Combination Therapy Stroke Trial: recombinant tissue-type plasminogen activator with/without lubeluzole

Cerebrovasc Dis. 2001;12(3):258-63. doi: 10.1159/000047713.

Abstract

Background: A neuroprotective drug may be safe and effective if given very early and in combination with recombinant tissue-type plasminogen activator (rt-PA) to acute stroke patients. No clinical trial has yet tested this hypothesis.

Objective: To assess the feasibility, safety and efficacy of simultaneously combining the neuroprotective drug lubeluzole with rt-PA.

Method: Patients who qualified for and received rt-PA within 3 h of symptom onset were randomly allocated 1:1 to lubeluzole (7.5 mg i.v. over 1 h, then continuous 5-day infusion of 10 mg/day) or placebo. Infusion of the study medication was started before the end of the 1-hour rt-PA infusion. Inclusion criteria were the same as those of the FDA-approved guidelines for rt-PA, plus National Institutes of Health Stroke Scale (NIHSS) >5 and absence of serious ventricular arrhythmia, atrioventricular block or Q-T >450 ms. EKG was continuously monitored until 48 h after treatment. The primary outcomes were adverse events, especially hemorrhage and severe arrhythmia, and functionality as determined by the Barthel Index divided into >70,0-70 and dead.

Results: 89 patients were randomized at 34 centers over 8 months. The study was terminated by the sponsor before the planned enrollment of 200 patients when a concurrent phase 3 trial of lubeluzole versus placebo given up to 8 h after stroke was negative. In our study, the mean NIHSS was 14.5, and the mean time from symptom onset to rt-PA was 2.5 h and to randomization to lubeluzole or placebo 3.2 h. Mortality was 26%, intracerebral hemorrhage occurred in 10% and serious adverse events in 51%. There were no differences between the two treatment groups in any of these variables, outcomes or in the Barthel Index or other measures of functionality.

Conclusion: Combining neuroprotective drugs such as lubeluzole simultaneously with rt-PA is feasible and safe. The efficacy of this strategy, using a potentially more effective neuroprotective agent, should be evaluated in an adequately powered clinical trial.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activities of Daily Living
  • Aged
  • Cerebral Hemorrhage / chemically induced
  • Double-Blind Method
  • Feasibility Studies
  • Female
  • Glasgow Coma Scale
  • Humans
  • Male
  • Neuroprotective Agents / adverse effects
  • Neuroprotective Agents / therapeutic use*
  • Piperidines / adverse effects
  • Piperidines / therapeutic use*
  • Plasminogen Activators / adverse effects
  • Plasminogen Activators / therapeutic use*
  • Prospective Studies
  • Recombinant Proteins / adverse effects
  • Recombinant Proteins / therapeutic use
  • Stroke / drug therapy*
  • Stroke / mortality
  • Stroke / physiopathology
  • Thiazoles / adverse effects
  • Thiazoles / therapeutic use*
  • Tissue Plasminogen Activator / adverse effects
  • Tissue Plasminogen Activator / therapeutic use*

Substances

  • Neuroprotective Agents
  • Piperidines
  • Recombinant Proteins
  • Thiazoles
  • Plasminogen Activators
  • Tissue Plasminogen Activator
  • lubeluzole