The primary outcome was a favorable functional outcome 90 days after randomization, defined as an mRS score of 0-2. In the main analysis of the whole population, this favorable outcome was achieved for 61.4% of the group that received nerinetide and for 59.2% of the placebo group, a nonsignificant difference. Secondary outcomes were also similar between the two groups.
But an exploratory analysis showed evidence that nerinetide’s treatment effect was modified by alteplase treatment. Among the patients who did not receive alteplase, use of nerinetide was associated with improved outcomes, whereas no benefit was found in the alteplase stratum. The difference in absolute risk slightly but not significantly favored placebo.
In the stratum that did not receive alteplase (40% of the trial population), the favorable mRS outcome was achieved by 59.3% of patients who received nerinetide, compared with 49.8% of those given placebo – a significant difference (adjusted risk ratio, 1.18; 95% confidence interval, 1.01-1.38).
There was also a 7.5% absolute risk reduction in mortality at 90 days post treatment with nerinetide for the patients who did not receive thrombolysis. This resulted in an approximate halving of the hazard of death (adjusted hazard ratio, 0.56).
In addition, infarct size was reduced in those patients who received nerinetide but not thrombolysis.
Among the patients who received alteplase, the proportion of patients who achieved an mRS of 0-2 was similar between groups, as were median infarct volumes.
The observed treatment effect modification by alteplase was supported by reductions in peak plasma nerinetide concentrations in the alteplase stratum, the researchers reported.
They said that the combination of the clinical results in the no-thrombolytic stratum and subsequent tests documenting that nerinetide is broken down by plasmin (which is generated by alteplase) “provide evidence that the clinical observation of effect modification is not a chance finding.” But they added: “This novel observation will require additional confirmation, and we cannot draw a definitive conclusion on treatment effect in this study.”