This study has been transitioned to CTIS with ID 2024-516124-34-00 check the CTIS register for the current data. Primary Objective:• To evaluate the effects of withdrawal of tiratricol treatment (placebo group) on serum total triiodothyronine (T3)…
ID
Source
Brief title
Condition
- Endocrine disorders congenital
- Thyroid gland disorders
- Neuromuscular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Proportion of participants who meet the rescue criterion (serum total
T3 > ULN) from samples obtained during the 30-day double-blind
Randomized Treatment Period
Secondary outcome
Secondary efficacy endpoints:
• Change in serum thyroid hormone variables (T3, T4, TSH, fT3, and fT4) from
baseline (start of the Randomized Treatment Period) to the end of
Randomized Treatment Period (completion or rescue)
• Change in serum thyroid hormone variables (T3, T4, TSH, fT3, and fT4) from
initiation of tiratricol administration at screening to the last
measurement prior to randomization (Cohort B only)
• Change in the cardiovascular variables from extended ECG assessments, 24-hour
ABPM, and heart rate assessments from the last measurement prior to the start
of the Randomized Treatment Period to the end of the Randomized Treatment
Period (completion or rescue)
• Serum concentrations of tiratricol
• Change in serum SHBG from baseline (start of the Randomized Treatment Period)
to the end of the Randomized Treatment Period (completion or
rescue)
• Time (days) from randomization to the time when the rescue criterion is met
or the time of completion of the Randomized Treatment Period (whichever comes
first)
Exploratory efficacy endpoints:
• Change in serum thyroid hormone variables (T3, T4, TSH, fT3, and fT4) from
baseline (start of the Randomized Treatment Period) to the end of the Follow-up
Period
• Change in serum thyroid hormone variables (T3, T4, TSH, fT3, and fT4) from
the end of the Randomized Treatment Period (completion or rescue) to the end of
the Follow-up Period
• Evaluation of sleep variables recorded in parent/caregiver diaries and
questionnaires from enrollment to completion of the study
• Number and structure of tiratricol metabolites
• Individual metabolite concentrations and metabolite:tiratricol ratios
• Population PK outputs for tiratricol
• Relationship between serum total T3 concentrations and serum concentrations
of tiratricol
• Relationship
Background summary
Thyroid hormone is important for the development of the brain and many other
tissues. To perform its action, the hormone needs to enter the cells of these
tissues via *gates/channels*. One of these gates is called MCT8. The brain
depends on MCT8 to allow thyroid hormone to enter. If MCT8 is not working
properly (as happens in MCT8 deficiency), less or no thyroid hormone will enter
the brain, resulting in developmental abnormalities. This is the cause of the
severe developmental delays and neurological problems which are seen in
patients with MCT8 deficiency.
At the same time, other body tissues, such as the muscles and liver, do not
depend on MCT8 to allow thyroid hormone to enter their cells. In patients with
MCT8 deficiency, the blood level of active thyroid hormone in these organs is
too high, which results in adverse effects such as muscle wasting, a low body
weight and peripheral thyrotoxicosis.
Unfortunately, there is no approved effective treatment for patients with MCT8
deficiency available at the moment. In the past, the standard treatment for
overactive thyroid, consisting of anti-thyroid medication in combination with
the administration of the thyroid hormone levothyroxine has been used in
patients with MCT8 deficiency. This (potentially) has a positive effect on the
negative effects of the increased level of the active thyroid hormone in body
tissues other than the brain. This treatment does not increase the level of
active thyroid hormone in the brain and is therefore not expected to have a
positive effect on the developmental disorder. This treatment is therefore not
currently used in patients with MCT8 deficiency.
Tiratricol (also known as Triac) is a specific kind of thyroid hormone that
does not need to use the MCT8 normal pathway for thyroid hormones to get into
the brain. The purpose of this research study is to learn more about the use of
the new study medicine tiratricol for the treatment of MCT8 deficiency. This
research study will include 16 boys from 4 years of age who all have MCT8
deficiency
Study objective
This study has been transitioned to CTIS with ID 2024-516124-34-00 check the CTIS register for the current data.
