five of these patients did not complete the study intervention: two were withdrawn due to parental choice (one because of travel time to the study centre, one because of severe comorbidity [severe epileptic seizures and hydrocephalus]), one was lost to follow-up, one developed Graves’ disease, and one patient died from sepsis. 40 (87%) patients completed the 12-month intervention period and thus were included in the analyses of secondary and exploratory endpoints. Ten (22%) patients who completed the follow-up were also included in the long-term (median 40·4 months, IQR 38·1–41·3) treatment extension period (appendix p 5).” (opens the source at this quote in a new tab)

Age, serum T3, bodyweight, and developmental status at baseline

“At baseline, the median age of the overall study population (n=46) was 7·1 years (range 0·8–66·8) and the mean serum T3 concentration was 4·91 nmol/L (SD 1·57), which was more than 1·6-times the upper limit of the normal range for age (table 1). The mean weight-for-age Z score was –2·84 (1·88) and 30 (65%) of the 46 enrolled patients were underweight (Z score less than –2). All patients had severe intellectual and motor disability: 41 (89%) of 46 patients were wheelchair-bound and had not reached early developmental milestones such as independent sitting.” (opens the source at this quote in a new tab)

Baseline characteristics table

Characteristic	Triac, n = 46
Age younger than 4 years, n (%)	“11 (24%)”
Age 4 to 10 years, n (%)	“19 (41%)”
Age 11 to 18 years, n (%)	“11 (24%)”
Adults older than 18 years, n (%)	“5 (11%)”
Male, n (%)	“46 (100%)”
White race, n (%)	“44 (96%)”
No or poor head control, n (%)	“32 (70%)”
Able to sit independently, n (%)	“5 (11%)”
Uses a feeding tube, n (%)	“20 (43%)”
Resting tachycardia (above the 90th percentile for age)	“19 (43%) of 44 patients with data available”
Systolic hypertension	“12 (34%) of 35 patients with baseline blood pressure measurements”

Prescribing information: Study 2 age and race

“The median age of participants was 7.1 years (range: 10 months to 66.8 years). The majority (96%) of participants were White, 2% were Asian and 2% were other races.” (opens the prescribing information at this quote)

German benefit assessment: age distribution

“A total of 46 patients aged between 10 months and 67 years (mean 10.4 years) were enrolled. Only 5 study participants were under 2 years of age and no patient was treated in the postnatal period.” (opens the source at this quote in a new tab)

Primary endpoint: serum T3 concentration at month 12

“In the 45 patients assessed for the primary endpoint, serum T3 concentrations had significantly decreased by month 12 (median 13·1 months [IQR 12·4–13·9]), with a mean decrease of 3·15 nmol/L (95% CI 2·68–3·62; p<0·0001; figure 1; table 2), equivalent to 61% (56–66) from baseline.” (opens the source at this quote in a new tab)

Co-primary endpoints: TSH, free and total T4, and reverse T3

“We also identified significant reductions in serum free T4 concentrations (mean decrease 6·1 pmol/L, 5·4–6·8; p<0·0001) and serum TSH concentrations (mean decrease 1·89 mU/L, 1·39–2·39; 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; (appendix p 7).” (opens the source at this quote in a new tab)

Primary and secondary outcomes, baseline to month 12

Outcome	Baseline, mean (SD)	Month 12, mean (SD)	Mean change (95% CI)	p value
T3, nmol/L (n = 45)	“4·97 (1·55)”	“1·82 (0·69)”	“–3·15 (–3·62 to –2·68)”	“<0·0001”
TSH, mU/L (n = 45)	“2·91 (1·68)”	“1·02 (1·14)”	“–1·89 (–2·39 to –1·39)”	“<0·0001”
Free T4, pmol/L (n = 45)	“9·5 (2·5)”	“3·4 (1·6)”	“–6·1 (–6·8 to –5·4)”	“<0·0001”
Total T4, nmol/L (n = 45)	“56·0 (13·0)”	“24·4 (9·4)”	“–31·6 (–35·2 to –28·0)”	“<0·0001”
Reverse T3, nmol/L (n = 45)	“0·12 (0·10)”	“0·04 (0·04)”	“–0·08 (–0·10 to –0·05)”	“<0·0001”
Weight-for-age Z score (n = 40)	“–2·98 (1·93)”	“–2·71 (1·79)”	“0·27 (0·03 to 0·50)”	“0·025”
Resting heart rate, bpm (n = 34)	“112 (23)”	“104 (17)”	“–9 (–16 to –2)”	“0·010”
Mean heart rate over 24 h, bpm (n = 31)	“102 (14)”	“97 (9)”	“–5 (–9 to –1)”	“0·012”
Systolic blood pressure, mm Hg (n = 32)	“108 (8)”	“102 (10)”	“–5 (–9 to –1)”	“0·0086”
Systolic blood pressure, percentile (n = 32)	“78 (24)”	“61 (29)”	“–18 (–29 to –6)”	“0·0037”
Diastolic blood pressure, mm Hg (n = 32)	“64 (9)”	“62 (9)”	“–2 (–6 to –2)”	“0·35”
Sex hormone-binding globulin, nmol/L (n = 39)	“212 (91)”	“178 (76)”	“–35 (–55 to –15)”	“0·0013”
Total cholesterol, mmol/L (n = 40)	“3·2 (0·7)”	“3·4 (0·7)”	“0·2 (0·0 to 0·3)”	“0·056”
Creatine kinase, U/L (n = 40)	“108 (90)”	“161 (117)”	“53 (27 to 78)”	“<0·0001”

