Zoektocht Naar Erfelijke MetaBole Aandoening (Dutch)/ Solve The Unsolved (English) (ZOEMBA/STU)

December 29, 2023 updated by: Clara van Karnebeek, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

The goal of this clinical trial is to integrate genomic (WES/WGS) and other -omics technologies in order to find the genetic causes, in 500 patients (children and adults) with an unexplained metabolic phenotype in whom standard care (genetic and metabolic evaluation) did not provide a diagnosis. The overall aim of this study is to diagnose patients with an unknown metabolic phenotype. In addition, we want to provide evidence that the combination of approaches and techniques used in this study will increase diagnostic yield compared to current separated approaches.

All participants will undergo a multi-omics(WES, WGS and metabolomics) approach to solve the unsolved genetic basis of their metabolic phenotype.

Study Overview

Status

Status

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

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

Rationale: Inborn Errors of Metabolism (IEM) are monogenic conditions in which the impairment of a biochemical pathway is intrinsic to the pathophysiology of the disease. Organ dysfunction results from intoxication and/or storage of metabolites, as well as a shortage of energy and building blocks. Rapid diagnosis of IEM enables initiation of targeted treatment (e.g. diet) slowing down or stopping the degenerative nature of the disease, resulting in significantly reduction of morbidity and mortality. A diagnosis also enables prognostication, access to community services and accurate genetic counselling for the patient and his/her family. Diagnosing IEM can be a major challenge, because of phenotypic heterogeneity and complex, expensive, diagnostic tests. Whole exome/ genome sequencing (WES/WGS) has revolutionized diagnostics of rare diseases and IEM, but still gives a negative or inconclusive result in >50% of cases. Addition of other omics technologies (metabolomics, glycomics, lipidomics, epigenomics, transcriptomics, proteomics) with integrated bioinformatics increases diagnostic yield, as it may point to the defective pathway allowing scrutinizing genes in genomic data or vice versa: it generates evidence of the deleterious functional impact of a DNA variants of unknown significance (VUS). In this study we will unite our national expertises and apply a multi-omics approach to solve the unsolved genetic basis of patients with a metabolic phenotype on a larger scale.

Objective: Integrating genomic (WES/WGS) and other -omics technologies in order to find the genetic causes, in 500 patients (children and adults) with an unexplained metabolic phenotype in whom standard care (genetic and metabolic evaluation) did not provide a diagnosis.

Study design: A prospective, diagnostic (deep phenotyping, WES/WGS and pan-omics) multicenter cohort study.

Study population: (In)capacitated patients (all ages/both genders) with a clinical (and/or family) history and abnormal additional examination (physical (neurological)/ biochemical/ radiological/ genetic) suspicious for an IEM, without diagnosis.

Main study parameters/endpoints: 1) identification of a genetic variant and alignment with its biochemical and phenotypical abnormalities; 2) evaluating the diagnostic yield of combined WES/WGS and omics techniques Methods used: Patients with unexplained metabolic phenotypes are referred (on paper) and discussed by the ZOEMBA (Zoektocht naar Erfelijke MetaBole Aandoening) team. Clinical phenotyping, bioinformatic reanalysis of WES data and additional metabolomics will be performed in all participants. In case still no diagnosis is made, a tailormade diagnostic plan is made combining deep WES, WGS, glycomics, lipidomics, epigenomics, transcriptomics and/or proteomics leading to: a known IEM, a candidate variant or no diagnosis. In case of a variant, additional functional studies (enzymatic assays, targeted omics, CRISPR/CAS, cell lines) will be performed to confirm the effect of the genetic variant on protein function. When still no diagnosis is established, matchmaking (genetic/phenotypical) through international databases might lead to a diagnosis.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

The study involves collection of clinical data, reanalysis of previously analysed genetic data, additional "omics" and functional testing. All participants will have between 1 and 3 clinical visits for this study (at the UMC of referral ) and a maximum of 2 telephone appointments with the arts-onderzoeker. Whenever possible study visits will be combined with regular hospital visits. Clinical data (clinical history, family history, physical examination, consultations, additional laboratory and/or radiological investigations) will be collected. A physical examination and blood and urine sampling will be performed in all participants at their first study visit. Any other already available biological samples (eg stored cell lines, dried blood spots, cerebrospinal fluid (CSF)) will be collected for re-analysis. For a selection of patients a skin biopsy will be performed at the 2nd clinical study visit for the use of functional studies. Potential burdens for participants are: the additional study visit(s), diagnostic procedures (e.g. blood, urine sampling and skin biopsy), as well as renewed (false) hope/uncertainty about finding a diagnosis. The potential benefit for all participants include: the opportunity to establish a diagnosis providing information on prognosis, (refinement of) management, genetic counselling with precise recurrence risk and option(s) for prenatal diagnosis.

