Targeting neuroprotection clinical trials to ischemic stroke patients with potential to benefit from therapy.
OBJECTIVE
Clinical trials of neuroprotective drugs have had limited success. We investigated whether selecting patients according to prognostic features would improve the statistical power of a trial to identify an efficacious treatment.


METHODS
Using placebo data from the Glycine Antagonist in Neuroprotection (GAIN) International and National Institute of Neurological Disorders and Stroke (NINDS) recombinant tissue plasminogen activator (rtPA) clinical trials, we developed and validated simple prognostic models for stroke trial end points: Barthel Index > or =95, modified Rankin Scale < or =1, National Institutes of Health Stroke Scale < or =1, and Glasgow Outcome Scale=1. Using these models, we simulated 1000 clinical trials and estimated, under several hypothetical treatment effect patterns of neuroprotection, the effect on statistical power of including only patients with moderate prognosis. We calculated the number of patients that would have to be enrolled to maintain the statistical power achieved in selecting the whole trial population. Reanalysis of actual data from the NINDS rtPA trials confirmed the results independently.


RESULTS
Selecting patients with moderate prognosis (predicted probability of favorable outcome 0.2 to 0.8) enabled a sample size reduction, without loss of statistical power, of between 54.6% (51.3% to 57.6%) and 68.6% (66.0% to 71.1%), depending on the treatment effect pattern and outcome measure. These benefits were largely due to the exclusion of patients with poor prognosis.


CONCLUSIONS
Targeting patients with potential to benefit enables a substantial sample size reduction without compromising statistical power or duration of recruitment. As part of a broader trial design strategy, informed use of prognostic data available acutely would help in identifying effective neuroprotective treatments.
Weir
Christopher J
CJ
Division of Cardiovascular and Medical Sciences, University of Glasgow, Gardiner Institute, Western Infirmary, Glasgow G11 6NT, UK. c.j.weir@clinmed.gla.ac.uk
Kaste
Markku
M
Lees
Kennedy R
KR
D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D002545:Brain Ischemia / Q000188:drug therapy*; D023381:Endpoint Determination; D005260:Female; D023261:Glasgow Outcome Scale; D006801:Humans; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018579:Patient Selection; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic / Q000379:methods* / Q000706:statistics & numerical data; D011994:Recombinant Proteins / Q000627:therapeutic use; D018401:Sample Size; D012720:Severity of Illness Index; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D016896:Treatment Outcome
D015415:Biomarkers; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator