Tiratricol Withdrawal for Monocarboxylate Transporter 8 Deficiency

(ReTRIACt Trial)

No longer 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether stopping the medication tiratricol affects T3 levels in males with MCT8 deficiency, a genetic condition that impacts thyroid hormone transport. Participants will either continue their tiratricol treatment or switch to a placebo (a harmless pill with no active drug) for 30 days. The researchers aim to determine if those on the placebo need to resume tiratricol due to increased T3 levels. This trial is suitable for males over 4 years old who have been diagnosed with MCT8 deficiency and are stable on tiratricol. As a Phase 3 trial, it represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment validation.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A previous study showed that tiratricol is safe for people with MCT8 deficiency. Research indicates that tiratricol treatment aids weight gain and partially balances thyroid hormones, which are crucial for health. Reports from long-term use, even up to six years, support its safety, with no major concerns raised.

Overall, tiratricol appears well-tolerated, meaning most people do not experience serious side effects. This suggests that tiratricol is generally safe for human use, especially for those with MCT8 deficiency. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for MCT8 deficiency?

Tiratricol is unique because it targets Monocarboxylate Transporter 8 (MCT8) deficiency, a rare genetic disorder, in a novel way. Unlike current treatments that focus on managing symptoms, Tiratricol works differently by potentially addressing the underlying hormonal imbalances linked to MCT8 deficiency. This could mean more direct and effective management of the condition, offering hope for improved outcomes for patients. Researchers are excited about Tiratricol because it might provide a more targeted approach, leading to better quality of life for those affected.

What is the effectiveness track record for tiratricol in treating MCT8 deficiency?

Research has shown that tiratricol, which participants in this trial may receive, effectively treats Monocarboxylate Transporter 8 (MCT8) deficiency. Studies have found that tiratricol can help patients gain weight and partly balance their thyroid hormone levels, which is crucial for managing this condition. Long-term data from up to 67 patients indicates that tiratricol remains effective and safe, even with several years of use. In both children and adults with MCT8 deficiency, tiratricol has consistently produced positive results. These findings suggest that tiratricol could be a promising treatment option for those affected by MCT8 deficiency. Participants in this trial may also receive a placebo as part of the study design. ^{1 2 4 6 7}

Who Is on the Research Team?

Andrew Bauer, MD

Principal Investigator

Children's Hospital of Philadelphia

W. E. Visser

Principal Investigator

Erasmus Medical Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Collaborator

Premier Research Group plc

Collaborator

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 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]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S2214624525000218

Real-World Tiratricol Treatment Outcomes and the ... Tiratricol treatment enabled weight gain and partial thyroid hormone normalization. Abstract. Monocarboxylate transporter 8 (MCT8) deficiency, ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8852204/

Long-Term Efficacy of T3 Analogue Triac in Children and ... Long-term efficacy of T3 analogue triac in children and adults with MCT8 deficiency: a real-life retrospective cohort study.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02396459

NCT02396459 | Triac Trial II in MCT8 Deficiency Patients This study will investigate the effect of treatment with tiratricol (also called Triac) in young boys (≤30 months) with MCT8 deficiency (also ...

4. egetis.com egetis.com/mfn_news/new-data-confirms-long-term-efficacy-and-safety-of-emcitate-in-mct8-deficiency-patients/

New data confirms long-term efficacy and safety of ... Strong data from long-term treatment, up to 6 years, of 67 patients with the company's leading drug candidate Emcitate (tiratricol) has been published.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11310894/

Unmet patient needs in monocarboxylate transporter 8 (MCT8 ... MCT8 deficiency is a rare, X-linked disorder arising from mutations in the SLC16A2 gene and resulting from dysfunctional thyroid hormone transport.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05911399?cond=Mct8%20%5C(Slc16A2%5C)-Specific%20Thyroid%20Hormone%20Cell%20Transporter%20Deficiency&rank=3

Expanded Access Program for Tiratricol in Patients With ... Adverse events (AEs) and serious adverse events (SAEs) will be recorded and reported as per FDA regulations. Official Title. Expanded Access Program for ...

7. thelancet.com thelancet.com/journals/landia/article/PIIS2213-8587(19)30155-X/fulltext

Effectiveness and safety of the tri-iodothyronine analogue ... Deficiency of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) causes severe intellectual and motor disability and high ...