Cerebrospinal Fluid Drainage (CSFD) in Acute Spinal Cord Injury

Study Overview
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Brief Summary
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The purpose of this Phase IIB randomized controlled trial is to evaluate the safety and efficacy of CSFD and to provide a preliminary clinical efficacy evaluation of the combination of CSFD and elevation of mean arterial pressure (MAP) in patients with acute spinal cord injury (SCI). The objectives of the trial are to evaluate (i) efficacy of reducing intrathecal pressure (ITP) by CSFD in patients with acute SCI; (ii) preliminary efficacy of combination of CSFD and elevation of MAP compared to elevation of MAP alone in improving neurologic motor outcomes in patients with acute SCI; and, (iii) safety of intensive CSFD in acute SCI patients.

Detailed Description
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Acute spinal cord injury (SCI) affects 10,000-14,000 persons per year in the United States (Burke, Linden et al. 2001). There are 150,000-300,000 persons living with significant disabilities from SCI at any given time (Bernhard, Gries et al. 2005). The average age of incident cases of SCI is 47 years and about 78% of the cases are males (DeVivo and Chen 2011). Estimates of the lifetime costs to care for someone with a SCI range from $325,000 to $1.35 million and the yearly cost to society reaches $8 billion (Sekhon and Fehlings 2001). With better long term care technologies, these costs are expected to continue to rise. Although there have been significant advances in accessibility for people with disabilities, the goal of medical science is to overcome the physiological barriers imposed by the injury itself and allow these individuals to regain their pre-injury level of neurological function (Rowland, Hawryluk et al. 2008). The injury to the spinal cord occurs in two phases. The first phase is the primary physical damage due to the impact energy of the compressive nature of the injury. The damage can be very complex with shearing of the axons, destruction of the cell bodies and disruption of the microvasculature at the site of injury. The secondary phase of the injury begins soon after the primary injury has occurred and can be influenced by many factors such as hypoxia, hypotension, and the extent of the primary injury. Spinal cord ischemia post-injury causes a significant increase in cell death and more significant neurological disability. Limiting tissue hypoperfusion post-injury can decrease the amount of cell death and axonal damage. Lumbar cerebrospinal fluid drainage (CSFD) together with increased mean arterial blood pressure (MAP) in the immediate post-injury period can reduce spinal cord tissue hypoperfusion. By reducing spinal cord hypoperfusion through elevation of MAP, less cell death and axonal damage will occur, leading to an improvement in neurological function. The feasibility of CSFD as a means for reducing the intrathecal pressure (ITP) in patients with acute SCI has been demonstrated in a small randomized controlled trial by Kwon et al (Kwon, Curt et al. 2009). The limitations were a small sample size, broad inclusion criteria, lack of statistical power calculation and restricted drainage regimen (maximum 10 mL per hour).

Official Title
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A Multi-Center, Randomized, Controlled, Trial of Cerebrospinal Fluid Drainage (CSFD) in Acute Spinal Cord Injury

Conditions
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Spinal Cord Injury

