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Biomarker for Hunter Disease (BioHunter) (BioHunter)

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ClinicalTrials.gov Identifier: NCT01330277
Recruitment Status : Recruiting
First Posted : April 6, 2011
Last Update Posted : May 14, 2019
Sponsor:
Information provided by (Responsible Party):
Centogene AG Rostock

Tracking Information
First Submitted Date April 4, 2011
First Posted Date April 6, 2011
Last Update Posted Date May 14, 2019
Actual Study Start Date August 20, 2018
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: January 22, 2019)
Sequencing of the Hunter disease related gene [ Time Frame: 4 weeks ]
Next-Generation Sequencing (NGS) of the IDS gene will be performed. The mutation will be confirmed by Sanger sequencing.
Original Primary Outcome Measures Not Provided
Change History Complete list of historical versions of study NCT01330277 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures
 (submitted: January 22, 2019)
The Hunter disease specific biomarker candidates finding [ Time Frame: 24 months ]
The quantitative determination of small molecules (molecular weight 150-700 kD, given as ng/μl) within a dried blood spot sample will be validated via liquid chromatography multiple reaction-monitoring mass spectrometry (LC/MRM-MS) and compared with a merged control cohort. The statistically best validated molecule will be considered as a disease specific biomarker.
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Biomarker for Hunter Disease (BioHunter)
Official Title Biomarker for Hunter Disease AN INTERNATIONAL, MULTICENTER, EPIDEMIOLOGICAL PROTOCOL
Brief Summary To establish the Biomarker of patients with Hunter Disease
Detailed Description

Hunter disease (mucopolysaccharidosis type II) is a lysosomal storage disease caused by deficiency of the enzyme iduronate-2-sulphatase. Deficiency of iduronate sulphatase enzyme causes accumulation of the products dermatan sulphate and heparan sulphate in lysosomes leading to cell death. Hunter disease can vary from mild to severe, depending on the level of enzyme deficiency. Features of the disease include dwarfism, enlarged liver and spleen, cardiovascular disorders and deafness.

Mutations in the IDS gene located at Xq28 causes loss of the iduronidate sulfatase enzyme. A pseudogene IDS2 also exists 20 kb from the active IDS gene. The pseudogene IDS2 shares homology to exon 2, intron 2, exon 3, intron 3 and intron 7 of the IDS gene.

Mutations that have been reported in the IDS gene in Hunter patients include gene rearrangements caused by recombination with the IDS2 gene (10 per cent patients), deletions of certain exons or the entire IDS gene (10 per cent patients) or small mutations including insertions, deletions and point mutations (80 per cent patients). To detect all possible types of mutations in the IDS gene causing Hunter disease, three procedures are necessary. These include Southern blot to look for gene rearrangements, multiplex dosage analysis to detect large deletions and DHPLC and sequencing to detect small mutations.

An accurate biochemical test is available for the diagnosis of Hunter disease consisting of the analysis of iduronate-2-sulfatase activity in plasma, leucocytes or cultured cells. This test should be considered before molecular analysis is undertaken. Molecular identification of the mutation in individuals with a confirmed diagnosis can be used for carrier testing and prenatal diagnosis in the family. The biochemical test is not reliable for identifying carriers.

Hunter syndrome (MPS II) affects a calculated estimate of approximately 1 in 155,000 live male births. Since Hunter syndrome is an inherited disorder (X-linked recessive) that primarily affects males, it is passed down from one generation to the next in a specific way. Nearly every cell in the human body has 46 chromosomes, with 23 derived from each parent. The I2S gene is located on the X chromosome. Females have two X chromosomes, one inherited from each parent, whereas males have one X chromosome that they inherit from their mother and one Y chromosome that they inherit from their father.

