Effect of Exercise on Biomarkers in SCT

The Effect of Exercise on Resting Biomarkers in Subjects With Sickle Cell Trait

This study measures the effect of exercise on a variety of biomarkers in blood and urine selected to evaluate the physiological pathways of hemolysis, myolysis, thrombosis, inflammation, and renal function in subjects with sickle cell trait. These pathways have been shown to be associated with adverse events in athletes and warfighters with SCT upon protracted, repeated, strenuous exertion. Changes in biomarkers post-exercise compared to pre-exercise (and compared to healthy controls) suggest activation of the associated pathway(s) which may contribute to exercise-related events in athletes and warfighters and subclinical complications in non-athletes.

Study Overview

• Status: Recruiting
• Conditions: Sickle Cell Trait
• Intervention / Treatment: Other: Exercise

Detailed Description

Subjects with sickle cell trait and healthy controls will be subjected to a single bout of moderate, controlled exercise on a treadmill. Blood and urine samples will be collected before exercise, immediately after exercise, and 24 hours after exercise. Fifteen biomarkers, three selected to evaluate each of the five physiologic pathways previously listed, will be tested at each of the three time points. Abnormal biomarkers before exercise suggest chronic pathway activation while exacerbated levels after exercise suggest further activation stimulated by exercise. Biomarker levels 24 hours post-exercise will be used to evaluate continued pathway activation or pathway recovery. By definition, 95% of health controls will show normal biomarker levels pre-exercise and biomarker patterns post-exercise will serve as the expected standard by which to compare the test subjects.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Tim R Randolph, PhD; Phone Number: 3149778688; Email: tim.randolph@health.slu.edu
• Study Contact Backup: Name: Kitty Newsham, PhD; Phone Number: 31497778507; Email: katherine.newsham@health.slu.edu

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63104-1111
      • Recruiting
      • Saint Louis University
      • Contact: Tim R Randolph, PhD; Phone Number: 314-977-8688; Email: tim.randolph@health.slu.edu
      • Contact: Katherine Newsham, PhD; Phone Number: 3149778507; Email: katherine.newsham@health.slu.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria: Sickle Cell Trait Group (AS)

• Health subjects with sickle cell trait (AS)
• Ages 18-70 years

Inclusion Criteria: Control group (AA)

• Healthy subjects without sickle cell trait (AA)
• Ages 18-70 years

Exclusion Criteria: Sickle Cell Trait group (AS) AND healthy controls (AA).

Subjects will be excluded if they:

• weigh less than 110 pounds,
• are pregnant,
• have hemoglobinopathies (other than sickle cell trait) as determined by Hb electrophoresis,
• have other self-reported conditions known to cause blood coagulation activation, myocyte destruction, hemolysis, chronic inflammation, or renal disease
• any condition that places subjects at risk during exercise.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SCT Group; Fifteen SCT subjects will be recruited, consented, screened, and enrolled if they meet inclusion and exclusion criteria. Each subject will undergo a single bout of standardized exercise on a treadmill. Subjects will self-select treadmill speed at 0% grade and begin. After 3 minutes the grade will be increased by 1% every 2 minutes until the target heart rate (70% of heart rate reserve) is reached. Speed and grade will be held constant for 15 minutes, marking the end of the session.	Other: Exercise; A single bout of standardized, moderate exercise
Active Comparator: Control Group; Five healthy subjects will be recruited, consented, screened, and enrolled if they meet inclusion and exclusion criteria. Each subject will undergo a single bout of standardized exercise on a treadmill. Subjects will self-select treadmill speed at 0% grade and begin. After 3 minutes the grade will be increased by 1% every 2 minutes until the target heart rate (70% of heart rate reserve) is reached. Speed and grade will be held constant for 15 minutes, marking the end of the session.	Other: Exercise; A single bout of standardized, moderate exercise

