Soluble Nogo-Receptor-Fc decoy (AXER-204) in patients with chronic cervical spinal cord injury in the USA: a first-in-human and randomised clinical trial.

BACKGROUND: Spinal cord injury (SCI) causes neural disconnection and persistent neurological deficits, so axon sprouting and plasticity might promote recovery. Soluble Nogo-Receptor-Fc decoy (AXER-204) blocks inhibitors of axon growth and promotes recovery of motor function after SCI in animals. This first-in-human and randomised trial sought to determine primarily the safety and pharmacokinetics of AXER-204 in individuals with chronic SCI, and secondarily its effect on recovery. METHODS: We conducted a two-part study in adults (aged 18-65 years) with chronic (>1 year) cervical traumatic SCI at six rehabilitation centres in the USA. In part 1, AXER-204 was delivered open label as single intrathecal doses of 3 mg, 30 mg, 90 mg, or 200 mg, with primary outcomes of safety and pharmacokinetics. Part 2 was a randomised, parallel, double-blind comparison of six intrathecal doses of 200 mg AXER-204 over 104 days versus placebo. Participants were randomly allocated (1:1) by investigators using a central electronic system, stratified in blocks of four by American Spinal Injury Association Impairment Scale grade and receipt of AXER-204 in part 1. All investigators and patients were masked to treatment allocation until at least day 169. The part 2 primary objectives were safety and pharmacokinetics, with a key secondary objective to assess change in International Standards for Neurological Classification of SCI (ISNCSCI) Upper Extremity Motor Score (UEMS) at day 169 for all enrolled participants. This trial is registered with ClinicalTrials.gov, NCT03989440, and is completed. FINDINGS: We treated 24 participants in part 1 (six per dose; 18 men, six women), and 27 participants in part 2 (13 placebo, 14 AXER-204; 23 men, four women), between June 20, 2019, and June 21, 2022. There were no deaths and no discontinuations from the study due to an adverse event in part 1 and 2. In part 2, treatment-related adverse events were of similar incidence in AXER-204 and placebo groups (ten [71%] vs nine [69%]). Headache was the most common treatment-related adverse event (five [21%] in part 1, 11 [41%] in part 2). In part 1, AXER-204 reached mean maximal CSF concentration 1 day after dosing with 200 mg of 412 000 ng/mL (SD 129 000), exceeding those concentrations that were efficacious in animal studies. In part 2, mean changes from baseline to day 169 in ISNCSCI UEMS were 1·5 (SD 3·3) for AXER-204 and 0·9 (2·3) for placebo (mean difference 0·54, 95% CI -1·48 to 2·55; p=0·59). INTERPRETATION: This study delivers the first, to our knowledge, clinical trial of a rationally designed pharmacological treatment intended to promote neural repair in chronic SCI. AXER-204 appeared safe and reached target CSF concentrations; exploratory biomarker results were consistent with target engagement and synaptic stabilisation. Post-hoc subgroup analyses suggest that future trials could investigate efficacy in patients with moderately severe SCI without prior AXER-204 exposure. FUNDING: Wings for Life Foundation, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences, National Institute on Drug Abuse, and ReNetX Bio.

Utilization of Robotic Exoskeleton for Overground Walking in Acute and Chronic Stroke.

