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

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.

• Tiratricol (Drug): 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.
• Placebo (Drug): 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.

Primary outcomes

• 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 outcomes

• 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 [From first tiratricol administration in Run-in/Dose Titration Period to End of Study (up to 26 weeks).]: Safety laboratory variables (full blood count, serum renal and liver biomarkers, total and low-density lipoprotein \[LDL\] cholesterol, and electrolytes).
• Safety endpoints: Number of participants with TEAEs related to vital signs variables [From first tiratricol administration in Run-in/Dose Titration Period to End of Study (up to 26 weeks).]: Standard vital signs variables (heart rate, temperature, respiration rate, blood pressure, and body weight).
• 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 [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)]: Body systems include cardiovascular system, general appearance, gastrointestinal system, head/eyes/ears/nose/throat, musculoskeletal system, and nervous system.

Sex: Male, ages: 4 Years to any

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.

• Andrew J. Bauer, MD, Principal investigator, Children's Hospital of Philadelphia
• W. E. Visser, MD, Principal investigator, Erasmus Medical Center