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Additional Phase I and Phase II Clinical Trials for Neuroprotective Pharmaceutical Agents during Acute SCI

Cethrin®

The release of pro-inflammatory cytokines and growth inhibitory proteins after a SCI results in enhanced signaling of the protein Rho. When Rho is activated, axon regrowth is inhibited. Cethrin®specifically inactivates Rho and therefore enables axons to regrow. In addition, Cethrin®has been shown to reduce inflammation by decreasing hematogenous monocytes, reducing glial scar formation and augmenting neuron remyelination (McKerracher & Guertin, 2013). Unlike most acute spinal cord drugs reviewed so far that have been delivered intravenously, Cethrin®is applied topically to the spinal cord during the time of surgery.

Minocycline

Another emerging neuroprotective drug is minocycline, a broad spectrum antibiotic. Minocycline is able to cross the blood-brain barrier and exhibits anti-inflammatory and anti-excitatory properties (Baptiste & Fehlings, 2006). Studies investigating SCI in animal models have suggested that this drug inhibits microglial proliferation, reduces cellular apoptosis and neutralizes free radicals (Yong et al. 2004). These properties have made it a promising candidate for neurological disorders such as Parkinson’s disease, stroke, and multiple sclerosis in addition to SCI (Casha et al. 2012).

Riluzole

During secondary injury, an influx of sodium enters nerve cells and instigates an osmotic response where the neurons begin to swell to dangerous levels. In response, calcium rushes into the cell and triggers an amplified sodium excretion from the cell. Subsequently, the high intracellular concentration of calcium results in glutamate release and therefore excitotoxicity (Wilson & Fehlings, 2014). Riluzole acts to block these sodium channels, thus preventing excitotoxicity. Animal studies have found spinal cord injured rats that received riluzole to have improved motor function, more brain stem neurons and a smaller lesion size after 6 weeks compared to rats that received different sodium channel blockers or a placebo (Schwartz & Fehlings, 2001). Earlier human trials with riluzole have led to its approval by the Food and Drug Administrationin the US for the treatment of amyotrophic lateral sclerosis (Wilson & Fehlings, 2014).

Table 10. Pharmaceutical Agents for Neuroprotection in Acute SCI in Phase I and II Clinical Trials

Author Year

Country

Research Design

PEDro

Sample Size

MethodsOutcomes
Cethrin®
Fehlings et al. 2011

Canada

Prospective Controlled Trial

Ninitial=48, Nfinal=35

Population: Age range=16-70 yr; Gender: male=84%, female=16%; Level of injury: cervical-thoracic; Severity of injury: complete=100%, incomplete=0%, AIS A.

Treatment: Patients received 1 of 5 doses of Cethrin®: 0.3 mg, 1 mg, 3 mg, 6 mg, and 9 mg at the time of spinal surgery.

Outcome Measures: The following during hospital stay: drug safety and tolerability, drug pharmacokinetics.

The following after 1 year: neurological recovery using AIS, ASIA motor function.

Chronicity: Individuals underwent spinal surgery within 7 days of sustaining injury.

1.     The authors conclude that Cethrin® is a safe and tolerable drug.

2.     The authors note there were no serious adverse effects related to the drug.

3.     Cethrin® exhibited little systemic exposure in patients.

4.     There was a large preliminary effect in ASIA motor scores with the most improvement seen in patients with cervical injuries who received 1 mg and 3 mg of Cethrin®*.

5.     There were very few improvements in sensory scores in patients who received varying doses of Cethrin®*.

6.     After one year, 31% of cervical injured patients and 6.3% of thoracic injured patients recovered at least 2 steps on the AIS,

*There were no statistical analyses performed.

 

Minocycline
Casha et al. 2012

Canada

RCT

PEDro=6

Ninitial=52, Nfinal=44

Population: Mean age=37 yr; Gender: male=77%, female=23%; Level of injury: cervical-thoracic; Severity of injury: complete=69%, incomplete=31%, AIS A-D.

Treatment: Patients were randomly assigned to receive either minocycline or a placebo with a subclavian central venous catheter for 7 days within 12 hr of injury. The first five patients received 200 mg twice daily (low dose), whereas all patients after that received an 800 mg loading dose and 400 mg twice daily (high dose).

