DOOR-STEP: A Desirability of Outcome Ranking Scale for Clinical Trials of Status Epilepticus Treatment
Abstract number :
3.08
Submission category :
2. Translational Research / 2A. Human Studies
Year :
2021
Submission ID :
1826456
Source :
www.aesnet.org
Presentation date :
12/6/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:54 AM
Authors :
Jaideep Kapur, MD, PhD - University of Virginia; James Chamberlain, MD – Professor, Pediatrics and Emergency Medicine, Children's National Health System; Robert Silbergleit – Emergency Medicine – University of Michigan; Jordan Elm – Biostatistics – Medical University of South Carolina; Eric Rosenthal – Neurology – Massachusetts General Hospital; Thomas Bleck – Neurology – Northwestern University Feinberg School of Medicine; Shlomo Shinnar – Neurology and Pediatrics – Montefiore Medical Center, Albert Einstein College of Medicine; Shahriar Zehtabchi – Emergency Medicine – Downstate Health Sciences University; Scott Evans – Biostatistics – George Washington University
Rationale: Previous clinical trials of status epilepticus (SE) treatment have used an approach separating binary success/non-success efficacy outcomes from safety outcomes. This approach fails to account for intermediate clinical outcomes and the balancing of harm and benefit inherent in the treatment of SE. For example, respiratory failure requiring intubation may be scored as a failure of efficacy even though SE may have been successfully aborted. Separating efficacy and safety outcomes also makes it more difficult to determine whether harms and benefits are occurring in the same patients.
Methods: We convened an expert panel of epileptologists, clinical neurophysiologists, neurocritical care physicians, and emergency physicians to determine a clinical continuum of desirable outcomes for SE. Experts anchored on a perfect outcome (resolved SE and improving mental status) and the worst possible outcome (life-threatening cardiac event or death) and determined intermediate clinical outcomes of graded desirability. Discussion occurred until consensus was achieved.
Results: For a drug intervention at time 0, with an initial expected pharmacodynamic effect by 10 minutes, we constructed a five-point Desirability of Outcome Ranking scale (Figure 1), consisting of the following outcomes (ranked best-to-worst):
1. No clinically evident or electrographic SE occurring after 10 minutes, not intubated, and mental status improving by 60 minutes.
2. No clinical or electrographic evidence of SE after 10 minutes, not intubated, but mental status not improving at 60 minutes.
3. No clinical or electrographic evidence of SE, AND either intubation OR the use of rescue medications.
4. Any clinical or electrographic evidence of SE after 10 minutes (i.e. seizures for 5 consecutive minutes or 8 cumulative minutes [16% seizure burden by time] or seizures persisting until administration of rescue medication).
5. Life-threatening adverse event or death.
Figure 2 depicts a retrospective hypothetical application of this method to the outcomes of the levetiracetam (LEV) arm of the Established Status Epilepticus Treatment Trial (in which outcomes were binary). We estimate that the DOOR-STEP methodology would have yielded the following outcome rates: 1) improved alertness without seizures, 41%; 2) persistent decreased mental status but no further seizures, 11%; 3) intubated but no further seizures, 10%; 4) continued or recurrent SE requiring additional medication, 38%; death, 0%. Acute EEG would improve discrimination between groups 2-4.
Conclusions: We propose a graded Desirability of Outcome Ranking scale for clinical trials of SE (DOOR-STEP). The scale is intuitive, has strong face validity, and allows for a balanced measurement of safety and efficacy as a single composite endpoint.
Funding: Please list any funding that was received in support of this abstract.: None.
Translational Research