Registry objective and hypothesis

“This study will investigate the effect of treatment with tiratricol (also called Triac) in young boys (≤30 months) with MCT8 deficiency (also called the Allan-Herndon-Dudley syndrome (AHDS)). The hypothesis tested is that treatment with tiratricol will have a beneficial effect on the hypothyroid state in the brain as well as the hyperthyroid state in peripheral organs and tissues in these patients.” (opens the source at this quote in a new tab)

Regulatory description of the study aim

“Triac Trial II is a 96-week study (Part I) designed to evaluate the effects of tiratricol on neurodevelopment in young (≤30 months of age) patients with MCT8 deficiency. In addition, the study provides data on treatment effects on serum T3, clinical aspects of thyrotoxicosis and safety data in the youngest patients, dosed with considerably higher doses than in previous clinical studies.” (opens the source at this quote in a new tab)

Principal investigator: early-treatment hypothesis

“Our research hypothesis when we designed the Triac Trial II, based on preclinical data and on exploratory outcomes we observed in Triac Trial I, was to investigate if young patients with MCT8 deficiency might have a neurocognitive benefit from tiratricol treatment, if the treatment is started early.” (opens the source at this quote in a new tab)

Registry dates and enrollment

Field	Quoted record
Study start (actual)	“2020-12-07”
Primary completion (estimated)	“2027-07-18”
Study completion (estimated)	“2027-08-18”
Recruitment status	“Active, not recruiting”

Registry study sites

Country	Site
United States	“Oregon Health & Science University (OHSU) Doernbecher Childrens Hospital”
United States	“Children's Hospital of Philadelphia”
Czechia	“Charles University and Motol University Hospital; The department of peadiatrics of the 2nd faculty of medicine”
Germany	“Charité - Universitätsmedizin Berlin Institut fur experimental paediatrische endokrinologie”
Netherlands	“Erasmus MC”

Screening period

“Results: Between Dec 3, 2020, and Jun 22, 2022, we screened 23 male patients.” (opens the source at this quote in a new tab)

Phase 2, open-label, multicentre, single-arm trial

“Methods: We performed a phase II, open-label, multicentre, clinical trial (NCT02396459), which investigated the effect of Triac treatment on the motor and cognitive development of male patients with MCT8 deficiency, aged 0-30 months at baseline.” (opens the source at this quote in a new tab)

Design field	Quoted record
Phase	“Phase 2”
Allocation	“N/A”
Interventional model	“Single Group Assignment”
Masking	“None (Open Label)”

Part I and long-term extension (Part II)

“Patients will initially be treated for 96 weeks with tiratricol, treatment effect will be evaluated after 96 weeks. After the 96 week treatment period, patients will enter Part II of the trial, evaluating long-term treatment.” (opens the source at this quote in a new tab)

“Part II of the study is a long-term extension with an additional 2 years of treatment and is currently on-going.” (opens the source at this quote in a new tab)

Registry inclusion criteria

“The participant should be aged between 0 and 30 months on the day of inclusion.” (opens the source at this quote in a new tab)
“The participant should be male and have a pathogenic mutation in the MCT8 gene.” (opens the source at this quote in a new tab)

Registry exclusion criteria

“Previous treatment with tiratricol.” (opens the source at this quote in a new tab)
“Previous treatment with LT4 and/or PTU and/or other anti-thyroid medication for a period longer than three months.” (opens the source at this quote in a new tab)
“Major illness or recent major surgery (within four weeks of baseline visit 1) unrelated to MCT8 deficiency.” (opens the source at this quote in a new tab)
“Patients with galactose intolerance, Lapp lactase deficiency or malabsorption of glucose or galactose (the IMP contains lactose).” (opens the source at this quote in a new tab)
“Treatment with another investigational drug or participation in other interventional trial within three months prior to baseline visit 1.” (opens the source at this quote in a new tab)

Dose titration and target serum T3 range

“The initial starting dose of tiratricol was 30-40 μg/kg/day (dose level 1).” (opens the source at this quote in a new tab)
“It was reasoned that tiratricol doses between 150 – 200 μg/kg/day would be a reasonable dose to administer in young children with MCT8 deficiency.” (opens the source at this quote in a new tab)
“Tiratricol was administered orally or through a feeding tube, with the dose divided into 1-3 administrations per day.” (opens the source at this quote in a new tab)

