Triac Trial II in MCT8 Deficiency Patients
Study Details
Study Description
Brief Summary
This study will investigate the effect of treatment with tiratricol (also called Triac) in young boys (≤30 months) with MCT8 deficiency (also called the Allan-Herndon-Dudley syndrome (AHDS)). 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 on neurodevelopment impairment caused by hypothyroidism and the thyrotoxicosis will be evaluated at an interim analysis after 12 months treatment and after 24 months treatment.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Detailed Description
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 (also called the Allan-Herndon-Dudley syndrome (AHDS)). 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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: MCT8 deficiency patients Triac treatment |
Drug: Triac
Triac, individually titrated dose
Other Names:
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Outcome Measures
Primary Outcome Measures
- Gross Motor Function Measure 88 (GMFM 88) total score [24 months]
To evaluate the effects of tiratricol on neurodevelopment in young MCT8 deficiency patients, measured by the Gross Motor Function Measure (GMFM)-88 assessment. Potential result values range from 0 to 100%, the latter being representative for a 4-year old healthy child. A high score is equivalent to better/more neurodevelopment and is therefore a better outcome than a low score.
- Bayley Scales of Infant Development III Gross Motor Skill Domain score [24 months]
To evaluate the effect of tiratricol treatment on neurodevelopment measured by the Bayley Scales of Infant Development (BSID-III) Gross Motor Skill Domain score. Potential total raw scores range from 0-72, and can be age-adjusted before analysis. A high score is equivalent to better/more neurodevelopment and is therefore a better outcome than a low score
Secondary Outcome Measures
- GMFM-88 individual item score 10 and 24. [24 months]
Evaluate the effect of Tiratricol treatment on specific motor milestones as defined by GMFM-88 individual item scores 10 and 24.
- Bayley Scales of Infant Development III score. [24 months]
To evaluate the effect of tiratricol treatment on neurodevelopment measured by the Bayley Scales of Infant Development (BSID-III). Five subscales of this assessment will be used: Cognitive, Receptive communication, Expressive communication, Fine motor and Gross motor. Potential total raw scores range from 0-91, 0-49, 0-48, 0-66 and 0-72 respectively, and can be age-adjusted before analysis. A high score is equivalent to better/more neurodevelopment and is therefore a better outcome than a low score. This holds true for all subscales.
- Serum T3 concentrations [24 months]
Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features.
- Tissue-specific markers of thyroid state: serum sex-hormone binding globulin concentrations for liver [24 months]
Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features.
- Tissue-specific markers of thyroid state: serum creatine kinase concentrations for muscles [24 months]
Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features.
- Tissue-specific markers of thyroid state: serum creatinine concentrations for kidneys [24 months]
Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features.
- Blood pressure [24 months]
Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features.
- Body weight [24 months]
Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features.
Other Outcome Measures
- Patient Quality of Life by Infant Toddler Quality of Life Questionnaire (ITQoL) [24 months]
To evaluate patient´s quality of life (QoL) by Infant Toddler Quality of Life (ITQoL-SF-47) questionnaire. Item responses are scored, summed, and transformed on a scale from 0 (worst health) to 100 (best health). A high score is equivalent to better parent-reported outcomes and is therefore a better outcome than a low score.
- Parent Quality of Life by Parenting Stress index (PSI-4 SF) [24 months]
To evaluate parent's quality of life (QoL) by Parenting Stress Index (PSI-4 SF) questionnaire. Results are given as raw scores, percentiles and T scores, where percentiles are the primary interpretive framework. Results from 16th - 84th percentile = Normal range, 85th - 89th Percentile = High range, 90th Percentile or higher = Clinically significant range.
- Evaluate the effect of tiratricol treatment on neurological symptoms (Hammersmith Infant Neurological Exam, HINE) [24 months]
Hammersmith Infant Neurological Exam (HINE)
- Evaluate the effect of tiratricol treatment on brain function (optional) (EEG) [24 months]
Brain function outcome (optional) evaluated by EEG
- Evaluate the effect of tiratricol treatment on brain function (optional) (BERA) [24 months]
Brain function outcome (optional) evaluated by Brainstem Evoked Response Audiogram (BERA)
- Evaluate the effect of tiratricol treatment on brain function (optional) (VEP) [24 months]
Brain function/brain imaging outcome (optional) evaluated by Visual Evoked Potentials (VEP)
- Evaluate the effect of tiratricol treatment on brain imaging (optional) [24 months]
Brain imaging outcome (optional) evaluated by MRI/MRS - in patients where this examination is scheduled as part of a clinical praxis (at the discretion of the investigator)
- Estimate the elimination half-life of tiratricol in young children, reported in hours (optional and provided a medical reason prevails). [24 months]
Measurement of serum T3 concentrations before and 2, 4, 8 and 24 hours after administration of tiratricol as part of pharmacokinetic profile (optional and provided a medical reason prevails)
- Estimate the maximum serum concentration of tiratricol in young children, reported in nmol/L (optional and provided a medical reason prevails). [24 months]
Measurement of serum T3 concentrations before and 2, 4, 8 and 24 hours after administration of tiratricol as part of pharmacokinetic profile (optional and provided a medical reason prevails)
- Evaluate the occurrence of episodes of tachycardia caused by the thyrotoxicosis. [24 months]
Evaluation of cardiac rhythm and number of episodes of tachycardia with 24 hour Holter ECG.
