High-Dose Lovastatin for Acute Ischemic Stroke: Results of the Phase I Dose Escalation Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART)

BACKGROUND: Hydroxymethylglutaryl coenzyme A reductase inhibitors ('statins') reduce the neuronal injury in dose-dependent fashion in rodent stroke models. We sought to determine whether lovastatin at doses above those currently approved can be administered safely within 24 h after an acute ischemic stroke. METHODS: We conducted a phase 1B dose-finding study using an adaptive design novel to stroke trials, the continual reassessment method, to find the highest tolerated dose of lovastatin. Planned doses were 1, 3, 6, 8 and 10 mg/kg/day for 3 days. The primary safety outcomes were myotoxicity and hepatotoxicity. The model was calibrated to select a dose causing 7-13% toxicity. RESULTS: We enrolled 33 patients (16 men/17 women, age range 23-82 years). Three patients were treated at 1 mg/kg, 10 at 3 mg/kg, 12 at 6 mg/kg, and 8 at 8 mg/kg. Thirty of the 33 patients (90.9%) completed at least 11 of 12 doses. Two patients at the 6-mg/kg dose level experienced transient mild elevations in transaminases without clinical sequelae. After an initial dose reduction, the dose was re-escalated to 8 mg/kg, and no further patients reached safety outcomes. No clinical liver disease, myopathy, or creatine phosphokinase elevations occurred. The final model-based toxicity at 8 mg/kg was 13%; no patient was treated at 10 mg/kg. CONCLUSIONS: Lovastatin at doses above those currently approved by the Food and Drug Administration is feasible for 3 days after an acute ischemic stroke and the maximum tolerated dose is estimated to be 8 mg/kg/day. Further randomized studies are warranted to confirm its safety and to demonstrate its efficacy in improving functional outcomes after stroke.