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

Study Overview
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Brief Summary
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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 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.

Detailed Description
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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.

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

Conditions
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Monocarboxylate Transporter 8 Deficiency, Allan-Herndon-Dudley Syndrome

Intervention / Treatment
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* Drug: Tiratricol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male participants diagnosed with a pathogenic mutation in the MCT8 gene, confirmed with a genetic test. Serum total T3 concentration above the ULN of the age specific normal range: 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 in the Screening Visit sample, or most recent standard of care sample prior to screening, for participants who have never received and/or currently not receiving tiratricol. 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. Signed and dated informed consent form from the parents or legal guardian. Exclusion Criteria: 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. Body weight <10 kg at the Screening Visit. Patients who are participating, or intend to participate, in other therapeutic and/or interventional clinical studies during the study period. History of allergic reactions to components of tiratricol or any excipients in the investigational product (IP). Participants with any contra-indication for treatment with tiratricol or any excipients in the IP. Participants using other T3 analogues, levothyroxine, or propylthiouracil. Randomization Criteria: In addition to the eligibility criteria, participants must meet further criteria at the time of randomization to enter the Randomized Treatment Period. Confirmation that the Stable Dose Criterion has been met. Absence of any new or exacerbated medical or surgical condition that fulfils Exclusion criterion #1. Confirmation that participant is at least 4 years of age at the time of randomization.

