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Thyroid Hormone Analog Therapy in MCT8 Deficiency: Triac Trial Patients

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ClinicalTrials.gov Identifier: NCT02060474
Recruitment Status : Completed
First Posted : February 12, 2014
Last Update Posted : April 16, 2019
Sponsor:
Collaborator:
ZonMw: The Netherlands Organisation for Health Research and Development
Information provided by (Responsible Party):
W. Edward Visser, Erasmus Medical Center

Brief Summary:

This therapeutical trial will be conducted in patients with the Allan-Herndon-Dudley Syndrome (AHDS), which is mutations in MCT8.

MCT8 is a thyroid hormone (TH) transporter which is crucial for the transport of TH from the blood into different tissues. Dysfunction of MCT8 results in a lack of TH (hypothyroidism) in tissues that depend on MCT8 for TH uptake. This local hypothyroidism in the brain of these patients causes severe psychomotor retardation.

In addition, TH serum parameters are highly abnormal in AHDS: high T3, low T4 and normal TSH levels. The high serum T3 levels cause local hyperthyroidism in tissues that do not depend on MCT8 for cellular transport of TH, resulting in a low body weight and reduced muscle mass.

Currently, no adequate treatment is available for the AHDS. A T3 analog that does not depend on MCT8 for its cellular entry could, at least partially, restore the abnormalities found in AHDS. Several in vivo, in vitro and animal studies have shown that the T3 analog Triac is a very promising candidate:

  1. Triac binds to the same TH receptors as T3;
  2. Cellular uptake of Triac does not depend on functional MCT8. Hence, in AHDS patients Triac will also be available in tissues that require functional MCT8 for TH uptake, e.g. the brain;
  3. In vitro studies have shown that neuronal cells differentiate equally well in the presence of either Triac or T3;
  4. In Mct8 deficient mice, Triac is taken up by the brain and suppresses serum TSH levels; consequently, serum T3 and T4 levels were lowered;
  5. Triac is the treatment of choice in patient with the resistance to thyroid hormone (RTH) syndrome. Patient with RTH have high serum TSH and thyroid hormone levels, which shows strong similarities to the profile found in AHDS patients; the longstanding experience with Triac in RTH indicates its safety and tolerability .

Thus, Triac treatment could result in normalization of the abnormal serum TH values in AHDS patients. Furthermore, Triac could replace the function of T3 in tissues that depend on MCT8 for TH uptake (e.g. brain).

The current trial will investigate if Triac treatment in ADHS patients

  1. reduces the toxic effects of the high T3 levels
  2. restores the local TH deficiency in brain.

Condition or disease Intervention/treatment Phase
Allan-Herndon-Dudley Syndrome Drug: Triac Phase 2

Detailed Description:

All patients were treated with Triac (Téatrois tablets 350 microgram, Rare Thyroid Therapeutics) by individualized dose-escalation, following a pre-defined dose-escalation protocol. After the initial dose of Triac (350 microgram) was administered and no predefined dose-limiting toxicities were observed, the daily dose was increased progressively in 350 microgram steps, with a goal of attaining serum total T3 concentrations within the target range of 1·4-2·5 nmol per liter. The maintenance Triac dose was continued throughout the rest of the study period, but could be further adjusted according to the dose-escalation protocol if T3 concentrations were outside the target range during control visits.

Patients were assessed for study outcomes at baseline and 12 months after starting Triac administration. In the interval, patients were evaluated and screened for clinical and biochemical signs of hypothyroidism or hyperthyroidism, adverse events were recorded and adherence to therapy was assessed. All study procedures were specified in standard operating procedures, and were performed by well-trained investigators. Neuropsychological tests were conducted according to their manual. All biochemical measurements were performed in a central laboratory (Erasmus Medical Centre). To account for any interference of Triac in the measurement of serum T3 concentrations, conventional methods were employed to correct for cross-reactivity.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 46 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Thyroid Hormone Analog Therapy of Patients With Severe Psychomotor Retardation Caused by Mutations in the MCT8 Thyroid Hormone Transporter: The Triac Trial.
Actual Study Start Date : October 2014
Actual Primary Completion Date : June 26, 2018
Actual Study Completion Date : June 26, 2018


Arm Intervention/treatment
Experimental: AHDS patients
all AHDS recruited for this study will be located in the experimental arm and will receive the investigational medicinal product Triac. The Triac dose will be individually titrated to the optimal dose level.
Drug: Triac
Triac is a naturally occuring T3 metabolite with similar bioactivity and receptor binding profile.
Other Name: Tiratricol, Téatrois, TA3




Primary Outcome Measures :
  1. serum T3 concentrations [ Time Frame: Participants will be evaluated with an expected average of 2 weeks during months 1-3 of the trial. During months 4-12, participants will be evaluated with an expected average of 6 weeks. For statistical analysis baseline and month 12 will be compared ]
    Serum T3 concentrations will be determined to assess the effect of Triac

  2. serum free T4 concentrations [ Time Frame: Participants will be evaluated with an expected average of 2 weeks during months 1-3 of the trial. During months 4-12 participants will be evaluated with an expected average of 6 weeks. For statistical analysis baseline and month 12 will be compared ]
    Serum free T4 concentrations will be determined to assess the effect of Triac (co-primary end-point, supportive to changes in T3).

  3. serum TSH concentrations [ Time Frame: Participants will be evaluated with an expected average of 2 weeks during months 1-3 of the trial. During months 4-12 participants will be evaluated with an expected average of 6 weeks. For statistical analysis baseline and month 12 will be compared ]
    Serum TSH concentrations will be determined to assess the effect of Triac (co-primary end-point, supportive to changes in T3).

