Allan-Herndon-Dudley Syndrome
Conditions
Keywords
Triac, MCT8, MCT8 deficiency, Allan-Herndon-Dudley Syndrome
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 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 3 years.
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 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 3 years and treatment effect will be evaluated after 3 years, 4 years and 5 years respectively from start of treatment.
Interventions
DRUGTiratricol
Tiratricol, individually titrated dose
Sponsors
Rare Thyroid Therapeutics International AB
Erasmus Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
No minimum to 30 Months
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Gross Motor Function Measure 88 (GMFM 88) total score | 96 weeks, Year 3, Year 4 and Year 5 | 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 | 96 weeks, Year 3, Year 4 and Year 5 | 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
| Measure | Time frame | Description |
|---|---|---|
| GMFM-88 individual item score 10 and 24. | 96 weeks, Year 3, Year 4 and Year 5 | 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). |
| Bayley Scales of Infant Development III score. | 96 weeks, Year 3, Year 4 and Year 5 | 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 | 96 weeks, Year 3, Year 4 and Year 5 | 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 | 96 weeks, Year 3, Year 4 and Year 5 | Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features. |
| Tissue-specific markers of thyroid state: serum creatine kinase concentrations for muscles | 96 weeks, Year 3, Year 4 and Year 5 | Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features. |
| Tissue-specific markers of thyroid state: serum creatinine concentrations for kidneys | 96 weeks, Year 3, Year 4 and Year 5 | Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features. |
| Blood pressure | 96 weeks, Year 3, Year 4 and Year 5 | Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features. |
| Body weight | 96 weeks, Year 3, Year 4 and Year 5 | Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features. |
Countries
Czechia, Germany, Netherlands, United States
Contacts
PRINCIPAL_INVESTIGATORW.E. Visser, MD, PhD
Erasmus Medical Center
STUDY_DIRECTORKristina Sjöblom Nygren, MD
Rare Thyroid Therapeutics International AB
PRINCIPAL_INVESTIGATORLindsey Nicol
Oregon Health& Science University (OHSU) Doernbecher Childrens Hospital
PRINCIPAL_INVESTIGATORJan Lebl
Charles University and Motol University Hospital
PRINCIPAL_INVESTIGATORHeiko Krude
Charité - Universitätsmedizin Berlin Institut fur experimental paediatrische endokrinologie
PRINCIPAL_INVESTIGATORAndrew Bauer, MD
Children's Hospital of Philadelphia
Outcome results
None listed