Minocycline and Perfusion Pressure Augmentation in Acute Spinal Cord Injury

NCT ID: NCT00559494

Last Updated: 2013-03-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 52 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2004-06-30
• Study Completion Date: 2010-08-31

Brief Summary

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.

Conditions

Spinal Cord Injuries

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Minocycline

Group Type: EXPERIMENTAL

Minocycline

Intervention Type: DRUG

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)

Placebo

Group Type: PLACEBO_COMPARATOR

placebo

Intervention Type: DRUG

Normal saline 250cc via central line similar to minocycline arm administration protocol

SCPP augmentation

Group Type: EXPERIMENTAL

SCPP augmentation

Intervention Type: PROCEDURE

maintenance of spinal cord perfusion pressure at 75 mmHg with fluids and inotrope protocol

SCPP control

Group Type: SHAM_COMPARATOR

SCPP control

Intervention Type: PROCEDURE

maintenance of Mean arterial pressure of \>65 mmHg with fluids and inotropes protocol without spinal cord perfusion pressure as target or guiding therapy

Interventions

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)

Intervention Type: DRUG

placebo

Normal saline 250cc via central line similar to minocycline arm administration protocol

Intervention Type: DRUG

SCPP augmentation

maintenance of spinal cord perfusion pressure at 75 mmHg with fluids and inotrope protocol

Intervention Type: 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

Intervention Type: PROCEDURE

Other Intervention Names

Minocin; control; saline

Eligibility Criteria

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

• Minimum Eligible Age: 16 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Paralyzed Veterans of America

OTHER

Sponsor Role: collaborator

American Association of Neurological Surgeons

OTHER

Sponsor Role: collaborator

Hotchkiss Brain Institute, University of Calgary

OTHER

Sponsor Role: collaborator

University of Calgary

OTHER

Sponsor Role: lead

Responsible Party

Steve Casha

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Steven Casha, MD PhD FRCSC

Role: PRINCIPAL_INVESTIGATOR

University of Calgary

R. John Hurlbert, MD PhD FRCSC

Role: PRINCIPAL_INVESTIGATOR

University of Calgary

David Zygun, MD MSc

Role: PRINCIPAL_INVESTIGATOR

University of Calgary

Locations

Foothills Medical Centre

Calgary, Alberta, Canada

Countries

Canada

References

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.

Reference Type: RESULT

PMID: 22505632 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 20418657 (View on PubMed)

Other Identifiers

PVA2414

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

17007

Identifier Type: -

Identifier Source: org_study_id