“The dose of tiratricol was escalated to target T3 at the lower limit of the normal range (LLN) down to 10% of the LLN, without dose limiting toxicities or side-effects.” (opens the source at this quote in a new tab)
“Patients were treated with a mean daily dose of 175 mcg/kg (compared to a mean dose in TRIAC trial I of 37 mcg/kg).” (opens the source at this quote in a new tab)
“A higher dose was applied with the aim to improve the severe neurocognitive phenotype of MCT8-deficiency.” (opens the source at this quote in a new tab)

Treatment duration and exposure

“Patients were initially treated for 96 weeks with tiratricol, and the treatment effect was evaluated after 96 weeks.” (opens the source at this quote in a new tab)

“Reflecting that only 1 patient discontinued the study, overall median exposure to tiratricol during Part I of the study was 97.1 weeks, range 2 to 107 weeks.” (opens the source at this quote in a new tab)

Co-primary and secondary endpoints

“The co-primary endpoints were GMFM-88 total score and BSID-III Gross Motor Skill Domain (age equivalent score) at week 96 compared to baseline and natural history scores from the TRIAC I study. T3 change from baseline was a secondary endpoint.” (opens the source at this quote in a new tab)

“Secondary outcomes included the effect of Triac on clinical and biochemical features related to thyrotoxicosis, and safety outcomes.” (opens the source at this quote in a new tab)

Registry description of the GMFM-88 and BSID-III co-primary measures

“To evaluate the effects of tiratricol on neurodevelopment in young MCT8 deficiency patients, measured by the Gross Motor Function Measure (GMFM)-88 assessment. Potential result values range from 0 to 100%, the latter being representative for a 4-year old healthy child. A high score is equivalent to better/more neurodevelopment and is therefore a better outcome than a low score.” (opens the source at this quote in a new tab)
“To evaluate the effect of tiratricol treatment on neurodevelopment measured by the Bayley Scales of Infant Development (BSID-III) Gross Motor Skill Domain score. Potential total raw scores range from 0-72, and can be age-adjusted before analysis.” (opens the source at this quote in a new tab)

Enrolled and analyzed population

Population	Quoted record
Enrollment (actual)	“22”

“Of the 22 patients included in the ITT population, all were defined as having severe MCT8 deficiency, based on their genetic mutation.” (opens the source at this quote in a new tab)

“A total of 21 patients (median age 16 months at baseline) completed the 96-week treatment period.” (opens the source at this quote in a new tab)

Historical control comparison and post-hoc analyses

“Primary outcomes were neurodevelopmental changes as measured by the Gross Motor Function Measure (GMFM)-88 and the Bayley Scales of Infant Development (BSID)-III gross motor domain, compared to untreated historical cohort patients aged 0-9 years. Post-hoc analyses focused on other neurodevelopmental domains.” (opens the source at this quote in a new tab)

Pre-specified historical control thresholds

“Improvements versus the pre-specified historical control thresholds (GMFM-88: 9.8%= upper limit of the 95% CI from 0-9 years aged TRIAC-I patients; threshold in the BSID-III Gross Motor Skills Domain: 2.34 years) were clearly not shown.” (opens the source at this quote in a new tab)

Safety analysis set

“Overall, 21 (95.5%) patients in the Safety Analysis Set (ITT population) reported 208 TEAEs in Part I of the study.” (opens the source at this quote in a new tab)

Screening, exclusion, discontinuation, and completion

“Results: Between Dec 3, 2020, and Jun 22, 2022, we screened 23 male patients. One patient was excluded due to previous levothyroxine treatment and another discontinued treatment because of personal circumstances. A total of 21 patients (median age 16 months at baseline) completed the 96-week treatment period.” (opens the source at this quote in a new tab)

“One patient withdrew from the study for other reasons prior to reporting any TEAEs.” (opens the source at this quote in a new tab)

Age, disease severity, and time since diagnosis

“Of the 22 patients included in the ITT population, all were defined as having severe MCT8 deficiency, based on their genetic mutation. Median age at time of enrolment was 16 months, range: 5 to 28 months, with most patients (63.6%) aged >12 months at baseline. The median time since diagnosis was 3 months, range 0 to 21 months.” (opens the source at this quote in a new tab)
“Two patients were younger than 6 months.” (opens the source at this quote in a new tab)