Stroke commonly results in gait deficits which impacts functional ambulation and quality of life. Robotic exoskeletons (RE) for overground walking are devices that are programmable to provide high dose and movement-impairment specific assistance thus offering new rehabilitation possibilities for recovery progression in individuals post stroke. The purpose of this investigation is to present preliminary utilization data in individuals with acute and chronic stroke after walking overground with an RE. Secondary analysis on a subset of individuals is presented to understand the mechanistic changes due to RE overground walking. Thirty-eight participants with hemiplegia secondary to stroke were enrolled in a clinical trial conducted at eight rehabilitation centers. Data is presented for four sessions of overground walking in the RE over the course of 2 weeks. Participants continued their standard of care if they had any ongoing therapy at the time of study enrollment. Gait speed during the 10 Meter Walk Test, Gait deviations and the Functional Ambulation Category (FAC) data were collected before (baseline) and after (follow-up) the RE walking sessions. Walking speed significantly increased between baseline and follow-up for participants in the chronic (p <0.01) and acute (p < 0.05) stage of stroke recovery. FAC level significantly improved (p < 0.05) and there were significantly fewer (p < 0.05) gait deviations observed for participants in the acute stages of stroke recovery between baseline and follow-up. Secondary analysis on a subset of eight participants indicated that after four sessions of overground walking with the RE, the participants significantly improved their spatial symmetry. The walk time, step count and ratio of walk time to up time increased from first session to the last session for participants in the chronic and acute stages of stroke. The RE was effectively utilized for overground walking for individuals with acute and chronic stroke with varying severity levels. The results demonstrated an increase in walking speed, improvement in FAC and a decrease in gait deviations (from baseline to follow-up) after four sessions of overground walking in the RE for participants. In addition, preliminary data indicated that spatial symmetry and step length also improved after utilization of an RE for overground walking.

Effects of intrathecal baclofen on perceived sexual functioning in men with spinal cord injury.

BACKGROUND/OBJECTIVE: Reports in the literature suggest that administration of intrathecal baclofen to control spasticity may have deleterious effects on erectile function in men with spinal cord injury (SCI). A prospective study was conducted to document any changes in perceived sexual function after implant of a baclofen pump. METHODS: Seven adult men with SCI (ASIA A or B) who received intrathecal baclofen through an implantable pump for treatment of severe spasticity were followed for an average of 670 days (22.4 months) after implant. Perceived sexual function was assessed using the Brief Sexual Function Inventory. Severity of spasticity and overall health-related quality of life were also assessed. RESULTS: Participants reported improvements in spasticity severity and overall health-related quality of life. Two of 7 participants reported some negative changes in perceived sexual function after baclofen pump implant, noted in the areas of reduced sex drive and problems with erections (frequency, rigidity, difficulty in achieving). However, most participants reported minimal effects on sexual function, and 2 participants reported marked improvement in perceived sexual function from pre- to post-implant. Analysis of changes in perceived sexual function over time suggest that problems may be associated with an increase in baclofen dose and may be reversible with a reduction in dose. CONCLUSIONS: Intrathecal baclofen may impact perceived sexual function particularly at higher doses. However, the effects seem to be reversible with withdrawal or reduction of baclofen administration.

Effect of co-morbid traumatic brain injury on functional outcome of persons with spinal cord injuries.

OBJECTIVE: This study was undertaken to determine if persons who sustain a spinal cord injury (SCI) and co-morbid brain injury (dual diagnosis [DDS]) evidence smaller functional gains and experience significantly longer rehabilitation lengths of stay than persons with only an SCI. DESIGN: This retrospective comparison study was performed at a 100-bed rehabilitation hospital specializing in acute SCI and traumatic brain injury rehabilitation. Summary scale outcome data of persons who sustained an SCI were compared with outcome data of a group of persons with a DDS. Comparisons were established by matching groups principally on level of SCI and admission Motor FIM trade mark score and secondarily on education, sex, and age. Outcome measures included admission Motor and Cognitive FIM score, discharge Motor and Cognitive FIM score, Motor and Cognitive FIM change, length of stay, and rehabilitation charges. RESULTS: Persons with a DDS evidenced a significantly more impaired Cognitive FIM score at admission and discharge from rehabilitation. Persons with a DDS also achieved a significantly lower Motor FIM change than persons with SCI. There were no significant differences between DDS and SCI groups regarding Cognitive FIM change, length of stay, or rehabilitation charges. Injury severity as defined by the Glasgow Coma Scale or intracranial lesions did not predict response to treatment in the DDS group. CONCLUSION: Persons with a DDS achieved smaller functional gains during rehabilitation than peers with SCI. Brain injuries seem to limit functional gains, although the relationship between brain injury severity and functional change is not linear. Prospective studies are needed to identify factors limiting functional gains in rehabilitation and assist in developing specific treatment programs for persons with SCI and brain injury.