Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Hematopoietic Stem Cell Dysfunction in the Elderly After Severe Injury

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02577731
Recruitment Status : Recruiting
First Posted : October 16, 2015
Last Update Posted : February 10, 2020
Sponsor:
Collaborator:
National Institute of General Medical Sciences (NIGMS)
Information provided by (Responsible Party):
University of Florida

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Trauma Injury Other: Bone marrow collection Other: Blood collection Other: Clinical data collection Not Applicable

Detailed Description:

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 250 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Hematopoietic Stem Cell Dysfunction in the Elderly After Severe Injury: Chronic Stress and Anemia Recovery Following Major Trauma
Study Start Date : January 2014
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : October 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Severe Trauma
Bone marrow collection. Blood collection. Clinical data collection.
Other: Bone marrow collection
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.

Other: Blood collection
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.

Other: Clinical data collection
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 admission, condition at the discharge and discharge facility.

Elective Hip Repair
Bone marrow collection. Blood collection. Clinical data collection.
Other: Bone marrow collection
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.

Other: Blood collection
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.

Other: Clinical data collection
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 admission, condition at the discharge and discharge facility.

Healthy Young Bone Marrow Control
Deidentified freshly isolated bone marrow samples from healthy young control subjects will be purchased for a tissue bank.
Other: Bone marrow collection
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.




Primary Outcome Measures :
  1. Analyze the genomics response of hematopoietic cells between the groups [ Time Frame: Baseline ]
    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. The HSCs will be phenotyped and sorted as CD34+ CD38- Thy1+ CD45RA-. HSCs will be lysed and the RNA genomic content will be isolated. The genomic content will then be processed onto a GeneChip® microarray to analyze the genomic expression.

  2. Analyze the muscle dysfunction between the groups for oxidative stress [ Time Frame: Baseline ]
  3. Analyze the muscle dysfunction between the groups for mitochondrial activity [ Time Frame: Baseline ]
  4. Analyze the muscle dysfunction between the groups for apoptosis [ Time Frame: Baseline ]
  5. Analyze the muscle dysfunction between the groups for autophagy [ Time Frame: Baseline ]

Secondary Outcome Measures :
  1. The pathophysiology of injury-associated persistent anemia through PB colony assays of blood. [ Time Frame: Baseline ]
  2. The pathophysiology of injury-associated persistent anemia through ELISA test of blood. [ Time Frame: Baseline ]

Other Outcome Measures:
  1. Analyze the genomics response of hematopoietic cells between the groups at additional follow-up surgery [ Time Frame: Approximately 8 months ]
    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. The HSCs will be phenotyped and sorted as CD34+ CD38- Thy1+ CD45RA-. HSCs will be lysed and the RNA genomic content will be isolated. The genomic content will then be processed onto a GeneChip® microarray to analyze the genomic expression.

  2. Analyze the muscle dysfunction between the groups at additional follow-up surgery for oxidative stress [ Time Frame: Approximately 8 months ]
  3. Analyze the muscle dysfunction between the groups at additional follow-up surgery for mitochondrial activity [ Time Frame: Approximately 8 months ]
  4. Analyze the muscle dysfunction between the groups at additional follow-up surgery for apoptosis [ Time Frame: Approximately 8 months ]
  5. Analyze the muscle dysfunction between the groups at additional follow-up surgery for autophagy [ Time Frame: Approximately 8 months ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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): NCT02577731


Contacts
Layout table for location contacts
Contact: Jennifer D Lanz, MSN 352-273-5497 jennifer.lanz@surgery.ufl.edu
Contact: Ruth J Davis, ASN 352-273-8759 ruth.davis@surgery.ufl.edu

Locations
Layout table for location information
United States, Florida
UF Health Shands Hospital at the University of Florida Recruiting
Gainesville, Florida, United States, 32610
Contact: Jennifer Lanz, MSN    352-273-5497    jennifer.lanz@surgery.ufl.edu   
Contact: Ruth Davis, ASN    352-273-8759    ruth.davis@surgery.ufl.edu   
Sub-Investigator: Frederick Moore, MD         
Sub-Investigator: Christiaan Leeuwenburgh, PhD         
Sub-Investigator: Alicia Mohr, MD         
Sub-Investigator: Moldawer Lyle, MD         
Sub-Investigator: Kalia Sadasivan, MD         
Sub-Investigator: Hari Parvateneni, MD         
Principal Investigator: Philip Efron, MD         
Sponsors and Collaborators
University of Florida
National Institute of General Medical Sciences (NIGMS)
Investigators
Layout table for investigator information
Principal Investigator: Philip Efron, MD University of Florida
Layout table for additonal information
Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT02577731    
Other Study ID Numbers: IRB201601386-N
1R01GM113945-01 ( U.S. NIH Grant/Contract )
IRB 106-2013 ( Other Identifier: Univeristy of Florida )
R01GM105893-07 ( U.S. NIH Grant/Contract )
OCR30562 ( Other Identifier: University of Florida )
First Posted: October 16, 2015    Key Record Dates
Last Update Posted: February 10, 2020
Last Verified: February 2020

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Florida:
Trauma
Additional relevant MeSH terms:
Layout table for MeSH terms
Wounds and Injuries