Attainment of the serum T3 target range

“In the post-hoc analyses to assess only the patients who completed 12 months of treatment, we found that 34 (85%) of 40 patients had attained serum T3 concentrations within the target range by month 12, and the remaining patients had concentrations just above the target range, but that their T3 measurements had been within the target range during the previous study assessment visit.” (opens the source at this quote in a new tab)
“By month 4, 35 (78%) of 45 patients had attained T3 concentrations within the target range (appendix p 6).” (opens the source at this quote in a new tab)

Secondary endpoints: bodyweight, heart rate, blood pressure, and tissue markers

“We assessed the secondary endpoints in the 40 patients who completed the 12-month treatment. We identified a significant increase in weight-for-age Z score at month 12 (0·27 SDs, 95% CI 0·03–0·50; p=0·0253; figure 1; table 2; appendix p 8), equating to a mean increase in body weight of 2·7 kg (1·9–3·5; p<0·0001); by contrast, in untreated patients, the bodyweight-for-age Z score has been shown to progressively reduce over time (appendix p 8).” (opens the source at this quote in a new tab)
“Between baseline and month 12, resting heart rate, as measured by electrocardiography, decreased by 9 bpm (95% CI 2–16; p=0·010), and mean heart rate, as measured by 24-h cardiac monitoring, decreased by 5 bpm (1–9; p=0·012; appendix p 9). Mean systolic blood pressure decreased over the 12-month study from the 78th percentile to the 61th percentile, equating to a change of 18 percentile points (95% CI 6–29; p=0·0037; table 2). The proportion of patients with systolic hypertension decreased from 34% (n=12/35) at baseline to 9% (n=3/32 at month 12).” (opens the source at this quote in a new tab)
“The serum concentrations of sex hormone-binding globulin decreased by 35 nmol/L (15–55; p=0·0013). However, mean serum total cholesterol concentration did not significantly change between baseline and month 12 (difference 0·2, 95% CI 0·0–0·3; p=0·056). Finally, serum creatine kinase concentrations increased by 53 U/L (27–78; p<0·0001) by month 12 (table 2; appendix p 10).” (opens the source at this quote in a new tab)

Exploratory endpoint: gross motor function

“The greatest increase in gross motor function was in patients in whom Triac treatment was started before age 4 years (figure 1).” (opens the source at this quote in a new tab)
“From the seven patients with a completely inactivating mutation who had started with Triac treatment before the age of 4 years, two reached this developmental stage by month 12 of treatment.” (opens the source at this quote in a new tab)

Post-hoc treatment extension period

“Post-hoc analyses of the treatment extension endpoints included ten patients. During the long-term treatment extension period, the reductions in T3 concentrations persisted in all patients (figure 2; appendix p 21) and reductions in TSH and free T4 concentrations were maintained (appendix pp 11,21).” (opens the source at this quote in a new tab)
“The improvement in bodyweight-for-age Z score was maintained, with a mean increase of 0·52 SDs (95% CI 0·02–1·02) at month 12 and 0·62 (0·12–1·12) at month 32, relative to baseline. Bodyweight (figure 2), height, and BMI trajectories improved relative to their anticipated natural course in seven (88%) of the eight paediatric patients (appendix p 12).” (opens the source at this quote in a new tab)

Prescribing information: Study 2 serum total T3, baseline to month 12

Variable	N	Baseline, mean (SD)	Month 12, mean (SD)	Difference, mean [95% CI]
T3, ng/dL	“45”	“323.4 (100.8)”	“118.3 (44.6)”	“-205.2 [-235.7; -174.6]”

“Data were imputed as Last Observation Carried Forward for patients who discontinued treatment prior to Month 12 visit.” (opens the prescribing information at this quote)

