Withdrawal of Tiratricol Treatment in Males With Monocarboxylate Transporter 8 Deficiency (MCT8 Deficiency): A Double-blind, Randomized, Placebo-controlled Study
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 20
- 试验地点
- 8
- 主要终点
- Rate of change from baseline in serum total T3 (ln-transformed) during the 30-day double-blind Randomized Treatment Period
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 4 Years 至 —（Child, Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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 (if serum total T3 concentration is not available, free T3 results from standard of care samples may be used)
- •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 #
- •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.
排除标准
- •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 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.
- •Confirmation that the "Stable Dose Criterion" has been met.
- •Absence of any new or exacerbated medical or surgical condition that fulfils Exclusion criterion #
- •Confirmation that participant is at least 4 years of age at the time of randomization.
研究组 & 干预措施
Tiratricol
干预措施: Tiratricol (Drug)
Placebo
干预措施: Placebo (Drug)
结局指标
主要结局
Rate of change from baseline in serum total T3 (ln-transformed) during the 30-day double-blind Randomized Treatment Period
时间窗: 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
时间窗: Baseline to Day 30
Rate of change from baseline in serum total T3 during the 30-day double blind Randomized Treatment Period.
时间窗: During the 30-day double blind Randomized Treatment Period.
Proportion of participants who meet the rescue criterion (serum total T3 > ULN) during the 30-day double-blind Randomized Treatment Period.
时间窗: During the 30-day double-blind Randomized Treatment Period.
次要结局
- 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))
- 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).)
- 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 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).)
- 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))
- Change in serum thyroid hormone variables (T3, T4, TSH, fT3, and fT4).(From i) baseline to the end of Randomized Treatment Period, ii) screening to End of Study, iii) initiation of tiratricol administration at enrolment to the last measurement prior to randomization.)
- Change in clinical endpoints: Heart Rate, Systolic Blood Pressure and Rate Pressure Product (heart rate × systolic blood pressure).(From i) baseline to the end of Randomized Treatment Period, ii) initiation of tiratricol administration at screening to the last measurement prior to randomization.)
- Change in clinical endpoints: Heart Rate, Systolic Blood Pressure, Rate Pressure Product (heart rate × systolic blood pressure) and body weight.(From Screening to End of Study.)
- Safety endpoints: Adverse events, Safety laboratory variables, Standard vital signs variables, Weight, ECG evaluations and Physical examinations.(From the start of the Run-in/Dose Titration Period to the end of study.)