Optical Imaging as a Tool for Monitoring Brain Function in Creatine Deficiency Syndromes

February 27, 2024 updated by: IRCCS Fondazione Stella Maris

Establishing Novel Functional Biomarkers for Creatine Deficiency Syndromes

The objective of this project is to explore the potential of functional near-infrared spectroscopy (fNIRS) as innovative functional biomarker for clinical trial readiness in Creatine Deficiency Syndromes (CDS), a group of rare neurodevelopmental disorders. Among these disorders, effective treatments are lacking for two. The limited availability of objective and quantitative biomarkers to monitor brain function poses challenges to advancing therapeutic research. With gene therapy trials on the horizon, the need for precise measurement to evaluate treatment efficacy is pressing. This project seeks to address this gap by assessing the prognostic reliability of both resting and task-evoked fNIRS. Arousal of participants will be also assessed through the measure of spontaneous heart rate (HR) fluctuations. The primary objectives of this pilot study are: 1. to determine the feasibility of fNIRS in individuals with CDS; 2. to collect pilot data on individuals with CDS to determine the patterns of cerebral oxygen consumption as measured by fNIRS; 3. to compare cerebral oxygen consumption changes at rest and from visual/auditory tasks in affected individuals versus age-appropriate healthy volunteers. The secondary objectives of this study are: 1. to correlate cerebral oxygen consumption changes from visual/auditory task in affected individuals to other measures of disease state (e.g., neuropsychological assessment, disease- specific severity rating scales); 2. to examine test-retest reliability of our fNIRS measures in both affected individuals and healthy controls.

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.

Detailed Description

This is a non-profit study of a cohort of patients with Creatine Deficiency Syndromes genetically determined as CTD, GAMT-D and age-matched healthy controls. The design of the study is observational, case-control. An imaging session using fNIRS (NIRSport2, NIRx Technologies) will be conducted during the visits scheduled for the individual participants. Participants will be assessed for optimal placement of the fNIRS probe on the head through measurement of the fiducial points on the scalp. With the NIRx NIRSPort2 system, the near-infrared sources and detectors are situated in a fabric cap resembling a swim cap that is applied like a hat and secured in place by a velcro chin strap. Once the probe is placed, fNIRS will be measured during a passive viewing/listening task administered on a computer. The montage consists of 8 red light-sources operating at 760 nm and 850 nm, and 7 detectors which can be easily placed into a textile EEG cap (EASYCAP, Herrsching, Germany, size according to head circumference). The systems that are utilized have been selected to be very child-friendly systems, involving no cleaning or abrasion of the scalp preparation and rapid application. Application procedures have been designed to minimize any discomfort to the participant. In parallel, ECG will be collected using the polygraphic input box that integrates the ECG with the fNIRS. ECG records the electrical activity generated by the heart and can be used to derive both the heart rate and the pattern of electrical activity as it moves through the heart. To measure ECG, two electrodes will be applied to the skin over the lower left ribcage and the upper right collar bone after the skin has been cleansed and prepared with either abrasive paper or preparation gel. In total, these measurements should take 30-40 minutes to complete (including application of the NIRS cap). Alongside fNIRS, neuropsychological assessments of affected individuals patients will be conducted. The following outcome measures will be collected assessing: i) cognitive performance (Leiter International Performance Scale, 3rd edition, PPVT-5, simple reasoning tasks on tablets and Vineland Adaptive Behaviour Scale); ii) behavioural disorder (BASC-3 and ABC-2 scales); iii) autistic-like features (SRS-2 and PPD-MRS). The cognitive tasks were chosen to be adapted to the cognitive deficit of affected individuals. A task on tablets with minimal verbal instruction will allow to assess reasoning abilities in severe to moderate ID patients that could not perform classical Wechsler scale (IQ test). Healthy controls will be asked to return 8-12 weeks post their initial visit to undergo repeat fNIRS testing for the purposes of examining test-retest reliability of the fNIRS measurement. If their schedule allows, affected individuals will also undergo repeat fNIRS testing. fNIRS is safe, non-invasive and generally well tolerated. The information obtained from this study will help identify outcome measures for drug testing in future therapeutic trials.

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.
30

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 Contact Backup

Study Locations

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

Creatine Deficiency Syndromes (CDS) are a family of three rare metabolic disorders (AGAT deficiency, AGAT-D, #602360, GAMT deficiency, GAMT-D, 601240 and Creatine Transporter Deficiency, CTD, #300352) negatively impacting brain development and its function. All CDS share a common, predominantly neurological, clinical presentation, including developmental delay, intellectual disabilities, disturbance of expressive and cognitive speech, psycho-motor impairment, autistic-like behavior, and seizures. Oral Cr supplementation leads to the attenuation of symptoms in AGAT-D patients, while for GAMT-D patients limited improvements can be achieved only at very high dosages. Effective treatments for CTD are completely missing as dietary supplementation with Cr, alone or in combination with its precursors, has very limited success.

Description

Inclusion Criteria:

CDS participants:

  • Age criteria: Between ages 2 years to 50 years old, inclusive at time of enrollment
  • Diagnosed with either CTD or GAMT-D with a previously identified pathogenic or likely pathogenic variant in the SLC6A8 or GAMT gene.
  • Must also meet the diagnostic criteria for CTD/GAMT-D.
  • May be female or male

Typically developing participants:

  • Age criteria: Between ages 2 years to 50 years old, inclusive at time of enrollment
  • Age- and sex-matched to the CDS participants
  • No underlying genetic diagnosis or past/chronic medical condition associated with increased risk for autism spectrum disorder (ASD) and/or ID
  • Typical neurodevelopment for age (no established diagnosis or clinical suspicion for ASD or ID)

Exclusion Criteria:

For CDS and Typically developing participants:

  • Unwilling or unable to comply with study procedures and assessments
  • Contraindications to fNIRS, such as uncooperative or destructive behaviors preventing lead placement or capture by fNIRS equipment
  • Traumatic loss of consciousness in the last year
  • Has taken an investigational drug as part of another research study, within 30 days prior to study enrollment
  • If participant is judged by the PI or Sub-I to be inappropriate for the study for any reason

For Typically developing participants:

  • Known or suspected cognitive impairment
  • Known history of MRI abnormality
  • Current use of psychotropic medications

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.
CTD affected individuals
Individuals with genetic diagnosis of CTD.
GAMT-D affected individuals
Individuals with genetic diagnosis of GAMT-D.
Neurotypical controls
Healthy volunteers without known health or medical issues.

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
Resting-state functional connectivity
Time Frame: 3 years
The comparison of resting-state fNIRS signal between affected individuals and healthy controls will allow to detect potential alterations of spontaneous brain activity and functional connectivity
3 years
Amplitude of sensory-evoked hemodynamic responses
Time Frame: 3 years
The analysis of the amplitude of sensory-evoked fNIRS signal will allow to assess whether this parameter is able to discriminate between affected individuals and healthy controls. The signal latency will be analysed as well.
3 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
Correlation between neurophysiology endpoints and the response on neuropsychological scale.
Time Frame: 3 years
The correlation analysis will allow to understand whether alterations of functional connectivity and/or sensory-evoked responses can be predictive of the severity of symptoms
3 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.
IRCCS Fondazione Stella Maris

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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.
October 6, 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.
June 15, 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.
December 15, 2025

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).
February 20, 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.
February 27, 2024

First Posted (Estimated)

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 5, 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.
March 5, 2024

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.
February 27, 2024

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.
February 1, 2024

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.
  • IMAGINER CREATINE

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

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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