Tiratricol Withdrawal for Monocarboxylate Transporter 8 Deficiency

(ReTRIACt Trial)

Recruiting at 6 trial locations

Overseen By Kristina Sjoblom Nygren

Age: Any Age

Sex: Male

Trial Phase: Phase 3

Sponsor: Rare Thyroid Therapeutics International AB

Must be taking: Tiratricol

Must not be taking: T3 analogues, Levothyroxine

Disqualifiers: Major illness, Recent surgery, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

16 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a double-blind, randomized phase 3 multicenter placebo-controlled study in at least 16 evaluable male participants diagnosed with MCT8 deficiency. Male participants, from 4 years of age (at randomization) and having demonstrated stable maintenance treatment with tiratricol, will be randomized to receive placebo or tiratricol for 30 days or until reaching rescue criterion (serum total triiodothyronine \[T3\] \> upper limit of normal \[ULN\] of the participant's normal range, for a sample collected during the 30-day Randomized Treatment Period). The research hypothesis to be tested is that, for participants in the placebo group, removal of tiratricol will lead to an increase of serum total T3 concentration, measured by liquid chromatography with tandem mass spectrometry (LC/MS/MS), above the ULN and requirement of rescue treatment with tiratricol, compared to those who continue to receive tiratricol.

Do I need to stop my current medications for this trial?

The trial requires participants to have stable maintenance treatment with tiratricol, but it does not specify if you need to stop other medications. However, you cannot use other T3 analogues, levothyroxine, or propylthiouracil during the study.

What data supports the effectiveness of the drug Tiratricol for Monocarboxylate Transporter 8 Deficiency?

Research shows that Triac (Tiratricol) can help improve symptoms in patients with MCT8 deficiency by reducing high T3 levels and supporting brain development, as it can enter cells without needing the MCT8 transporter. Studies in both humans and mice indicate that Triac can alleviate peripheral thyrotoxicosis and improve neurological outcomes. ^{1 2 3 4 5}

Is Tiratricol (Triac) safe for humans?

Research shows that Tiratricol (Triac) has been used in treating MCT8 deficiency, and it is generally considered safe for this condition. However, it is important to note that its effects and safety profile may vary, and it should be used under medical supervision. ^{2 3 4 6 7}

How is the drug Tiratricol unique for treating MCT8 deficiency?

Tiratricol (TRIAC) is unique for treating MCT8 deficiency because it is a thyroid hormone analogue that can reduce the high levels of T3 (a thyroid hormone) in the body, which are not effectively managed by standard thyroid hormone treatments. It helps alleviate peripheral thyrotoxicosis (excess thyroid hormone effects outside the brain) and may prevent further neurological damage, offering a novel approach where other treatments are limited. ^{1 2 3 4 7}

Research Team

Andrew Bauer, MD

Principal Investigator

Children's Hospital of Philadelphia

W. E. Visser

Principal Investigator

Erasmus Medical Center

Eligibility Criteria

This trial is for male participants aged 4 or older with MCT8 deficiency, a genetic condition. They must have been on stable tiratricol treatment and not have major illnesses or surgeries that could affect the study. Participants need to weigh at least 10 kg and cannot be in other studies or have allergies to tiratricol components.

Inclusion Criteria

I am a male with a confirmed MCT8 gene mutation.

Signed and dated informed consent form from the parents or legal guardian

Your thyroid hormone levels are too high according to your age, or you are currently being treated with tiratricol.

Exclusion Criteria

Major illness or recent major surgery unrelated to MCT8 deficiency (in the principal investigator's judgement), defined as conditions requiring repeated hospitalizations that are likely to confound ability to participate in the trial, major illness in the 3 months prior to the screening visit that is likely to confound the ability of the participant to participate fully within the trial and/or confound the assessment of serum total T3 and/or safety, major surgery within the 3 months prior to the screening visit or planned to take place during the study, including but not limited to major abdominal/thoracic/neurosurgical procedures, major/minor abdominal and/or maxillofacial surgery that may inhibit the administration and/or absorption of study drug, body weight <10 kg at the Screening Visit, patients who are participating, or intend to participate, in other therapeutic and/or interventional clinical studies during the study period, history of allergic reactions to components of tiratricol or any excipients in the investigational product (IP), participants with any contra-indication for treatment with tiratricol or any excipients in the IP, participants using other T3 analogues, levothyroxine, or propylthiouracil

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Run-in/Dose Titration

Participants receive open-label tiratricol to establish a stable maintenance dose

4-16 weeks

Every 4 weeks (in-person)

Randomized Treatment

Participants are randomized to receive either tiratricol or placebo for 30 days or until rescue criterion is met

4 weeks

Day 1, Day 8, Day 15, Day 22, Day 30 (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 weeks

Week 1, Week 6 (in-person)

Treatment Details

Interventions

• Placebo
• Tiratricol

Trial Overview The study tests if stopping tiratricol increases serum total T3 levels compared to those who continue it. It's a double-blind, randomized trial where males with MCT8 deficiency either receive placebo or continue tiratricol for up to 30 days.

Participant Groups

Group I: Tiratricol Experimental Treatment 1 Intervention

Group II: Placebo Placebo Group 1 Intervention

Tiratricol is already approved in European Union for the following indications:

Approved in European Union as Emcitate for:

• Peripheral thyrotoxicosis in patients with monocarboxylate transporter 8 (MCT8) deficiency

Who Is Running the Clinical Trial?

