Clinical trial NCT01257828: Efficacy of Riluzole in Surgical Treatment for Cervical Spondylotic Myelopathy (CSM-Protect)
Official title: Efficacy of Riluzole in Patients With Cervical Spondylotic Myelopathy Undergoing Surgical Treatment. A Randomized, Double-Blind, Placebo-controlled Multi-Center Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cervical Spondylotic Myelopathy
Lead sponsor: AOSpine North America Research Network
Sponsor class: NETWORK
First posted: 2010-12-10
Enrollment: 270
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Modified Japanese Orthopedic Association Score (mJOA)
timeFrame: Before the surgery, 180 days
Secondary outcomes:
measure: Nurick Score
timeFrame: Pre-surgical, 180 days
measure: SF-36v2.0
timeFrame: Before the surgery, 180 days
measure: Neck Disability Index (NDI)
timeFrame: Before the surgery, 180 days
measure: Cervical Pain Numeric Rating Scale
timeFrame: Before the surgery, 180 days
measure: EQ-5D
timeFrame: Before the surgery, 180 days
measure: American Spinal Injury Association Score (ASIA)
timeFrame: Before the surgery, 180 days
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Barrow Neurological Institute
state: Arizona
city: Sacramento
country: United States
facility: UC Davis Spine Center
state: California
city: San Francisco
country: United States
facility: University of California - San Francisco
state: California
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Kansas City
country: United States
facility: Kansas University Medical Center
state: Kansas
city: Baton Rouge
country: United States
facility: Louisiana State University
state: Louisiana
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University Orthopaedics
state: Missouri
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Philadelphia
country: United States
facility: Rothman Institute Orthopaedics
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Seattle
country: United States
facility: Harborview Medical Center
state: Washington
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: University of Toronto Hospital
state: Ontario
city: Montral
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Montreal
country: Canada
facility: Montreal Neurological Institute
state: Quebec
city: Saskatoon
country: Canada
facility: University of Saskatchewan, Royal University Hospital
state: Saskatchewan
Study officials:
affiliation: University Health Network, Toronto
name: Michael Fehlings, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Washington
name: Branko Kopjar, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.