Objective: effect of withdrawal on serum total T3

“Objective: To assess the effects of withdrawal of tiratricol vs continued treatment on serum total T3 concentrations.” (opens the source at this quote in a new tab)

Planned purpose of the study at enrollment

“After a dialogue with the FDA, Egetis is conducting a randomized, placebo-controlled pivotal study in 16 evaluable patients to verify the results on T3 levels seen in previous clinical trials and publications.” (opens the source at this quote in a new tab)

International multicenter study

“The efficacy of EMCITATE in patients with MCT8 deficiency was evaluated in an international, multicenter study (Study 1; NCT05579327) that consisted of three study periods as follows:” (opens the prescribing information at this quote)

Study closure after the pre-NDA meeting

“As recommended by the FDA, the Statistical Analysis Plan (SAP) for the ReTRIACt trial will be revised and the study will be closed.” (opens the source at this quote in a new tab)
“Topline results will be communicated during the fourth quarter of 2025.” (opens the source at this quote in a new tab)
“Data accrued to date will be included in the NDA.” (opens the source at this quote in a new tab)

Randomized withdrawal design

“The ReTRIACt study (clinicaltrials.gov identifier NCT05579327) is a double-blind, multicenter, placebo-controlled, randomized, withdrawal study in patients with MCT8 deficiency.” (opens the source at this quote in a new tab)

Phase and randomization ratio

“Methods: ReTRIACt (NCT05579327) was a phase 3, multicenter, double-blind, randomized, placebo-controlled study.” (opens the source at this quote in a new tab)
“Male subjects ≥4 years of age on stable maintenance treatment with tiratricol were randomized 1:1 to receive placebo or tiratricol for 30 days (randomized treatment period, RTP) or until reaching the rescue criterion (serum total T3 above upper limit of normal, measured by LCMS/MS).” (opens the source at this quote in a new tab)

Prescribing information: three study periods

“Study 1 (NCT05579327) was a 3-period, multicenter study with an up to 16-week, open-label, titration period followed by a 30-day randomized double-blind, placebo-controlled withdrawal period, then a 6-week open-label treatment period.” (opens the prescribing information at this quote)

Study period	Description
Screening period	“6-week run-in period for participants already treated with EMCITATE (Cohort A) and a 16-week dose-titration period for participants newly started on EMCITATE (Cohort B).”
Randomized treatment period	“30-day double-blind, placebo-controlled, randomized withdrawal period, which provided data for the primary efficacy endpoints.”
Follow-up period	“6-week open-label treatment period.”

Age, sex, and stable maintenance treatment

“Males 4 years of age and above who demonstrated stable maintenance treatment with tiratricol, were randomized to continue tiratricol or receive placebo for 30 days or until reaching the rescue criterion (serum total triiodothyronine [T3] > upper limit of normal [ULN]).” (opens the source at this quote in a new tab)

Prescribing information: stable dose criterion for randomization

“The stable dose criterion was defined as at least 4 weeks of treatment with a fixed daily dose of EMCITATE and at least 2 consecutive serum total T3 results within the target range (between 80% of the lower limit of normal and no higher than the 75th percentile of the normal range).” (opens the prescribing information at this quote)

Prescribing information: screening-period titration

“Twenty participants with MCT8 deficiency were enrolled during the Screening Period: 10 participants in Cohort A, who were already receiving EMCITATE treatment, and 10 participants in Cohort B, who were started on EMCITATE 350 mcg daily.” (opens the prescribing information at this quote)
“The EMCITATE dose was titrated by 350 mcg daily every 2 weeks based on serum total T3 to achieve the stable dose criterion.” (opens the prescribing information at this quote)
“The mean duration of treatment with EMCITATE during this period was 86 days in Cohort A and 77 days in Cohort B.” (opens the prescribing information at this quote)

Prescribing information: randomized treatment and follow-up periods

“Serum total T3 was measured weekly during this period.” (opens the prescribing information at this quote)
“If the rescue criterion was met, the subject stopped the blinded study treatment and re-initiated EMCITATE at the pre-randomization dose.” (opens the prescribing information at this quote)
“After completion of the RTP, 14 participants entered a 6-week follow-up period and received EMCITATE at the stable maintenance dose received prior to randomization.” (opens the prescribing information at this quote)

Primary endpoints

“Primary endpoints were the rate of change in serum total T3 and the proportion of subjects requiring rescue during the RTP.” (opens the source at this quote in a new tab)

