1. Normalization of the abnormal serum TH parameters and thereby improving the clinical condition of the AHDS patients2. Observation of changes in cognitive and motor function.
ID
Source
Brief title
Condition
- Endocrine disorders congenital
- Thyroid gland disorders
- Congenital and peripartum neurological conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1) Serum TSH, T4, vrij T4, T3, rT3 and Triac levels
Secondary outcome
1) Body weight, blood pressure and heart rate
2) Serum levels of markers that reflect peripheral thyroid hormone action: a.o.
serum steroid hormone binding globuline (SHBG) and lipids (liver), serum beta
Ctx and alkalisch phosphatase (bone) and serum kreatine kinase (muscle).
3) Motor function, using the Gross Motor Function Measure
4) Cognitive function using the Bayley Scales of Infant Development III or
Wechsler Preschool and Primary Scale of Intelligence II
5) Adaptive behavior according to Vineland adaptive behavior
scale
6) Basal Metabolic Rate using the Doubly labeled Water method
7) The frequency and nature of adverse events
Background summary
This therapeutic trial will be conducted in patients with the
Allan-Herndon-Dudly Syndrome (AHDS). AHDS is caused by mutations in MCT8.
MCT8 is a thyroid hormone (TH) transporter protein, which is crucial for TH
transport from the blood into different tissues. Loss of functional MCT8
results in strong decrease in intracellular TH levels (hypothyroidism) in
tissues that depend on MCT8 for TH uptake. Local hypothyroidism in the brain of
AHDS patients results in delayed neuronal growth and maturation. Consequently,
AHDS patients present with severe psychomotor retardation.
In addition, AHDS patients have characteristic abnormalities in TH serum
parameters: high T3, low T4 and normal TSH. The high T3 levels result in local
hyperthyroidism in tissues that do not depend on MCT8 for TH uptake. This
results in low body weight, muscle atrophy and an increased basal metabolism.
Currently no adequate therapy for these patients is available. A T3-analog that
does not require MCT8 for its cellular uptake could restore part of the
clinical phenotype. Several in vitro and animal studies have shown that the T3
analog Triac has a great potential.
Triac treatment could restore the abnormal TH serum parameters and Triac could
replace the function of T3 in tissues that depend on MCT8 for TH uptake. This
will result in 1) reduction of the toxic effects of the high T3 serum values
leading to an increase in body weight and muscle mass and 2) restoration of
adequate thyromimetic effects in tissues that depend on MCT8 for TH uptake
which could have beneficial effects on the neurological phenotype.
Study objective
1. Normalization of the abnormal serum TH parameters and thereby improving the
clinical condition of the AHDS patients
2. Observation of changes in cognitive and motor function.
Study design
Prospective interventional cohort study.
All included patients will receive the study medicine Triac. There will not be
randomization or blinding. The daily Triac dose will be titrated individually
based on serum thyroid hormone levels.
Intervention
Oral tablets of Triac, in 2-5 daily doses, during a study period of 12 months.
Study burden and risks
The burden of participation will consist of 10 extra hospital visits. During
control visits a routine physical examination and vena punctures will be
performed. In addition, during the baseline visit and at the end of the study
an extensive neurocognitive, cardiac and metabolic evaluation will take place.
Most control visits will coincide with appointments for regular care and will
therefore form a minimal burden for the patients. All study procedures, except
for vena punctures, are non-invasive and have no physical or emotional risk for
the patients. Vena punctures are minimally invasive and have only mild risks.
There is worldwide experience with the application of Triac treatment in
patients with abnormal TH serum values, including children. Reported
side-effects are mainly dose-related and consist of symptoms of
hyperthyroidism. Overdosing will be prevented by close follow-up and evaluation
of recruited patients and by applying individual dose titration. Side-effect
are transient and will subside within 2 days after dose reduction.
Given the scope of this study, it has to be conducted in patients with AHDS.
The benefits of Triac treatment are listed in the background section.
Dr Molewaterplein 50
Rotterdam 3015 GE
NL
Dr Molewaterplein 50
Rotterdam 3015 GE
NL
Listed location countries
Age
Inclusion criteria
clinical relevant and genetically confirmed mutation in the MCT8 gene, leading to the AHDS phenotype
Exclusion criteria
- Major illness or recent major surgery (within 4 weeks) unrelated to AHDS
- Patients who are participating in ongoing RCTs of therapeutic interventions (including clinical trials of investigational medicinal products);
- Patients that have any major contra-indication for Triac treatment (severe cardiac decompensation (NYHA 4), coronary insufficiency, severe cardiac arrhytmias, Galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-000178-20-NL |
| ClinicalTrials.gov | NCT02060474 |
| CCMO | NL47771.078.14 |