Triac Trial II
Effect van T3-analoog Triac op de hersenontwikkeling van jonge patiënten met MCT8 deficiëntie.
Rationale: This therapeutic trial will be conducted in patients with MCT8 deficiency (also called Allan-Herndon-Dudley Syndrome (AHDS)), which is due to mutations in monocarboxylate transporter (MCT)8. MCT8 is a thyroid hormone transporter which is crucial for the transport of thyroid hormone from the blood into different tissues. Defective MCT8 results in a lack of thyroid hormone (hypothyroidism) in tissues that are dependent on MCT8 for thyroid hormone uptake, such as the brain. Hypothyroidism in the brain results in severe intellectual and motor disability. Another important feature of this disease is the high serum T3 concentrations in the blood. This results in hyperthyroidism in tissues that are not dependent on MCT8 for their thyroid hormone supply. As a result, patients with MCT8 deficiency have clinical features of thyrotoxicosis such as low body weight, elevated heart rate and reduced muscle mass.
Preclinical studies have shown that the T3 analogue tiratricol is transported into cells in an MCT8-independent manner. In animal models mimicking MCT8 deficiency, Triac has been shown to normalize brain development if administrated during early postnatal life.
Recently, Triac Trial I (NCT02060474) has shown that tiratricol treatment in patients with MCT8 deficiency improves key clinical and biochemical features caused by the toxic effects of the high T3 concentrations. No drug related serious adverse events have occurred during Triac Trial I.
This study will investigate the effect of treatment with tiratricol in young boys (≤30 months) with MCT8 deficiency. The hypothesis tested is that treatment with tiratricol will have a beneficial effect on the hypothyroid state in the brain as well as the hyperthyroid state in peripheral organs and tissues in these patients. Patients will be treated for 24 months with tiratricol, treatment effect will be evaluated at an interim analysis after 12 months treatment and after 24 months treatment.
Primary objective: To evaluate the effects of tiratricol on neurodevelopment in young MCT8 deficiency patients.
- Evaluate the effect of Tiratricol treatment on specific motor development milestones by individual item scores in the Gross Motor Function Measure.
- Evaluate the effect of tiratricol treatment on neurodevelopment in young MCT8 deficient patients as measured by the Bayley Scales of Infant Development (BSID-III)
- Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features (serum T3 concentrations, tissue specific markers of thyroid hormone action).
Study design: A single-arm, open-label, international multi-centre clinical trial.
Study population: Male patients diagnosed with MCT8 deficiency from newborn to 30 months of age. Twelve to twenty-two patients will be included in the study from countries where potentially eligible patients will be identified. Potential countries include: the Netherlands, Czech Republic, France, Germany, Italy, UK, USA.
Intervention: Tiratricol will be administered, to all patients, orally or through feeding tube in an individual dose titrated based on serum T3 response. The dose will be divided into 1-3 administrations per day.
GMFM-88 total score and BSID Gross Motor Skill Domain compared to natural history scores from untreated patients.
- GMFM-88 individual item score 10 and 24 compared to natural history scores from untreated patients.
- Age equivalent (AE) score from the BSID-III compared to natural history AE scores from untreated patients.
- Serum T3 (efficacy), peripheral thyroid hormone status (serum SHBG; serum creatine kinase, creatinine, blood pressure and body weight) (efficacy).
1. Patient/Parent Quality of Life by Infant Toddler Quality of Life Questionnaire (ITQoL) and Parenting Stress index (PSI-4 SF).
- Hammersmith Infant Neurological Exam (HINE).
- Brain function/brain imaging outcome (optional) evaluated by
- EEG, Brainstem Evoked Response Audiogram (BERA), Visual Evoked Potentials (VEP)
- MRI/MRS – in patients where this examination is scheduled as part of a clinical praxis (at the discretion of the investigator)
- Pharmacokinetic properties will be evaluated by frequent blood sampling in patients who needs to be closely monitored due to dosing or safety reasons.
- Cardiovascular function; heart rate, tachycardia (by 24h Holter).
Ferdy S. van Geest, MD
W. Edward Visser, MD, PhD
Dr. W. Edward Visser, Rotterdam
Prof. Jan Lebl, Prague
Dr. Athanasia Stoupa, Paris
Dr. Isabelle Oliver, Toulouse
Prof. Heiko Krude, Berlin
Prof. Marco Cappa, Rome
Dr. Davide Tonduti, Milan
Prof. Krishna Chatterjee, Cambridge
Prof. Stephen Lafranchi, Portland
Dr. Andrew Bauer, Philadelphia