Gainesville, Florida 32610


Purpose:

Traumatic injury is a leading cause of morbidity and mortality in young adults, and remains a substantial economic and health care burden. Despite decades of promising preclinical and clinical investigations in trauma, investigators understanding of these entities is still incomplete, and few therapies have shown success. During severe trauma, bone marrow granulocyte stores are rapidly released into the peripheral circulation. This release subsequently induces the expansion and repopulation of empty or evacuated space by hematopoietic stem cells (HSCs). Although the patient experiences an early loss of bone marrow myeloid-derived cells, stem cell expansion is largely skewed towards the repopulation of the myeloid lineage/compartment. The hypothesis is that this 'emergency myelopoiesis' is critical for the survival of the severely traumatized and further, failure of the emergency myelopoietic response is associated with global immunosuppression and susceptibility to secondary infection. Also, identifying the release of myeloid derived suppressor cells (MDSCs) in the circulation of human severe trauma subjects. This process is driven by HSCs in the bone marrow of trauma subjects. Additionally, MDSCs may have a profound effect on the nutritional status of the host. The appearance of these MDSCs after trauma is associated with a loss of muscle tissue in these subjects. This muscle loss and possible increased catabolism have huge effects on long term outcomes for these subjects. It is the investigator's goal to understand the differences that occur in these in HSCs and muscle cells as opposed to non-injured and non-infected controls. This work will lead to a better understanding of the myelopoietic and catabolic response following trauma.


Study summary:

This is a prospective study to understand how trauma injuries changes the hematopoeitic stem cells (HSCs) in the bone marrow and muscle cells after trauma injury in elderly subjects is different when compared to non-injured subjects. There will be three groups for this study: 1) Elective hip surgery subjects, 2) Trauma subjects and 3) deidentified bone marrow of healthy controls. Samples of bone marrow and a blood sample will be collected at the time of surgery. The deidentified bone marrow of healthy controls will come from a tissue bank. The blood will be used to perform PB colony assays, ELISAs to test for the following parameters: EPO, G-CSF, Reticulocyte, iron levels and cytokines and inflammatory markers. The bone marrow and blood samples will be processed and sorted to isolate hematopoeitic stem cells for genomic content to determine genomic expression, oxidative stress, mitochondrial activity, apoptosis, autophagy, analysis of circulating erythroid progenitor cells, reticulocytes, granulocyte-colony stimulating factor assays, erythropoietin and iron levels. Clinical data and hemodynamic measurements will be collected daily while subjects are hospitalized and trauma surgery subjects will be followed to evaluate for malunion and subsequent additional surgical procedures for repair.


Criteria:

Severe Trauma Population Inclusion criteria will be: 1. All adults (age ≥18 to 54) 2. Blunt and/or penetrating trauma resulting in long bone or pelvic fractures requiring ORIF or closed reduction percutaneous pinning (CRPP). 3. Blunt and/or penetrating trauma patient with either: 1. hemorrhagic shock defined by: i. systolic BP (SBP) ≤ 90 mmHg or ii. mean arterial pressure≤ 65 mmHg or iii. base deficit (BD) ≥ 5 meq or iv. lactate ≥ 2 2. Or injury severity score (ISS) greater than or equal to 15. 4. All adults (age 55 and older) require: 1. Blunt and/or penetrating trauma resulting in log bone or pelvic fractures requiring ORIF or CRPP 2. Either hemorrhagic shock defined by: i. Systolic BP (SBP) ≤ 90 mmHg or ii. Mean arterial pressure ≤ 65 mmHg or iii. Base deficit (BD) ≥5 meq or iv. Lactate ≥ 2 3. Or Injury Severity Score (ISS) greater than or equal to 15. 5. Ability to obtain Informed Consent prior to OR repair of injury. Exclusion Criteria will be: 1. Patients not expected to survive greater than 48 hours. 2. Prisoners. 3. Pregnancy. 4. Patients receiving chronic corticosteroids or immunosuppression therapies. 5. Previous bone marrow transplantation. 6. Patients with End Stage Renal Disease. 7. Patients with any pre-existing hematological disease. Elective Hip Repair Population Inclusion criteria will be: 1. All adults (age ≥18) 2. Patient undergoing elective hip repair for non-infectious reasons. 3. Ability to obtain Informed Consent prior to operation. Exclusion Criteria will be: 1. Pregnancy. 2. Prisoners. 3. Patients receiving chronic corticosteroids or immunosuppression therapies. 4. Previous Chemotherapy or Radiation. 5. Pre-existing conditions such as pathological fractures, cancer, history of HIV, or history of connective tissue disease. 6. Previous bone marrow transplantation. 7. Patients with End Stage Renal Disease. 8. Patients with any pre-existing hematological disease.