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in reticulocyte count	Reticulocytes will be counting using a manual microscopic method (New Methylene Blue) from blood collected in EDTA and reported as percentage of reticulocytes per 100 erythrocytes. Elevated reticulocytes suggest the bone marrow response to hemolysis.	Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill
Change in erythrocyte morphology amounts	Blood collected in EDTA will be smeared on a microscope slide, stained with Wright stain, and analyzed for abnormal morphologic forms with a particular interest in sickle cells. Each abnormal erythrocyte morphologic form will be reported on a Likert scale from 1-4+ as follows: 1+ (few abnormal cells); 2+ (approximately 1/3 abnormal cells); 3+ (approximately 1/2 abnormal cells); 4+ (>1/2 abnormal cells). Increasing numbers of sickle cells in response to exercise may be associated with increased hemolysis, myocyte destruction, inflammation, initiation of coagulation, and renal dysfunction.	Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill
Change in haptoglobin level	Haptoglobin will be measured on serum collected in a clot tube and reported as mg/dL (milligrams/deciliter) using a radial immunodiffusion method. Low haptoglobin levels suggest intravascular hemolysis.	Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill
Change in potassium (K+) level	Potassium will be measured in serum collected in a clot tube, analyzed by ion selective electrode, and reported in mEq/L (milliequivalents/liter) or mmole/L (millimoles/liter). Elevated potassium levels suggest intravascular hemolysis.	Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill
Change in creatine kinase (CK) level	Creatine kinase will be measured in serum from a clot tube, analyzed spectrophotometrically by enzyme kinetics and reported in U/L (units [of enzyme activity]/liter. Elevated creating kinase levels suggest myocyte destruction in the post-exercise environment.	Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill
Change in serum myoglobin level	Myoglobin will be measured in urine, analyzed by electrochemiluminescent Immunoassay or nephelometry and reported in ng/mL (nanograms/milliliter). Elevated myoglobin suggests myocyte destruction.	Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill
Change in urine myoglobin level	Myoglobin will be measured in urine, analyzed by electrochemiluminescent immunoassay or nephelometry and reported in mg/L (milligrams/liter). Elevated myoglobin suggests myocyte destruction.	Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill
Change in D-dimer level	D-dimer will be measured in citrated plasma, analyzed by immunoturbidimetry and reported in ug/mL (micrograms/milliliter). Elevated D-dimer suggests the initiation of abnormal clotting or an inflammatory reaction.	Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill
Change in fibrin monomer level	Fibrin monomer will be measured in citrated plasma, analyzed by the hemeagglutination method, and reported as negative (normal) or positive (abnormal). Elevated fibrin monomers suggest the initiation of coagulation.	Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill
Change in antithrombin III (ATIII) level	Antithrombin III will be measured in serum from a clot tube, analyzed by radial immunodiffusion, and reported in mg/dL (milligrams/deciliter). Low antithrombin III levels suggest the initiation of coagulation.	Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill
Change in C-reactive protein (CRP) level	C-reactive protein will be measured in serum from a clot tube, analyzed by radial immunodiffusion, and reported in mg/dL (milligrams/deciliter). Elevated C-reactive protein suggest an inflammatory reaction.	Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill
Change in erythrocyte sedimentation rate (ESR) level	Erythrocyte sedimentation rate will be measured on whole blood collected in EDTA using the Wintrobe method and reported in mm/hr (millimeters/hour). An elevated erythrocyte sedimentation rate suggests an inflammatory reaction.	Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill
Change in 11-dehydrothrombaxaneB2 (11-DTXB2) level	11-dehydrothromboxane B2 will be measured in urine using an enzyme-linked immunosorbant assay (ELISA) and will be reported as pg/mL of creatinine (picogram/milliliter of creatinine). 11-dehydrothrombozane B2 is a direct measure of platelet activation and an indirect measure of an inflammatory reaction.	Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill
Change in complete urinalysis results	A 10 parameter dipstick and a microscopic examination of urine will be performed on each urine sample collected. Each of the 10 dipstick parameters will be reported according to the package insert. We will pay particular attention to intact RBCs on the dipstick and sediment as an indicator of glomerular dysfunction, free hemoglobin as an indicator of hemolysis, elevated protein as an indicator of renal dysfunction or hemoglobinuria or myoglobinuria (hemolysis), and specific gravity interpreted in the context of blood and protein levels (and glucose) as an indicator of renal dysfunction.	Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill
Change in microalbumin level	Microalbumin will be measured in urine with a dipstick using the sulfonephthalein dye method as an indicator of renal dysfunction and reported in mg/L (millighrams/liter).	Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill

Collaborators and Investigators

• Sponsor: St. Louis University
• Collaborators: American Society for Clinical Laboratory Science
• Investigators: Principal Investigator: Tim R Randolph, PhD, St. Louis University

Study record dates

Study Major Dates

• Study Start (Actual): December 27, 2021
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: February 11, 2020
• First Submitted That Met QC Criteria: February 13, 2020
• First Posted (Actual): February 17, 2020

Study Record Updates

• Last Update Posted (Actual): January 12, 2024
• Last Update Submitted That Met QC Criteria: January 10, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Sickle Cell Trait
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Sickle Cell Trait
• Other Study ID Numbers: 30577

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: A final de-identified database of study data will be generated and used for data sharing. Written data sharing requests from outside researchers will be reviewed by the PI and other members of the research team. Sharing will require a written agreement between the involved parties, which specifies the following: (1) what data will be shared, (2) who will have access to the shared data, (3) how the data will be shared and where the shared data will be stored (including details about security for data transfer and storage), (4) when the data will be shared, and (5) details about the data (i.e. data formats/transformations for sharing, meta-data to be included, etc.). The agreement will also require a commitment to using the data only for the specified research purposes and a commitment to destroying or returning the data after analyses are completed. Before sharing occurs, the written agreement will also be reviewed and approved by the the appropriate University units.
• IPD Sharing Time Frame: Data will be available beginning 3 months after article publication for a period of 3 years after article publication
• IPD Sharing Access Criteria: Proposals from outside investigators requesting permission to access data can be made to the PI at tim.randolph@health.slu.edu
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No