Nutritional status, feeding, heart rate, and blood pressure

“A large proportion of patients (54.5%) was under-weight at baseline.” (opens the source at this quote in a new tab)
“The majority of this young patient population had some difficulties with swallowing and choking, and there were 6 patients (27.3%) with a feeding tube at baseline.” (opens the source at this quote in a new tab)
“Two (9.5%) patients had resting heart rate (pulse rate) above the 90th percentile for the corresponding age, using cut-offs described in Fleming et al. 2011, and were defined as having tachycardia at baseline (compared with 40.9% of patients in TRIAC I).” (opens the source at this quote in a new tab)
“Thirteen (72.2%) patients had systolic hypertension at baseline based on definitions in Flynn et al. 2017 (compared with 34.3% in TRIAC I).” (opens the source at this quote in a new tab)

Co-primary endpoints versus historical controls

Co-primary endpoint	Mean difference versus untreated historical cohort after 96 weeks
GMFM-88 total score	“-2.42, 95%CI -4.36 to -0.48”
BSID-III gross motor domain	“0.21, 90%CI -0.19 to 0.61”

“Post-hoc analyses suggested small, significant, improvements in expressive language, fine motor, and cognition compared to untreated historical cohort patients.” (opens the source at this quote in a new tab)
“Conclusions: In this phase II, open-label, multicentre, clinical trial, we found no significant treatment effect of Triac on gross motor outcomes in young paediatric male patients with MCT8 deficiency.” (opens the source at this quote in a new tab)

Co-primary endpoints: change from baseline

“In TRIAC II, very small numerical increases were observed at week 96 versus baseline on the primary endpoints reflecting neurodevelopment assessed by GMFM-88 total score (baseline mean 5.62%, week 96 mean 7.39%) and BSID-III Gross Motor Skills Domain (age equivalent score; baseline mean 2.0, week 96 mean 2.6).” (opens the source at this quote in a new tab)
“Overall, the observed small changes in the GMFM-88 total score and the BSID-III Gross Motor Skills Domain and other BSID-III domains (cognitive, receptive communication, expressive communication, and fine motor skills) may reflect the change in development that would have been observed without treatment.” (opens the source at this quote in a new tab)
“Overall, the CHMP concluded that the results of TRIAC-II did not support that tiratricol may beneficially influence the severe neurological phenotype of AHDS.” (opens the source at this quote in a new tab)

Sponsor topline report

“The numerical improvements versus baseline observed on the primary endpoints of neurocognitive development assessed by the GMFM-88 and BSID-III scales did not show a statistically significant improvement versus historical controls.” (opens the source at this quote in a new tab)
“Among key secondary endpoints, total serum thyroid hormone T3 concentrations were reduced significantly and durably in all patients, thereby verifying tiratricol’s ability to alleviate thyrotoxicosis in MCT8 deficiency patients.” (opens the source at this quote in a new tab)

Secondary endpoints: serum T3, body weight, blood pressure, and atrial ectopy

“Mean serum T3 decreased by 3.24 nmol/L from 4.31 nmol/L at baseline to 1.07 nmol/L at week 96 (p<0.0001). From around week 12, serum T3 levels had reached a maximum reduction and did not decrease further with increasing dose of tiratricol.” (opens the source at this quote in a new tab)
“Following 96 weeks of treatment there was a 3.4 kg improvement in mean body weight (p<0.0001) that corresponded to a significant improvement in body weight for age MCT8 Z scores (1.129; p=0.0011), thus showing a somewhat larger than expected body weight increase from baseline compared to an untreated MCT8 deficiency population.” (opens the source at this quote in a new tab)
“Importantly, results on heart rate and systolic blood pressure in TRIAC II suggested higher-than-optimal dosing from a peripheral thyrotoxicosis perspective: there was an increase in SBP from 103.9 at baseline to 110.1 at week 96; DBP remained largely unchanged.” (opens the source at this quote in a new tab)
“In TRIAC II, the mean number of PACs per day was 19.2 at baseline.” (opens the source at this quote in a new tab)
“PAC rate was markedly reduced at Week 96 of TRIAC II, with a mean of 2.2 events per day.” (opens the source at this quote in a new tab)