- Evaluate the occurrence of premature atrial complexes (PACs) caused by the thyrotoxicosis. [24 months]
Evaluation of occurrence of PACs with 24 hour Holter ECG.
- Evaluate the occurrence of other arrhythmias caused by the thyrotoxicosis. [24 months]
Descriptive evaluation of occurrence of other arrhythmias with 24 hour Holter ECG.
- Evaluate the occurrence of structural cardiac anomalies in patients [24 months]
Evaluation of the occurrence of structural cardiac anomalies using routine trans-thoracic cardiac ultrasound.
- Number of participants with Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and discontinuations due to Adverse Events (AEs) [24 months]
An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An SAE is defined as an AE or suspected adverse reaction that at any dose results in any of the following outcomes: death; life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; a congenital anomaly/birth defect. Severity was graded as 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). TEAEs are defined as AEs with onset on or after the time of initiation of study drug administration.
- Serum free T4 (FT4) concentrations [24 months]
Evaluate the effect of tiratricol on FT4 concentrations to ensure patient safety.
- Serum total T4 (T4) concentrations [24 months]
Evaluate the effect of tiratricol on T4 concentrations to ensure patient safety.
- Serum tiratricol concentrations [24 months]
Evaluate tiratricol concentrations in serum, as estimated based on measured T3 concentrations in serum.
- Serum thyroid stimulating hormone (TSH) concentrations [24 months]
Evaluate the effect of tiratricol on TSH concentrations to ensure patient safety.
- Serum reverse T3 (rT3) concentrations [24 months]
Evaluate the effect of tiratricol on rT3 concentrations to ensure patient safety.
- Serum Alanine (Amino) Transaminase (ALAT) concentrations [24 months]
Evaluate the effect of tiratricol on ALAT concentrations to ensure patient safety.
- Serum Aspartate (Amino) Transaminase (ASAT) concentrations [24 months]
Evaluate the effect of tiratricol on ASAT concentrations to ensure patient safety
- Serum gamma-glutamyl transferase (gGT) concentrations [24 months]
Evaluate the effect of tiratricol on gGT concentrations to ensure patient safety.
- Serum alkaline phosphatase concentrations [24 months]
Evaluate the effect of tiratricol on alkaline phosphatase concentrations to ensure patient safety.
- Serum albumin concentrations [24 months]
Evaluate the effect of tiratricol on albumin concentrations to ensure patient safety.
- Serum urea concentrations [24 months]
Evaluate the effect of tiratricol on urea concentrations to ensure patient safety.
- Serum sodium concentrations [24 months]
Evaluate the effect of tiratricol on sodium concentrations to ensure patient safety.
- Serum potassium concentrations [24 months]
Evaluate the effect of tiratricol on potassium concentrations to ensure patient safety.
- White blood cell total and differential count [24 months]
Evaluate the effect of tiratricol on white blood cell total and differential count to ensure patient safety.
- Red blood cell count [24 months]
Evaluate the effect of tiratricol on red blood cell count to ensure patient safety.
- Platelet count [24 months]
Evaluate the effect of tiratricol on platelet cell count to ensure patient safety.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Signed and dated informed consent form from the parents or legal guardian.
-
Parents stated willingness to comply with all study procedures and availability for the duration of the study.
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The participant should be aged between 0 and 30 months on the day of inclusion.
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The participant should be male and have a pathogenic mutation in the MCT8 gene.
Exclusion Criteria:
-
Previous treatment with tiratricol.
-
Previous treatment with a combination of Propylthiouracil (PTU) and Levothyroxine (LT4).
-
Previous treatment with LT4 for a period longer than three months. Treatment with LT4 within three months of baseline visit.
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Major illness or recent major surgery (within four weeks of baseline visit 1) unrelated to MCT8 deficiency.
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Known allergic reactions to components of the IMP. Patients with galactose intolerance, Lapp lactase deficiency or malabsorption of glucose or galactose (the IMP contains lactose).
-
Treatment with another investigational drug or participation in other interventional trial within three months prior to baseline visit 1.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Erasmus MC | Rotterdam | Netherlands | 3015 GD |
Sponsors and Collaborators
- Rare Thyroid Therapeutics International AB
- Erasmus Medical Center
Investigators
- Principal Investigator: W.E. Visser, MD, PhD, Erasmus MC
- Study Director: Peder Walberg, MD, Rare Thyroid Therapeutics
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- MCT8-2019-2