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Effect of Exercise on Biomarkers in SCT

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ClinicalTrials.gov Identifier: NCT04273022
Recruitment Status : Suspended (Due to the Covid-19 pandemic, Saint Louis University suspended human research studies that did not meet specific criteria, which this study did not meet.)
First Posted : February 17, 2020
Last Update Posted : November 30, 2020
Sponsor:
Collaborator:
American Society for Clinical Laboratory Science
Information provided by (Responsible Party):
Tim Randolph, PhD, MT (ASCP), St. Louis University

Tracking Information
First Submitted Date  ICMJE February 11, 2020
First Posted Date  ICMJE February 17, 2020
Last Update Posted Date November 30, 2020
Estimated Study Start Date  ICMJE August 31, 2021
Estimated Primary Completion Date August 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 21, 2020)
  • Change in reticulocyte count [ Time Frame: Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill ]
    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.
  • Change in erythrocyte morphology amounts [ Time Frame: Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill ]
    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.
  • Change in haptoglobin level [ Time Frame: Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill ]
    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.
  • Change in potassium (K+) level [ Time Frame: Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill ]
    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.
  • Change in creatine kinase (CK) level [ Time Frame: Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill ]
    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.
  • Change in serum myoglobin level [ Time Frame: Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill ]
    Myoglobin will be measured in urine, analyzed by electrochemiluminescent Immunoassay or nephelometry and reported in ng/mL (nanograms/milliliter). Elevated myoglobin suggests myocyte destruction.
  • Change in urine myoglobin level [ Time Frame: Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill ]
    Myoglobin will be measured in urine, analyzed by electrochemiluminescent immunoassay or nephelometry and reported in mg/L (milligrams/liter). Elevated myoglobin suggests myocyte destruction.
  • Change in D-dimer level [ Time Frame: Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill ]
    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.
  • Change in fibrin monomer level [ Time Frame: Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill ]
    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.
  • Change in antithrombin III (ATIII) level [ Time Frame: Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill ]
    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.
  • Change in C-reactive protein (CRP) level [ Time Frame: Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill ]
    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.
  • Change in erythrocyte sedimentation rate (ESR) level [ Time Frame: Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill ]
    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.
  • Change in 11-dehydrothrombaxaneB2 (11-DTXB2) level [ Time Frame: Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill ]
    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.
  • Change in complete urinalysis results [ Time Frame: Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill ]
    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.
  • Change in microalbumin level [ Time Frame: Immediately before, immediately after, & 24 hours after a single bout of submaximal exercise on a treadmill ]
    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).
Original Primary Outcome Measures  ICMJE
 (submitted: February 13, 2020)
  • Fifteen biomarkers (12 in blood and 3 in urine) will be measured immediately before a single bout of submaximal exercise in both the test group (SCT) and the control group (healthy without SCT). [ Time Frame: Immediately before a single bout of submaximal exercise on a treadmill ]
    Blood and urine will be collected immediately before the exercise session and fifteen biomarkers will be measured to assess five physiological pathways. To evaluate hemolysis, the following biomarkers will be measured: reticulocyte count, erythrocyte morphology, haptoglobin, potassium. To evaluate myolysis, the following biomarkers will be measured: creatine kinase, serum myoglobin, urine myoglobin. To evaluate thrombosis, the following biomarkers will be measured: D-dimer, fibrin monomer, antithrombin III. To evaluate Inflammation, the following biomarkers will be measured: C-reactive protein, erythrocyte sedimentation rate, 11-dehydrothromboxane B2 (urine). To evaluate renal function the following biomarkers will be measured: complete urinalysis and microalbumin.
  • Fifteen biomarkers (12 in blood and 3 in urine) will be measured immediately after a single bout of submaximal exercise in both the test group (SCT) and the control group (healthy without SCT). [ Time Frame: Immediately after a single bout of submaximal exercise on a treadmill ]
    Blood and urine will be collected immediately after the exercise session and fifteen biomarkers will be measured to assess five physiological pathways. To evaluate hemolysis, the following biomarkers will be measured: reticulocyte count, erythrocyte morphology, haptoglobin, potassium. To evaluate myolysis, the following biomarkers will be measured: creatine kinase, serum myoglobin, urine myoglobin. To evaluate thrombosis, the following biomarkers will be measured: D-dimer, fibrin monomer, antithrombin III. To evaluate Inflammation, the following biomarkers will be measured: C-reactive protein, erythrocyte sedimentation rate, 11-dehydrothromboxane B2 (urine). To evaluate renal function the following biomarkers will be measured: complete urinalysis and microalbumin.
  • Fifteen biomarkers (12 in blood and 3 in urine) will be measured approximately 24 hours after a single bout of submaximal exercise in both the test group (SCT) and the control group (healthy without SCT). [ Time Frame: Approximately 24 hours after a single bout of submaximal exercise on a treadmill ]
    Blood and urine will be collected approximately 24 hours after an exercise session and fifteen biomarkers will be measured to assess five physiological pathways. To evaluate hemolysis, the following biomarkers will be measured: reticulocyte count, erythrocyte morphology, haptoglobin, potassium. To evaluate myolysis, the following biomarkers will be measured: creatine kinase, serum myoglobin, urine myoglobin. To evaluate thrombosis, the following biomarkers will be measured: D-dimer, fibrin monomer, antithrombin III. To evaluate Inflammation, the following biomarkers will be measured: C-reactive protein, erythrocyte sedimentation rate, 11-dehydrothromboxane B2 (urine). To evaluate renal function the following biomarkers will be measured: complete urinalysis and microalbumin.
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effect of Exercise on Biomarkers in SCT
Official Title  ICMJE The Effect of Exercise on Resting Biomarkers in Subjects With Sickle Cell Trait
Brief Summary 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.
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  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Intervention Model Description:
SCT subjects will be evaluated for activation of five physiological pathways by measuring 15 biomarkers before and after a single bout of moderate exercise. The control group will confirm normal biomarkers at rest and determine the natural response to moderate exercise.
Masking: Single (Outcomes Assessor)
Masking Description:
Blood and urine samples will be assigned a random code. Testing personnel will be blinded to whether samples are pre- or post-exercise and whether from the SCT or control group.
Primary Purpose: Diagnostic
Condition  ICMJE Sickle Cell Trait
Intervention  ICMJE Other: Exercise
A single bout of standardized, moderate exercise
Study Arms  ICMJE
  • 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.
    Intervention: Other: 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.
    Intervention: Other: Exercise
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  ICMJE Suspended
Estimated Enrollment  ICMJE
 (submitted: February 13, 2020)
20
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 1, 2022
Estimated Primary Completion Date August 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04273022
Other Study ID Numbers  ICMJE 30577
Has Data Monitoring Committee Yes
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  ICMJE
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Time Frame: Data will be available beginning 3 months after article publication for a period of 3 years after article publication
Access Criteria: Proposals from outside investigators requesting permission to access data can be made to the PI at tim.randolph@health.slu.edu
Responsible Party Tim Randolph, PhD, MT (ASCP), St. Louis University
Study Sponsor  ICMJE St. Louis University
Collaborators  ICMJE American Society for Clinical Laboratory Science
Investigators  ICMJE
Principal Investigator: Tim R Randolph, PhD St. Louis University
PRS Account St. Louis University
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP