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Gait Examination in Patients With Hemophilia in Austria (JOSEPHA)

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ClinicalTrials.gov Identifier: NCT03541811
Recruitment Status : Recruiting
First Posted : May 31, 2018
Last Update Posted : July 3, 2018
Sponsor:
Collaborators:
Medical University of Vienna
Shire
Information provided by (Responsible Party):
Peter Putz, FH Campus Wien, University of Applied Sciences

Brief Summary:

Hemophilia is an inherited disease caused by deficiency in varying degrees of clotting factors VIII and IX. Depending on the percentage of clotting factor in the blood the disease is categorized as "severe" (<1%, characterized by spontaneous bleedings), "moderate" (1-5%) and "mild" (>5%). If untreated, recurrent bleeding into the synovial joints often results in irreversible damage due to destruction of the cartilages and progressive joint impairment.

3d-gait analysis has been demonstrated as valid method to assess abnormal gait patterns and to monitor disease progression in patients with hemophilia (PWH). Furthermore, its outcomes facilitate the design of individually tailored therapeutic programs. In contrast to radiological examinations, 3d-gait analyses take place under weight-bearing conditions, which is a relevant issue in terms of weight-induced pain.

This study aims to explore the applicability of 3-d gait analysis as biomarker (gait deviation index) for functional impairments in PWH. Besides 3-d gait scores, secondary endpoints such as biomarkers reflecting cartilage damage and a laterality-ratio of leg muscle mass (in the case of one-sided target joints) will be tested for their ability to detect functional impairments in young adults with hemophilia.

Based on sample size calculation, 24 subjects aged 16-49 years, able to walk without aids or assistance will be included in each of the two groups: control (healthy, male), PWH (severe or moderate, treated prophylactically). Subjects suffering from functional impairments caused by other conditions than hemophilia, patients with bleedings within 30 days prior to the examination, PWH treated with immune-tolerance therapy and/or not successfully treated present or past high-titer factor VIII or FIX inhibitor will be excluded.

Subjects will pass through a set of examinations (medical history, clinical examination, 3d-gait analysis, anthropometrics, body composition analysis, venipuncture, and urine sampling) and carry an accelerometer device for seven consecutive days.

Confounder adjusted group differences will be assessed by ANCOVA with contrasts and Bonferroni correction. Correlations between the applied examination approaches will be assessed.

An evidence based health promotion program including follow-up examinations, physical activity promotion, and tailored physiotherapy are being envisaged as a follow-up project (JOSEPHA phase 2).


Condition or disease Intervention/treatment
Hemophilia Diagnostic Test: 3-d gait examination (level walking) Diagnostic Test: Anthropometrics and body composition assessment Diagnostic Test: Biomarkers Diagnostic Test: Clinical examination Diagnostic Test: Habitual physical activity tracking (accelerometer based)

Study Type : Observational
Estimated Enrollment : 48 participants
Observational Model: Cohort
Time Perspective: Cross-Sectional
Official Title: Joint-health Outcome Scoring: Exploration in Patients With Hemophilia in Austria (JOSEPHA Phase 1)
Actual Study Start Date : July 2, 2018
Estimated Primary Completion Date : November 2018
Estimated Study Completion Date : March 2019

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
patients with hemophilia (16-45y)
not applicable (no intervention administered)
Diagnostic Test: 3-d gait examination (level walking)

Instrumented 3d-gait-analysis will be carried out in the movement lab of the FH (Fachhochschule; University of Applied Sciences) Campus Wien - University of Applied Sciences. The system used is a 10 camera T40S Vicon system with two floor-mounted AMTI OR6/7-2000 force plates. For assessing gait the Plug-in-Gait Lower Body Model with 14 mm retroreflective skin-mounted markers is implemented in the capturing software Vicon Nexus 2.2. The specific parameters will be extracted from the reporting software Vicon Polygon 4.2.

Markers will be placed by one experienced examiner. Subjects will be instructed to walk barefoot on a 10 meters walkway at self-paced walking speed until five right and five left valid first force plate strikes are captured.

Other Name: Vicon

Diagnostic Test: Anthropometrics and body composition assessment
Body height will be measured with the stadiometer Seca 213 to the next 0.1cm. Body size and weight will be measured without shoes and outerwear. A correction of 1 kg will be subtracted for clothing. Body weight and body composition will be assessed with the medical body composition analyzer Seca mBCA 515 based on bioelectric impedance analysis.

Diagnostic Test: Biomarkers

Blood will be collected into Vacuette serum-separating tubes and will be kept at room temperature for 30 min. Samples will be centrifuged at 1500g for 10 min and serum aliquots will be stored at 80 C until use. Urine samples will be collected into Vacuette tubes containing no additive from non-fasted individuals between 8:00 and 12:00 a.m. Urine samples will be kept at 4 °C for a maximum of 8 h, and then aliquoted and stored at 80 °C.