  4. serum total T4 concentrations [ Time Frame: Participants will be evaluated with an expected average of 2 weeks during months 1-3 of the trial. During months 4-12 participants will be evaluated with an expected average of 6 weeks. For statistical analysis baseline and month 12 will be compared ]
    Serum total T4 concentrations will be determined to assess the effect of Triac(co-primary end-point, supportive to changes in T3).

  5. serum reverse T3 concentrations [ Time Frame: Participants will be evaluated with an expected average of 2 weeks during months 1-3 of the trial. During months 4-12 participants will be evaluated with an expected average of 6 weeks. For statistical analysis baseline and month 12 will be compared ]
    Serum reverse T3 concentrations will be determined to assess the effect of Triac(co-primary end-point, supportive to changes in T3).


Secondary Outcome Measures :
  1. Heart rate [ Time Frame: baseline and month 12 will be compared ]
    Heart rate will be measures with an ECG and 24 h ambulatory monitoring

  2. serum sex-hormone binding globulin concentrations [ Time Frame: baseline and month 12 will be compared ]
    serum sex-hormone binding globulin concentrations will be measured as a proxi-parameter for tissue thyroid hormone status in the liver.

  3. Body weight [ Time Frame: baseline and month 12 will be compared ]
    Body weight will be measured in kg

  4. Blood pressure [ Time Frame: baseline and month 12 will be compared ]
    Blood pressure will be measured in mmHg

  5. serum total cholesterol concentrations [ Time Frame: baseline and month 12 will be compared ]
    serum total cholesterol concentrations will be measured as a proxi-parameter for tissue TH status in the liver.

  6. serum creatine kinase concentrations [ Time Frame: baseline and month 12 will be compared ]
    serum creatine kinase concentrations will be measured as a proxi-parameter for tissue TH status in the muscles.


Other Outcome Measures:
  1. Monitoring of adverse effects. [ Time Frame: up to one year (= whole study period) ]
    Family members and caregivers of the included patients will be asked to report all adverse effects to one of the investigators.

  2. A routine trans-thoracic cardiac ultrasound [ Time Frame: 12 months ]
    the effects of Triac on the heart function will be measured using cardiac ultrasonography during the first visit (T0) and after 12 months (T12), reflecting the effect of Triac on the heart over a period of 1 year.

  3. ECG [ Time Frame: Participants will be evaluated with an expected average of 2 weeks during months 1-3 of the trial. During months 4-12 participants will be evaluated with an expected average of 6 weeks. ]
    The effect of Triac on the heart rhythm will be assessed with an ECG

  4. Bone Mineral Density (total body) [ Time Frame: Bone mineral density will be measured during the first visit of the trial (T0) and after 12 months (T12) reflecting the effect of Triac over a 1 year period ]
    Bone mineral density of total body will be measured by DXA scan

  5. Motor function, using the Gross Motor Function Measure [ Time Frame: baseline and month 12 will be compared ]
    motor function will be measured during the first visit of the trial (T0) and after 12 months (T12) reflecting the effect of Triac over a 1 year period

  6. Cognitive function using the Bayley Scales of Infant Development III [ Time Frame: baseline and month 12 will be compared ]
    cognitive function will be measured during the first visit of the trial (T0) and after 12 months (T12) reflecting the effect of Triac over a 1 year period

  7. Adaptive behavior by the Vineland adaptive behavior scale [ Time Frame: baseline and month 12 will be compared ]
    adaptive behavior will be measured during the first visit of the trial (T0) and after 12 months (T12) reflecting the effect of Triac over a 1 year period

  8. Bone Mineral Density of ultradistal ulna [ Time Frame: Bone mineral density will be measured during the first visit of the trial (T0) and after 12 months (T12) reflecting the effect of Triac over a 1 year period ]
    Bone mineral density of ultradistal ulna will be measured by DXA scan

  9. Bone Mineral Density of ultradistal radius [ Time Frame: Bone mineral density will be measured during the first visit of the trial (T0) and after 12 months (T12) reflecting the effect of Triac over a 1 year period ]
    Bone mineral density of ultradistal radius will be measured by DXA scan



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Ages Eligible for Study:   up to 99 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • clinically relevant mutation in the MCT8 gene, resulting in the clinical phenotype of AHDS.

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);
  • Known allergy to components in Triac tablets;
  • Patients that have any contra-indication for Triac treatment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02060474


Locations
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Netherlands
Erasmus Medical Center
Rotterdam, South-Holland, Netherlands, 3000 CA
Sponsors and Collaborators
Erasmus Medical Center
ZonMw: The Netherlands Organisation for Health Research and Development
Investigators
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Principal Investigator: W.E. Visser, dr, Erasmus Medical Center

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Responsible Party: W. Edward Visser, Dr., Erasmus Medical Center
ClinicalTrials.gov Identifier: NCT02060474     History of Changes
Other Study ID Numbers: MCT8-2014-1
2014-000178-20 ( EudraCT Number )
First Posted: February 12, 2014    Key Record Dates
Last Update Posted: April 16, 2019
Last Verified: April 2019

Keywords provided by W. Edward Visser, Erasmus Medical Center:
Allan-Herndon-Dudley Syndrome
MCT8
Triac
Therapeutic Trial

Additional relevant MeSH terms:
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Muscle Hypotonia
Muscular Atrophy
Mental Retardation, X-Linked
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Atrophy
Pathological Conditions, Anatomical
Intellectual Disability
Neurobehavioral Manifestations
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Heredodegenerative Disorders, Nervous System
Hormones
Guaifenesin
Phenylpropanolamine
Chlorpheniramine, phenylpropanolamine drug combination
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Expectorants
Respiratory System Agents
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Appetite Depressants
Anti-Obesity Agents
Sympathomimetics