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Triac Trial II in MCT8 Deficiency Patients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02396459
Recruitment Status : Active, not recruiting
First Posted : March 24, 2015
Last Update Posted : October 31, 2022
Sponsor:
Collaborator:
Erasmus Medical Center
Information provided by (Responsible Party):
Rare Thyroid Therapeutics International AB

Brief Summary:
This study will investigate the effect of treatment with tiratricol (also called Triac) in young boys (≤30 months) with MCT8 deficiency (also called the Allan-Herndon-Dudley syndrome (AHDS)). The hypothesis tested is that treatment with tiratricol will have a beneficial effect on the hypothyroid state in the brain as well as the hyperthyroid state in peripheral organs and tissues in these patients. Patients will initially be treated for 96 weeks with tiratricol, treatment effect on neurodevelopment impairment caused by hypothyroidism and peripheral thyrotoxicosis will be evaluated after 96 weeks treatment. Patients will be offered to continue on treatment for an additional 2 years.

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

Detailed Description:

This therapeutic trial will be conducted in patients with MCT8 deficiency (also called Allan-Herndon-Dudley Syndrome (AHDS)), which is due to mutations in monocarboxylate transporter (MCT)8. MCT8 is a thyroid hormone transporter which is crucial for the transport of thyroid hormone from the blood into different tissues. Defective MCT8 results in a lack of thyroid hormone (hypothyroidism) in tissues that are dependent on MCT8 for thyroid hormone uptake, such as the brain. Hypothyroidism in the brain results in severe intellectual and motor disability. Another important feature of this disease is the high serum T3 concentrations in the blood. This results in hyperthyroidism in tissues that are not dependent on MCT8 for their thyroid hormone supply. As a result, patients with MCT8 deficiency have clinical features of thyrotoxicosis such as low body weight, elevated heart rate and reduced muscle mass.

Preclinical studies have shown that the T3 analogue tiratricol is transported into cells in an MCT8-independent manner. In animal models mimicking MCT8 deficiency, Triac has been shown to normalize brain development if administrated during early postnatal life.

Recently, Triac Trial I (NCT02060474) has shown that tiratricol treatment in patients with MCT8 deficiency improves key clinical and biochemical features caused by the toxic effects of the high T3 concentrations. No drug related serious adverse events have occurred during Triac Trial I.

This study will investigate the effect of treatment with tiratricol in young boys (≤30 months) with MCT8 deficiency (also called the Allan-Herndon-Dudley syndrome (AHDS)). The hypothesis tested is that treatment with tiratricol will have a beneficial effect on the hypothyroid state in the brain as well as the hyperthyroid state in peripheral organs and tissues in these patients. Patients will initially be treated for 96 weeks with tiratricol, treatment effect will be evaluated after 96 weeks. After the 96 week treatment period, patients will enter Part II of the trial, evaluating long-term treatment. Patients will be followed for an additional 2 years and treatment effect will be evaluated after 3 years and 4 years respectively from start of treatment.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 22 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Tiratricol Treatment of Children With Monocarboxylate Transporter 8 Deficiency: Triac Trial II
Actual Study Start Date : December 7, 2020
Estimated Primary Completion Date : June 2024
Estimated Study Completion Date : June 2026


Arm Intervention/treatment
Experimental: MCT8 deficiency patients
Triac treatment
Drug: Triac
Triac, individually titrated dose
Other Names:
  • Tiratricol
  • Teatrois




Primary Outcome Measures :
  1. Gross Motor Function Measure 88 (GMFM 88) total score [ Time Frame: 96 weeks ]
    To evaluate the effects of tiratricol on neurodevelopment in young MCT8 deficiency patients, measured by the Gross Motor Function Measure (GMFM)-88 assessment. Potential result values range from 0 to 100%, the latter being representative for a 4-year old healthy child. A high score is equivalent to better/more neurodevelopment and is therefore a better outcome than a low score.