All biomarkers (except vitamin D and CRP) will be measured in duplicates using standard enzyme-linked immunosorbent assay (ELISA) kits. Serum samples will be assessed for the level of sCOMP, sC1,2C, and sCS846, IL-6, IL-1, sTNFR1 and sTNFR2. Vitamin D and CRP will be measured using automated immunoassay. In urine samples uCTX-II will be determined and these levels will be corrected for creatinine levels (Jaffé method, in-house validated method).


Diagnostic Test: Clinical examination
Hemophilia joint health score (HJHS) will be assessed. Height will be measured with a stadiometer (SECA 213), weight with a medical scale (Marsden M-420) and leg length according to the Plug-in-Gait protocol with a measuring tape from the Anterior Spina Iliaca Superior to the distal aspect of the Medial Malleolus. Further anthropometrical parameters taken will be knee distance and malleoli distance by using a caliper. Gait relevant passive joint ROM of the knee, hip and ankle will be assessed by means of a handheld goniometer. The flexibility of hamstring muscles will be expressed as Popliteal Angle measured with a goniometer with the subjects supine and the hip in 90° flexion.

Diagnostic Test: Habitual physical activity tracking (accelerometer based)
Participants will be instructed to wear an Actigraph wGT3X-BT tri-axial accelerometer permanently over a period of seven consecutive days with an elastic band on right hand sided hip. Data will be process with software ActiLife version 6.13. Cut-offs of at least 10 hours daily wear-time and a minimum of three valid weekdays and one valid weekend day will be applied for data cleaning. Count sampling epoch will be set at one minute. The so called Freedson Adult VM2 Cut-Offs will be applied to categorize physical activity intensities. The so called Freedson VM3 Combination will be applied for the estimation of activity energy expenditure.
Other Name: ActiGraph GT9X Link

peer-matched healthy control
not applicable (no intervention administered)
Diagnostic Test: 3-d gait examination (level walking)

Instrumented 3d-gait-analysis will be carried out in the movement lab of the FH (Fachhochschule; University of Applied Sciences) Campus Wien - University of Applied Sciences. The system used is a 10 camera T40S Vicon system with two floor-mounted AMTI OR6/7-2000 force plates. For assessing gait the Plug-in-Gait Lower Body Model with 14 mm retroreflective skin-mounted markers is implemented in the capturing software Vicon Nexus 2.2. The specific parameters will be extracted from the reporting software Vicon Polygon 4.2.

Markers will be placed by one experienced examiner. Subjects will be instructed to walk barefoot on a 10 meters walkway at self-paced walking speed until five right and five left valid first force plate strikes are captured.

Other Name: Vicon

Diagnostic Test: Anthropometrics and body composition assessment
Body height will be measured with the stadiometer Seca 213 to the next 0.1cm. Body size and weight will be measured without shoes and outerwear. A correction of 1 kg will be subtracted for clothing. Body weight and body composition will be assessed with the medical body composition analyzer Seca mBCA 515 based on bioelectric impedance analysis.

Diagnostic Test: Biomarkers

Blood will be collected into Vacuette serum-separating tubes and will be kept at room temperature for 30 min. Samples will be centrifuged at 1500g for 10 min and serum aliquots will be stored at 80 C until use. Urine samples will be collected into Vacuette tubes containing no additive from non-fasted individuals between 8:00 and 12:00 a.m. Urine samples will be kept at 4 °C for a maximum of 8 h, and then aliquoted and stored at 80 °C.

All biomarkers (except vitamin D and CRP) will be measured in duplicates using standard enzyme-linked immunosorbent assay (ELISA) kits. Serum samples will be assessed for the level of sCOMP, sC1,2C, and sCS846, IL-6, IL-1, sTNFR1 and sTNFR2. Vitamin D and CRP will be measured using automated immunoassay. In urine samples uCTX-II will be determined and these levels will be corrected for creatinine levels (Jaffé method, in-house validated method).


Diagnostic Test: Clinical examination
Hemophilia joint health score (HJHS) will be assessed. Height will be measured with a stadiometer (SECA 213), weight with a medical scale (Marsden M-420) and leg length according to the Plug-in-Gait protocol with a measuring tape from the Anterior Spina Iliaca Superior to the distal aspect of the Medial Malleolus. Further anthropometrical parameters taken will be knee distance and malleoli distance by using a caliper. Gait relevant passive joint ROM of the knee, hip and ankle will be assessed by means of a handheld goniometer. The flexibility of hamstring muscles will be expressed as Popliteal Angle measured with a goniometer with the subjects supine and the hip in 90° flexion.

