Allan-Herndon-Dudley SyndromePhase 2NCT02060474
Thyroid Hormone Analog Therapy in MCT8 Deficiency: Triac Trial Patients
A Phase 2 study testing Triac in people with Allan-Herndon-Dudley Syndrome, run by Erasmus Medical Center at 1 site in Netherlands.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 1 day to 99 years, men only
- Conditions the study is for
- Allan-Herndon-Dudley Syndrome
- What is being tested?
- Triac
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 46 participants
- Where
- 1 siteNetherlands
- Study dates
- Oct 2014to 26 Jun 2018
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 day to 99 years
- Men only
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- clinically relevant mutation in the MCT8 gene, resulting in the clinical phenotype of AHDS.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
Erasmus Medical Center
Rotterdam, South Holland, 3000 CA
About this study
Official title: 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.
Read more
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:
- Triac binds to the same TH receptors as T3;
- 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;
- In vitro studies have shown that neuronal cells differentiate equally well in the presence of either Triac or T3;
- In Mct8 deficient mice, Triac is taken up by the brain and suppresses serum TSH levels; consequently, serum T3 and T4 levels were lowered;
- 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
- reduces the toxic effects of the high T3 levels
- restores the local TH deficiency in brain.
Read the 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.
- Conditions
- Allan-Herndon-Dudley Syndrome
- Being tested
- Triac
- Keywords
- Allan-Herndon-Dudley Syndrome, MCT8, Triac, Therapeutic Trial
- Medical subject headings
- Allan-Herndon-Dudley syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TriacDrug
Also called Tiratricol, Téatrois, TA3
Triac is a naturally occuring T3 metabolite with similar bioactivity and receptor binding profile.
| Study group | Role | What they receive |
|---|---|---|
| AHDS patients | Experimental | 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. Receives: Drug: Triac |
What is being measured
The primary outcome is the main question the study is designed to answer.
serum T3 concentrations
Serum T3 concentrations will be determined to assess the effect of Triac
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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 outcomes (6)
Heart rate
Heart rate will be measures with an ECG and 24 h ambulatory monitoring
Measured: 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.
Measured: baseline and month 12 will be compared
Body weight
Body weight will be measured in kg
Measured: baseline and month 12 will be compared
Blood pressure
Blood pressure will be measured in mmHg
Measured: 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.
Measured: 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.
Measured: baseline and month 12 will be compared
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Feb 2014 (estimated)
- Study startOct 2014
- Primary completion26 Jun 2018
- Study completion26 Jun 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Allan-Herndon-Dudley SyndromeStudies of the same condition, open and under way.
- More trials run by Erasmus Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 46 participants (actual)
Sponsor and investigators
- Lead sponsor
- Erasmus Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- ZonMw: The Netherlands Organisation for Health Research and Development
- Responsible party
- Principal investigator, W. Edward Visser, Erasmus Medical Center
- Investigators
- W.E. Visser, dr,, Principal investigator, Erasmus Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02060474
- Sponsor's protocol ID
- MCT8-2014-1
- Other IDs
- 2014-000178-20, 2014
- Status last verified
- Apr 2019
- First submitted
- 5 Feb 2014
- Last updated
- 16 Apr 2019
- Results posted
- No
- Data monitoring committee
- Yes
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.
PubMed 31377265
Study at a glance
From the registry record, last updated by the sponsor on 16 Apr 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Thyroid Hormone Analog Therapy of Patients With Severe Psychomotor Retardation Caused by Mutations in the MCT8 Thyroid Hormone Transporter: The Triac Trial.
- ClinicalTrials.gov ID
- NCT02060474
- Acronym / sponsor ID
- MCT8-2014-1
- Conditions
- Allan-Herndon-Dudley Syndrome
- Keywords
- Allan-Herndon-Dudley Syndrome, MCT8, Triac, Therapeutic Trial
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 46 participants (actual)
- Lead sponsor
- Erasmus Medical CenterUniversity, hospital or other
- Collaborators
- ZonMw: The Netherlands Organisation for Health Research and Development
- Study start
- Oct 2014 (actual)
- Primary completion
- 26 Jun 2018 (actual)
- Study completion
- 26 Jun 2018 (actual)
- First posted
- 12 Feb 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- Triac binds to the same TH receptors as T3;
- 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;
- In vitro studies have shown that neuronal cells differentiate equally well in the presence of either Triac or T3;
- In Mct8 deficient mice, Triac is taken up by the brain and suppresses serum TSH levels; consequently, serum T3 and T4 levels were lowered;
- 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
- reduces the toxic effects of the high T3 levels
- restores the local TH deficiency in brain.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| AHDS patients | Experimental | Drug: Triacall 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. |
Who may qualify
- Ages
- 1 day to 99 years
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (1 listed)
- clinically relevant mutation in the MCT8 gene, resulting in the clinical phenotype of AHDS.
Key exclusion criteria (4 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TriacAlso: Tiratricol, Téatrois, TA3Triac is a naturally occuring T3 metabolite with similar bioactivity and receptor binding profile. | Drug | AHDS patients |
Primary outcome
serum T3 concentrations
Time frame: 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 T3 concentrations will be determined to assess the effect of Triac
serum free T4 concentrations
Time frame: 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 will be determined to assess the effect of Triac (co-primary end-point, supportive to changes in T3).
serum TSH concentrations
Time frame: 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 will be determined to assess the effect of Triac (co-primary end-point, supportive to changes in T3).
serum total T4 concentrations
Time frame: 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 will be determined to assess the effect of Triac(co-primary end-point, supportive to changes in T3).
serum reverse T3 concentrations
Time frame: 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 will be determined to assess the effect of Triac(co-primary end-point, supportive to changes in T3).
6 secondary outcomes
Heart rate
Time frame: baseline and month 12 will be compared
serum sex-hormone binding globulin concentrations
Time frame: baseline and month 12 will be compared
Body weight
Time frame: baseline and month 12 will be compared
Blood pressure
Time frame: baseline and month 12 will be compared
serum total cholesterol concentrations
Time frame: baseline and month 12 will be compared
serum creatine kinase concentrations
Time frame: baseline and month 12 will be compared
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Apr 2019.
- Derived from this study: PubMed 31377265Groeneweg 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
W.E. Visser, dr, principal investigator
Erasmus Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Triac in people with Allan-Herndon-Dudley Syndrome, run by Erasmus Medical Center at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 16 Apr 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
serum T3 concentrations (time frame: 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). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02060474, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Apr 2019; AzTrials last refreshed its copy on 6 Nov 2026.