Early TRIAC intervention case report

20 evidence topics · 1 source

Objective

Stated aim of the case report

“This case report describes a case of MCT8 deficiency treated with Triac, providing additional clinical evidence about the effect of Triac on peripheral as well as neurocognitive features, while neurodevelopment and myelination continued.” (opens the source at this quote in a new tab)

Location and study date

Institution

Characteristic	Value
Institution	“Şanlıurfa Training and Research Hospital, Clinic of Pediatric Endocrinology, Şanlıurfa, Turkey”

Study design

Single-patient case report with scheduled assessments

“The patient was assessed for clinical and biochemical signs of peripheral hyperthyroidism and neurodevelopmental changes, at baseline, 6 months and 12 months after start of treatment with Triac.” (opens the source at this quote in a new tab)

Eligibility criteria

Referral and genetic diagnosis

“A five-month-old boy was referred to the neurology clinic for feeding difficulty, hypotonia and developmental delay.” (opens the source at this quote in a new tab)
“Clinical exome sequencing conducted at 12 months for the etiologic investigation of the hypotonic infant revealed a de novo novel, hemizygous pathogenic variant (c.430+1G>C chrX: 73641903) in SLC16A2 and MCT8 deficiency was diagnosed” (opens the source at this quote in a new tab)

Treatment

Treatment initiation and dose titration

“As soon as the diagnosis of MCT8 deficiency was confirmed and required local approvals were completed, Triac (Emcitate tablets, 350 mcg, Egetis Therapeutics, Klara Norra Kyrogata 26, Stockholm, Sweden) was started at 21 months via the compassionate use programme.” (opens the source at this quote in a new tab)
“After an initial dose of 175 mcg/day of Triac, fT3 dramatically decreased to 4.7 nmol/L (N=3.1-6.8) within two weeks.” (opens the source at this quote in a new tab)
“An individualized dose escalation of 175 mcg steps with a goal of attaining normal serum fT3 concentration was conducted using frequent clinic visits.” (opens the source at this quote in a new tab)
“After one year of treatment, fT3 concentration was reduced to 7.5 pmol/L (N=3.1-6.8), serum fT4 was 3.09 pmol/L (N=12-22) and daily dose of Triac was increased eventually to 1500 mcg/ day (133 mcg/kg/day) three times a day, po.” (opens the source at this quote in a new tab)

Concomitant treatment

“As dystonia remained prominent at six months of treatment, oral baclofen was started to ease pain and increase quality of life.” (opens the source at this quote in a new tab)

Study outcomes

Rationale for using BSID-III composite scores as a neurodevelopmental outcome

Gap in neurodevelopmental evidence

“However evaluation of neurocognitive outcome in Triac treated pediatric patients with MCT8 deficiency, especially before completion of brain development and myelination, are lacking” (opens the source at this quote in a new tab)
“Earlier clinical trials on the efficacy of Triac were not designed to detect neurodevelopmental outcomes and study populations’ age was very variable” (opens the source at this quote in a new tab)

Neurodevelopmental assessment method

“Comprehensive developmental assessment was performed by a developmental-behavioral pediatrician.” (opens the source at this quote in a new tab)
“Detailed developmental history and a standardized assessment tool, Bayley Scales of Infant Development 3rd Edition (BSID-III) were used” (opens the source at this quote in a new tab)

Thyroid hormone assay

“TH were measured using an immunoassay (Roche Modular E170 Immunology Analyzer, Hague Rd, Indianopolis, USA).” (opens the source at this quote in a new tab)

Statistical analysis description

Number of participants (Planned and analyzed)

Individual participant

“The importance of this case is that it reports an in-depth clinical experience with an infant with MCT8 deficiency who was administered Triac.” (opens the source at this quote in a new tab)

Description of analysis sets

Not applicable.

