Triac Trial II in MCT8 Deficiency Patients

Allan-Herndon-Dudley Syndrome Clinical Trial

Official title:

Tiratricol Treatment of Children With Monocarboxylate Transporter 8 Deficiency: Triac Trial II

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02396459
• Other study ID #: MCT8-2019-2
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: December 7, 2020
• Est. completion date: June 2026

Study information

• Verified date: May 2024
• Source: Rare Thyroid Therapeutics International AB
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 initially be treated for 96 weeks with tiratricol, treatment effect on neurodevelopment impairment caused by hypothyroidism and peripheral thyrotoxicosis will be evaluated after 96 weeks treatment. Patients will be offered to continue on treatment for an additional 2 years.

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 initially be treated for 96 weeks with tiratricol, treatment effect will be evaluated after 96 weeks. After the 96 week treatment period, patients will enter Part II of the trial, evaluating long-term treatment. Patients will be followed for an additional 2 years and treatment effect will be evaluated after 3 years and 4 years respectively from start of treatment.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 22
• Est. completion date: June 2026
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: Male
• Age group: N/A to 30 Months

Eligibility

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.
• The participant should be aged between 0 and 30 months on the day of inclusion.
• The participant should be male and have a pathogenic mutation in the MCT8 gene.

Exclusion Criteria:

• Previous treatment with tiratricol.
• Previous treatment with LT4 and/or PTU and/or other anti-thyroid medication for a period longer than three months. Patients previously treated with LT4 for a shorter period than 3 months may be included in the study (baseline visit) six weeks (or longer) after last dose of LT4 if two consecutive analyses show stable TFT*. Patients treated with PTU and/or other anti-thyroid medication for a shorter period than three months may be included in the study (baseline visit) six weeks (or longer) after last dose.
• Major illness or recent major surgery (within four weeks of baseline visit 1) unrelated to MCT8 deficiency.
• 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.

Related Conditions & MeSH terms

• Allan-Herndon-Dudley Syndrome

Intervention

Drug:
• Triac
Triac, individually titrated dose

Locations

Country	Name	City	State
Czechia	Charles University and Motol University Hospital; The department of peadiatrics of the 2nd faculty of medicine	Praha
Germany	Charité - Universitätsmedizin Berlin Institut fur experimental paediatrische endokrinologie	Berlin
Netherlands	Erasmus MC	Rotterdam
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Oregon Health & Science University (OHSU) Doernbecher Childrens Hospital	Portland	Oregon

Sponsors (2)

Lead Sponsor	Collaborator
Rare Thyroid Therapeutics International AB	Erasmus Medical Center