Ages Eligible for Study
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Minimum Age: 4 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients having demonstrated stable maintenance treatment with tiratricol will be randomized to receive placebo or tiratricol for 30 days or until reaching rescue criterion (serum total T3 > ULN of the participant's normal range, for a sample collected during the 30-day Randomized Treatment Period). In other words, the patients will be randomized to complete withdrawal of tiratricol treatment (placebo) for 30 days or to continue with the stable tiratricol maintenance treatment for 30 days. If during the 30 days, a rescue criterion (serum total T3 > ULN of the participant's normal range) is reached, the randomized treatment will be stopped, and the patient will go back on unblinded tiratricol treatment. Serum total T3 concentrations measured during the Randomized Treatment Period that are below the LLN of the normal range will not lead to any modifications to the blinded study drug administration schedule of daily tiratricol dosing.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tiratricol<br> | Drug: Tiratricol<br>* 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.<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants who meet the rescue criterion (serum total T3 > ULN) from samples obtained 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 from baseline (start of the Randomized Treatment Period) to the end of Randomized Treatment Period (completion or rescue) | Variables of interest are triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), and free thyroxine (fT4) | Baseline to Day 30 or until rescue criterion is met | 
| Change in serum thyroid hormone variables (T3, T4, TSH, fT3, and fT4) from initiation of tiratricol administration at Screening to the last measurement prior to randomization (Cohort B only) |  | Screening Visit to the end of the Dose Titration Period (approximately 16 weeks) | 
| Change in the cardiovascular variables from extended ECG assessments from the last measurement prior to the start of the Randomized Treatment Period to the end of the Randomized Treatment Period (completion or rescue) | Extended ECG assessments include PR interval, RR interval, QRS interval, QT interval, and corrected QT interval (both correction methods QTcB and QTcF), measured in milliseconds | 1-2 days prior to baseline to Day 30 or until rescue criterion is met | 
| Change in the cardiovascular variables from 24-hour ambulatory blood pressure monitoring (ABPM) assessments | Assessments taken from the last measurement prior to the start of the Randomized Treatment Period to the end of the Randomized Treatment Period (completion or rescue) | 1-2 days prior to baseline to Day 30 or until rescue criterion is met | 
| Change in the cardiovascular variables from extended heart rate assessments from the last measurement prior to the start of the Randomized Treatment Period to the end of the Randomized Treatment Period (completion or rescue) |  | 1-2 days prior to baseline to Day 30 or until rescue criterion is met | 
| Number of participants with normal/abnormal and not clinically significant/clinically significant cardiovascular variables from extended assessments | Variables of interest include ECG, blood pressure, and heart rate assessments, from the last measurement prior to the start of the Randomized Treatment Period to the end of the Randomized Treatment Period (completion or rescue) | 1-2 days prior to baseline to Day 30 or until rescue criterion is met | 
| Serum concentrations of tiratricol |  | Screening Period, Days 1, 8, 15, 22, and 30, Follow-up Period (up to approximately 26 weeks) | 
| Change in serum sex hormone binding globulin from baseline (start of the Randomized Treatment Period) to the end of the Randomized Treatment Period (completion or rescue) |  | Baseline to Day 30 or until rescue criterion is met | 
| Time (days) from randomization to the time when the rescue criterion is met or the time of completion of Randomized Treatment Period (whichever comes first) |  | Baseline to Day 30 or until rescue criterion is met | 
| Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) | Number of participants with AEs and SAEs graded between Grade 1 (mild) and Grade 5 (death) | Run-in/Dose Titration Period to end of study (up to approximately 26 weeks) | 
| Values and change from baseline in safety laboratory variables (full blood count) | Blood samples will be taken at the Screening Visit, every 4 weeks during the Run-in/Dose Titration Period, Baseline and Randomization Visit on Day 1, Day 8, Day 15, Day 22, then either on Day 30 (for participants who complete the study) or at Week 1 of the 6-week Follow-up Period (for participants who met the rescue criterion during the Randomized Treatment Period), and additionally at the End of Study Visit for all participants | Screening to end of study (up to approximately 26 weeks) | 
| Values and change from baseline in safety laboratory variables (serum renal and liver biomarkers) | Blood samples will be taken at the Screening Visit, every 4 weeks during the Run-in/Dose Titration Period, Baseline and Randomization Visit on Day 1, Day 8, Day 15, Day 22, then either on Day 30 (for participants who complete the study) or at Week 1 of the 6-week Follow-up Period (for participants who met the rescue criterion during the Randomized Treatment Period), and additionally at the End of Study Visit for all participants | Screening to end of study (up to approximately 26 weeks) | 
| Values and change from baseline in safety laboratory variables (total and low-density lipoprotein cholesterol) | Blood samples will be taken at the Screening Visit, every 4 weeks during the Run-in/Dose Titration Period, Baseline and Randomization Visit on Day 1, Day 8, Day 15, Day 22, then either on Day 30 (for participants who complete the study) or at Week 1 of the 6-week Follow-up Period (for participants who met the rescue criterion during the Randomized Treatment Period), and additionally at the End of Study Visit for all participants | Screening to end of study (up to approximately 26 weeks) | 
| Number of participants with abnormal findings in vital signs | Variables include temperature, respiratory rate, pulse rate, and blood pressure | Baseline to end of study (approximately 10 weeks) | 
| Number of participants with abnormal 24-hour ABPM findings (clinically significant and not clinically significant) |  | Screening to end of study (up to approximately 26 weeks) | 
| Change from baseline in weight |  | Baseline to end of study (approximately 10 weeks) | 
| Number of participants with abnormal 12-lead electrocardiogram (ECG) findings (clinically significant and not clinically significant) |  | Screening to end of study (up to approximately 26 weeks) | 
| Number of participants with abnormal extended electrocardiogram (ECG) findings (clinically significant and not clinically significant) |  | 1-2 days prior to baseline to Day 30 or until rescue criterion is met | 
| Change from baseline to end of study for ECG measures (PR interval, RR interval, QRS interval, QT interval, corrected QT interval [both correction methods QTcB and QTcF]) | ECG measures are in milliseconds | Baseline to end of study (approximately 10 weeks) | 
| Change from baseline to end of study for ECG measures (heart rate descriptive analysis) |  | Baseline to end of study (approximately 10 weeks) | 
| Number of participants with abnormal findings in the complete physical examination |  | Screening to end of study (up to approximately 26 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MCT8, MCT8 deficiency, Allan-Herndon-Dudley syndrome, Tiratricol, Triac