Diagnostic Test: Habitual physical activity tracking (accelerometer based)
Participants will be instructed to wear an Actigraph wGT3X-BT tri-axial accelerometer permanently over a period of seven consecutive days with an elastic band on right hand sided hip. Data will be process with software ActiLife version 6.13. Cut-offs of at least 10 hours daily wear-time and a minimum of three valid weekdays and one valid weekend day will be applied for data cleaning. Count sampling epoch will be set at one minute. The so called Freedson Adult VM2 Cut-Offs will be applied to categorize physical activity intensities. The so called Freedson VM3 Combination will be applied for the estimation of activity energy expenditure.
Other Name: ActiGraph GT9X Link




Primary Outcome Measures :
  1. Gait Deviation Index (GDI) [ Time Frame: May 2018 - Oct 2018 (anticipated) ]
    Score expressing overall gait physiology; resulting from 3-d gait analysis [dimensionless]


Secondary Outcome Measures :
  1. Kinematic gait parameters [ Time Frame: May 2018 - Oct 2018 (anticipated) ]
    Functional range of motion Hip, Knee, Ankle [°]

  2. Walking velocity [ Time Frame: May 2018 - Oct 2018 (anticipated) ]
    [m sec-1]

  3. Walking cadence [ Time Frame: May 2018 - Oct 2018 (anticipated) ]
    [steps min-1]

  4. Step length [ Time Frame: May 2018 - Oct 2018 (anticipated) ]
    [m]

  5. Stance phase duration [ Time Frame: May 2018 - Oct 2018 (anticipated) ]
    [% gait cycle]

  6. Swing phase duration [ Time Frame: May 2018 - Oct 2018 (anticipated) ]
    [% gait cycle]

  7. Body composition analysis [ Time Frame: May 2018 - Oct 2018 (anticipated) ]
    Bioelectrical impedance derived body fat rate [kg, %], fat-free mass [kg, %]

  8. Biomarkers measured from serum and urine [ Time Frame: May 2018 - Oct 2018 (anticipated) ]
    sCOMP, sC1,2C, sCS846, uCTX-II, Vit D, CRP

  9. Background factors (age) [ Time Frame: May 2018 - Oct 2018 (anticipated) ]
    [years]

  10. Background factors (level of education) [ Time Frame: May 2018 - Oct 2018 (anticipated) ]
    International Standard Classification of Education (ISCED)

  11. Background factors (type and severity of hemophilia) [ Time Frame: May 2018 - Oct 2018 (anticipated) ]
    Type and severity of hemophilia

  12. Background factors (type and history of substitutional therapy ) [ Time Frame: May 2018 - Oct 2018 (anticipated) ]
    Type and history of substitutional therapy

  13. Background factors (history of joint bleedings) [ Time Frame: May 2018 - Oct 2018 (anticipated) ]
    annualized bleeding rate

  14. Background factors (inhibitors & immune-tolerance therapy) [ Time Frame: May 2018 - Oct 2018 (anticipated) ]
    Inhibitors & immune-tolerance therapy history

  15. Hemophilia joint health score (HJHS) [ Time Frame: May 2018 - Oct 2018 (anticipated) ]
    Clinical score [dimensionless]


Biospecimen Retention:   Samples Without DNA
blood, urine


Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years to 49 Years   (Child, Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

Test group population will be recruited at the clinical hemophilia center and pediatric unit of the Medical University of Vienna (patients with hemophila have biannual appointments)

Test group participants are asked to invite a friend at the same age (+/- 3 years; between 16 and 45y) to participate in the sense of a peer-matched control

Criteria

Inclusion Criteria (test group):

  • Provide signed and dated informed consent form (additionally from guardian for participants aged under 18 years)
  • Willing to comply with all study procedures and be available for the duration of the study
  • Diagnosed severe or moderate hemophilia A or B
  • Age between 16 and 49 years
  • Able to walk without aids or assistance
  • Treated with prophylactic substitution, initiated until the age of 18 years

Inclusion Criteria (control group):

  • Provide signed and dated informed consent form (additionally from guardian for participants aged under 18 years)
  • Willing to comply with all study procedures and be available for the duration of the study
  • Male
  • Age between 16 and 49 years (no blood samples for participants aged under 18 years)
  • Physiological and symmetric gait pattern without using aids or assistance

Exclusion Criteria:

  • Subjects suffering from functional impairments caused by other conditions than hemophilia
  • PWH with joint bleedings within 30 days prior to the examination (applies for test group only)
  • PWH treated with immune-tolerance therapy and/or not successfully treated present or past high-titer factor VIII or FIX inhibitor (applies for test group only)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03541811


Contacts
Contact: Peter Putz, Dr +431606687 ext 1723 peter.putz@fh-campuswien.ac.at

Locations
Austria
FH Campus Wien - University of Applied Sciences Recruiting
Vienna, Austria, 1100
Contact: Peter Putz, Dr.    +43 1 606 6877 ext 1723    peter.putz@fh-campuswien.ac.at   
Sponsors and Collaborators
FH Campus Wien, University of Applied Sciences
Medical University of Vienna
Shire
Investigators
Principal Investigator: Peter Putz, Dr FH Campus Wien, Department Health Sciences

Responsible Party: Peter Putz, Researcher, FH Campus Wien, University of Applied Sciences
ClinicalTrials.gov Identifier: NCT03541811     History of Changes
Other Study ID Numbers: JOSEPHA Phase 1
First Posted: May 31, 2018    Key Record Dates
Last Update Posted: July 3, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Peter Putz, FH Campus Wien, University of Applied Sciences:
gait
motion capture
hemophilia joint health score
physical activity
body composition
gait deviation index
hemophilia

Additional relevant MeSH terms:
Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn