Clinical trial NCT02396459: Triac Trial II in MCT8 Deficiency Patients
Official title: Tiratricol Treatment of Children with Monocarboxylate Transporter 8 Deficiency: Triac Trial II
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Allan-Herndon-Dudley Syndrome
Keywords: Triac
MCT8
MCT8 deficiency
Allan-Herndon-Dudley Syndrome
Lead sponsor: Rare Thyroid Therapeutics International AB
Sponsor class: INDUSTRY
Collaborators: name: Erasmus Medical Center
First posted: 2015-03-24
Enrollment: 22
Sex: MALE
Maximum age (years): 30
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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 2 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 2 years and treatment effect will be evaluated after 3 years and 4 years respectively from start of treatment.

Eligibility 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.
* 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.

Primary outcomes:
measure: Gross Motor Function Measure 88 (GMFM 88) total score
timeFrame: 96 weeks
measure: Bayley Scales of Infant Development III Gross Motor Skill Domain score
timeFrame: 96 weeks
Secondary outcomes:
measure: GMFM-88 individual item score 10 and 24.
timeFrame: 96 weeks
measure: Bayley Scales of Infant Development III score.
timeFrame: 96 weeks
measure: Serum T3 concentrations
timeFrame: 96 weeks
measure: Tissue-specific markers of thyroid state: serum sex-hormone binding globulin concentrations for liver
timeFrame: 96 weeks
measure: Tissue-specific markers of thyroid state: serum creatine kinase concentrations for muscles
timeFrame: 96 weeks
measure: Tissue-specific markers of thyroid state: serum creatinine concentrations for kidneys
timeFrame: 96 weeks
measure: Blood pressure
timeFrame: 96 weeks
measure: Body weight
timeFrame: 96 weeks
Other outcomes:
measure: Patient Quality of Life by Infant Toddler Quality of Life Questionnaire (ITQoL)
timeFrame: 96 weeks
measure: Parent Quality of Life by Parenting Stress index (PSI-4 SF)
timeFrame: 96 weeks
measure: Evaluate the effect of tiratricol treatment on neurological symptoms (Hammersmith Infant Neurological Exam, HINE)
timeFrame: 96 weeks
measure: Evaluate the effect of tiratricol treatment on brain function (optional) (EEG)
timeFrame: 96 weeks
measure: Evaluate the effect of tiratricol treatment on brain function (optional) (BERA)
timeFrame: 96 weeks
measure: Evaluate the effect of tiratricol treatment on brain function (optional) (VEP)
timeFrame: 96 weeks
measure: Evaluate the effect of tiratricol treatment on brain imaging (optional)
timeFrame: 96 weeks
measure: Estimate the elimination half-life of tiratricol in young children, reported in hours (optional and provided a medical reason prevails).
timeFrame: 96 weeks
measure: Estimate the maximum serum concentration of tiratricol in young children, reported in nmol/L (optional and provided a medical reason prevails).
timeFrame: 96 weeks
measure: Evaluate the occurrence of episodes of tachycardia caused by the thyrotoxicosis.
timeFrame: 96 weeks
measure: Evaluate the occurrence of premature atrial complexes (PACs) caused by the thyrotoxicosis.
timeFrame: 96 weeks
measure: Evaluate the occurrence of other arrhythmias caused by the thyrotoxicosis.
timeFrame: 96 weeks
measure: Evaluate the occurrence of structural cardiac anomalies in patients
timeFrame: 96 weeks
measure: Number of participants with Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and discontinuations due to Adverse Events (AEs)
timeFrame: 96 weeks
measure: Serum free T4 (FT4) concentrations
timeFrame: 96 weeks
measure: Serum total T4 (T4) concentrations
timeFrame: 96 weeks
measure: Serum tiratricol concentrations
timeFrame: 96 weeks
measure: Serum thyroid stimulating hormone (TSH) concentrations
timeFrame: 96 weeks
measure: Serum reverse T3 (rT3) concentrations
timeFrame: 96 weeks
measure: Serum Alanine (Amino) Transaminase (ALAT) concentrations
timeFrame: 96 weeks
measure: Serum Aspartate (Amino) Transaminase (ASAT) concentrations
timeFrame: 96 weeks
measure: Serum gamma-glutamyl transferase (gGT) concentrations
timeFrame: 96 weeks
measure: Serum alkaline phosphatase concentrations
timeFrame: 96 weeks
measure: Serum albumin concentrations
timeFrame: 96 weeks
measure: Serum urea concentrations
timeFrame: 96 weeks
measure: Serum sodium concentrations
timeFrame: 96 weeks
measure: Serum potassium concentrations
timeFrame: 96 weeks
measure: White blood cell total and differential count
timeFrame: 96 weeks
measure: Red blood cell count
timeFrame: 96 weeks
measure: Platelet count
timeFrame: 96 weeks
Locations:
city: Portland
country: United States
facility: Oregon Health & Science University (OHSU) Doernbecher Childrens Hospital
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Praha
country: Czechia
facility: Charles University and Motol University Hospital; The department of peadiatrics of the 2nd faculty of medicine
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin Institut fur experimental paediatrische endokrinologie
city: Rotterdam
country: Netherlands
facility: Erasmus MC
Study officials:
affiliation: Erasmus Medical Center
name: W.E. Visser, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rare Thyroid Therapeutics International AB
name: Kristina Sjöblom Nygren, MD
role: STUDY_DIRECTOR
affiliation: Oregon Health& Science University (OHSU) Doernbecher Childrens Hospital
name: Stephen LaFranchi_Nicol
role: PRINCIPAL_INVESTIGATOR
affiliation: Charles University and Motol University Hospital
name: Jan Lebl
role: PRINCIPAL_INVESTIGATOR
affiliation: Charité - Universitätsmedizin Berlin Institut fur experimental paediatrische endokrinologie
name: Heiko Krude
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital of Philadelphia
name: Andrew Bauer, MD
role: PRINCIPAL_INVESTIGATOR
References: