Withdrawal of Tiratricol Treatment in Males With Monocarboxylate Transporter 8 Deficiency (MCT8 Deficiency) (ReTRIACt)

Withdrawal of Tiratricol Treatment in Males With Monocarboxylate Transporter 8 Deficiency (MCT8 Deficiency): A Double-blind, Randomized, Placebo-controlled Study

This is a double-blind, randomized phase 3 multicenter placebo-controlled study in at least 16 evaluable male participants diagnosed with MCT8 deficiency. Male participants, from 4 years of age (at randomization) and having demonstrated stable maintenance treatment with tiratricol, will be randomized to receive placebo or tiratricol for 30 days or until reaching the rescue criterion (serum total triiodothyronine [T3] > upper limit of normal [ULN] of the participant's normal range, for a sample collected during the 30-day Randomized Treatment Period). The research hypothesis to be tested is that, for participants in the placebo group, removal of tiratricol will lead to an increase of serum total T3 concentration, measured by liquid chromatography with tandem mass spectrometry (LC/MS/MS), above the ULN and requirement of rescue treatment with tiratricol, compared to those who continue to receive tiratricol.

Study Overview

• Status: Completed
• Conditions: Monocarboxylate Transporter 8 Deficiency; Allan-Herndon-Dudley Syndrome
• Intervention / Treatment: Drug: Tiratricol; Drug: Placebo

Detailed Description

The Screening Period includes a Screening Visit and a period of open-label treatment in which a stable maintenance dose of tiratricol, essential for progression into the Randomized Treatment Period, will be established. The duration of this period will vary depending on whether the participant is currently receiving treatment with tiratricol at the time of enrollment in the study (Cohort A), or if they are considered to be tiratricol treatment-naïve (Cohort B). Participants are considered to be tiratricol-naïve if they have never previously been administered tiratricol, or have previously received tiratricol but are not receiving tiratricol at the time of enrollment.

For participants in Cohort A, once eligibility is confirmed during the Screening Visit, the study starts with a Run-in Period to ensure that participants are being administered a stable dose of tiratricol, as determined by meeting the Stable Dose Criterion.

For participants in Cohort B, once eligibility is confirmed during the Screening Visit, the study starts with a Dose Titration Period to allow titration to a stable dose of tiratricol, as determined by meeting the Stable Dose Criterion.

The Stable Dose Criterion is defined as at least 4 weeks' treatment (during the period from the start of screening to randomization) at a fixed daily dose that is targeting a serum total T3, measured by LC/MS/MS, at the lower limit of normal (LLN) with at least 2 consecutive serum total T3 results that are within the study titration range: within 20% below the LLN to the 75th percentile of the normal range for serum total T3 (i.e., LLN + 0.75×[ULN-LLN]).

An evaluable participant is defined as a participant who completes the Randomized Treatment Period either by completing 30 days of double-blind treatment without meeting the rescue criterion or by meeting the rescue criterion.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 3

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Netherlands
  • Rotterdam, Netherlands, 3015 GD
    • Erasmus MC
• United Kingdom
  • Cambridge, United Kingdom
    • Addenbrooke's Hospital
• United States
  • Florida
    • Kissimmee, Florida, United States, 34746
      • Rare Disease Research, LLC
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Rare Disease Research, LLC
  • Missouri
    • St Louis, Missouri, United States, 63104
      • SSM Health Cardinal Glennon Children's Hospital
  • North Carolina
    • Hillsborough, North Carolina, United States, 27278
      • Rare Disease Research, LLC
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Texas
    • Webster, Texas, United States, 77598
      • Tranquil Clinical and Research Consulting Services

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male participants diagnosed with a pathogenic mutation in the MCT8 gene, confirmed with a genetic test.

2. Serum total T3 concentration above the ULN of the age specific normal range:

   1. at the time of diagnosis (or the closest sample taken prior to first ever treatment with tiratricol) for participants who are currently treated with tiratricol (if serum total T3 concentration is not available, free T3 results from standard of care samples may be used)
   2. in the Screening Visit sample:

   i. For participants who have never received and/or are currently not receiving tiratricol.

   ii. For participants who stopped prohibited medications per exclusion criterion #6.

3. Participants will be aged 4 years or older at the time of randomization. Participants entering screening who are <4 years of age but expected to be aged 4 years at randomization should be discussed with the medical monitor.
4. Signed and dated informed consent form from the parents or legal guardian.

