Dose-Response Relationship of Ambulatory Load and Cartilage - Pilot Study (COMP)

The research question is if there is a dose-response relationship between blood biomarkers for articular cartilage and the magnitude of physiological load. To investigate this load induced biomarker change, the participants will complete a 30-minute walking test under three loading conditions: A: 80%, B: 100% C: 120% of their respective bodyweight (Fig. 1).

The main biomarker we are interested in is called cartilage oligomeric matrix protein (COMP). Serum COMP levels are increased immediately after 30-min running but there is no dose-response relationship shown yet.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Other: Increased load; Other: Reduced load

Detailed Description

The current state of research in the field and of our own research clearly shows that the in vivo mechanobiology of articular cartilage is poorly understood. Previous results of changes in cartilage biomarker concentrations after ambulatory exercise raise the following question:

Do load-induced changes in blood biomarkers for articular cartilage (COMP) depend on the physiological load magnitude? To generate initial data for answering this question, we will establish the experimental framework to systematically study the in vivo mechanobiology of human articular cartilage to address the following aims.

• To obtain pilot data for investigating the in vivo dose-response relationship of weight-bearing and blood levels of mechanosensitive biomarker of articular cartilage using controlled load- bearing as experimental paradigm.
• To provide pilot data for comparing ambulatory biomechanics between the controlled load- bearing conditions.

The experimental setting consists of a 30-minutes walking stress test under three loading conditions: A: 80 %, B: 100% and C: 120% bodyweight. Unloading will be achieved through an unloading system and additional loading with an adjustable weight vest. Before and after the walking stress test, venous blood samples will be taken at five time points. The biomarker concentration is measured with a commercial available enzyme-linked immunosorbent assay (ELISA).

Hypothesis Our working hypothesis is that there is a dose-response relationship between the temporarily increased or decreased load and the load-induced change in COMP level in the blood serum. We assume that serum COMP concentration increases with increasing accumulated load on the knee cartilage simulated through the three different loading conditions.

Design The design of the pilot study is a controlled multimodal data collection (biological, biomechanical) with block randomization. Specifically, we will collect blood samples and biomechanical (kinematic and pressure) data. We will determine the relationship between the serum blood concentration and the biomechanical data.

Because this is a cross-over study, all participants will perform the same three walking stress tests but in random order. Each participant of the study will be tested for 2.5 hours on 3 separate days.

Method In this experiment, we will test 24 healthy participants (12 male, 12 female) on 3 test days under three different loading conditions in a randomized block design. On each test day, participants will complete walking stress test for 30-minutes with A: 80%, B: 100% and C: 120% of their bodyweight. Through the modified bodyweight we generate higher or lower forces on the knee cartilage, which should affect the COMP concentration in the blood serum.

To measure the change in serum COMP concentration, blood samples will be taken at five time points before and after the walking stress test. The blood samples are taken by a study nurse. For the venipuncture, a thin, sterile, disposable vein catheter is placed in the antecubital vein. The catheter stays in the vein for the entire 2.5 hours of the experiment. Blood samples will be collected and allowed to clot for 30-minutes. Serum will be separated and frozen in aliquots to -20°C within 1 hour of collection and then transferred for storage at -80°C until assayed. Serum biomarker concentrations will be determined using commercial ELISAs.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Switzerland
  • Basel Stadt
    • Basel, Basel Stadt, Switzerland, 4031
      • University Hospital Basel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 30 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age between 18 and 30 years
• being physically active (> 2/week)
• body mass index (BMI) <30 kg/m2

Exclusion Criteria:

• previous knee injury
• neuromuscular condition affecting gait

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Normal load; Healthy subjects walking for 30 minutes on a treadmill with normal body weight
Experimental: Increased load; Healthy subjects walking for 30 minutes on a treadmill with 20% additional body weight	Other: Increased load; Participants walk with 120% body weight achieved with a weight vest
Experimental: Reduced load; Healthy subjects walking for 30 minutes on a treadmill with 20% lower body weight	Other: Reduced load; Participants walk with 80% body weight achieved by a dynamic unloading system

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Load-induced serum Cartilage Oligomeric Matrix Protein concentration	Change in serum concentration during 30-minute walking exercise determined by commercial ELISA 30 min before to 2 hours after 30-minute walking exercise	3 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall ground reaction force impulse	Area under the ground reaction curve multiplied by number of steps taken during 30-minute walking exercise	30 minutes
Dynamic range of motion lower extremity joints	Min to max joint angles (ankle, knee, hip) measured using RehaGait (inertial measurement units)	30 minutes

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Age	Age in years	At enrollment
Sex	male or female	At enrollment
Body mass index	BMI in kg/m2	At enrollment
Knee function	Knee Osteoarthritis Outcome Score measured by questionnaire (best score: 100 - no limitations; worst score: 0)	At enrollment

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Collaborators: University of Erlangen-Nürnberg
• Investigators: Principal Investigator: Annegret Muendermann, PhD, University Hospital, Basel, Switzerland

Study record dates

Study Major Dates

• Study Start (Actual): July 5, 2017
• Primary Completion (Actual): September 30, 2017
• Study Completion (Actual): July 31, 2019

Study Registration Dates

• First Submitted: February 27, 2018
• First Submitted That Met QC Criteria: February 27, 2018
• First Posted (Actual): March 6, 2018

Study Record Updates

• Last Update Posted (Actual): September 18, 2019
• Last Update Submitted That Met QC Criteria: September 17, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Biomarker; Articular cartilage; Ambulatory load
• Other Study ID Numbers: 2017-01006

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