BM-MNCs for Lower Extremity Compartment Syndrome Injury

Study Overview
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Brief Summary
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This is a phase 1 study to assess safety and tolerability of intramuscular administration of two different doses of autologous bone marrow mononuclear cells (BM-MNCs) for treatment of lower extremity injury complicated by compartment syndrome injury.

Detailed Description
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The primary objectives are to assess safety and tolerability of a high and low dose of autologous bone marrow mononuclear cells. Secondary objectives include evaluation of potential responses of the BM-MNC therapy. This is a two-stage, randomized, unblinded, multicenter (two sites), controlled phase 1 clinical trial to evaluate the safety of two different doses of intramuscular injections of autologous bone marrow mononuclear cells, commonly known as a type of stem cell. Acute compartment syndrome injury is a mixed soft tissue injury due to a trauma that causes edema leading to excessive pressure in the muscle compartment. This type of injury frequently results in permanent reduction in function and disability. A total of 18 participants that have undergone a fasciotomy for treatment of a lower leg compartment syndrome will be enrolled with 6 assigned to the control (observational) group, 6 to the low cell-dose group and 6 to the high cell-dose group. The treatment arm will receive a single dose (high or low) of autologous BM-MNCs 5 - 9 days post injury and fasciotomy and a minimum of 3 months of standard of care physical rehabilitation. An observational control arm will not receive cells post fasciotomy but will undergo a standard of care course of physical therapy and will be followed for comparison to assess early safety signals and potential benefit.

Official Title
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Autologous Bone Marrow Mononuclear Cell Administration for Lower Extremity Compartment Syndrome Injury

Conditions
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Compartment Syndrome Traumatic Lower Extremity

