Thrombosis and Neurocognition in Klinefelter Syndrome

The Haemostatic Balance and Neurocognitive Phenotype in Klinefelter Syndrome - The Effect of Testosterone Treatment

The haemostatic balance and neurocognitive capability of men with Klinefelter syndrome is compared to healthy controls by using specific biochemical assays for coagulation and fibrinolysis and a selection of neuropsychological tests and brain fMRI. Furthermore, the effect of gonadal status and any effects of long- or short-term testosterone treatment on the above mentioned parameters are investigated.

Study Overview

• Status: Completed
• Conditions: Thrombosis; Klinefelter Syndrome

Detailed Description

Klinefelter syndrome (KS) affects approximately 1 in every 600 males, but remains severely underdiagnosed. Men with KS are more prone to a wide range of diseases including thrombotic disorders. Also, neurocognitive function is impaired in KS. The background for the increased thrombosis proneness is not understood, and also it is not understood how testosterone treatment affects the thrombosis risk in KS. The effects of testosterone treatment on neurocognition in KS is also not completely understood. However, it is speculated that testosterone treatment at an early point could help improve the overall neurocognitive performance.

In this study 30 males with KS receiving testosterone treatment, 30 males with KS not receiving testosterone treatment and 60 matched healthy male controls are included. After initial examination including blood testing and neurocognitive testing, the subjects are followed for 18 months and examined a second time. After initial examination the group of previously untreated KS males will be put on standard testosterone treatment according to current guidelines.

Groups will be compared by measuring and array of markers for coagulation and fibrinolysis, including thrombin generation and fibrin structure analysis, to assess the haemostatic balance. Also, a wide array of neurocognitive tests and brain fMRI is applied to compare the neurocognitive function between the groups.

• Study Type: Observational
• Enrollment (Actual): 90

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark, 8000
    • Department for Endocrinology and Internal Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

• Sampling Method: Non-Probability Sample

Study Population

Men with Klinefelter syndrome identified through clinics for fertility, endocrinology and genetics. Healthy controls from the general population living in Central Denmark Region.

Description

Inclusion Criteria:

• Klinefelter syndrome with 47 XXY karyotype
• Healthy male

Exclusion Criteria:

• Known thrombophilia
• Previous thrombotic event
• Chronic or acute illness affecting the haemostatic balance (e.g. diabetes, cancer).
• Previous or current disease affecting the brain
• Weight above 120 kg
• Current abuse of stimulants affecting the brain
• Unability to complete MR-scan (e.g. claustrophobia, internal metal objects)

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Testosterone naïve KS; Men with Klinefelter syndrome without testosterone treatment. After initial examination standard treatment with testosterone will be effectuated according to current guidelines.
Testosterone treated KS; Men with Klinefelter syndrome receiving testosterone treatment
Controls 1; Matched healthy male controls for testosterone naive KS
Controls 2; Matched healthy male controls for testosterone treated KS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differences in thrombin generation	Thrombin generation using the CAT assay is assessed as ETP (nM thrombin), peak height (nM thrombin) and lag time (minutes). All variables are assessed at inclusion and after a 18 month follow-up. Groups are compared statistically at each time point and any changes during follow-up is also analysed.	Time 0 and after 18 months followup
Differences in fibrin clot properties	Fibrin clot properties is assessed by fibrin structure analysis in plasma samples. All variables are assessed at inclusion and after a 18 month follow-up. Groups are compared statistically at each time point and any changes during follow-up is also analysed.	Time 0 and after 18 months followup
Difference in neurocognition	neurocognition is assessed using a wide array of psychological tests (e.g. Wais-III, Stroop test, Wisconsin Card Sorting Test and others) All variables are assessed at inclusion and after a 18 month follow-up. Groups are compared statistically at each time point and any changes during follow-up is also analysed.	Time 0 and after 18 months followup

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differences in blood coagulation and fibrinolysis parameters between groups	Coagulation and fibrinolysis can not be adequately assessed by analysis of a single parameter. To evaluate the overall status of these systems an array of analyses are needed, and further more need to be interpreted by experts within the field. Thus, severeal markers of coagulation and fibrinolysis including INR, APTT, single coagulation factors, PAI-1 and others are to be assessed at inclusion and after a 18 month follow-up. Groups are compared statistically at each time point and any changes during follow-up is also analysed. Besides applying statistics, the compiled results will also be interpreted by experts within the field to provide an overall characterization of the haemostatic balance in the individual groups and by comparison to each other.	Time 0 and after 18 months followup
Differences in fMRI between groups	fMRI will be performed to evaluate the response in the brain to various stimuli and tests, with the overall purpose of examining speech, memory and other cognition related features.	Once at followup

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Aarhus University Hospital; University of Southern Denmark; Sygehus Lillebaelt; Hospital of South West Jutland
• Investigators: Study Chair: Claus H Gravholt, MD, Prof., Department of Endocrinology and Internal Medine and Department of Molecular Medicine; Principal Investigator: Simon Chang, MD, Unit for Thrombosis Research; Principal Investigator: Anne Skakkebæk, MD, PhD, Department of Clinical Genetics

Study record dates

Study Major Dates

• Study Start: September 1, 2015
• Primary Completion (ACTUAL): August 21, 2019
• Study Completion (ACTUAL): August 21, 2019

Study Registration Dates

• First Submitted: August 10, 2015
• First Submitted That Met QC Criteria: August 14, 2015
• First Posted (ESTIMATE): August 18, 2015

Study Record Updates

• Last Update Posted (ACTUAL): August 22, 2019
• Last Update Submitted That Met QC Criteria: August 21, 2019
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: Testosterone; Neurocognition
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Endocrine System Diseases; Disease; Gonadal Disorders; Disorders of Sex Development; Urogenital Abnormalities; Congenital Abnormalities; Genetic Diseases, Inborn; Embolism and Thrombosis; Chromosome Disorders; Sex Chromosome Disorders; Sex Chromosome Disorders of Sex Development; Hypogonadism; Syndrome; Thrombosis; Klinefelter Syndrome
• Other Study ID Numbers: 2015_KS_TESTOSTERONE