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Completed

NCT Number: NCT02060474

Thyroid Hormone Analog Therapy in MCT8 Deficiency: Triac Trial Patients

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.

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Key information

Conditions

Allan-Herndon-Dudley Syndrome

Age range

1 day–99 year

Sex eligibility

Male

Study type

Interventional

Phase

Phase 2

Primary location

Erasmus Medical Center

Rotterdam, South Holland, 3000 CA, Netherlands

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Triac

Drug

Triac is a naturally occuring T3 metabolite with similar bioactivity and receptor binding profile.

Other names: Tiratricol, Téatrois, TA3

Primary outcomes

  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 outcomes

  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 outcomes

  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

Sponsors and collaborators

Lead sponsor

Erasmus Medical Center

Other

Collaborators

  • ZonMw: The Netherlands Organisation for Health Research and Development

Registry information

Official study title

Thyroid Hormone Analog Therapy of Patients With Severe Psychomotor Retardation Caused by Mutations in the MCT8 Thyroid Hormone Transporter: The Triac Trial.

Important dates

Study start
2014
Primary completion
2018
Study completion
2018
First posted
Feb 12, 2014
Registry last updated
Apr 16, 2019

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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