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.
Interventional

Enrollment (Actual)

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.
334

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

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

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

No

Description

Inclusion Criteria:

Patients with an unexplained metabolic phenotype defined as: neurological symptoms and/or abnormalities on (physical) examination suggestive of an inborn error of metabolism (energy deficiency, intoxication type or storage type):

Energy deficiency: neurological (repeated rhabdomyolysis, verified exercise intolerance, neuropathy, myopathy, ataxia), ophthalmological (retinitis pigmentosa (RP)), otological (hearing loss, deafness), endocrine (hypoparathyroidism, hypoglycemia) Intoxication: neurological (encephalopathy, regression, movement disorder, psychiatric symptoms), ophthalmological (lens luxation), organic (liver and kidney function abnormalities) Storage: neurological (regression, psychiatric symptoms), ophthalmological (cataract/corneal clouding), skin (angiokeratomas), blood (cytopenias), organic (hepatosplenomegaly, cardiac hypertrophy, skeletal abnormalities, short stature, coarse facial features, umbilical/inguinal hernia)

AND / OR one or more of the following suggesting a deficient metabolic pathway or process:

  • abnormal metabolites in body fluids (CSF, urine, blood)
  • functional studies at a biochemical/cellular level indicative of a metabolic deficiency (e.g. respiratory chain complex analysis)
  • organ dysfunction (e.g. liver or kidney failure)
  • an abnormal clinical function test (protein loading test, fasting test, meal test, validated exercise test, non-ischaemic underarm test)
  • abnormalities on imaging (neuro-imaging (including spectroscopy); X-rays (dysostoses or other bone abnormalities); ultrasound (enlarged liver/spleen))
  • a VUS (variant of unknown significance) in a gene involved in metabolism

AND no diagnosis despite extensive clinical, metabolic and genetic investigations

  • SNP-array/array-CGH: inconclusive results
  • metabolic screening according to up to date clinical protocols: inconclusive results
  • WES (open or gene panel): no class 4 or 5 variants in a known (OMIM annotated) disease related gene that can fully explain the phenotype of the patient

Exclusion Criteria:

A patient will be excluded from participation in this study if:

  • after discussion by the ZOEMBA team (see Methods) he/she is suspected to have:

    • a genetic condition for which there is a simpler and more cost-effective test available for diagnosis
    • a complex genetic disorder (caused by a combination of multiple genes and/or environmental influences)
    • a condition that is thought to be caused by factors that are non-genetic, such as infection, injury or toxic exposure
  • he/she is unable to follow the study protocol (e.g. additional blood samples)

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

  • Primary Purpose: Diagnostic
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
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.
Experimental: The unsolved
(In)capacitated patients (all ages/both genders) with a clinical (and/or family) history and abnormal additional examination (physical (neurological)/ biochemical/ radiological/ genetic) suspicious for an IEM, without diagnosis.
Diagnostic test: Untargeted metabolomics
Untargeted metabolomics in bloodspots and in plasma
Genetic: WES and WGS
WES reanalysis and WGS analysis
Other Names:
  • Genomics

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
Diagnostic yield
Time Frame: 3 years
Number of patients diagnosed
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.
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

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.
Stichting Metakids

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Clara DM van Karnebeek, Professor, Amsterdam UMC and United for Metabolic Diseases (UMD)

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.

Helpful Links

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.
December 10, 2019

Primary Completion (Actual)

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.
December 31, 2021

Study Completion (Actual)

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 31, 2021

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).
December 29, 2023

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.
December 29, 2023

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.
January 10, 2024

Study Record Updates

Last Update Posted (Actual)

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.
January 10, 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.
December 29, 2023

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.
December 1, 2023

More Information

Terms related to this study

Keywords

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.
  • ZOEMBA

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

To make data Findable (according to FAIR principles), data will be shared internationally with other authorized researchers through the existing, well-managed, secure, large-scale, controlled-access web-based, repository of the RD-Connect platform (https://platform.rd-connect.eu/).

IPD Sharing Time Frame

3 years

IPD Sharing Access Criteria

RD-connect access

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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