Clinical Trial: Triac Trial II in MCT8 Patients

Study Status: Not yet recruiting
Recruit Status: Not yet recruiting
Study Type: Interventional

Official Title: Effects of the Thyroid Hormone Analog Triac on the Neurocognitive Phenotype in Patients With Severe Psychomotor Retardation Caused by Mutations in the MCT8 Thyroid Hormone Transporter: The Triac Trial

Brief Summary:

Triac Trial II will assess the effects of Triac therapy on several neurocognitive end-points in patients with the Allan-Herndon-Dudley Syndrome (AHDS).

Patients with the AHDS suffer from severe psychomotor retardation. A mutation in the TH transporter protein Monocarboxylate transporter 8 (MCT8) results in reduced thyroid hormone (TH) levels in de brain, leading to an impaired neuronal differentiation. The severe neurological phenotype is accompanied by increased T3 levels in the blood, resulting in a variety of thyrotoxic symptoms such as tachycardia, increased metabolism, weight loss and a low muscle mass.

Currently, Triac Trial I (NCT02060474) investigates if Triac treatment in AHDS patients reduces the toxic effects of the high T3 levels. In addition, the safety of Triac administration in AHDS patients is assessed.

In Triac Trial II we will focus on the effects of Triac on the neurocognitive development.


Detailed Summary:

This therapeutical trial will be conducted in patients with the Allan-Herndon-Dudley Syndrome (AHDS), which is due to 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 re
    Sponsor: Erasmus Medical Center

    Current Primary Outcome: Structural and functional changes of the brain by brain imaging: MRI [ Time Frame: 60 months ]

    Scans will be will be performed during the first visit of the trial (T0) and every 12 months (T12)


    Original Primary Outcome: Same as current

    Current Secondary Outcome:

    • EEG [ Time Frame: 60 months ]
      Brain activity and detection and monitoring of epileptic activity by Electroencephalography (EEG) Timeframe: during the first visit of the trial (T0) and every 12 months (T12)
    • serum T3 [ Time Frame: 60 months ]
      Participants will be evaluated with an expected average of 2 weeks during months 1-3 of the trial. Thereafter, participants will be evaluated with an expected average of 4 months.
    • tissue-specific markers of thyroid state [ Time Frame: 60 months ]
      Participants will be evaluated with an expected average of 2 weeks during months 1-3 of the trial. Thereafter, participants will be evaluated with an expected average of 4 months.
    • Motor function by Gross Motor Function Measure (GMFM) [ Time Frame: 60 months ]
      Motor function will be assessed every 12 months using the GMFM
    • Cognitive function by Bayley Scales of Infant Development III or Wechsler Preschool and Primary Scale of Intelligence (WPPSI) II [ Time Frame: 60 months ]
      The cognitive function will be assessed every 12 months using the Bayley Scales of Infant Development III or Wechsler Preschool and Primary Scale of Intelligence (WPPSI) II depending on the estimated cognitive age.
    • Adaptive behavior by the Vineland adaptive behavior scale [ Time Frame: 60 months ]
      Adaptive behavior will be assessed every 12 months using the Vineland adaptive behavior scale


    Original Secondary Outcome: Same as current

    Information By: Erasmus Medical Center

    Dates:
    Date Received: March 7, 2015
    Date Started: July 2016
    Date Completion: December 2022
    Last Updated: January 25, 2016
    Last Verified: January 2016