Efficacy of Riluzole in Surgical Treatment for Cervical Spondylotic Myelopathy (CSM-Protect) (CSM-Protect)

Efficacy of Riluzole in Patients With Cervical Spondylotic Myelopathy Undergoing Surgical Treatment. A Randomized, Double-Blind, Placebo-controlled Multi-Center Study

CSM (Cervical spondylotic myelopathy) is the most common cause of spinal cord injury worldwide. While there is evidence from the recently completed SpineNet prospective study that surgical decompression is an effective treatment for CSM, it is clear that many patients have remaining neurological impairment. While surgery is relatively safe, approximately 3% of patients maintain a neurological problem. Given this background and data from preclinical models of non-traumatic and traumatic spinal cord injury, there is strong evidence to consider the potential benefit of adding a neuroprotective drug which aids in the treatment of patients with CSM whom are undergoing surgical decompression. Riluzole is FDA-approved for the treatment of amyotrophic lateral sclerosis, which has some similar clinical features to CSM. Riluzole is currently under investigation for traumatic spinal cord injury. Given this background, there is a strong basis to consider studying the potential neurological benefits of Riluzole as a treatment to surgical decompression in patients with CSM.

Study Overview

• Status: Completed
• Conditions: Cervical Spondylotic Myelopathy
• Intervention / Treatment: Drug: Placebo medication; Drug: riluzole

• Study Type: Interventional
• Enrollment (Actual): 270
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N-2T9
      • University of Calgary
  • Ontario
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michael's Hospital
    • Toronto, Ontario, Canada, M5T 2S8
      • University of Toronto Hospital
  • Quebec
    • Montral, Quebec, Canada, H3H 2L9
      • McGill University Health Centre
    • Montreal, Quebec, Canada, H3A 2B4
      • Montreal Neurological Institute
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N 0W8
      • University of Saskatchewan, Royal University Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Barrow Neurological Institute
  • California
    • Sacramento, California, United States, 95816
      • UC Davis Spine Center
    • San Francisco, California, United States, 94143
      • University of California - San Francisco
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Emory University School of Medicine
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Kansas University Medical Center
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70803
      • Louisiana State University
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University Orthopaedics
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
    • Philadelphia, Pennsylvania, United States, 19107
      • Rothman Institute Orthopaedics
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia
  • Washington
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age between 18 and 80 years

• Diagnosis of symptomatic cervical spondylotic myelopathy defined as a combination of:

  1. one or more of the following symptoms:

     • Numb hands
     • Clumsy hands
     • Impairment of gait
     • Bilateral arm paresthesiae
     • l'Hermitte's phenomena
     • Weakness And,

  2. one or more of the following signs:

     • Corticospinal distribution motor deficits
     • Atrophy of hand intrinsic muscles
     • Hyperreflexia
     • Positive Hoffman sign
     • Upgoing plantar responses
     • Lower limb spasticity
     • Broad based, unstable gait And,
  3. MRI evidence of cervical spondylotic myelopathy
• Scheduled for an elective surgery for cervical spondylotic myelopathy
• Preoperative mJOA score ≥8 and ≤14

• Women of child bearing potential must be:

  • Postmenopausal defined as amenorrhea for at least 2 years.
  • Surgically sterile, (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy)
  • Abstinent (at the discretion of the investigator)
  • Having other congenital or medical condition that prevents subject from becoming pregnant
  • If sexually active, be practicing an effective method of birth control such as hormonal prescription oral contraceptives, progesterone implants or injections, intrauterine device (IUD), or male partner with a vasectomy. A double-barrier method such as condoms, diaphragms or cervical caps with spermicidal foam, cream or gel may be used as a birth control method.
  • Women of childbearing potential must have a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test or a negative urine pregnancy test at screening before the first dose of study drug is received.

Exclusion Criteria:

• Previous surgery for CSM
• Concomitant symptomatic lumbar stenosis
• CSM symptoms due to cervical trauma (at the discretion of the investigator)
• Hypersensitivity to riluzole or any of its components
• Neutropenia measured as absolute neutrophil count (ANC) measured in cells per microliter of blood of < 1500 at screening visit
• Creatinine level of > 1.2 milligrams (mg) per deciliter (dl) in males or > 1.1 milligrams per deciliter in females at screening visit Liver enzymes (ALT or AST) 3x higher than normal values at screening visit.
• Liver enzymes (ALT or AST) 3x higher than normal values at screening visit.
• Subject will be using any of the following medications which are classified as CYP1A2 inhibitors or inducers*during the course of the drug regimen:

Inhibitors:

• Ciprofloxacin
• Enoxacin
• Fluvoxamine
• Methoxsalen
• Mexiletine
• Oral contraceptives
• Phenylpropanolamine
• Thiabendazole
• Zileuton

Inducers:

• Montelukast

• Phenytoin

  *Note: no washout period required; if these medications are discontinued, subjects are eligible to be enrolled in the trial.