Addition of the T3 rate-of-change endpoint after FDA comments

“Furthermore, based on comments from the FDA, the Statistical Analysis Plan (SAP) of the ReTRIACt study was revised, and the study was closed.” (opens the source at this quote in a new tab)
“A Primary Endpoint 1 (PE1), evaluating rate of change in serum total T3 during the double-blind Randomized Treatment Period, was added to the previously described Primary Endpoint 2 (PE2), based on the T3 rescue criterion.” (opens the source at this quote in a new tab)

Sponsor rationale: serum T3 as the biochemical driver of disease

“ReTRIACt study provides randomized controlled evidence of tiratricol’s pharmacodynamic effect on T3, the key biochemical driver of disease morbidity and mortality.” (opens the source at this quote in a new tab)

Prescribing information: primary efficacy endpoints and rescue criterion

“The two primary efficacy endpoints were: 1) Rate of change from baseline in serum total T3 during the 30-day Randomized Treatment Period; 2) Proportion of participants who met the rescue criterion during the 30-day Randomized Treatment Period.” (opens the prescribing information at this quote)

Planned number of evaluable participants

“After a dialogue with the FDA, Egetis is conducting a randomized, placebo-controlled pivotal study in 16 evaluable patients to verify the results on T3 levels seen in previous clinical trials and publications.” (opens the source at this quote in a new tab)

Prescribing information: randomized population

“Fifteen participants (8 participants from Cohort A and 7 participants from Cohort B) achieved the stable dose criterion and were randomized (1:1) to receive placebo or continue EMCITATE treatment for 30 days or until the rescue criterion, defined as the serum total T3 above the upper limit of normal (ULN), was met.” (opens the prescribing information at this quote)

Multiplicity control and handling of a discontinuation

“Type I Error is controlled via alpha recycling, testing PE1 first, and if PE1 is met, PE2 will then be tested.” (opens the source at this quote in a new tab)
“One patient randomized to tiratricol discontinued (not drug related) during the randomized treatment period, which per the SAP was imputed as rescue in PE2, leading to a 4 (placebo) versus 1 (tiratricol) comparison for PE2 (p=0.182).” (opens the source at this quote in a new tab)

Prescribing information: analysis set and model

Analysis element	Quoted record
Analysis set for both primary endpoints	“Full Analysis Set”
Model for primary endpoint 1	“Estimates from random effects model”

Prescribing information: enrollment, randomization, and follow-up

“Twenty participants with MCT8 deficiency were enrolled during the Screening Period: 10 participants in Cohort A, who were already receiving EMCITATE treatment, and 10 participants in Cohort B, who were started on EMCITATE 350 mcg daily.” (opens the prescribing information at this quote)
“After completion of the RTP, 14 participants entered a 6-week follow-up period and received EMCITATE at the stable maintenance dose received prior to randomization.” (opens the prescribing information at this quote)

Discontinuation during the randomized treatment period

“One subject randomized to tiratricol discontinued during the RTP due to non-medical family reasons.” (opens the source at this quote in a new tab)

Prescribing information: age, sex, and race of enrolled participants

“The median age of the 20 participants enrolled in the study was 11 years, ranging from 5 to 31 years. All subjects were male. There were 65% White, 15% Black or African Americans, 5% Asian, 5% American Indian or Alaska Native and 10% other races.” (opens the prescribing information at this quote)

Prescribing information: baseline serum total T3 by arm

“The mean (SD) change from baseline to the end of the Randomized Treatment Period in total T3 levels was 64.6 (12.7) ng/dL from a baseline of 109.1 ng/dL in the placebo arm and -0.2 (12.5) ng/dL from a baseline of 100.5 ng/dL in the tiratricol arm.” (opens the prescribing information at this quote)

Prescribing information: primary endpoint 1, total T3 rate of change

Measure	Placebo	Tiratricol
N	“8”	“7”
T3 rate of change [95% CI]	“1.6 [1.2; 2.1]”	“1.1 [0.8; 1.3]”

Comparison	Value
Ratio of T3 rate of change, placebo/tiratricol [95% CI]	“1.5 [1.0; 2.2] (p-value=0.034)”

“The mean (SD) change from baseline to the end of the Randomized Treatment Period in total T3 levels was 64.6 (12.7) ng/dL from a baseline of 109.1 ng/dL in the placebo arm and -0.2 (12.5) ng/dL from a baseline of 100.5 ng/dL in the tiratricol arm.” (opens the prescribing information at this quote)
“The treatment difference (95% CI) in total T3 change from baseline at the end of randomized treatment period was 64.8 ng/dL (44.7, 84.8) for placebo versus tiratricol arm.” (opens the prescribing information at this quote)
“After withdrawal of EMCITATE, all 8 participants randomized to placebo had an increase in serum total T3 during the randomized treatment period (range: 31.9 to 135.4 ng/dL) that was larger than what was seen in the 7 patients randomized to continue EMCITATE (range: -15.6 to 26.0 ng/dL).” (opens the prescribing information at this quote)