Intervention / Treatment
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* Biological: Intramuscular administration of autologous BM-MNCs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females and males 18 - 70 years old Has single or multiple compartment syndrome of the lower leg that includes the anterior tibial compartment Trauma patients with lower extremity CS requiring fasciotomy that can be treated with autologous BM-MNC therapy on day 5-9 post-fasciotomy Ability to sign an informed patient consent form Access and willingness to complete a standard of care course of rehabilitation therapy and 24 months follow-up evaluations Ability to close the fasciotomy wound per physician assessment Anterior compartment muscle volume between 100 - 280 cc as determined by MRI/CT Within the institutions' clinical reference ranges for HbA1C Negative HIV test · - Non-fracture, closed fracture or compound fracture type I (wound less than 1cm & compound from within out) (Gustilo-Anderson classification) Female subjects must be of non-childbearing potential or must be using adequate contraception If female subject is of childbearing potential, subject must have a negative pregnancy test at screening Willing and able to adhere to the study schedule Exclusion Criteria: Prior compartment syndrome of same limb; Active malignancy or has undergone treatment for a malignancy in the preceding 5 years as indicated in past medical history or self-report if medical records do not accompany subject or are unable to be collected (basal cell carcinoma non-exclusionary); HIV positive as indicated by past medical history, self-report, or positive HIV test; Diagnosis of Type 1 or Type 2 diabetes with elevated HbA1C consistent with diabetes;(controlled diabetes acceptable, diabetes medication for other diagnosis acceptable) Diagnosis of chronic lower extremity vascular disease as diagnosed by current physician diagnosis, indicated in past medical history, or self-report if medical records do not accompany subject or are unable to be collected; Patients unable to sign an informed patient consent; Anticipated amputation of involved limb; Neurological conditions (i.e. spinal cord injury or traumatic brain injury) that may prevent full participation in CS rehabilitation or potentially confound study outcome measures (i.e. balance and gait) per physician discretion Current systemic infection; Local infection of the involved muscle group; Use of ventilator that would preclude rehabilitation protocols; Lack of access or unwillingness to complete standard of care course of physical therapy rehabilitation; Life expectancy 12 months or less; Bone marrow disorders (i.e. leukemia, aplastic anemia, lymphoma) ; Inability to close the fasciotomy wound or lower extremity burns that may affect wound closure Extensive tissue loss due to debridement resulting in insufficient residual tissue for stem cell administration and subsequent engraftment Lower extremity compound fracture type II or III (Gustilo-Anderson classification); Anterior tibialis muscle volume less than 100 cc or greater than 280 cc as determined by MRI/CT; Evidence of any past or present clinically significant medical condition that would impair wound healing History or clinical manifestations of significant renal, hepatic, cardiovascular, metabolic, neurologic, psychiatric, or other condition that would preclude participation in the study as determined by the investigator or the investigator's designee; Any reason, considered by the principal investigator or designee, to preclude subject enrollment in the study that might represent a threat to the subject's health or safety.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a two-stage, randomized, unblinded, multicenter (two sites), controlled phase 1 clinical trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Autologous BM-MNCs High Dose<br>Administration of autologous bone marrow mononuclear cells at High dose (700,000 cells/cc of tissue) | Biological: Intramuscular administration of autologous BM-MNCs<br>* Intramuscular administration of autologous BM-MNCs at either a low or high cell dose.<br>|
| No Intervention: Observational Control<br>Standard of care provided for subjects that have undergone a fasciotomy following a diagnosis of compartment syndrome. No autologous bone marrow mononuclear cells will be administered. | |
| Experimental: Autologous BM-MNCs Low Dose<br>Administration of autologous bone marrow mononuclear cells at a Low dose (350,000 cells/cc of tissue) | Biological: Intramuscular administration of autologous BM-MNCs<br>* Intramuscular administration of autologous BM-MNCs at either a low or high cell dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as determined by incidence of combined adverse events related to study agent intervention | Local and systemic reactions, serious adverse events and unexpected serious adverse events. | Enrollment through 24 months | 
| Efficacy as determined by muscle strength | Change in muscle strength compared to baseline and contralateral leg as measured by manual muscle testing and Biodex. | 6 weeks, 3 months, 6 months, and 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as determined by evidence of tumor formation | Magnetic resonance imaging (MRI) and/or computed tomography (CT) | Baseline through 12 months | 
| Efficacy as determined by muscle regeneration | Magnetic resonance imaging (MRI) and/or computed tomography (CT) to measure muscle volume | Baseline through 12 months | 
| Nerve conduction | Nerve conduction velocity test | Baseline and 6 months | 
| Wound healing | Number of days until wound closure at the site of fasciotomy of the anterior compartment. | Baseline through 12 months | 
| Lower extremity sensation | Sensation as measured by Semmes Weinstein Monofilament. | Baseline through 12 months | 
| Ankle range of motion | Range of Motion (ROM): active and passive dorsi/plantar flexion ROM assessed using a goniometer. | Baseline through 12 months | 
| Gait analysis | Change in gait kinematics: gait will be recorded using a Tekscan Pressure Mapping system where each sequential footstep is recorded along with synchronized video. | Week 6 through 12 months | 
| Gait endurance | Gait endurance measured using the 6-Minute Walk Test. | Week 6 through 12 months | 
| Gait speed | Gait speed measured using the 10 Meter Walk Test. | Week 6 through 12 months | 
| Balance | Balance assessed by single limb stance time. | Week 6 through 12 months | 
| Questionnaire - Pain | Pain measured using the Numeric Pain Rating Scale (NPRS). The participant is asked to make three pain ratings (0 to 10; 0 - no pain, 10 - worst pain), corresponding to current, best and worst pain experienced over the past 24 hours. The average of the 3 ratings is used to represent the patient's level of pain over the previous 24 hours. | Baseline through 24 months | 
| Questionnaire - Function | Lower extremity function assessed using the Lower Extremity Functional Scale (LEFS). Total score (0 to 80; higher score = better outcome) is reported as a sum of 20 responses regarding functional activities (0 - extreme difficulty or unable to perform, 4 - no difficulty). | Baseline through 24 months | 
| Questionnaire - Physical Activity | Physical activity measured by the international physical activity questionnaire (IPAQ). Scores are reported as categorical (low, moderate, high) and/or continuous (metabolic equivalent minutes per week). | Baseline through 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mononuclear cells