Clinical Trials Update

Posted by Sam Maddox in Research News on January 10, 2017 # Research

Clinical trial updates: here are several current studies that hope to improve recovery after spinal cord injury.

First, a simple potential therapy that involves no drug, no surgery, no invasive anything except breathing air with reduced oxygen in a series of 90-second doses over a period of a few days. This is known as acute intermittent hypoxia (AIH). It seems too simple, and perhaps counterintuitive; yes, of course too much oxygen deprivation is certainly a bad thing, but a little bit of AIH causes stress to the nervous system, sets off cellular responses that improve breathing and even enhances nerve growth and plasticity, and thus improves walking. I’ve covered hypoxia several times, in 2012 and 2013.

In a small 2014 study of patients with chronic incomplete spinal cord injures, it was reported that AIH improved walking speed and distance, especially when combined with overgrround walk-training. Now, three other clinical trials are ongoing to further evaluate the effect of short term oxygen deprivation, all being conducted at Emory University in Atlanta, Randy D. Trumbower, principal investigator.

The four trials are similar; one is looking at the effect of AIH plus caffeine. One trial, funded by Wings for Life, is recruiting people with motor incomplete SCI C4 - T12 at least one year post-injury. The trial will test the hypothesis that “AIH exposure will increase maximum voluntary leg strength, increase multi-joint reflex excitability of leg muscles and increase walking performance in persons with incomplete cervical SCI.”

From the listing in ClinicalTrials.gov for the Wings for Life trial:

Accumulating evidence suggests that repeatedly breathing low oxygen levels for brief periods (intermittent hypoxia) is a safe and effective treatment strategy to promote meaningful functional recovery in persons with chronic spinal cord injury. Repetitive exposure to mild hypoxia triggers a cascade of events in the spinal cord, including new protein synthesis and increased sensitivity in the circuitry necessary for breathing and walking. Recently, the investigators demonstrated that daily (5 consecutive days) of intermittent hypoxia stimulated walking enhancement in persons with chronic spinal cord injury.

Viva Vagus, redux: we reported last year on the beneficial effect toward SCI recovery by stimulating the vagus nerve. We noted that after a cervical spinal cord injury in an animal model, vagus nerve stim plus rehab helped rats recover 75 percent more forelimb strength than those that got rehabilitation alone.

A clinical trial is now recruiting up to 135 patients (four groups – two healthy cohorts, one considered overweight, and one with SCI) to test the effect of a non-invasive stimulation device – not for motor recovery per se but to see if the stim can reduce autonomic dysfunction. For the SCI group, they’re looking for motor-complete participants, T1 – T6, at least a year post- injury who use intermittent catheterization. The work is from the Miami Project, Mark S. Nash, principal investigator.

The study is called “Vagal Nerve Stimulation to Reduce Inflammation and Hyperadrenergia.” Inflammation you probably know; hyperadrenergia is a bit more complicated, involving an excess production of adrenergic activity – production of adrenaline (epinephrine) or noradrenaline (norepinephrine) – in the autonomic nervous system.

Trial documents note that the device study hopes to learn more about balancing the autonomic nervous system; out of balance neurotransmission can lead to issues related to heart function and blood pressure regulation (autonomic dysreflexia in the SCI model). The autonomic system, comprised of sympathetic and parasympathetic branches, is disrupted after injury. From the documentation:

It has been thought that electrical stimulation devices could be used to restore balance to the nervous system. Because most of the imbalance seems to happen due to too much sympathetic activity, the investigator plans to focus on the parasympathetic branch. Specifically, the investigator hopes to restore balance by targeting the vagus nerve, which is the main communicator of the parasympathetic branch. The study will examine whether the investigator can decrease sympathetic activity and chronic inflammation by increasing parasympathetic activity.

Advil study: Here’s a new trial recruiting acute SCI patients to test the safety of high doses of a commonly used over-the-counter pain medication, ibuprofen, e.g. Advil. The work is from Charite University, Berlin, with Jan M. Schwab as PI. (Schwab’s main appointment is at Ohio State). The trial, called “SCISSOR – Spinal Cord Injury Study on Small molecule-derived Rho inhibition: a clinical study protocol” is looking for motor complete injuries, C4 – T4, four-to-24 days post-injury.

Research has shown that ibuprofen, an anti-inflammatory drug, neutralizes an enzyme that blocks axon growth. The drug works by inhibiting Rho, which is a key pathway for several molecules that limit nerve regeneration. Animals studies reported better motor recovery after Rho inhibition via ibuprofen.

From the paper:

A major reason for the poor prognosis of central nervous system (CNS) injury is the incapacity of axons to regrow within the CNS. Molecular barriers preventing axonal regeneration after SCI are situated in the environment of the injured axon, that is, in the scar tissue and myelin or myelin debris. The molecules such as chondroitin sulfate proteoglycans (CSPGs), Nogo-A, myelin-associated glycoprotein (MAG), oligodendrocyte-myelin glycoprotein (OMgp), ephrins and repulsive guidance molecule A (RGMa) are upregulated after CNS injury and interfere with a repertoire of cognate receptors on the axon membrane as reviewed elsewhere. Signals from those receptors converge on the Rho pathway.

. . . A standard treatment to promote neuronal plasticity after SCI is not yet available. Based on preclinical investigations in established animal models, a better recovery of neurological function in cases of acute SCI is anticipated from making use of ‘small-molecule’ Rho inhibition.

Notice that these trials are all based on a solid science, and are low-cost and non-invasive; they’re not aiming for the “cure,” but they may pan out to be clinically meaningful.

One more mention in the cheap and easy zone: the Riluzole in Spinal Cord Injury Study, partly funded by the Reeve Foundation and the Department of Defense in support of the North American Clinical Trials Network (NACTN) sites. This trial continues to enroll acute SCI patients. Riluzole is thought to be a neuroprotective drug, limiting damage in the area of injury. At year end, the trial had enrolled 69 patients (out of 351) and ten (out of 50) in a detailed study of the drug’s pharmacology (to pinpoint dosing by knowing how the body actually processes to the drug).