ISC 2009: Laser Stroke Treatment Fails Primary End Point, but Phase 3 Trial Planned

Susan Jeffrey

February 25, 2009

February 25, 2009 (San Diego, California) — Final results of a randomized trial of transcranial laser therapy (TLT) to treat acute ischemic stroke failed to meet its primary end point of efficacy, although it was safe and well tolerated. However, a new trial with the same therapy is set to go ahead, this time excluding severe stroke patients, whom the subgroup analysis suggested did not appear to benefit from therapy.

Results from the NeuroThera Effectiveness and Safety Trial-2 (NEST-2) were presented here at the American Stroke Association International Stroke Conference 2009 and published simultaneously online in Stroke.

Dr. Justin A. Zivin

"Secondary analysis suggests there was benefit in the moderate to moderately severe strokes, and as a result of all this, we are quite encouraged, and a multinational phase 3 study is planned, which will be called NEST-3," Justin A. Zivin, MD, PhD, from the University of California, San Diego, in La Jolla, told attendees here. Dr. Zivin and Werner Hacke, MD, PhD, from the University of Heidelberg, in Germany, will be cochairs for the new trial.

Mechanisms Unclear

TLT is an investigational approach to acute ischemic stroke treatment using near-infrared laser. Interestingly, when pushed, Dr. Zivin confessed that they don't really know how it works, but they speculate that effects that have been demonstrated with TLT, including reduced apoptosis, increased energy metabolism, or enhanced neurogenesis, may play a role in the benefit that has been seen with this approach in preclinical and clinical studies.

Treatment is a noninvasive procedure using a laser device. The probe is applied to 20 specific locations around the head for 2 minutes each, regardless of the location of the occlusion. It can be used up to 24 hours after symptom onset. The wavelength is 808 nm, which is near-infrared, nonionizing, and invisible. The procedure has to be conducted in a laser-safe environment by a trained user and protective eyewear worn. The subject's hair is removed to permit consistent energy introduction, Dr. Zivin noted. For this study, the lens was refrigerated for patient comfort and to preserve blinding.

NEST-1, published previously, had shown efficacy and safety of TLT (Lampl Y et al. Stroke 2007;38:1843-1849). NEST-2, presented here, was nearly identical to NEST-1 but was larger and included patients up to 90 years of age. It was a double-blind, randomized, phase 2/3 study comparing TLT with a sham control. Stroke patients who had received thrombolysis or those with evidence of hemorrhagic infarct were excluded.

The primary end point was a favorable outcome defined as a modified Rankin Scale (mRS) score of 0 to 2 at 90 days. A total of 660 patients, enrolled from 57 centers in 4 countries, were randomized within 24 hours of their stroke; 331 received TLT and 327 received sham therapy. National Institutes of Health Stroke Scale (NIHSS) scores ranged from 7 to 22, "which is quite a broad range," he noted.

At 90 days, there was a trend toward better outcomes among patients receiving TLT, but this did not reach statistical significance.

NEST-2: Primary End Point at 90 Days by Treatment

End Point TLT, n (%) Sham Control, n (%) Odds Ratio (95% CI) P
Modified Rankin Scale score 0 – 2 120 (36.3) 101 (30.9) 1.38 (0.95 – 2.00) .094

Comparable results were seen for the other end points, including the overall shift in mRS and change in NIHSS scores.

Subset analyses favored treatment for all but those with the most severe strokes, those with baseline NIHSS scores of 16 or more, Dr. Zivin noted. "Had those patients been eliminated from the trial, the difference between the sham and treatment would have been almost 10%, and the P value would have been statistically significant," he said. "However, this was a post hoc analysis and can be used only for hypothesis-generation purposes."

Importantly, mortality and serious adverse events were not different between the groups.

NEST-2: Mortality and Serious Adverse Events by Treatment

End Point TLT (%) Sham Control (%)
Mortality 17.5 17.4
Serious adverse events 37.8 41.8

Dr. Zivin noted that there was no effect of time from stroke onset to treatment onset within the 24-hour time window, with no difference seen between those treated from 0 to 12 hours compared with those receiving treatment from 12 to 24 hours after onset.

After the presentation, Mark Alberts, MD, professor of neurology at Northwestern University Feinberg School of Medicine, in Chicago, Illinois, and also a NEST-2 investigator, asked Dr. Zivin if he was disturbed about this lack of relationship between time from onset and the effect of treatment.

"I was surprised, I must admit that," Dr. Zivin replied. "Inevitably, at some point there must be a time-to-treatment effect, but we simply just didn't see it in these data, and we looked as hard as we could."

The planned NEST-3 trial will still exclude patients treated with tissue plasminogen activator (tPA), but they also now have funding from the NIH for another trial, in which TLT will be used in patients whether or not they have received thrombolysis, Dr. Zivin told reporters here.

Severe patients will also be excluded from NEST-3, from these data probably those with an NIHSS score of 16 or more. "That hasn't been conclusively decided, but that's about right," he said.

The study was funded by PhotoThera, based in Carlsbad, California. Dr. Zivin has received honoraria from PhotoThera; disclosures for coauthors appear in the paper. Dr. Alberts and Dr. Hacke are also editorial advisors to Medscape Neurology & Neurosurgery.

International Stroke Conference 2009: Abstract 195. Presented February 20, 2009.

Stroke. Published online February 20, 2009. Abstract

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