Completed Research Studies

10. Title: A Phase II, Double-Blind, Placebo-Controlled, Multicenter Study to Assess the Efficacy and Safety of HP184 at 100, 200, and 400 mg Doses Administered Orally Once Daily for Twenty-Four Weeks in Adult Subjects with Chronic Spinal Cord Injury (CSCI).

Purpose: The purpose of this study is to evaluate the effect of HP184 as compared to placebo on improvements of muscle strength in subjects with motor incomplete spinal cord injury. The study will also help us determine the safety and tolerability of HP184 when administered for 24 weeks in subjects with chronic spinal cord injury as well as the effect of HP184 on the walking function and spasticity.

Principal Investigator: Ralph J. Marino, MD
Co-Investigator(s): Anthony S. Burns, MD

Background: There are currently no available therapies for restoring motor function in subjects with chronic spinal cord injury (SCI), a population estimated at 250,000 in the USA alone. Although many pharmaceutical products are used to treat subjects with SCI, these are almost exclusively directed to the amelioration of individual symptoms, such as pain and spasticity or the treatment of dependent conditions, such as pressure sores and bladder infections. Even a treatment with minimal effectiveness might represent a major improvement in the quality of life for subjects with SCI. Literature suggests that clinically significant improvements may be obtained with 4-aminopyridine (4-AP), a K+ channel blocker. (1,2,3,4) However, the use of 4-AP is limited by various side effects associated with central nervous system activation, which include restlessness, confusion, and infrequently reported findings of generalized tonic-clonic seizure (5,6,7)

HP184 (N-[N-propyl]-N-[3-fluoro-4-pyridinyl]-1H-3-methylindole-1-amine hydrochloride) is a sodium and potassium channel blocker. It has demonstrated activity as a voltage dependent blocker of potassium currents in PC12 cells, and as a use- and frequency dependent blocker of sodium channels. (8,9). Use-dependent sodium channel blockers act more effectively during conditions of cellular depolarization. They demonstrate little or no effect on normal neuronal signaling, but enable the blockade of sodium channels during seizures, head trauma, or ischemia. (10) Many of these agents are cerebroprotective in animal models of these pathological conditions.

In a rat compression model of spinal cord injury with mild intensity, HP184 significantly improved motor function (operationally defined as open field walking analysis) when orally administered (3, 10 and 20 mg/kg, po) to rats with an established, (25 day - post injury) spinal cord injury. This improvement was equaled by the improvement observed with 4-AP (0.6 mg/kg, ip). Drugs were administered on days 25, 26 and 27. The baseline walking analysis of the animals, prior to drug administration, showed no statistical differences across groups. Rats were sacrificed on day 30, and spinal cords were removed. Histochemical myelin staining (using Luxol Fast Blue) showed that spinal cords from the vehicle-treated group had extensive myelin loss. HP184 was then tested in a more severe injury paradigm.

In a second study, HP184 (3 mg/kg, po) significantly improved motor function in rats with long-standing (35 day - post injury) spinal cord injury of moderate intensity. Statistically significant improvement in open field walking was observed for HP184 dose groups in both studies described above.

Further, multiple dose studies in moderately injured rats (compression model) have confirmed the effectiveness of once a day oral dosing with HP184 at 3, 1, and 0.3 mg/kg. In summary, HP184 has been shown to be efficacious, as determined by the improvement in walking ability in a rat model of spinal cord injury.

Criteria for Enrollment: Individuals with chronic (defined as at least 18 months post initial injury) motor incomplete, spinal cord injury, aged 18 to 65 years.

Status: Study Completed

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