Prescribing information: primary endpoint 2, rescue criterion

Outcome	Tiratricol, N=7	Placebo, N=8
Rescue criterion not met, n (%)	“6 (85.7)”	“4 (50.0)”
Rescue criterion met, n (%)	“1* (14.3)”	“4 (50.0)”

Comparison	Value
Difference in proportions, placebo minus tiratricol	“0.36”
95% CI	“-0.16, 0.77”

“One participant who discontinued prematurely during the Randomized Treatment Period was considered to have met the rescue criterion.” (opens the prescribing information at this quote)

Prescribing information: secondary heart rate and blood pressure endpoints

“Secondary efficacy endpoints assessing mean changes in heart rate and systolic blood pressure from screening until pre-randomization and from screening until end of study showed a trend towards numerical improvements in participants in Cohort B (treatment-naïve), while heart rate and blood pressure remained stable in participants in Cohort A (previously-treated).” (opens the prescribing information at this quote)

Primary endpoints in SI units, observed-case rescue analysis, and reinitiation

“The Primary Endpoint 1 (PE1), rate of change in serum T3 during the Randomized Treatment Period, showed a statistically significant difference between placebo and tiratricol (ratio of T3 rate of change (placebo/tiratricol): 1.494 [95% CI: 1.035; 2.155]; p=0.034).” (opens the source at this quote in a new tab)
“The results show a complete separation of the two groups with all 8 patients randomized to placebo having an increase in serum T3 during the randomized treatment period (range: 0.49 – 2.08 nmol/L), larger than all 7 patients randomized to continue tiratricol (range: -0.24 – 0.40 nmol/L).” (opens the source at this quote in a new tab)
“In the placebo group, 4 patients met the rescue criterion during the randomized treatment period compared to 0 patients randomized to tiratricol (p=0.070 on observed cases of rescue).” (opens the source at this quote in a new tab)
“One patient randomized to tiratricol discontinued (not drug related) during the randomized treatment period, which per the SAP was imputed as rescue in PE2, leading to a 4 (placebo) versus 1 (tiratricol) comparison for PE2 (p=0.182).” (opens the source at this quote in a new tab)
“All patients randomized to placebo showed an expected decrease in serum T3 levels following reinitiation of tiratricol in the follow-up period.” (opens the source at this quote in a new tab)

Congress report: estimated relative change in serum T3 over 30 days

Arm	Estimated increase in serum T3 over the 30-day randomized treatment period
Placebo	“59%”
Tiratricol	“6%”

“All subjects randomized to placebo had an expected decrease in serum T3 upon reinitiation of tiratricol in the follow-up period.” (opens the source at this quote in a new tab)
“Conclusions: In this placebo-controlled trial of tiratricol in subjects with MCT8 deficiency, we showed that withdrawal of tiratricol results in a significant increase in serum T3.” (opens the source at this quote in a new tab)

Prescribing information: Study 1 adverse reactions

Adverse reaction	Study 1, EMCITATE, N = 20, n (%)
Diarrhea	“0”
Vomiting	“2 (10)”
Rash	“2 (10)”
Hyperhidrosis	“1 (5)”

Serious adverse events and death

“Tiratricol was well-tolerated: six serious adverse events were reported in four subjects; none were considered treatment-related.” (opens the source at this quote in a new tab)
“There was one death due to aspiration pneumonia and resultant respiratory failure.” (opens the source at this quote in a new tab)

Summary

ReTRIACt enrolled 20 participants and randomized 15 of them (eight to placebo withdrawal, seven to continued tiratricol); in 2024 the manufacturer described the planned study as including 16 evaluable participants. The study was closed at the FDA's recommendation, and the analysis plan was revised to add the T3 rate-of-change endpoint (primary endpoint 1) before that endpoint was reported. Primary endpoint 1 met its significance criterion (ratio 1.5, 95% CI 1.0 to 2.2; p=0.034). For the rescue endpoint (primary endpoint 2), the difference in proportions was 0.36 with a 95% CI of -0.16 to 0.77 (p=0.182); one discontinuation in the tiratricol group for non-medical family reasons was counted as rescue, and the observed-case comparison was 4 versus 0 (p=0.070). The randomized period lasted at most 30 days and evaluated withdrawal after stable maintenance treatment; it did not evaluate treatment initiation or long-term clinical outcomes. The prescribing information reports adverse reactions for all 20 enrolled participants and does not report them by randomized arm. The congress report lists six serious adverse events in four participants and one death from aspiration pneumonia, none considered treatment-related. Enrolled participants were aged 5 to 31 years, so the study did not include infants.