• Systemic infection such as AIDS, HIV, and active hepatitis
• Active malignancy defined as history of invasive malignancy, except if the patient has received treatment and displayed no clinical signs and symptoms for at least five years
• Recent history (less than 3 years) of chemical substance dependency or significant psychosocial disturbance that may impact the outcome or study participation
• Breastfeeding at screening visit and plan to continue during the course of the study drug
• Unlikely to comply with the follow-up evaluation schedule
• Unlikely to comply with investigational drug regime
• Participation in a clinical trial of another investigational drug or device within the past 30 days
• Is a prisoner
• Unable to converse, read or write English at elementary school level

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo medication and decompressive cervical spine surgery	Drug: Placebo medication; 50mg BID orally for 14 days prior to surgery and 28 days after the surgery
Experimental: Riluzole; Riluzole in dose 50mg BID for 14 days prior to surgery and 28 days after the decompressive spine surgery	Drug: riluzole; 50mg BID orally for 14 days prior to surgery and 28 days after the surgery; Other Names: Rilutek

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Modified Japanese Orthopedic Association Score (mJOA)	The mJOA is a clinician administered scale. It evaluates four clinical dimensions; motor dysfunction score for upper and lower extremities, sensation loss and sphincter dysfunction. The total score ranges from 0 (worst) to 18 (best).	Before the surgery, 180 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nurick Score	Nurick score is a simple measure of neurological dysfunction and ranges from 0 (best) to 6 (worst).	Pre-surgical, 180 days
SF-36v2.0	The SF36v2.0 is a health-related quality of life instrument that evaluates health status accross eight health dimensions.	Before the surgery, 180 days
Neck Disability Index (NDI)	The NDI evaluates patient self-reported functional outcomes related to neck conditions. The NDI score ranges from 0 (best) to 100 (worst).	Before the surgery, 180 days
Cervical Pain Numeric Rating Scale	Simple numeric rating scale with choises of answers from 0 (no pain) to 10 (worst imaginable pain)	Before the surgery, 180 days
EQ-5D	EQ-5D™ is a standardised instrument for use as a measure of health outcome. It provides a simple descriptive profile and a single index value for health status.	Before the surgery, 180 days
American Spinal Injury Association Score (ASIA)	The ASIA impairment scale describes a person's functional impairment as a result of their spinal cord injury.	Before the surgery, 180 days

Collaborators and Investigators

• Sponsor: AOSpine North America Research Network
• Investigators: Principal Investigator: Michael Fehlings, MD, University Health Network, Toronto; Study Director: Branko Kopjar, MD, University of Washington

Publications and helpful links

General Publications

• Fehlings MG, Wilson JR, Karadimas SK, Arnold PM, Kopjar B. Clinical evaluation of a neuroprotective drug in patients with cervical spondylotic myelopathy undergoing surgical treatment: design and rationale for the CSM-Protect trial. Spine (Phila Pa 1976). 2013 Oct 15;38(22 Suppl 1):S68-75. doi: 10.1097/BRS.0b013e3182a7e9b0.
• Fehlings MG, Badhiwala JH, Ahn H, Farhadi HF, Shaffrey CI, Nassr A, Mummaneni P, Arnold PM, Jacobs WB, Riew KD, Kelly M, Brodke DS, Vaccaro AR, Hilibrand AS, Wilson J, Harrop JS, Yoon ST, Kim KD, Fourney DR, Santaguida C, Massicotte EM, Kopjar B. Safety and efficacy of riluzole in patients undergoing decompressive surgery for degenerative cervical myelopathy (CSM-Protect): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial. Lancet Neurol. 2021 Feb;20(2):98-106. doi: 10.1016/S1474-4422(20)30407-5. Epub 2020 Dec 22.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2012
• Primary Completion (Actual): December 15, 2017
• Study Completion (Actual): June 1, 2018

Study Registration Dates

• First Submitted: October 23, 2010
• First Submitted That Met QC Criteria: December 8, 2010
• First Posted (Estimate): December 10, 2010

Study Record Updates

• Last Update Posted (Actual): November 2, 2018
• Last Update Submitted That Met QC Criteria: November 1, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Hematologic Diseases; Spinal Cord Diseases; Bone Marrow Diseases; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Neuroprotective Agents; Protective Agents; Anticonvulsants; Riluzole
• Other Study ID Numbers: SPN-10-001