Intervention / Treatment
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* Procedure: CSFD and elevation of MAP
* Procedure: Maintenance of MAP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18-75 years inclusive; Diagnosis of acute SCI; Injury is less than 24 hours old; ISNCSCI Impairment Scale Grade A, B or C based upon first ISNCSCI evaluation after arrival to the hospital; Neurological level of injury between C4-C8 based upon first ISNCSCI evaluation after arrival to the hospital; Women of childbearing potential must have a negative serum β-hCG pregnancy test or a negative urine pregnancy test; Patient is willing to participate in the study; Informed consent document signed by patient or witnessed informed consent document; No contraindications for study treatment(s); Able to cooperate in the completion of a standardized neurological examination by ISNCSCI standards (includes patients who are on a ventilator). Exclusion Criteria: Injury arising from penetrating mechanism; Significant concomitant head injury defined by a Glasgow Coma Scale (GCS) score < 14 with a clinically significant abnormality on a head CT (head CT required only for patients suspected to have a brain injury at the discretion of the investigator); Pre-existing neurologic or mental disorder which would preclude accurate evaluation and follow-up (i.e. Alzheimer's disease, Parkinson's disease, unstable psychiatric disorder with- hallucinations and/or delusions or schizophrenia); Prior history of SCI; Recent history (less than 1 year) of chemical substance dependency or significant psychosocial disturbance that may impact the outcome or study participation, in the opinion of the investigator; Is a prisoner; Participation in another clinical trial within the past 30 days; Acquired immune deficiency syndrome (AIDS) or AIDS-related complex; Active malignancy or history of invasive malignancy within the last five years, with the exception of superficial basal cell carcinoma or squamous cell carcinoma of the skin that has been definitely treated. Patients with carcinoma in situ of the uterine cervix treated definitely more than 1 year prior to enrollment may enter the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CSFD with elevation of MAP<br>Subjects will receive CSFD and elevation of MAP. Treatments will be 120 hours (5 days) from time treatment is initiated (time 0), and within 24 hours of time of injury. Initiation of CSFD will occur after decompression (during surgery) with a target ITP of 10 mmHg. MAP elevation (norepinephrine drip; goal 100-110 mmHg) will start during surgery, simultaneously with CSFD. 10 mL of CSF will be collected daily for routine lab testing. Post-surgery subjects will be transferred to an intensive care unit (ICU) for duration of treatment or longer if clinically indicated. Target MAP will be sustained within 100-110 mmHg for 5 days. Norepinephrine drip will be used to maintain MAP goal. Subjects will receive other treatment per standard of care at the participating investigational sites. | Procedure: CSFD and elevation of MAP<br>* Lumbar drain placement with CSFD with elevation of MAP<br>|
| Active Comparator: Maintenance of MAP<br>Subjects will receive elevation of MAP (norepinephrine drip; goal 85-90 mm Hg). Target MAP will be sustained within 85-90 mmHg in the control group for 5 days. Duration of elevation of MAP treatment will be 120 hours (5 days) from time treatment is (time 0). Subjects will receive the same treatment as the subjects in investigational arm except for the initiation of the CSFD and less aggressive MAP elevation. They will have a drain placed the same way as the experimental subjects. While drain is in place, 10 mL of cerebrospinal fluid will be collected daily for laboratory testing. After that, ITP will be monitored but CSFD will not be initiated. Subjects will receive other treatment per standard of care at participating investigational sites. | Procedure: Maintenance of MAP<br>* Lumbar drain placement without CSFD and with maintenance of MAP<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in ITP | ITP will be measured in both groups every hour for the duration of study treatment for a total of 121 measurements consisting of one pre-treatment measurement (time 0 hours) and 120 measurements during the treatment (time 1-120 hours). | 120 hours | 
| Change in International Standards for Classification of Spinal Cord Injury Motor Score (ISNCSCI, formerly ASIA) | ISNCSCI Motor Score will be obtained at hospital arrival (baseline), 72 hours post-injury, 84 days and 180 days post-treatment. The primary endpoint is difference between the Motor Score at 180 days and baseline. | 180 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ISNCSCI Grade |  | Change in ISNCSCI grade between 180 days and baseline | 
| ISNCSCI Sensory Scores |  | Change in ISNCSCI Sensory Scores (Light Touch and Pin Prick) between 180 days and baseline | 
| ISNCSCI Upper Extremity Motor Score |  | Change in ISNCSCI Upper Extremity Motor Score between 180 days and baseline | 
| ISNCSCI Lower Extremity Motor Score |  | Change in ISNCSCI Lower Extremity Motor Score between 180 days and baseline | 
| Spinal Cord Independence Measure (SCIM) |  | Spinal Cord Independence Measure (SCIM) at 180 days | 
| Pain level per patient report | Using a numeric pain rating scale, subjects will indicate level of pain at time measure occurs | Pain Numeric Rating Scale (NRS) at 180 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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spinal cord injury (SCI)