If a male has an abnormal copy of the I2S gene, he will develop Hunter syndrome. A male can obtain an abnormal copy of the I2S gene in one of two ways. His mother is often a carrier; i.e., she has one abnormal and one normal I2S gene, and she passes along the abnormal gene to him. However, during egg and sperm formation, a mutation can develop in the I2S gene on his X chromosome. In this second case, the mother is not a carrier and the risk of a spontaneous mutation occurring again in a future sibling is low but not zero. Females can carry one abnormal copy of the I2S gene and are usually not affected. Hunter syndrome has rarely been reported to occur also in females.

New methods, like mass-spectrometry give a good chance to characterize in the blood of affected patents specific metabolic alterations that allow to diagnose in the future the disease earlier, with a higher sensitivity and specificity. In a pilot study, Compound 312 has been identified as a sensitive and specific biomarker. The structure and pathophysiological role will have to be illucidated further; however preliminary data suggests that Compound 312 is a feasible biomarker for Hunter syndrome. After the verification of Compound 312 as a biomarker for Hunter syndrome, quantification and validation of Compound 312 in saliva will allow for an easier detection method in the future.

Though Hunter syndrome is a pan-ethnic disorder, the prevalence of this autosomal-recessive disorder is elevated in countries with a higher frequency of consanguinity. Therefore, we estimate that every 400th newborn in Arabian countries may be eligible for inclusion due to high-grade suspicion of Hunter syndrome, while approximately every 2000th newborn in non-Arabian countries may be eligible.

The validation of this new biochemical marker from the blood of the affected patients is the goal of the study.

Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
Laboratory parameters are the proof of deficiency or absence of the enzyme iduronate-2-sulfatase (I2S). For this purpose, a 7, 5 ml EDTA-blood or a dry blood spot filter card a will be sent to the central laboratory. The analyses will be done at the Centogene AG Am Strande 7 18055 Rostock Germany
Sampling Method Probability Sample
Study Population Patients with Hunter Disease or profound suspicion for Hunter disease
Condition
  • Inguinal Hernia
  • Tonic-clonic
  • Glaucoma
Intervention Not Provided
Study Groups/Cohorts Observation
Patients with Hunter Disease or profound suspicion for Hunter disease
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: August 8, 2018)
1000
Original Estimated Enrollment
 (submitted: April 4, 2011)
80
Estimated Study Completion Date June 2021
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria

INCLUSION CRITERIA:

  • Informed consent will be obtained from the patient and their parents/legal guardians before any study related procedures.
  • Patients of both gender at 1 day of age
  • The patient has a diagnosis of Hunter syndrome based upon biochemical and/or genetic criteria or patients who are profoundly suspicious for Hunter disease
  • High-grade suspicion present, if one or more criteria are valid:

    • Positive family anamnesis for Hunter syndrome
    • Inguinal hernia without identifiable cause
    • Tonic-clonic seizures without identifiable cause
    • Eye symptoms without identifiable cause: corneal clouding or glaucoma
    • Pulmonary symptoms without identifiable cause: upper airway obstruction, cardiopulmonary disease

EXCLUSION CRITERIA:

  • No Informed consent from the patient and their parents/legal guardians before any study related procedures.
  • No diagnosis of Hunter syndrome or no valid criteria for high-grade suspicion of Hunter syndrome
Sex/Gender
Sexes Eligible for Study: All
Ages Child, Adult, Older Adult
Accepts Healthy Volunteers No
Contacts
Contact: Arndt Rolfs, Prof +4938180113500 ext 500 arndt.rolfs@centogene.com
Listed Location Countries Algeria,   Brazil,   Bulgaria,   Egypt,   Germany,   Greece,   Hungary,   India,   Iran, Islamic Republic of,   Poland,   Serbia
Removed Location Countries  
 
Administrative Information
NCT Number NCT01330277
Other Study ID Numbers BH 06-2018
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: Undecided
Responsible Party Centogene AG Rostock
Study Sponsor Centogene AG Rostock
Collaborators Not Provided
Investigators
Principal Investigator: Arndt Rolfs, Prof. Centogene AG Rostock
PRS Account Centogene AG Rostock
Verification Date January 2019