Understanding, Diagnosis and Monitoring of Thyroid Hormone Action Defects (ADAM-THAD)

August 25, 2025 updated by: Istituto Auxologico Italiano

Advancing Understanding, Diagnosis and Monitoring of Thyroid Hormone Action Defects (ADAM-THAD)

The goal of this observational study is to learn about the neurological and cardiological phenotype of patients with resistance to thyroid hormone (RTH) syndromes beta and alpha (RTHß and RTHa) due to dominant negative variants in the genes encoding the thyroid hormone receptors alpha (THRA) and beta (THRB).

The main question[s] it aims to answer are:

  • Define frequency and improve early diagnosis for RTH syndromes
  • Developing tools to accelerate diagnosis of RTH syndromes
  • Development and validation of monitoring tools

Participants, recruited at neonatal screening or from cohorts of patients with unexplained specific neuro-cognitive or cardiovascular phenotypes will be submitted to biochemical and genetic investigations. In addition pluripotent stem cells will be generated from peripheral blood cells of RTHs patients and studied in vitro to understand the molecular mechanisms underlying neurological and cardiovascular consequences. In vitro and clinical data, will be correlated to identify biomarkers for monitoring treatment.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

TH action defects (THAD) are a group of rare syndromes characterized by abnormal thyroid hormone (TH) cell signaling due to defective transport, metabolism or action of TH via binding with nuclear receptors (TRs): there are two TRs, the alpha (TRa) and beta (TRß) receptors. Among them, mutations of THRA or THRB genes cause two distinct syndromes with Resistance to Thyroid Hormone (RTH) action whose incidence was estimated 1:20,000-50,000 newborns, likely representing the most frequent THAD forms. RTHa is due to dominant negative (DN) heterozygous mutations in THRA and characterized by dramatic manifestations in TRa-expressing tissues resembling untreated congenital hypothyroidism (CH).

RTHß is due to DN heterozygous THRB mutations, which cause variable TH resistance in TRß-expressing tissues (hypothalamus, pituitary, liver), resulting in distinctive biochemical signature (high free TH and unsuppressed TSH) together with additional features like deafness, impaired color vision and thyrotoxic-related symptoms (goiter, tachyarrhythmias, osteoporosis, anxiety and Attention-Deficit/Hyperactivity Disorder, ADHD).

Outstandingly, early treatment with TH or its analogues is expected to reduce most of the adverse consequences of RTHs but early/neonatal diagnosis is presently not feasible due to the lack of accurate biomarkers. Indeed, uniform characterization is essential for a rare disease, and establishment of clear-cut endocrine fingerprints for RTHa and RTHß are essential for a timely diagnosis.

In addition, the wide application of next generation sequencing (NGS) has yielded an unprecedented wealth of genetic information, calling for proper instruments to distinguish benign from pathogenic variants.

Finally, biomarkers for monitoring treatment of these conditions have not been established or validated.

This study aim to:

  1. develop neonatal screening strategies for THAD and give unprecedented epidemiological characterization of RTHs in Italy
  2. understand the pathogenicity of newly discovered THRB or THRA variants in in vivo model or identify new mechanisms
  3. generate induced pluripotent stem cells from RTH patients to understand the molecular mechanisms underlying neurological and cardiovascular consequences and correlate in vitro and clinical data, with the final goal to identify potential biomarkers for monitoring treatment of these rare diseases.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
150

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • Italy
      • Milan, Italy, 20145
        • Recruiting
        • Istituto Auxologico Italiano IRCCS
        • Contact:
          • Irene Campi, MD, PhD
      • Milan, Italy
        • Recruiting
        • Department of Endocrine & Metabolic Diseases, San Luca Hospital
        • Contact:
          • Luca Persani, Prof

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Sampling Method

Non-Probability Sample

Study Population

Newborn patients (a) with normal TSH, but T3 and other TH metabolites suggestive of RTH syndromes, we will be submitted to genetic analysis

Cohorts of patients (b) with unexplained: i) mental retardation and delayed development or epilepsy (ii) autism spectrum disorders (iii) growth maturation defects (iv) early onset cardiovascular diseases (v) with inappropriate tachycardia (vi) with ADHD or learning disorders (vii) early onset tachyarrhythmias, will be submitted to genetic analysis

Patients with RTH syndromes already diagnosed and followed in the collaborating centers

Description

Inclusion Criteria:

- biochemical signature suggestive of RTHs syndromes at birth (a) or symptoms suggestive of RTHs syndromes (b) or known diagnosis of RTHs syndromes (c)

Exclusion Criteria:

  • none

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
RTH Syndromes
Patients with THRA or THRB gene mutations
Genetic: NGS sequencing
analysis of candidate genes for RTHs syndromes, transporters defects or gene involved in thyroid hormone metabolism. Whole exome sequencing (WES) in a minority of cases
Diagnostic test: serological tests
assessment of T4, T3 and other TH metabolites (LC-MS) in serum and dried blood spots

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Direct differentiation of THRA mutant patients-derived human induced pluripotent stem cells (hiPSCs) to neural progenitors (hiPSc-CNeu) and cardiomyocyte (hiPSC-CMs)
Time Frame: two years
Molecular characterization and electrophysiological characterization of hiPSc-CNeu and hiPSC-CMs carrying THRA and THRB variants and comparison with matched controls
two years
To identify TH-target genes involved in determining stemness, proliferation potential and differentiation of hiPSC
Time Frame: two years
Transcriptome analysis of hiPSc-CNeu and hiPSC-CMs
two years
Number of Newborns With Abnormal Thyroid Hormone Levels Suggestive of Resistance to Thyroid Hormone (RTH) Syndromes, as Measured in Dried Blood Spots (DBS).
Time Frame: two years
Thyroid hormone levels determinations in DBS of newborns
two years
Frequency of Phenotypic Changes in Zebrafish Zygotes Microinjected with Human TR Variants, as a Measure of the Functional Impact of THRA and THRB Variants of Uncertain Significance (VUS).
Time Frame: two years
Functional impact of THRA and THRB variant of uncertain significance (VUS) in the zebrafish model microinjected with different human TR variants
two years

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Generation of a comprehensive RTH database
Time Frame: two years
To establish a comprehensive RTH database including whole clinical/genetic/biochemical data of RTH patients, in view of the generation of a disease registry.
two years
Prevalence of Resistance to Thyroid Hormone (RTH) Syndromes in Specific Cohorts of Patients with Unexplained Phenotypes
Time Frame: two years
To search novel RTHa cases in cohorts of patients with unexplained: i) mental retardation and delayed development or epilepsy (ii) autism spectrum disorders (iii) growth maturation defects (iv) early onset cardiovascular diseases. For RTHß, we aim to screen patients (i) with inappropriate tachycardia (ii) with ADHD or learning disorders (iii) early onset tachyarrhythmias.
two years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Istituto Auxologico Italiano

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Federico II University
ASST Fatebenefratelli Sacco

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 1, 2023

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
October 31, 2025

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
January 31, 2026

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
March 6, 2024

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 6, 2024

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
March 13, 2024

Study Record Updates

Last Update Posted (Estimated)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
September 2, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 25, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 05M202

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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