Thyroid Hormone Analog Therapy in MCT8 Deficiency: Triac Trial Patients

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

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.

Study Overview

• Status: Completed
• Conditions: Allan-Herndon-Dudley Syndrome
• Intervention / Treatment: Drug: Triac

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.

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • South-Holland
    • Rotterdam, South-Holland, Netherlands, 3000 CA
      • Erasmus Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 97 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: Tiratricol, Téatrois, TA3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart rate	Heart rate will be measures with an ECG and 24 h ambulatory monitoring	baseline and month 12 will be compared
serum sex-hormone binding globulin concentrations	serum sex-hormone binding globulin concentrations will be measured as a proxi-parameter for tissue thyroid hormone status in the liver.	baseline and month 12 will be compared
Body weight	Body weight will be measured in kg	baseline and month 12 will be compared
Blood pressure	Blood pressure will be measured in mmHg	baseline and month 12 will be compared
serum total cholesterol concentrations	serum total cholesterol concentrations will be measured as a proxi-parameter for tissue TH status in the liver.	baseline and month 12 will be compared
serum creatine kinase concentrations	serum creatine kinase concentrations will be measured as a proxi-parameter for tissue TH status in the muscles.	baseline and month 12 will be compared

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Monitoring of adverse effects.	Family members and caregivers of the included patients will be asked to report all adverse effects to one of the investigators.	up to one year (= whole study period)
A routine trans-thoracic cardiac ultrasound	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.	12 months
ECG	The effect of Triac on the heart rhythm will be assessed with an 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.
Bone Mineral Density (total body)	Bone mineral density of total body will be measured by DXA scan	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
Motor function, using the Gross Motor Function Measure	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	baseline and month 12 will be compared
Cognitive function using the Bayley Scales of Infant Development III	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	baseline and month 12 will be compared
Adaptive behavior by the Vineland adaptive behavior scale	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	baseline and month 12 will be compared
Bone Mineral Density of ultradistal ulna	Bone mineral density of ultradistal ulna will be measured by DXA scan	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	Bone mineral density of ultradistal radius will be measured by DXA scan	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

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development
• Investigators: Principal Investigator: W.E. Visser, dr,, Erasmus Medical Center

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2014
• Primary Completion (Actual): June 26, 2018
• Study Completion (Actual): June 26, 2018

Study Registration Dates

• First Submitted: February 5, 2014
• First Submitted That Met QC Criteria: February 10, 2014
• First Posted (Estimate): February 12, 2014

Study Record Updates

• Last Update Posted (Actual): April 16, 2019
• Last Update Submitted That Met QC Criteria: April 12, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: MCT8; Triac; Allan-Herndon-Dudley Syndrome; Therapeutic Trial
• Other Study ID Numbers: MCT8-2014-1; 2014-000178-20 (EudraCT Number)