Exclusion Criteria:

1. Major illness or recent major surgery unrelated to MCT8 deficiency (in the principal investigator's judgement), defined as:

   • Conditions requiring repeated hospitalizations that are likely to confound ability to participate in the trial.
   • Major illness in the 3 months prior to the Screening Visit that is likely to confound the ability of the participant to participate fully within the trial and/or confound the assessment of serum total T3 and/or safety.
   • Major surgery within the 3 months prior to the Screening Visit or planned to take place during the study, including but not limited to major abdominal/thoracic/neurosurgical procedures.
   • Major/minor abdominal and/or maxillofacial surgery that may inhibit the administration and/or absorption of study drug.
2. Body weight <10 kg at the Screening Visit.
3. Patients who are participating, or intend to participate, in other therapeutic and/or interventional clinical studies during the study period.
4. History of allergic reactions to components of tiratricol or any excipients in the investigational product (IP).
5. Participants with any contra-indication for treatment with tiratricol or any excipients in the IP.
6. Participants who have used other T3 analogues, levothyroxine, propylthiouracil, or other antithyroid medications within 6 weeks of screening.

Randomization Criteria:

In addition to the eligibility criteria, participants must meet further criteria at the time of randomization to enter the Randomized Treatment Period.

1. Confirmation that the "Stable Dose Criterion" has been met.
2. Absence of any new or exacerbated medical or surgical condition that fulfils Exclusion criterion #1.
3. Confirmation that participant is at least 4 years of age at the time of randomization.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo tablets will be identical in appearance to tiratricol tablets but contain no tiratricol. Treatment will be administered orally or via PEG tube; tablets will be suspended in water and, if needed, mixed with mashed food for oral administration or administered in water through the PEG tube as applicable. During the Randomized Treatment Period, participants will receive the same number of tablets as the stable dose of open-label tiratricol they were receiving before randomization.
Experimental: Tiratricol	Drug: Tiratricol; Tiratricol tablets are flat tablets that contain 350 µg tiratricol. Treatment will be administered orally or via percutaneous endoscopic gastrostomy (PEG) tube; tablets will be suspended in water and, if needed, mixed with mashed food for oral administration or administered in water through the PEG tube as applicable.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Rate of change from baseline in serum total T3 (ln-transformed) during the 30-day double-blind Randomized Treatment Period	Baseline to Day 30
Proportion of participants who meet the rescue criterion (serum total T3 > ULN) during the 30-day double-blind Randomized Treatment Period	Baseline to Day 30