  2. Bayley Scales of Infant Development III Gross Motor Skill Domain score [ Time Frame: 96 weeks ]
    To evaluate the effect of tiratricol treatment on neurodevelopment measured by the Bayley Scales of Infant Development (BSID-III) Gross Motor Skill Domain score. Potential total raw scores range from 0-72, and can be age-adjusted before analysis. A high score is equivalent to better/more neurodevelopment and is therefore a better outcome than a low score


Secondary Outcome Measures :
  1. GMFM-88 individual item score 10 and 24. [ Time Frame: 96 weeks ]
    GMFM-88 individual item score 10 ("lifts head upright") and item score 24 ("sit on mat"), GMFM Domain B (Sitting) - summary score of all items 18-37 ; Motor milestone responder analysis of Section 2 of the Hammersmith Infant Neurological Examination (HINE).

  2. Bayley Scales of Infant Development III score. [ Time Frame: 96 weeks ]
    To evaluate the effect of tiratricol treatment on neurodevelopment measured by the Bayley Scales of Infant Development (BSID-III). Five subscales of this assessment will be used: Cognitive, Receptive communication, Expressive communication, Fine motor and Gross motor. Potential total raw scores range from 0-91, 0-49, 0-48, 0-66 and 0-72 respectively, and can be age-adjusted before analysis. A high score is equivalent to better/more neurodevelopment and is therefore a better outcome than a low score. This holds true for all subscales.

  3. Serum T3 concentrations [ Time Frame: 96 weeks ]
    Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features.

  4. Tissue-specific markers of thyroid state: serum sex-hormone binding globulin concentrations for liver [ Time Frame: 96 weeks ]
    Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features.

  5. Tissue-specific markers of thyroid state: serum creatine kinase concentrations for muscles [ Time Frame: 96 weeks ]
    Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features.

  6. Tissue-specific markers of thyroid state: serum creatinine concentrations for kidneys [ Time Frame: 96 weeks ]
    Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features.

  7. Blood pressure [ Time Frame: 96 weeks ]
    Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features.

  8. Body weight [ Time Frame: 96 weeks ]
    Evaluate the effect of tiratricol on clinical and biochemical thyrotoxic features.


Other Outcome Measures:
  1. Patient Quality of Life by Infant Toddler Quality of Life Questionnaire (ITQoL) [ Time Frame: 96 weeks ]
    To evaluate patient´s quality of life (QoL) by Infant Toddler Quality of Life (ITQoL-SF-47) questionnaire. Item responses are scored, summed, and transformed on a scale from 0 (worst health) to 100 (best health). A high score is equivalent to better parent-reported outcomes and is therefore a better outcome than a low score.

  2. Parent Quality of Life by Parenting Stress index (PSI-4 SF) [ Time Frame: 96 weeks ]
    To evaluate parent's quality of life (QoL) by Parenting Stress Index (PSI-4 SF) questionnaire. Results are given as raw scores, percentiles and T scores, where percentiles are the primary interpretive framework. Results from 16th - 84th percentile = Normal range, 85th - 89th Percentile = High range, 90th Percentile or higher = Clinically significant range.

  3. Evaluate the effect of tiratricol treatment on neurological symptoms (Hammersmith Infant Neurological Exam, HINE) [ Time Frame: 96 weeks ]
    Hammersmith Infant Neurological Exam (HINE)

  4. Evaluate the effect of tiratricol treatment on brain function (optional) (EEG) [ Time Frame: 96 weeks ]
    Brain function outcome (optional) evaluated by EEG

  5. Evaluate the effect of tiratricol treatment on brain function (optional) (BERA) [ Time Frame: 96 weeks ]
    Brain function outcome (optional) evaluated by Brainstem Evoked Response Audiogram (BERA)

  6. Evaluate the effect of tiratricol treatment on brain function (optional) (VEP) [ Time Frame: 96 weeks ]
    Brain function/brain imaging outcome (optional) evaluated by Visual Evoked Potentials (VEP)