Results

Participant disposition

Follow-up and adherence

“Assessment of neurodevelopmental milestones and signs of hyperthyroidism were evaluated at baseline, 6 months and 12 months after treatment.” (opens the source at this quote in a new tab)
“After identifying adherence issues where there have been times where the patient did not receive treatment for 3-4 consecutive days, the patient was hospitalized for a short time-period and Triac dose adjustment was made.” (opens the source at this quote in a new tab)
“Problems with adherence to treatment were mainly linked to socioeconomic factors, as well as the populous family structure.” (opens the source at this quote in a new tab)

Baseline characteristics

Clinical and biochemical findings at referral to endocrinology (19 months)

“On physical examination, he was underweight (8.1 kg, -2.9 SDS) but his length was 80 cm (-1.3 SDS).” (opens the source at this quote in a new tab)
“Endocrine evaluation revealed normal TSH (2.83 mIU/mL), low fT4 (6.24 pmol/L N=12-22) and increased fT3 (15.65 pmol/L N=3.1-6.8) (Table 1) with an elevated T3/T4 ratio over 0.75.” (opens the source at this quote in a new tab)

Neurodevelopmental status before treatment

“At baseline, prior to Triac (21-months-old) developmental history revealed that developmental milestones were not achieved and BSID-III composite scores for cognitive [55; 95% confidence interval (CI): 51-67], language (47; 95% CI: 43-58) and motor (46; 95% CI: 43-58) evaluation were below two SDS for age.” (opens the source at this quote in a new tab)

Efficacy results

Neurodevelopmental outcomes at 6 and 12 months

“At six months of Triac treatment, BSID-III composite scores remained below two SDS for age but he started to habituate to objects, recognize and smile at his mother, respond to a person’s voice by turning his head, raise his face while in prone position and hold his head steady for a few seconds while in sitting position.” (opens the source at this quote in a new tab)
“At 12 months, BSID-III composite scores remained unchanged (below two SDS for age), but he started to respond to his name by turning his head, follow a person across the room with eyes and head, and hold his head steady for at least 15 seconds and dystonia was improved.” (opens the source at this quote in a new tab)
“Regression was not observed in any developmental domain.” (opens the source at this quote in a new tab)

Peripheral thyrotoxicosis outcomes

“By seven months of treatment, the goal of attaining normal serum fT3 was achieved continuously.” (opens the source at this quote in a new tab)
“Without change in caloric consumption per kilograms, body weight for length SDS have improved significantly at six months of treatment which was sustained until 12 months afte start of Triac.” (opens the source at this quote in a new tab)
“Systolic and diastolic blood pressure was decreased and stabilized by 12 months of Triac treatment (Table 1).” (opens the source at this quote in a new tab)
“Mild elevation in ALT, AST and CK improved within six months” (opens the source at this quote in a new tab)

Clinical and biochemical measures at baseline and after 12 months of treatment

Measure	Baseline (21 months of age)	12 months after treatment start
Weight SDS	“-2.9”	“-1.8”
Resting heart rate, bpm (percentile)	“150 (90th-99th)”	“95 (25th)”
TSH, mIU/mL	“0.8”	“0.7”
Free T3, pmol/L	“11.7”	“7.5”

Free T3 immunoassay interference during treatment

“Despite precise treatment, extremely high fT3 (45.1 and 39 pmol/L at the sixth and ninth months of treatment, respectively) were observerd.” (opens the source at this quote in a new tab)
“This unexpected, drastic increase was presumed to be explained by molecular interference of Triac and fT3 in the biochemical analysis, and Triac dose was not changed.” (opens the source at this quote in a new tab)

Health-related quality of life and patient-reported outcomes

No evidence found.

Safety results

Drug-related adverse effects

“No drug related toxicity, need for dose reduction or adverse effect was encountered.” (opens the source at this quote in a new tab)
“He developed upper respiratory tract infection three times during this period which was not attributed to Triac, since they resolved while drug was continued.” (opens the source at this quote in a new tab)

Study limitations

Summary

This is one participant followed without a comparator. BSID-III composite scores remained below two SDS for age at 6 and 12 months despite attainment of individual developmental milestones. The report also describes adherence interruptions of 3 to 4 consecutive days, suspected free T3 immunoassay interference, and oral baclofen introduced at 6 months. These factors limit attribution of changes to tiratricol. The maintenance dose (1,500 mcg/day, 133 mcg/kg/day) was higher than doses previously described, and a single participant provides no estimate of adverse-event frequency.

Limitations stated by the authors

“Although an improvement in developmental composite scores during follow-up assessments were not observed, an improvement in critical developmental milestones were present.” (opens the source at this quote in a new tab)
“It may have taken longer in the current patient due to poor adherence, especially in the first months of treatment.” (opens the source at this quote in a new tab)
“The Triac dose (136 mcg/ kg/day) required to normalize fT3 was much higher in the present case than previously described (23-48 mcg/kg/day)” (opens the source at this quote in a new tab)