Minocycline and Perfusion Pressure Augmentation in Acute Spinal Cord Injury

A Pilot Study to Assess Clinical Safety and Tolerance of Minocycline and Spinal Perfusion Pressure Augmentation in Acute Spinal Cord Injury

While research in animal models of spinal cord injury have provided many promising insights, human studies have failed to produce effective therapies. We propose to investigate the drug Minocycline (a metalloproteinase inhibitor) for the treatment of spinal cord injured patients aiming to limit neurological injury and improve neurological outcome. This drug influences several secondary injury mechanisms implicated in spinal cord injury and has been effective in improving outcome after spinal cord injury in animal models. We also propose to examine the safety and feasibility of spinal cord perfusion pressure augmentation with a protocol of IV fluids and inotrope medications versus standard maintenance of mean arterial pressure in subjects who exhibit a decrease in perfusion pressure to less than 75 mmHg. The purpose of this pilot study is 1) to evaluate the feasibility of a clinical trial protocol for Minocycline in patients with acute spinal cord injury, and 2) to ensure adequate drug dosing and metabolic effect. After undergoing a process of informed consent, patients agreeing to participate in the study will be randomized to placebo or treatment groups in a double-blind fashion. Clinical neurological examinations, patient-reported quality of life, and functional independence categorization will be combined with serum and cerebrospinal fluid laboratory investigations to establish some of the pharmacological properties and the safety profile of this medication in this group of patients. In addition, patient tolerance to the dosing regimen will be assessed. The results of this study will provide the preliminary data necessary to plan for a larger prospective, randomized, controlled, double-blind clinical trial to assess efficacy and to further assess safety.

Study Overview

• Status: Completed
• Conditions: Spinal Cord Injuries
• Intervention / Treatment: Drug: Minocycline; Drug: placebo; Procedure: SCPP augmentation; Procedure: SCPP control

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • Foothills Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 16 or over
• Motor complete or motor incomplete acute spinal cord injury involving bony spinal levels between C0 and T11
• Patient able to provide informed consent
• Randomization and commencement of administration of first drug dose within 12 hours of injury
• surgical decompression if needed to be performed within 24 hours of the injury
• subjects exhibiting spinal cord perfusion pressure (lumbar drain transduced pressure - mean arterial pressure)> 75 mmHg will be randomized to active augmentation protocol versus maintenance of mean arterial pressure

Exclusion Criteria:

• Acute spinal cord injury >12 hours old
• Isolated sensory deficit, motor intact
• Isolated cauda equina injury or injury at bony level T12 or below
• History of systemic lupus erythematosus (SLE)
• Pre-existing hepatic or renal disease
• Tetracycline hypersensitivity
• Pregnancy or breast feeding
• Isolated sensory deficit
• Isolated radicular motor deficit
• Significant leukopenia (white blood cell count < ½ times the lower limit of normal) at screening
• Elevated liver function tests (AST, ALT, alkaline phosphatase, or total bilirubin > 2 times the upper limit of normal) at screening
• Presence of systemic disease that might interfere with patient 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 from SCPP randomization

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: placebo; Normal saline 250cc via central line similar to minocycline arm administration protocol; Other Names: saline; control
Experimental: Minocycline	Drug: Minocycline; Minocycline IV BID x 7 days (first 10 patients 200 mg/dose, subsequent patients adjusted based on pharmacodynamic profiling to 800 mg loading dose, tapered 100 mg each dose to 400 mg then maintain at 400mg until day 7); Other Names: Minocin
Experimental: SCPP augmentation	Procedure: SCPP augmentation; maintenance of spinal cord perfusion pressure at 75 mmHg with fluids and inotrope protocol
Sham Comparator: SCPP control	Procedure: SCPP control; maintenance of Mean arterial pressure of >65 mmHg with fluids and inotropes protocol without spinal cord perfusion pressure as target or guiding therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Protocol compliance, feasibility and adverse events	2 years

Secondary Outcome Measures

Outcome Measure	Time Frame
American Spinal Injury Association - motor score (primary clinical outcome) and sensory scores	2 years
Short Form 36 - Quality of Life Assessment	2 years
Functional Independence Measure	2 years
London Handicap Scale	2 years
Spinal Cord Injury Measure	2 years
CSF collection (6/day) and biochemical assays	7 days
Sequential Anatomical MRI	1 year

Collaborators and Investigators

• Sponsor: University of Calgary
• Collaborators: Hotchkiss Brain Institute, University of Calgary; American Association of Neurological Surgeons; Paralyzed Veterans of America
• Investigators: Principal Investigator: Steven Casha, MD PhD FRCSC, University of Calgary; Principal Investigator: R. John Hurlbert, MD PhD FRCSC, University of Calgary; Principal Investigator: David Zygun, MD MSc, University of Calgary

Publications and helpful links

General Publications

• Casha S, Zygun D, McGowan MD, Bains I, Yong VW, Hurlbert RJ. Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury. Brain. 2012 Apr;135(Pt 4):1224-36. doi: 10.1093/brain/aws072.
• Carnini A, Casha S, Yong VW, Hurlbert RJ, Braun JE. Reduction of PrP(C) in human cerebrospinal fluid after spinal cord injury. Prion. 2010 Apr-Jun;4(2):80-6. doi: 10.4161/pri.4.2.11756. Epub 2010 Apr 10.

Study record dates

Study Major Dates

• Study Start: June 1, 2004
• Primary Completion (Actual): August 1, 2010
• Study Completion (Actual): August 1, 2010

Study Registration Dates

• First Submitted: November 14, 2007
• First Submitted That Met QC Criteria: November 14, 2007
• First Posted (Estimate): November 16, 2007

Study Record Updates

• Last Update Posted (Estimate): March 18, 2013
• Last Update Submitted That Met QC Criteria: March 15, 2013
• Last Verified: March 1, 2013

More Information

Terms related to this study

• Keywords: incomplete spinal cord injury; traumatic; complete spinal cord injury; central cord spinal cord injury
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Trauma, Nervous System; Spinal Cord Diseases; Wounds and Injuries; Spinal Cord Injuries; Anti-Infective Agents; Anti-Bacterial Agents; Minocycline
• Other Study ID Numbers: 17007; PVA2414 (Other Grant/Funding Number: Paralyzed Veterans of America)