Trials evaluate unwitnessed strokes, new uses for drugs

a friday session duringThe use of three drugs — tPA for patients who had unwitnessed strokes, natalizumab to reduce infarct volume following acute ischemic stroke, and glyburide to reduce brain edema after a large hemispheric stroke — were the focus of three late-breaking clinical trial results presented during the final plenary at ISC 2016 in Los Angeles.

MR WITNESS examines tPA use in unwitnessed strokes

New data suggest the possibility of extending the time frame for thrombolysis. The MR WITNESS Trial showed that intravenous tPA is safe and feasible for patients with unwitnessed stroke who meet certain MRI criteria, said lead author Lee H. Schwamm, MD, executive vice chair of neurology and director of acute stroke services at Massachusetts General Hospital in Boston.

“We know it is safe, and we have a signal for efficacy,” Schwamm said during his presentation. “But we really do not know if it is effective. I would discourage anyone from thinking that we have a new treatment for unwitnessed stroke.”

Currently, tPA is not provided to patients whose strokes are not witnessed. However, recent studies suggest that patients with stroke onset of less than three hours show a specific DWI-positive, FLAIR-negative MRI pattern and may be candidates for tPA treatment.

The open-label Phase II study used an MR “witness” to confirm that the onset of stroke was less than 3.5 hours, leaving 60 minutes to administer tPA. The primary outcomes matched the pivotal ECASS3 trial for tPA, any symptomatic ICH with a 4-point increase in NIHSS score or death. Treatment was started a median of 11.5 hours from the time patients were last seen well.

Of the study’s 80 patients, only one had a symptomatic ICH, 1.25 percent, comparable to the 5.30 percent of ECASS3. Investigators are preparing a larger study for approval.

ACTION fails to reach primary endpoint

The ACTION trial failed its primary objective, but provided data encouraging investigators to continue research, said Jacob Elkins, MD, MAS, senior director of clinical development for Biogen. ACTION examined the use of natalizumab, an α4β1 integrin agonist indicated for multiple sclerosis and Crohn’s disease, to reduce inflammation and infarct volume following acute ischemic stroke.

The randomized, double-blinded trial compared 79 acute ischemic stroke patients who received natalizumab to 82 patients who received placebo. The primary endpoint was the change in infarct volume from baseline to day 5. Secondary endpoints included the NIHSS score, the Modified Rankin Score and the Barthel Index. Exploratory endpoints included Montreal Cognitive Assess and Stroke Impact Scale-16 scores.

Natalizumab did not affect infarct volume growth compared to placebo, Elkins said of the Biogen-funded study. The drug did show improvements in mRS of 1 or less at 30 days (OR=2.88) and BI of 95 or greater at day 90 (OR=1.91), median SIS-16 (OR=1.80) and MoCA of 26 or greater (OR=2.03) at 90 days. Mortality and serious adverse events were similar in the two groups.

“The clinical findings of benefit are consistent with a more diffuse process of ischemia rather than a process focused at the infarct site,” Elkins said. “Based on the magnitude of these clinical benefits, these results warrant further clinical study of this intervention in stroke.”

GAMES RP examines use of diabetes medicine to reduce edema

The GAMES RP trial investigating the use of intravenous glyburide failed to reach its primary objective, but had encouraging results to continue investigations, said lead author W. Taylor Kimberly, MD, PhD, associate director of the Neuroscience Intensive Care Unit at Massachusetts General Hospital. Glyburide, which is used in oral formulations to treat type 2 diabetes, was studied to see if it could reduce brain edema after a large hemispheric stroke.

Because brain edema is a new therapeutic target, there is uncertainty about the appropriate clinical endpoints, Kimberly said. In addition to the primary endpoint of edema volume, the randomized, controlled phase II trial included clinical and intermediate endpoints intended to enhance knowledge about brain edema, guide interpretation of clinical outcomes and inform future trial design.

A total of 83 large hemispheric stroke patients were enrolled at 18 U.S. centers, with 44 patients receiving IV glyburide within 10 hours of stroke onset and 39 receiving placebo, he said. The primary outcomes were mRS and avoidance of decompressive craniectomy.

There was no difference between the treatment and placebo groups in the primary outcome or in serious adverse events, Kimberly said. There was a 50 percent reduction in mortality for glyburide (p=0.06), a decrease in death from neurological causes (p=0.03) and a decrease in edema deaths (p=0.008) for glyburide compared to placebo.

The glyburide group also showed a significant reduction in midline shift (p=0.0006) and average matrix metallopeptidase 9 (MMP-9) (p=0.006). Midline shift is indicative of edema and MMP-9 is a plasma biomarker associated with stroke and edema, he said.

“Our goal was to gain experience and develop an understanding of how this drug works to guide the development of a pivotal phase III trial,” Kimberly said. “We are very enthusiastic about moving into GAMES-3 to assess improvement in clinical outcomes.”