HONOLULU – The investigational agent DP-b99 provides no more neuroprotection than placebo for patients with acute ischemic stroke, according to the results of the phase III Membrane-Activated Chelator Stroke Intervention trial.
"There is no evidence that this drug offers any clinical benefit when administered within 9 hours of symptom onset," lead investigator Dr. Kennedy Lees said in a late-breaking abstract session at the International Stroke Conference.
Dr. Kennedy Lees
DP-b99 is a first-in-class, membrane-activated ion chelator of zinc, which has been associated with cell signaling and, if overloaded, can be a precursor for cell death and subsequent brain degeneration following a stroke.
"The theory is that if you chelate the signaling within the membrane, you could improve the outcome and reduce the damage," said Dr. Lees, who is with the University of Glasgow, Scotland.
DP-b99 produced promising results in animal models and two phase II studies at a daily dose of 1 mg/kg for 4 days. In one of those trials, a 4-day course of DP-b99 failed to significantly alter the primary endpoint of change in National Institutes of Health Stroke Scale (NIHSS) score at 90 days, but significantly improved recovery at 90 days, as measured by modified Rankin Scale scores. In addition, patients with moderate stroke severity (NIHSS score of 10-16) appeared to gain a particular advantage from DP-b99 therapy, experiencing a significant change in NIHSS scores by day 90 (Stroke 2008;39:1774-8).
Based on these intriguing findings, the double-blind, multicenter phase III MACSI (Membrane-Activated Chelator Stroke Intervention) trial was restricted to patients within 9 hours of acute ischemic stroke onset who had a baseline NIHSS score of 10-16, were not treated with the recombinant TPA drug alteplase (Activase), and had cortical stroke findings. At the time of a preplanned futility analysis, 446 patients had been randomly assigned to intravenous DP-b99 for 4 consecutive days or placebo.
The 218 Dp-b99 patients and 219 controls with at least one outcome in the intent-to-treat analysis were reasonably balanced, with the exception of controls being slightly younger (69.7 years vs. 73 years) and less likely to have had a previous stroke (17% vs. 22%), noted Dr. Lees, professor of cerebrovascular medicine at the University of Glasgow, Scotland. Median NIHSS scores were 13 and 12.5, respectively.
The study’s primary endpoint, ordinal modified Rankin score distributions at 90 days, were not significantly different between the placebo and DP-b99 groups (P = .105), even when adjusted for baseline age and NIHSS score (P = .21).
Moreover, fewer patients treated with DP-b99 than placebo achieved a modified Rankin score of 0 or 1 (odds ratio, 0.64) or a NIHSS score of 0 or 1 (OR, 0.69), and both groups had similar time at home within the first 90 days (OR, 1.28) and mortality (OR, 0.90).
The trial was stopped due to futility, although the authors reluctantly went on to perform subgroup analyses at the behest of Stroke, which simultaneously published the results online (Stroke 2013 Feb. 7 [doi: 10.1161/strokeaha.111.000013]).
"The bottom line: no effect there," regardless of whether the data were cut by gender, history of prior stroke, premorbid modified Rankin Score 0 or deficit, onset to treatment time, or age, Dr. Lees said at the conference, sponsored by the American Heart Association.
D-Pharm sponsored the trial. The authors received fees and expenses for their role on the MACSI trial steering committee. Dr. Lees and his coauthors reported relationships with drug and device companies, but none directly related to MACSI.