Prescribing information: Study 2 secondary endpoints at month 12

“At Month 12, there was a mean (95% confidence interval) change of: -4.1 (-8.1, -0.1) mmHg from a baseline of 107.1 mmHg in systolic blood pressure (N = 35 participants); -8.9 (-15.6, -2.3) beats per minute (bpm) from a baseline of 112.4 bpm in heart rate (N = 34 participants), 0.22 (-0.01, 0.45) from a baseline of -2.85 in body weight-for-age Z-score (N = 45 participants) and 0.51 (0.25, 0.76) from a baseline of 0.46 in body weight-for-age Z-score in an untreated MCT8 patient population (N = 36 participants).” (opens the prescribing information at this quote)

German benefit assessment: anthropometric results against a healthy reference population

“The data on body height and body weight in relation to the healthy reference population (WHO reference population) were used for the present benefit assessment. However, it should be noted that the present analyses also include data from adults who have already completed their physical development. In the TRIAC I study, there was no significant change in the z-score compared to baseline for body weight as well as body height at the end of the study.” (opens the source at this quote in a new tab)

Regulatory assessment of neurodevelopmental delay

“Emcitate did not improve neurodevelopmental delay.” (opens the source at this quote in a new tab)

Prospectively collected quality-of-life and neurocognitive endpoints

“The patient-reported endpoints of Gross Motor Function Measure-88 (GMFM-88), Bayley Scales of Infant and Toddler Development - Third Edition (BSID-III) and Vineland Adaptive Behaviour Scales - Second Edition (VABS-II) on neurocognitive development collected in the TRIAC I study were not used for the benefit assessment due to the low return rates (< 70%).” (opens the source at this quote in a new tab)
“No endpoints on quality of life were collected in the TRIAC I study.” (opens the source at this quote in a new tab)

Caregiver-reported outcomes from Triac Trial I: results

“The most prominent changes upon Triac treatment reported by caregivers were improved interaction (22/39), greater alertness (19/39), improved motor skills (12/39), improved head control (7/39), and improved sleep (8/39). For one patient, also negative changes were reported, specifically increased constipation and higher unsettledness.” (opens the source at this quote in a new tab)
“Compared to the baseline visit, excessive perspiration was much less reported (48,6% vs. 8,1%) and less hyposialia (30,6% vs 22,2%) was observed by the caregivers at the end study visit. Seizures and continence were reportedly unchanged. All parents (40/40) preferred to continue Triac treatment.” (opens the source at this quote in a new tab)

Adverse events and treatment-related adverse events

“All 46 patients who received at least one dose of Triac were included in drug safety analyses. 43 (93%) patients had at least one adverse event (table 3; appendix p 22). Triac treatment was continued during hospital admission in all but one patient. All seven adverse events that were suspected to be related to Triac treatment, which occurred in six (13%) patients, were mild: three patients had a transient increase in perspiration and three patients reported transient irritability. The onset of these events coincided with the start of Triac treatment or modification in Triac dose and resolved spontaneously after a few days. No patients required a dose reduction or discontinued participation because of drug-related toxicity.” (opens the source at this quote in a new tab)

Serious adverse events and death

“26 serious adverse events that were considered unrelated to treatment occurred in 18 (39%) patients (mostly hospital admissions because of infections).” (opens the source at this quote in a new tab)
“Most serious adverse events were intermittent infections that were treated with antibiotics and supportive care. All serious adverse events were considered to be secondary to MCT8 deficiency and, thus, unrelated to Triac (table 3). In three patients with preexisting seizures, an increase in seizure frequency was reported.” (opens the source at this quote in a new tab)
“One patient died from pulmonary sepsis leading to multiorgan failure; post-mortem examination confirmed the clinical diagnosis, and other causes were excluded.” (opens the source at this quote in a new tab)

Adverse events in more than 10% of participants, serious events, and severity

Adverse event	Participants with at least one event, n (%), N = 46	Number of events
Total adverse events	“43 (93%)”	“150”
Gastroenteritis	“11 (24%)”	“12”
Nasopharyngitis	“11 (24%)”	“14”
Influenza or influenza-like illness	“9 (20%)”	“12”
Upper-respiratory-tract infection	“9 (20%)”	“9”
Bronchitis	“6 (13%)”	“6”
Diarrhoea	“5 (11%)”	“5”
Vomiting	“5 (11%)”	“5”
Otitis media	“5 (11%)”	“5”
Serious adverse events	“18 (39%)”	“26”
Fatal adverse events	“1 (2%)”	“1”
Adverse events leading to premature treatment discontinuation (autoimmune thyroid disorder)	“1 (2%)”	“1”
Severe adverse events	“4 (9%)”	“4”
Moderate adverse events	“4 (9%)”	“5”
Mild adverse events	“40 (87%)”	“141”
Probable relation to the study drug	“6 (13%)”	“7”