Outcome Measures: The following during hospital stay and after the patient plateaued in motor function (i.e. 3-12 months post SCI): ASIA motor function, ASIA sensory function, functional recovery using Functional Independence Measure (FIM), Spinal Cord Independence Measure, the London Handicap Scale and Short Form 36 questionnaire, and adverse events.

Chronicity: Individuals studied were within 12 hr of sustaining injury.

Initial Analysis

1.     After three months, there were no significant differences in motor function between patients who received minocycline and those who received placebo (p=0.20). The most improvement was seen in patients with cervical injuries (p=0.05), whereas no significant improvement was seen among patients with thoracic injuries (p=0.20).

2.     There were no significant differences in pinprick (p=0.15) or light touch (p=0.27) scores between patients who received minocycline and those who received placebo.

3.     There were no significant differences in any functional recovery measure between patients who received minocycline and patients who received placebo (p>0.05).

4.     Adverse events did not vary significantly among the placebo, low dose, or high dose minocycline groups (p>0.05).

Riluzole
Grossman et al. 2014

USA

Cohort

Ninitial=36, Nfinal=35

Population: Age range=18-69 yr; Gender: male=83%, female=17%; Level of injury: cervical-thoracic; Severity of injury: complete=53%, incomplete=47%, AIS A-C.

Treatment: Patients were administered riluzole (50g twice daily within 12 hr of injury for 7 days). Patients were compared to others in the North American Clinical Trials Network SCI Registry who did not receive riluzole. 39% of patients in riluzole group and 58% of patients in registry group received corticosteroids according to hospital protocol.

Outcome Measures: The following during hospital stay and 90 days and 180 days after injury: the pharmacokinetics of the drug, adverse event outcomes, ASIA motor function, ASIA sensory function, neurological recovery based on AIS, functional recovery using Spinal Cord Independence Measure (SCIM).

Chronicity: Individuals were screened and enrolled in the study within 12 hr of sustaining injury.

 

1.     The plasma concentration and systemic exposure to riluzole varied significantly among patients (p<0.05).

2.     There were no significant differences in adverse event outcomes between patients who received riluzole and the registry group, however a mild to moderate elevation of liver enzymes was observed in riluzole group compared to baseline measurements (p>0.05).

Analyses comparing patients with cervical injuries only:

3.     After 90 days, patients who received riluzole experienced significant improvement in motor function compared to patients in registry (p=0.021). This difference was no longer seen after 180 days (p>0.05).

4.     After 90 and 180 days, there were no significant differences in sensory function between patients who received riluzole and patients in the registry (p>0.05).

5.     A higher percentage of patients who received riluzole converted to a higher grade than patients from the registry.

6.     After 180 days, there were no significant differences in functional recovery based on SCIM scores between patients who received riluzole and patients in the registry (p>0.05).

Analyses comparing patients with thoracic injuries only:

7.     The authors note the 8 patients with thoracic injuries gained motor function, pinprick sensation, and improved by at least 1 grade on the AIS, however no statistical analyses were reported. The authors did not mention improvements in light touch sensation or functional recovery using SCIM scores.

Discussion

Despite the small sample sizes and open label protocols, Cethrin®, Minocycline and Riluzole show initial promise in terms of effectiveness for treating acute SCI and safe administration in humans; further trials are recommended.

Conclusion

There is level 2 evidence (from one prospective controlled trial; Fehlings et al. 2011) that Cethrin® is a safe and tolerable drug, and may promote neurological recovery in acute SCI individuals.

There is level 1b evidence (from one RCT; Casha et al. 2012) that minocycline is not effective in promoting motor or sensory recovery in acute SCI individuals.

There is level 2 evidence (from one cohort study; Grossman et al. 2014) that riluzole may be effective in promoting long term motor or sensory recovery in acute SCI individuals.

Cethrin® is a safe and tolerable drug, but its effect on neurological recovery remains unknown during the acute phase post SCI.

Minocycline is not effective for neurological recovery during the acute phase post SCI.

Riluzole may be effective for neurological recovery during the acute phase post SCI.