  7. Evaluate the effect of tiratricol treatment on brain imaging (optional) [ Time Frame: 96 weeks ]
    Brain imaging outcome (optional) evaluated by MRI/MRS - in patients where this examination is scheduled as part of a clinical praxis (at the discretion of the investigator)

  8. Estimate the elimination half-life of tiratricol in young children, reported in hours (optional and provided a medical reason prevails). [ Time Frame: 96 weeks ]
    Measurement of serum T3 concentrations before and 2, 4, 8 and 24 hours after administration of tiratricol as part of pharmacokinetic profile (optional and provided a medical reason prevails)

  9. Estimate the maximum serum concentration of tiratricol in young children, reported in nmol/L (optional and provided a medical reason prevails). [ Time Frame: 96 weeks ]
    Measurement of serum T3 concentrations before and 2, 4, 8 and 24 hours after administration of tiratricol as part of pharmacokinetic profile (optional and provided a medical reason prevails)

  10. Evaluate the occurrence of episodes of tachycardia caused by the thyrotoxicosis. [ Time Frame: 96 weeks ]
    Evaluation of cardiac rhythm and number of episodes of tachycardia with 24 hour Holter ECG.

  11. Evaluate the occurrence of premature atrial complexes (PACs) caused by the thyrotoxicosis. [ Time Frame: 96 weeks ]
    Evaluation of occurrence of PACs with 24 hour Holter ECG.

  12. Evaluate the occurrence of other arrhythmias caused by the thyrotoxicosis. [ Time Frame: 96 weeks ]
    Descriptive evaluation of occurrence of other arrhythmias with 24 hour Holter ECG.

  13. Evaluate the occurrence of structural cardiac anomalies in patients [ Time Frame: 96 weeks ]
    Evaluation of the occurrence of structural cardiac anomalies using routine trans-thoracic cardiac ultrasound.

  14. Number of participants with Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and discontinuations due to Adverse Events (AEs) [ Time Frame: 96 weeks ]
    An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An SAE is defined as an AE or suspected adverse reaction that at any dose results in any of the following outcomes: death; life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; a congenital anomaly/birth defect. Severity was graded as 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). TEAEs are defined as AEs with onset on or after the time of initiation of study drug administration.

  15. Serum free T4 (FT4) concentrations [ Time Frame: 96 weeks ]
    Evaluate the effect of tiratricol on FT4 concentrations to ensure patient safety.

  16. Serum total T4 (T4) concentrations [ Time Frame: 96 weeks ]
    Evaluate the effect of tiratricol on T4 concentrations to ensure patient safety.

  17. Serum tiratricol concentrations [ Time Frame: 96 weeks ]
    Evaluate tiratricol concentrations in serum, as estimated based on measured T3 concentrations in serum.

  18. Serum thyroid stimulating hormone (TSH) concentrations [ Time Frame: 96 weeks ]
    Evaluate the effect of tiratricol on TSH concentrations to ensure patient safety.

  19. Serum reverse T3 (rT3) concentrations [ Time Frame: 96 weeks ]
    Evaluate the effect of tiratricol on rT3 concentrations to ensure patient safety.

  20. Serum Alanine (Amino) Transaminase (ALAT) concentrations [ Time Frame: 96 weeks ]
    Evaluate the effect of tiratricol on ALAT concentrations to ensure patient safety.

  21. Serum Aspartate (Amino) Transaminase (ASAT) concentrations [ Time Frame: 96 weeks ]
    Evaluate the effect of tiratricol on ASAT concentrations to ensure patient safety

  22. Serum gamma-glutamyl transferase (gGT) concentrations [ Time Frame: 96 weeks ]
    Evaluate the effect of tiratricol on gGT concentrations to ensure patient safety.

  23. Serum alkaline phosphatase concentrations [ Time Frame: 96 weeks ]
    Evaluate the effect of tiratricol on alkaline phosphatase concentrations to ensure patient safety.