Study is Available At:


Original ID:

IRB201601386-N


NCT ID:

NCT02577731


Secondary ID:

1R01GM113945-01


Study Acronym:


Brief Title:

Hematopoietic Stem Cell Dysfunction in the Elderly After Severe Injury


Official Title:

Hematopoietic Stem Cell Dysfunction in the Elderly After Severe Injury: Chronic Stress and Anemia Recovery Following Major Trauma


Overall Status:

Recruiting


Study Phase:

N/A


Genders:

N/A


Minimum Age:

18 Years


Maximum Age:

N/A


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

University of Florida


Oversight Authority:

United States: Institutional Review Board


Reasons Why Stopped:


Study Type:

Interventional


Study Design:


Number of Arms:

3


Number of Groups:

0


Total Enrollment:

250


Enrollment Type:

Anticipated


Overall Contact Information

Official Name:Philip Efron, MD
Principal Investigator
University of Florida
Primary Contact:Jennifer D Lanz, MSN
352-273-5497
jennifer.lanz@surgery.ufl.edu
Backup Contact:Ruth J Davis, ASN
352-273-8759
ruth.davis@surgery.ufl.edu

Study Dates

Start Date:January 2014
Completion Date:October 2020
Completion Type:Anticipated
Primary Completion Date:August 2020
Primary Completion Type:Anticipated
Verification Date:August 2019
Last Changed Date:August 8, 2019
First Received Date:October 1, 2015

Study Outcomes

Outcome Type:Primary Outcome
Measure:Analyze the genomics response of hematopoietic cells between the groups
Time Frame:Baseline
Safety Issues:False
Description:Through negative isolation columns and flow sorting to isolate the hematopoietic stem cells (HSCs) from a sample for appropriate analysis. The sample will then be enriched using a lineage depletion column which will remove all mature hematopoietic cells.
Outcome Type:Primary Outcome
Measure:Analyze the muscle dysfunction between the groups for oxidative stress
Time Frame:Baseline
Safety Issues:False
Outcome Type:Primary Outcome
Measure:Analyze the muscle dysfunction between the groups for mitochondrial activity
Time Frame:Baseline
Safety Issues:False
Outcome Type:Primary Outcome
Measure:Analyze the muscle dysfunction between the groups for apoptosis
Time Frame:Baseline
Safety Issues:False
Outcome Type:Primary Outcome
Measure:Analyze the muscle dysfunction between the groups for autophagy
Time Frame:Baseline
Safety Issues:False
Outcome Type:Secondary Outcome
Measure:The pathophysiology of injury-associated persistent anemia through PB colony assays of blood.
Time Frame:Baseline
Safety Issues:False
Outcome Type:Secondary Outcome
Measure:The pathophysiology of injury-associated persistent anemia through ELISA test of blood.
Time Frame:Baseline
Safety Issues:False

Study Interventions

Intervention Type:Other
Name:Bone marrow collection
Description:Bone marrow will be collected from the patient at time of orthopedic repair in the operating room. A second sample may be collected if the patient is required to return to the operating room for further repair of orthopedic injury.
Arm Name:Severe Trauma
Intervention Type:Other
Name:Blood collection
Description:Blood sample collection will be collected from the patient at time of orthopedic repair in the operating room. A second sample may be collected if the patient is required to return to the operating room for further repair of orthopedic injury.
Arm Name:Severe Trauma
Intervention Type:Other
Name:Clinical data collection
Description:Clinical data collection will encompass demographic information, past and present medical records, laboratory, microbiology, and all other test results, x-ray, CT, MRI, US and all other imaging test results, records about any medication received during admission, records of physical exam during admission, records of all vital signs and hemodynamic monitoring during admission, records of any procedure or intervention during admission, records of any procedure or intervention during hospital admis
Arm Name:Severe Trauma

Study Arms

Study Arm Type:Other
Arm Name:Healthy Young Bone Marrow Control
Description:Deidentified freshly isolated bone marrow samples from healthy young control subjects will be purchased for a tissue bank.
Study Arm Type:Other
Arm Name:Elective Hip Repair
Description:Bone marrow collection. Blood collection. Clinical data collection.
Study Arm Type:Other
Arm Name:Severe Trauma
Description:Bone marrow collection. Blood collection. Clinical data collection.

Study Agencies

Agency Class:Other
Agency Type:Lead Sponsor
Agency Name:University of Florida
Agency Class:NIH
Agency Type:Collaborator
Agency Name:National Institute of General Medical Sciences (NIGMS)

Sample and Retention Information

There are no available Sample and Retention Information

Study References

There are no available Study References

Data Source: ClinicalTrials.gov

Date Processed: January 21, 2020

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