Caffeinol Safe in Combination With Thrombolysis in Stroke

Susan Jeffrey

February 22, 2008

February 22, 2008 (New Orleans, Louisiana) — A phase 1 study of caffeinol, a neuroprotectant agent combining caffeine and ethanol, suggests it can be given safely after tissue plasminogen activator (tPA) with some signal of improved outcome in ischemic stroke patients compared with historical controls.

In 10 patients who received tPA and caffeinol, there was no increase in hemorrhagic transformation, and a higher proportion of these patients achieved a modified Rankin Score (mRS) of 0 or 1, indicating little or no disability compared with the historical cohort.

These preliminary results were presented here at the American Stroke Association International Stroke Conference 2008. Study coauthor James C. Grotta, MD, from the University of Texas Health Science Center, in Houston, holds a patent on caffeinol.

"We've seen that there is a suggestion of benefit here, and we have prepared a randomized trial to study tPA vs tPA plus caffeinol," Sheryl Martin-Schild, MD, PhD, from the University of Texas Health Science Center, told a press conference here.

"It's a promising medication, it can be given easily and was very well tolerated, and if it does have the kind of effect in large populations that we've seen in this small group, it could be a major improvement in protection of the brain in the setting of stroke."

Jeffrey Saver, MD, vice chair of the American Heart Association Stroke Council and professor of neurology at the Geffen School of Medicine at the University of California, Los Angeles, commented on the findings.

"This was a small study; it was not a randomized controlled study, so it's a hypothesis-generating, exploratory study," he said. "It suggests that there is a potential signal of efficacy from caffeinol, and there's good reason to proceed with a definitive randomized trial."

Caffeine and Ethanol Cocktail

Caffeinol, a simple combination of caffeine and ethanol given intravenously, has been shown in 2 previous studies in different rodent models to reduce cortical damage and enhance neurological recovery. Similar efficacy was seen with the combination of caffeinol and tPA in these models, without any increase in hemorrhagic transformation, the authors note.

In the current phase 1 study, they tested the dosing, safety, and short-term outcome with caffeinol as an adjunct to IV tPA in acute stroke patients. Patients were included if they presented with a clinical syndrome compatible with ischemic stroke, with clinical signs localizing to the cortex, and were treated with tPA within 3 hours and caffeinol within 6 hours of symptom onset.

Caffeinol was given as a 2-hour infusion, for a dose of caffeine of 8 mg/kg or 9 mg/kg and a dose of ethanol ranging from 0.3 mg/kg to 0.4 mg/kg.

A group of historical controls were taken from records of stroke patients treated with tPA at their institution's emergency department between 2004 and 2007 within 3 hours of symptom onset who would have met the inclusion criteria for this study.

In all, 10 patients received caffeinol and tPA, compared with 90 patients who received tPA alone. There were some differences between the groups: patients in the tPA-alone cohort had significantly lower baseline glucose levels and showed a trend toward lower median baseline National Institutes of Health Stroke Scale (NIHSS) scores, compared with the group that received tPA and caffeinol. The caffeinol group also had a nonsignificantly shorter time to tPA treatment, and none had early ischemic changes, they point out.

However, there was no difference in the rate of hemorrhagic transformation between patients receiving caffeinol and tPA vs those who received tPA alone. In addition, a significantly higher percentage of patients achieved an mRS of 0 or 1, indicating no or minimal residual deficits.

Phase 1 Results with tPA and Caffeinol vs tPA Alone in Historical Controls

Variable tPA + Caffeinol (n = 10) tPA Alone (n = 90) P
Age 60 + 19 67 + 15 .211
Median baseline NIHSS 18 13 .128
Glucose 178 + 86 141 + 51 .046
Time from onset to tPA treatment 113.44 + 32.10 131.51 + 29.10 .287
Symptomatic ICH, n (%) 1 (10) 3 (3) .348
mRS 0 – 1 at discharge, n (%) 6 (60) 23 (26) .032
ICH = intracranial hemorrhage

"This study suggests that IV tPA followed by caffeinol is safe and may lead to a better outcome in acute stroke patients compared with historical controls treated with IV tPA alone," the authors write.