  24. Serum albumin concentrations [ Time Frame: 96 weeks ]
    Evaluate the effect of tiratricol on albumin concentrations to ensure patient safety.

  25. Serum urea concentrations [ Time Frame: 96 weeks ]
    Evaluate the effect of tiratricol on urea concentrations to ensure patient safety.

  26. Serum sodium concentrations [ Time Frame: 96 weeks ]
    Evaluate the effect of tiratricol on sodium concentrations to ensure patient safety.

  27. Serum potassium concentrations [ Time Frame: 96 weeks ]
    Evaluate the effect of tiratricol on potassium concentrations to ensure patient safety.

  28. White blood cell total and differential count [ Time Frame: 96 weeks ]
    Evaluate the effect of tiratricol on white blood cell total and differential count to ensure patient safety.

  29. Red blood cell count [ Time Frame: 96 weeks ]
    Evaluate the effect of tiratricol on red blood cell count to ensure patient safety.

  30. Platelet count [ Time Frame: 96 weeks ]
    Evaluate the effect of tiratricol on platelet cell count to ensure patient safety.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 30 Months   (Child)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Signed and dated informed consent form from the parents or legal guardian.
  • Parents stated willingness to comply with all study procedures and availability for the duration of the study.
  • The participant should be aged between 0 and 30 months on the day of inclusion.
  • The participant should be male and have a pathogenic mutation in the MCT8 gene.

Exclusion Criteria:

  • Previous treatment with tiratricol.
  • Previous treatment with LT4 and/or PTU and/or other anti-thyroid medication for a period longer than three months. Patients previously treated with LT4 for a shorter period than 3 months may be included in the study (baseline visit) six weeks (or longer) after last dose of LT4 if two consecutive analyses show stable TFT*. Patients treated with PTU and/or other anti-thyroid medication for a shorter period than three months may be included in the study (baseline visit) six weeks (or longer) after last dose.
  • Major illness or recent major surgery (within four weeks of baseline visit 1) unrelated to MCT8 deficiency.
  • Known allergic reactions to components of the IMP. Patients with galactose intolerance, Lapp lactase deficiency or malabsorption of glucose or galactose (the IMP contains lactose).
  • Treatment with another investigational drug or participation in other interventional trial within three months prior to baseline visit 1.

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): NCT02396459


Locations
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United States, Oregon
Oregon Health & Science University (OHSU) Doernbecher Childrens Hospital
Portland, Oregon, United States, 97239
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Czechia
Charles University and Motol University Hospital; The department of peadiatrics of the 2nd faculty of medicine
Praha, Czechia, 15006
Germany
Charité - Universitätsmedizin Berlin Institut fur experimental paediatrische endokrinologie
Berlin, Germany, 13353
Netherlands
Erasmus MC
Rotterdam, Netherlands, 3015 GD
Sponsors and Collaborators
Rare Thyroid Therapeutics International AB
Erasmus Medical Center
Investigators
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Principal Investigator: W.E. Visser, MD, PhD Erasmus MC
Study Director: Kristina Sjöblom Nygren, MD Rare Thyroid Therapeutics
Principal Investigator: Stephen LaFranchi_Nicol Oregon Health& Science University (OHSU) Doernbecher Childrens Hospital
Principal Investigator: Jan Lebl Charles University and Motol University Hospital
Principal Investigator: Heiko Krude Charité - Universitätsmedizin Berlin Institut fur experimental paediatrische endokrinologie
Principal Investigator: Andrew Bauer, MD Children's Hospital of Philadelphia
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Responsible Party: Rare Thyroid Therapeutics International AB
ClinicalTrials.gov Identifier: NCT02396459    
Other Study ID Numbers: MCT8-2019-2
First Posted: March 24, 2015    Key Record Dates
Last Update Posted: October 31, 2022
Last Verified: October 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Rare Thyroid Therapeutics International AB:
Triac
MCT8
MCT8 deficiency
Allan-Herndon-Dudley Syndrome