Countries where clinical trial is conducted

United States,  Czechia,  Germany,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Patient Quality of Life by Infant Toddler Quality of Life Questionnaire (ITQoL)	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.	96 weeks
Other	Parent Quality of Life by Parenting Stress index (PSI-4 SF)	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.	96 weeks
Other	Evaluate the effect of tiratricol treatment on neurological symptoms (Hammersmith Infant Neurological Exam, HINE)	Hammersmith Infant Neurological Exam (HINE)	96 weeks
Other	Evaluate the effect of tiratricol treatment on brain function (optional) (EEG)	Brain function outcome (optional) evaluated by EEG	96 weeks
Other	Evaluate the effect of tiratricol treatment on brain function (optional) (BERA)	Brain function outcome (optional) evaluated by Brainstem Evoked Response Audiogram (BERA)	96 weeks
Other	Evaluate the effect of tiratricol treatment on brain function (optional) (VEP)	Brain function/brain imaging outcome (optional) evaluated by Visual Evoked Potentials (VEP)	96 weeks
Other	Evaluate the effect of tiratricol treatment on brain imaging (optional)	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)	96 weeks
Other	Estimate the elimination half-life of tiratricol in young children, reported in hours (optional and provided a medical reason prevails).	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)	96 weeks
Other	Estimate the maximum serum concentration of tiratricol in young children, reported in nmol/L (optional and provided a medical reason prevails).	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)	96 weeks
Other	Evaluate the occurrence of episodes of tachycardia caused by the thyrotoxicosis.	Evaluation of cardiac rhythm and number of episodes of tachycardia with 24 hour Holter ECG.	96 weeks
Other	Evaluate the occurrence of premature atrial complexes (PACs) caused by the thyrotoxicosis.	Evaluation of occurrence of PACs with 24 hour Holter ECG.	96 weeks
Other	Evaluate the occurrence of other arrhythmias caused by the thyrotoxicosis.	Descriptive evaluation of occurrence of other arrhythmias with 24 hour Holter ECG.	96 weeks
Other	Evaluate the occurrence of structural cardiac anomalies in patients	Evaluation of the occurrence of structural cardiac anomalies using routine trans-thoracic cardiac ultrasound.	96 weeks
Other	Number of participants with Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and discontinuations due to Adverse Events (AEs)	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.	96 weeks
Other	Serum free T4 (FT4) concentrations	Evaluate the effect of tiratricol on FT4 concentrations to ensure patient safety.	96 weeks
Other	Serum total T4 (T4) concentrations	Evaluate the effect of tiratricol on T4 concentrations to ensure patient safety.	96 weeks
Other	Serum tiratricol concentrations	Evaluate tiratricol concentrations in serum, as estimated based on measured T3 concentrations in serum.	96 weeks
Other	Serum thyroid stimulating hormone (TSH) concentrations	Evaluate the effect of tiratricol on TSH concentrations to ensure patient safety.	96 weeks
Other	Serum reverse T3 (rT3) concentrations	Evaluate the effect of tiratricol on rT3 concentrations to ensure patient safety.	96 weeks
Other	Serum Alanine (Amino) Transaminase (ALAT) concentrations	Evaluate the effect of tiratricol on ALAT concentrations to ensure patient safety.	96 weeks
Other	Serum Aspartate (Amino) Transaminase (ASAT) concentrations	Evaluate the effect of tiratricol on ASAT concentrations to ensure patient safety	96 weeks
Other	Serum gamma-glutamyl transferase (gGT) concentrations	Evaluate the effect of tiratricol on gGT concentrations to ensure patient safety.	96 weeks
Other	Serum alkaline phosphatase concentrations	Evaluate the effect of tiratricol on alkaline phosphatase concentrations to ensure patient safety.	96 weeks
Other	Serum albumin concentrations	Evaluate the effect of tiratricol on albumin concentrations to ensure patient safety.	96 weeks
Other	Serum urea concentrations	Evaluate the effect of tiratricol on urea concentrations to ensure patient safety.	96 weeks
Other	Serum sodium concentrations	Evaluate the effect of tiratricol on sodium concentrations to ensure patient safety.	96 weeks
Other	Serum potassium concentrations	Evaluate the effect of tiratricol on potassium concentrations to ensure patient safety.	96 weeks
Other	White blood cell total and differential count	Evaluate the effect of tiratricol on white blood cell total and differential count to ensure patient safety.	96 weeks
Other	Red blood cell count	Evaluate the effect of tiratricol on red blood cell count to ensure patient safety.	96 weeks
Other	Platelet count	Evaluate the effect of tiratricol on platelet cell count to ensure patient safety.	96 weeks
Primary	Gross Motor Function Measure 88 (GMFM 88) total score	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.	96 weeks
Primary	Bayley Scales of Infant Development III Gross Motor Skill Domain score	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	96 weeks
Secondary	GMFM-88 individual item score 10 and 24.	GMFM-88 individual item score 10 ("lifts head upright") and item score 24 ("sit on mat"), GMFM Domain B (Sitting) - summary score of all items 18-37 ; Motor milestone responder analysis of Section 2 of the Hammersmith Infant Neurological Examination (HINE).	96 weeks
Secondary	Bayley Scales of Infant Development III score.	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.	96 weeks
Secondary	Serum T3 concentrations	Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features.	96 weeks
Secondary	Tissue-specific markers of thyroid state: serum sex-hormone binding globulin concentrations for liver	Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features.	96 weeks
Secondary	Tissue-specific markers of thyroid state: serum creatine kinase concentrations for muscles	Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features.	96 weeks
Secondary	Tissue-specific markers of thyroid state: serum creatinine concentrations for kidneys	Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features.	96 weeks
Secondary	Blood pressure	Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features.	96 weeks
Secondary	Body weight	Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features.	96 weeks