Thyroid Hormone Analog Therapy in MCT8 Deficiency: Triac Trial Patients

NCT02060474 | Completed Phase 2 DMC

• 2 other identifiers: MCT8-2014-12014-000178-20
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 1

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. 1.Triac binds to the same TH receptors as T3;
2. 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. 3.In vitro studies have shown that neuronal cells differentiate equally well in the presence of either Triac or T3;
4. 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. 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 .
6. 6.reduces the toxic effects of the high T3 levels
7. 7.restores the local TH deficiency in brain.

Conditions

Allan-Herndon-Dudley Syndrome

Keywords

Allan-Herndon-Dudley Syndrome; MCT8; Triac; Therapeutic Trial

Outcome Measures

Primary Outcomes (5)

• serum T3 concentrations

  Serum T3 concentrations will be determined to assess the effect of Triac

  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

  Serum free T4 concentrations will be determined to assess the effect of Triac (co-primary end-point, supportive to changes in T3).

  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

  Serum TSH concentrations will be determined to assess the effect of Triac (co-primary end-point, supportive to changes in T3).

  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

  Serum total T4 concentrations will be determined to assess the effect of Triac(co-primary end-point, supportive to changes in T3).

  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

  Serum reverse T3 concentrations will be determined to assess the effect of Triac(co-primary end-point, supportive to changes in T3).

  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

Secondary Outcomes (6)

• Heart rate

  baseline and month 12 will be compared

• serum sex-hormone binding globulin concentrations

  baseline and month 12 will be compared

• Body weight

  baseline and month 12 will be compared

• Blood pressure

  baseline and month 12 will be compared

• serum total cholesterol concentrations

  baseline and month 12 will be compared

Other Outcomes (9)

• Monitoring of adverse effects.

  up to one year (= whole study period)

• A routine trans-thoracic cardiac ultrasound

  12 months

• ECG

  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.

Study Arms (1)

AHDS patients

EXPERIMENTAL

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

Interventions

Triac DRUG

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

Also known as: Tiratricol, Téatrois, TA3

AHDS patients

Eligibility Criteria

• Age: 1 Day - 99 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Erasmus Medical Center: lead
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator

Study Sites (1)

Erasmus Medical Center

Rotterdam, South Holland, 3000 CA, Netherlands

Location

Related Publications (1)

• Groeneweg S, Peeters RP, Moran C, Stoupa A, Auriol F, Tonduti D, Dica A, Paone L, Rozenkova K, Malikova J, van der Walt A, de Coo IFM, McGowan A, Lyons G, Aarsen FK, Barca D, van Beynum IM, van der Knoop MM, Jansen J, Manshande M, Lunsing RJ, Nowak S, den Uil CA, Zillikens MC, Visser FE, Vrijmoeth P, de Wit MCY, Wolf NI, Zandstra A, Ambegaonkar G, Singh Y, de Rijke YB, Medici M, Bertini ES, Depoorter S, Lebl J, Cappa M, De Meirleir L, Krude H, Craiu D, Zibordi F, Oliver Petit I, Polak M, Chatterjee K, Visser TJ, Visser WE. Effectiveness and safety of the tri-iodothyronine analogue Triac in children and adults with MCT8 deficiency: an international, single-arm, open-label, phase 2 trial. Lancet Diabetes Endocrinol. 2019 Sep;7(9):695-706. doi: 10.1016/S2213-8587(19)30155-X. Epub 2019 Jul 31.

  PMID: 31377265 DERIVED

MeSH Terms

Conditions

Allan-Herndon-Dudley syndrome

Interventions

3,3',5-triiodothyroacetic acid

Study Officials

• W.E. Visser, dr,

  Erasmus Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr.

Study Record Dates

• First Submitted: February 5, 2014
• First Posted: February 12, 2014
• Study Start: October 1, 2014
• Primary Completion: June 26, 2018
• Study Completion: June 26, 2018
• Last Updated: April 16, 2019

Record last verified: 2019-04

Locations

NL (1)