Rare Thyroid Therapeutics International AB

Lead Sponsor

Trials

4

Recruited

60+

Premier Research Group plc

Industry Sponsor

Trials

65

Recruited

74,200+

John Ratliff

Premier Research Group plc

Chief Executive Officer since 2024

MBA

Dr. Milena Kanova-Petrova

Premier Research Group plc

Chief Medical Officer since 2024

MD

Egetis Therapeutics

Industry Sponsor

Trials

10

Recruited

920+

Findings from Research

In a study involving four children with MCT8 deficiency treated with the thyroid hormone analog DITPA for 26-40 months, DITPA effectively normalized elevated thyroid hormone levels and improved metabolic parameters without adverse effects.

The treatment led to significant improvements, including weight stabilization and a reduction in hypermetabolism, indicating that DITPA could be a promising alternative therapy for children with MCT8 deficiency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diiodothyropropionic acid (DITPA) in the treatment of MCT8 deficiency. Verge, CF., Konrad, D., Cohen, M., et al.[2021]

In a phase 2 trial involving 46 patients with MCT8 deficiency, treatment with the T3 analogue Triac significantly reduced serum T3 concentrations from 4.97 nmol/L to 1.82 nmol/L over 12 months, indicating effective management of peripheral thyrotoxicosis.

Triac treatment was associated with a decrease in thyroid-stimulating hormone (TSH) and free T4 levels, with only mild treatment-related adverse events reported, suggesting it is a safe and effective option for alleviating symptoms in patients with this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Groeneweg, S., Peeters, RP., Moran, C., et al.[2022]

MCT8 deficiency leads to a unique condition where patients experience hypothyroidism in the brain while having high levels of T3 in the rest of the body, which can affect neurodevelopment.

The treatment with TRIAC, a thyroid hormone analogue, has been assessed in 4 patients, showing its potential to manage peripheral hyperthyroidism and possibly slow down neurological decline, although specific outcomes from the treatment were not detailed in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment with TRIAC in pediatric patients with MCT8. Gazek, N., Feller, AL., Vaiani, E., et al.[2023]

In Mct8-deficient mice, treatment with therapeutic doses of triiodothyroacetic acid (TRIAC) successfully normalized plasma T3 levels but significantly decreased T4 levels, indicating a complex interaction with thyroid hormone regulation.

TRIAC treatment did not enhance the expression of T3-dependent genes in the brain, suggesting that while it affects plasma hormone levels, it may lead to a state of brain hypothyroidism due to insufficient TRIAC levels in the brain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Triiodothyroacetic Acid Treatment in Mct8 Deficiency: A Word of Caution. Bárez-López, S., Obregon, MJ., Martínez-de-Mena, R., et al.[2020]

The study shows that the thyroid hormone analog Triac (TA3) can effectively bypass the defective MCT8 transporter, allowing for normal uptake in cells from patients with Allan-Herndon-Dudley syndrome, which is caused by MCT8 mutations.

In animal models, treatment with TA3 restored T3-dependent neural differentiation, suggesting that TA3 could be a promising therapeutic strategy to improve brain development in individuals with MCT8-related disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro and mouse studies supporting therapeutic utility of triiodothyroacetic acid in MCT8 deficiency. Kersseboom, S., Horn, S., Visser, WE., et al.[2020]

3,3',5-triiodothyroacetic acid (TA3) is a thyroid hormone analog that has potential therapeutic applications, particularly for treating resistance to thyroid hormone syndromes like MCT8 deficiency.

TA3 differs from the bioactive hormone T3 in how it is transported across cell membranes and its ability to activate specific thyroid hormone receptors, which may influence its effectiveness as a treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Triiodothyroacetic acid in health and disease. Groeneweg, S., Peeters, RP., Visser, TJ., et al.[2017]

The thyroid hormone analog TRIAC significantly interferes with commercial total and free T3 assays, leading to overestimation of T3 levels in patients, which could mislead clinical assessments.

Due to this cross-reactivity, it is recommended that patients on TRIAC therapy use alternative nonimmunoassay-based methods for monitoring T3 hormone levels to ensure accurate thyroid function evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Triiodothyroacetic Acid Cross-Reacts With Measurement of Triiodothyronine (T3) on Various Immunoassay Platforms. Chan, SL., Refetoff, S., Babic, N., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Diiodothyropropionic acid (DITPA) in the treatment of MCT8 deficiency. [2021]

2. England pubmed.ncbi.nlm.nih.gov

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. [2022]

3. Argentina pubmed.ncbi.nlm.nih.gov

Treatment with TRIAC in pediatric patients with MCT8. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Effect of Triiodothyroacetic Acid Treatment in Mct8 Deficiency: A Word of Caution. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

In vitro and mouse studies supporting therapeutic utility of triiodothyroacetic acid in MCT8 deficiency. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Triiodothyroacetic acid in health and disease. [2017]

7. England pubmed.ncbi.nlm.nih.gov

Triiodothyroacetic Acid Cross-Reacts With Measurement of Triiodothyronine (T3) on Various Immunoassay Platforms. [2022]