Feasible With Hypothermia and tPA

In a separate feasibility study, the Texas researchers also examined whether caffeinol could be given along with both tPA and hypothermia. The combination of caffeinol and hypothermia has been shown to be "robustly effective" in animal models, they note.

The trial was not randomized; 20 patients eligible for tPA were enrolled to receive additional caffeinol and hypothermia. Caffeinol was given within 4 hours of symptom onset. Hypothermia was instituted within 5 hours of symptom onset and continued for 24 hours with a target of 33° to 35° C, followed by 12 hours of rewarming. The protocol included meperidine and buspirone to treat shivering, and IV tPA was given to patients who met eligibility criteria.

Of the 20 patients, 14 received tPA followed by caffeinol and hypothermia, 3 of the remaining patients had contraindications to tPA, and 3 received tPA and either caffeinol or hypothermia.

Their approach to cooling patients changed over the course of the study, with the result that the last 5 of 18 patients were cooled faster and spent a longer time in target cooling range, using a combination of surface cooling and iced saline.

There were 3 deaths, 1 from symptomatic hemorrhage in a patient who received tPA, 1 from malignant edema, and 1 from unrelated medical complications. No adverse events were attributed to caffeinol, but there were 9 infections, including 4 cases of pneumonia, in patients who were successfully cooled. One patient had reduced respiratory drive due to meperidine, requiring bilevel positive airway pressure.

"We conclude that it is feasible to treat acute ischemic stroke patients with combined therapy including IV tPA, caffeinol, and hypothermia, with a learning curve," Dr. Martin-Schild told attendees here. The rates of symptomatic hemorrhage were not higher than those observed in clinical trials, and there were no adverse events that were attributed to the caffeinol, she noted.

"We think that the method of induction of hypothermia has a significant impact on the success of the intervention," Dr. Martin-Schild added. "Patients are going to require high doses of sedatives to tolerate hypothermia sometimes, and the rates of infection, specifically pneumonia, really should be a major safety end point in future studies of hypothermia."

They are moving forward in conjunction with the University of San Diego to do a phase 3 trial that will randomize patients eligible for tPA to 1 of 4 groups: tPA with no additional treatment; tPA plus caffeinol; tPA plus hypothermia; and tPA plus caffeinol and hypothermia.

Cautious Process

Only about 30 patients have been treated with caffeinol to date, but no serious adverse effects in addition to drowsiness have been seen, Dr. Martin-Schild said. However, they do not use the agent in patients with congestive heart failure, significant fluid overload, or any unstable arrhythmias, she noted. There is also some indication from the animal studies that although animals chronically exposed to high levels of caffeine appeared to still benefit from the therapy, those chronically exposed to alcohol did not.

Many more patients will need to be treated before it can be concluded that the agent is safe, but investigation with the agent has nevertheless been moving relatively slowly, Dr. Martin-Schild acknowledged. Many previously promising neuroprotectant agents have failed, making them doubly careful with how they are proceeding with this one, she said.

"That's part of why there's been a perceived slowness to a large-scale phase 3 study of caffeinol — we want this to be a success, so we're spending time maximizing each step in the process to give it its best chance of demonstrating the effect that we hope will carry over from animal models to humans," she said.

Preliminary Work

Commenting on the study for Medscape Neurology & Neurosurgery, American Stroke Association program committee chair Philip B. Gorelick, MD, from the University of Illinois College of Medicine, in Chicago, said he has been following the development of caffeinol with some interest, particularly in light of the dismal success of many other neuroprotectant agents over recent years.

He pointed out that the demographic imbalances in the cohorts compared in the tPA vs tPA/caffeinol trial, although the P values were not significant, would have been expected to make a difference in a larger group, differences such as a 7-year disparity in age.

"This was very preliminary work; it looks promising, but it's going to require large-scale validation," Dr. Gorelick said. "It certainly has basic science backing, it seems to be safe, and this exploratory work looks promising, but I wouldn't bet my carotid artery yet that it's going to work. I hope it does work, believe me. We're in trouble right now. We need something that works."

Coauthor Dr. James Grotta has a patent on caffeinol. The study was funded by SPOTRIAS and a grant from the National Institutes of Health to the University of Texas-Houston Medical School Stroke Program.

International Stroke Conference 2008: Abstracts P95, 19. Presented February 20, 2008 and February 19, 2008.

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