Principal Investigator: Dr. Steve Casha
Study Design: Phase III prospective randomized double-blind placebo-controlled multi-centre trial
Proposed Indication: Cervical spinal cord injury (SCI) presenting within 12 hours of injury
Objectives: To assess the efficacy of intravenous minocycline in improving neurological and functional outcome after acute traumatic non-penetrating SCI
• Age 16 or over
• Acute traumatic non-penetrating cervical SCI with a neurological level of injury (NLI) between C1 and C8 (inclusive) as defined by the International Standards for the Neurological Classification of Spinal Cord Injury (ISNCSCI) examination, resulting in a total motor score less than 100
• Patient able to provide informed consent
• Consent, randomization and administration of first dose (drug or placebo) within 12 hours of injury
• History of systemic lupus erythematosus (SLE)
• Pre-existing hepatic or renal disease
• Tetracycline hypersensitivity
• Pregnancy or breast feeding
• Isolated radicular motor deficit
• Significant leucopenia (white blood cell count < ½ times the lower limit of normal) at screening
• Elevated liver function tests (AST, ALT, alkaline phosphatase, GGT or total bilirubin > 2 times the upper limit of normal) at screening OR if no known liver disease, or significant risk factors for liver disease, LFTs may be completed post enrollment. If, once received, they are found to be elevated, follow the CTCAE criteria in Section 8
• Presence of systemic disease that in the opinion of the investigator/responsible physician might interfere with subject safety, compliance or evaluation of the condition under study (e.g. insulin-dependent diabetes, Lyme disease, clinically significant cardiac disease, HIV, HTLV-1)
• Associated traumatic conditions interfering with informed consent or outcome assessment (e.g. closed head injury, liver contusion)
• Known uncorrected severe coronary artery disease or evidence of active coronary ischemia (ECG changes, positive Troponin) will be excluded, as they may not tolerate the standardized protocol for hemodynamic management
Safety Endpoints: The incidence and severity of adverse events will be compared in the treatment and placebo groups
Primary Outcome Measure
Treatment (minocycline) group’s – placebo group’s change in ISNCSCI motor score (defined as the average change in ISNCSCI motor score at 3, 6 and 12 months from baseline)
Secondary Outcome Measure
Change in ISNCSCI sensory scores (calculated as above), Change in ISNCSCI impairment grade, SF-36v2™ quality of life assessment, Spinal Cord Injury Measure (SCIM)
After informed consent, subjects participating in the study will undergo insertion of a subclavian central venous line for drug delivery and a radial arterial catheter for blood pressure monitoring. For subjects in the treatment arm, minocycline will be administered for one week following acute SCI in 12 hourly doses of 800 mg + 700 mg on Day 1, 600 mg + 500 mg on Day 2, and 400 mg thereafter from Day 3 thru Day 7. The drug will be prepared in 250 ml normal saline and infused over 30 minutes. In those subjects randomized to placebo, a 250 ml saline infusion will be delivered intravenously every twelve hours instead of the active drug.
In all cases where there is ongoing spinal cord compression, decompression will be achieved as soon as possible but no later than 24 hours after injury. Decompression may be in the form of external traction or surgical intervention, per local standard of care.
Hemodynamic management will be directed by a guideline-driven standardized protocol aimed at maintaining mean arterial pressure (MAP) ≥ 85 mm Hg (Canadian sites) for 7 days.
A nurse clinician/research coordinator blinded to the treatment arm will monitor data acquisition, perform daily screening for adverse effects, and administer quality of life (SF-36 v2™ and SCIM) questionnaires at week 6, month 3, month 6, year 1. A specifically trained physician or clinician will perform formal neurological examination (ISNCSCI) at the time of admission and on days 3, 7, and at week 3, week 6, month 3, month 6 and 1 year. Formal outpatient clinic follow-up will be scheduled in accordance with these time points.