Primary Objective:
• To evaluate the effects of withdrawal of tiratricol treatment (placebo group)
on serum total triiodothyronine (T3) concentrations, measured by liquid
chromatography with tandem mass spectrometry (LC/MS/MS), and the
requirement for rescue treatment with tiratricol as compared to continuing
tiratricol treatment (tiratricol group), in males diagnosed with MCT8
deficiency and on a stable maintenance dose of tiratricol
Secondary Objectives:
• To evaluate the safety and tolerability of tiratricol treatment
• To evaluate the effect of tiratricol treatment upon serum thyroid hormone
measurements, sex hormone binding globulin (SHBG), and cardiovascular
measurements
• To evaluate the serum concentrations of tiratricol
Exploratory Objectives:
• To evaluate the effect of tiratricol treatment upon serum thyroid hormone
measurements (from baseline to the end of the Follow-up Period)
• To evaluate the effect of tiratricol treatment upon basic sleep measurements
as
recorded in parent/caregiver diaries and questionnaires
• To investigate the presence and identity of metabolites of tiratricol
• To explore the relationship between pharmacokinetics (PK) and safety and
efficacy endpoints, and the impact of participant characteristics on PK
Study design
This is a 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 on stable maintenance
treatment with tiratricol, will be randomized to receive placebo or tiratricol
for 30 days.
Intervention
Participants from study Cohorts A and B who meet the Stable Dose Criterion and
all randomization criteria will enter the Randomized Treatment Period. These
participants will be randomized 1:1 in a double-blind manner to receive
treatment for 30 days or until the rescue criterion is met (whichever comes
first) in one of the following arms:
Tiratricol group: Continue the participant*s stable maintenance dose of
tiratricol treatment as administered in the Run-in/Dose Titration Period (when
Stable Dose Criterion confirmed).
Placebo group: Same frequency of dosing, and number of tablets per dose, as the
stable maintenance dose prior to randomization using matched placebo tablets.
Study burden and risks
Given the low quality of life, the absence of an effective therapy, the
expected beneficial effects on chronic thyrotoxicosis in patients with MCT8
deficiency, the risks to and the burden for the participants will be at least
in proportion to the potential value of the research and the beneficial effects
for the participating MCT8 deficiency patients. In addition, participants will
be invited to participate in a compassionate-use program after they finish the
present study, which offers the benefit of continued access to a potentially
effective treatment, when there are no alternatives available.
Klara Norra Kyrkogata 26
Stockholm SE 111 22
SE
Klara Norra Kyrkogata 26
Stockholm SE 111 22
SE
Listed location countries
Age
Inclusion criteria
1. Male participants diagnosed with a pathogenic mutation in the MCT8 gene,
confirmed with a genetic test.
2. Serum total T3 concentration above the ULN of the age-specific normal range:
a) at the time of diagnosis (or the closest sample taken prior to first ever
treatment with tiratricol) for participants who are currently treated with
tiratricol
b) in the Screening Visit sample, or most recent standard of care sample prior
to screening, for participants who have never received and/or currently not
receiving tiratricol.
3. Participants will be aged 4 years or older at the time of randomization.
Participants entering screening who are <4 years of age but expected to be aged
4 years at randomization should be discussed with the medical monitor.
4. Signed and dated informed consent form from the parents or legal guardian.
Exclusion criteria
1. 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.
2. Body weight <10 kg at the Screening Visit.
3. Patients who are participating, or intend to participate, in other
therapeutic
and/or interventional clinical studies during the study period.
4. History of allergic reactions to components of tiratricol or any excipients
in
the investigational product (IP).
5. Participants with any contra-indication for treatment with tiratricol or any
excipients in the IP.
6. Participants using other T3 analogues, levothyroxine, or propylthiouracil.
In addition to these eligibility criteria, participants must meet further
criteria at the time
of randomization to enter the Randomized Treatment Period.
Randomization criteria:
1. Confirmation that the *Stable Dose Criterion* has been met.
2. Absence of any new or exacerbated medical or surgical condition that fulfils
Exclusion criterion #1.
3. Confirmation that participant is at least 4 years of age at the time of
randomization.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-516124-34-00 |
| EudraCT | EUCTR2022-001478-78-NL |
| ClinicalTrials.gov | NCT05579327 |
| CCMO | NL81812.078.22 |