Cardiac, bone, and liver safety measures

“Of the safety measures prespecified in the protocol (appendix p 14–16), no clinically relevant changes in cardiac structure or function were identified.” (opens the source at this quote in a new tab)
“Serum β-carboxy-terminal collagen crosslinks increased by 0·14 µg/L (95% CI 0·03–0·25) and bone-specific alkaline phosphatase concentrations increased by 8·4 µg/L (2·7–14·1), without affecting bone mineral density (appendix p 23), consistent with the physiological increase of bone turnover markers in paediatric patients during development.” (opens the source at this quote in a new tab)
“25 (54%) of 46 patients showed mildly increased serum concentrations of alanine aminotransferase, aspartate aminotransferase, or γ-glutamyl transferase at baseline, which was attributed to the concomitant use of hepatotoxic medications, and these concentrations did not increase further during the study. Two (4%) patients showed an increase in aminotransferase concentrations that were attributed to commencement or dose adjustment of anticonvulsant drugs with known hepatotoxicity (levetiracetam and lamotrigine).” (opens the source at this quote in a new tab)

Prescribing information: Study 2 adverse reactions

Adverse reaction	Study 2, EMCITATE, N = 46, n (%)
Diarrhea	“6 (13)”
Vomiting	“5 (11)”
Rash	“4 (9)”
Hyperhidrosis	“3 (7)”

Prescribing information: Study 2 transient increases in heart rate and systolic blood pressure during titration

“In Study 2, transient increases in heart rate and systolic blood pressure” (opens the prescribing information at this quote)
“were observed in 35% and 26% of participants, respectively, during the titration period. In addition, 30% of participants experienced at least one adverse reaction potentially related to thyrotoxicosis during the trial (diarrhea, hyperhidrosis, irritability, insomnia, nightmares), with most of these adverse reactions occurring during the titration period” (opens the prescribing information at this quote)

German benefit assessment: adverse event reporting

“Adverse events (AEs) occurred in more than 90% of patients (only presented additionally). Serious AEs (SAEs) were documented in almost 40% of the study participants and 2% thereof discontinued the study due to AEs. For the endpoint "severe AEs", there were uncertainties regarding the operationalisation of the severity grading, which could also not be clarified as part of the written statements made by the pharmaceutical company. Based on the information available, it cannot be ruled out that severe AEs were under-assessed.” (opens the source at this quote in a new tab)
“Overall, interpretation and assessment of the data on side effects are not possible due to the missing control group.” (opens the source at this quote in a new tab)

Summary

Triac Trial I was an open-label, single-arm, phase 2 trial in which 46 participants were enrolled, 45 were included in the primary analysis, and 40 completed 12 months of treatment. The investigators state that the absence of a control group and the open-label design do not allow causality to be proven, that the sample size did not allow control for factors other than the intervention, that few adults were enrolled, and that missing measurements and withdrawals may have caused selection bias. The trial was not designed to assess neurodevelopment. The G-BA did not identify validated evidence linking a given change in serum T3 to individual symptoms, found no significant change in bodyweight or height z-scores against a WHO reference population, did not use the neurocognitive endpoints because fewer than 70% of assessments were returned, noted that no quality-of-life endpoints were collected, and could not rule out under-assessment of severe adverse events. The caregiver-reported outcomes come from a post-hoc analysis of an open-label trial.

Limitations stated by the investigators

“Inherent to studies in such a heterogeneous population, the effect size of outcomes varied within the study cohort, suggesting inter-individual variation in degree of benefit between patients. The small sample size did not allow identification or statistical control for factors other than the intervention that might modulate treatment effects. Another limitation was the small number of adult patients enrolled in the study, as a consequence of high mortality during childhood. Moreover, the low physical and cognitive abilities of the participants, a feature that is inherent to the disorder, precluded recording some study parameters in all patients. Together with study withdrawals, this issue might have, unavoidably, caused selection bias in the data used for statistical analyses.” (opens the source at this quote in a new tab)
“Although our study design, including the absence of a control group and open-label design, does not enable us to prove causality, the observed unidirectional changes in serum T3 concentrations can likely be attributed to Triac treatment, given the substantial evidence from preclinical and clinical studies on the effects of Triac” (opens the source at this quote in a new tab)
“Our trial was not designed to detect whether Triac also modulates neurodevelopment in human MCT8 deficiency, since the study did not include specific neurodevelopmental outcomes and enrolled patients of all ages. Therefore, most patients studied would have passed the small window of opportunity to modulate brain development.” (opens the source at this quote in a new tab)

German benefit assessment: absence of a comparator

“However, no conclusions on the extent of the additional benefit for the mortality category could be derived due to the absence of comparator data.” (opens the source at this quote in a new tab)
“Overall, the available data can nevertheless only be interpreted with difficulty in terms of their significance, as no assessment is possible on the basis of the non-comparator data in comparison to the natural course of the disease in the present patient population.” (opens the source at this quote in a new tab)
“Overall, quantification of the extent of the additional benefit on the basis of the available study results is not possible due to the lack of comparison.” (opens the source at this quote in a new tab)