Overview of treatment-emergent adverse events in Part I

Event category	Participants, N=22, n (%)	Events
Any treatment-emergent adverse event (TEAE)	“21 (95.5)”	“208”
Any TEAE at least possibly related to study treatment	“13 (59.1)”	“20”
Any TEAE leading to discontinuation of study treatment	“0”	“0”
Any TEAE of CTC Grade 3 or higher	“13 (59.1)”	“19”
Any serious treatment-emergent adverse event (SAE)	“10 (45.5)”	“26”
Any SAE at least possibly related to study treatment	“1 (4.5)”	“2”
Any SAE leading to death	“0”	“0”

Treatment-related adverse events and serious adverse events

“The most frequently reported TEAEs that were considered by the investigator to be at least possibly related to study treatment were in the gastrointestinal disorders MedDRA SOC, including diarrhoea reported by 3 (13.6%) patients.” (opens the source at this quote in a new tab)
“Nervous system disorders of seizure/partial seizures/dyskinesia were reported in 3 (13.6%) patients.” (opens the source at this quote in a new tab)
“Two treatment-related TEAEs of hypothyroidism were reported after tiratricol was abruptly withdrawn in 2 patients.” (opens the source at this quote in a new tab)
“Overall, these generally mild (CTCAE Grade 1) or moderate (CTCAE Grade 2) TEAEs resolved without any change in tiratricol dose.” (opens the source at this quote in a new tab)
“As previously observed in TRIAC trial I, the most frequently reported SAEs were in the MedDRA SOCs of infections and infestations (10 SAEs in 6 (27.3%)) patients, and nervous system disorders (4 SAEs in 3 (13.6%)) patients.” (opens the source at this quote in a new tab)

Heart rate and bone markers at the higher dose

“However, with the high Emcitate mean dose in TRIAC II (175 µg/kg), the TH-like effects of Emcitate came into play so that a relevant reduction in mean HR was not observed (baseline 115 bpm, Week 96, 113.2 bpm).” (opens the source at this quote in a new tab)
“Thus, in TRIAC II, Emcitate tended to cause bone loss whereas in TRIAC I, there was a tendency to increased bone mass.” (opens the source at this quote in a new tab)

Congress and sponsor reports of tolerability

“No patients discontinued due to severe adverse events.” (opens the source at this quote in a new tab)

“The trial confirmed the well-tolerated safety profile seen in previous clinical studies, despite higher dosing per kg body weight compared to previous studies.” (opens the source at this quote in a new tab)

Summary

Triac Trial II was a single-arm, open-label phase 2 trial that enrolled 22 participants aged 5 to 28 months (median 16 months), of whom 21 completed 96 weeks. Neurodevelopmental outcomes were compared with historical scores from untreated participants in Triac Trial I; the co-primary endpoints were not met (GMFM-88 mean difference -2.42; BSID-III gross motor mean difference 0.21). The absence of a concurrent control group limits the separation of treatment effect from expected development, and the post-hoc improvements in other domains were not pre-specified. Only two participants were younger than 6 months at baseline. The trial targeted serum T3 at or below the lower limit of normal with a mean dose of 175 mcg/kg, compared with 37 mcg/kg in Triac Trial I; the EMA assessment reported increases in systolic blood pressure and markers of bone loss at these doses, and the G-BA excluded the trial from the German benefit assessment because its titration targets differed from the product information. Serious adverse events occurred in 10 of 22 participants (45.5%). The results summarized here come from a regulatory assessment, a manufacturer topline report, a registry record, and a 2026 congress abstract.

Regulatory appraisal: uncontrolled design, timing, and dose

“It may be, that the window of opportunity had been closed in the majority of TRIAC-II patients; only two patients were below six months at baseline.” (opens the source at this quote in a new tab)
“The preliminary TRIAC II data did not show an effect of tiratricol on neurodevelopment, despite the inclusion of a younger patient population and the application of considerably higher tiratricol doses.” (opens the source at this quote in a new tab)

German benefit assessment: dosing outside the product information

“The data are unsuitable for the present benefit assessment since the specifications for the triiodothyronine (T3) target values for dose titration in this study deviate significantly from the requirements in the product information, thus higher maintenance doses being used.” (opens the source at this quote in a new tab)