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in serum thyroid hormone variables (T3, T4, TSH, fT3, and fT4)		From i) Baseline to Day 30, ii) Screening to End of Study (up to 26 weeks), iii) first tiratricol administration in Run-in/Dose Titration Period to last measurement prior to randomization (up to 16 weeks)
Change in clinical endpoints: Heart rate		From i) Baseline to Day 30, ii) Screening to End of Study (up to 26 weeks), iii) first tiratricol administration in Run-in/Dose Titration Period to last measurement prior to randomization (up to 16 weeks)
Change in clinical endpoints: Systolic blood pressure		From i) Baseline to Day 30, ii) Screening to End of Study (up to 26 weeks), iii) first tiratricol administration in Run-in/Dose Titration Period to last measurement prior to randomization (up to 16 weeks)
Change in clinical endpoints: Rate pressure product (heart rate × systolic blood pressure)		From i) Baseline to Day 30, ii) Screening to End of Study (up to 26 weeks), iii) first tiratricol administration in Run-in/Dose Titration Period to last measurement prior to randomization (up to 16 weeks)
Change in clinical endpoints: Heart rate Z scores		From i) Baseline to Day 30, ii) Screening to End of Study (up to 26 weeks), iii) first tiratricol administration in Run-in/Dose Titration Period to last measurement prior to randomization (up to 16 weeks)
Change in clinical endpoints: Body weight		From i) Screening to End of Study (up to 26 weeks), ii) first tiratricol administration in Run-in/Dose Titration Period to last measurement prior to randomization (up to 16 weeks).
Safety endpoints: Number of participants with treatment-emergent adverse events (TEAEs)		From first tiratricol administration in Run-in/Dose Titration Period to End of Study (up to 26 weeks).
Safety endpoints: Number of participants with TEAEs related to clinical laboratory tests	Safety laboratory variables (full blood count, serum renal and liver biomarkers, total and low-density lipoprotein [LDL] cholesterol, and electrolytes).	From first tiratricol administration in Run-in/Dose Titration Period to End of Study (up to 26 weeks).
Safety endpoints: Number of participants with TEAEs related to vital signs variables	Standard vital signs variables (heart rate, temperature, respiration rate, blood pressure, and body weight).	From first tiratricol administration in Run-in/Dose Titration Period to End of Study (up to 26 weeks).
Safety endpoints: 12-lead Electrocardiograms (ECGs): Number of clinically significant abnormal results (investigator interpretations)		At Screening, Day 1, and End of Study (up to 26 weeks).
Safety endpoints: Physical examinations: Number of clinically significant abnormal results	Body systems include cardiovascular system, general appearance, gastrointestinal system, head/eyes/ears/nose/throat, musculoskeletal system, and nervous system.	From i) first tiratricol administration in Run-in/Dose Titration Period to last measurement prior to randomization (up to 16 weeks), ii) Baseline to Follow-up (up to 10 weeks)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in serum thyroid hormone variables from baseline (start of the Randomized Treatment Period) to the end of the Follow-up Period	Variables of interest are T3, T4, TSH, fT3, and fT4	Baseline to the end of the Follow-up Period (approximately 10 weeks)
Change in serum thyroid hormone variables from the end of the Randomized Treatment Period to the end of the Follow-up Period	Variables of interest are T3, T4, TSH, fT3, and fT4	End of the Randomized Treatment Period (or when rescue criterion was met) to the end of the Follow-up Period (approximately 6 weeks)
Number of tiratricol metabolites in serum	Metabolite identifiers will be listed	Run-in/Dose Titration Period to end of study (up to approximately 26 weeks)
Structure of tiratricol metabolites in serum	Structural characteristics of tiratricol metabolites will be listed	Run-in/Dose Titration Period to end of study (up to approximately 26 weeks)
Tiratricol metabolite concentrations in serum		Run-in/Dose Titration Period to end of study (up to approximately 26 weeks)
Ratios of tiratricol metabolite to tiratricol concentrations in serum		Run-in/Dose Titration Period to end of study (up to approximately 26 weeks)
Values of serum concentrations of tiratricol (pharmacokinetics)	Trough and peak serum concentrations will be determined using samples taken prior to and between 15 and 80 minutes after first daily dose of tiratricol	Once during Run-in/Dose Titration Period (up to approximately 6 or 16 weeks) and at the Week 2 visit during the Follow-up Period
Correlation between serum concentrations of tiratricol and serum total T3 concentrations	The relationship between serum total T3 concentrations and serum concentrations of tiratricol will be examined	Run-in/Dose Titration Period to end of study (up to approximately 26 weeks)
Correlation between adverse drug reactions (ADRs) and serum concentrations of tiratricol	The relationship between ADRs, AEs reported as related to study drug, and serum concentrations of tiratricol will be examined	Run-in/Dose Titration Period to end of study (up to approximately 26 weeks)

Collaborators and Investigators

• Sponsor: Rare Thyroid Therapeutics International AB
• Collaborators: Egetis Therapeutics; Premier Research
• Investigators: Principal Investigator: Andrew J. Bauer, MD, Children's Hospital of Philadelphia; Principal Investigator: W. E. Visser, MD, Erasmus Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): July 21, 2023
• Primary Completion (Actual): July 22, 2025
• Study Completion (Actual): September 3, 2025

Study Registration Dates

• First Submitted: September 29, 2022
• First Submitted That Met QC Criteria: October 11, 2022
• First Posted (Actual): October 13, 2022

Study Record Updates

• Last Update Posted (Actual): April 8, 2026
• Last Update Submitted That Met QC Criteria: April 2, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: MCT8; MCT8 deficiency; Allan-Herndon-Dudley syndrome; Tiratricol; Triac
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Genetic Diseases, Inborn; Neurobehavioral Manifestations; Heredodegenerative Disorders, Nervous System; Intellectual Disability; Genetic Diseases, X-Linked; Atrophy; Allan-Herndon-Dudley syndrome; 3,3',5-triiodothyroacetic acid
• Other Study ID Numbers: MCT8-2021-3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No