Selecting Patients for Intra-Arterial Therapy in the Context of a Clinical Trial for Neuroprotection

Stroke. 2016 Dec;47(12):2979-2985. doi: 10.1161/STROKEAHA.116.013881. Epub 2016 Nov 1.

Abstract

Background and purpose: The advent of intra-arterial neurothrombectomy (IAT) for acute ischemic stroke opens a potentially transformative opportunity to improve neuroprotection studies. Combining a putative neuroprotectant with recanalization could produce more powerful trials but could introduce heterogeneity and adverse event possibilities. We sought to demonstrate feasibility of IAT in neuroprotectant trials by defining IAT selection criteria for an ongoing neuroprotectant clinical trial.

Methods: The study drug, 3K3A-APC, is a pleiotropic cytoprotectant and may reduce thrombolysis-associated hemorrhage. The NeuroNEXT trial NN104 (RHAPSODY) is designed to establish a maximally tolerated dose of 3K3A-APC. Each trial site provided their IAT selection criteria. An expert panel reviewed site criteria and published evidence. Finally, the trial leadership designed IAT selection criteria.

Results: Derived selection criteria reflected consistency among the sites and comparability to published IAT trials. A protocol amendment allowing IAT (and relaxed age, National Institutes of Health Stroke Scale, and time limits) in the RHAPSODY trial was implemented on June 15, 2015. Recruitment before and after the amendment improved from 8 enrolled patients (601 screened, 1.3%) to 51 patients (821 screened, 6.2%; odds ratio [95% confidence limit] of 4.9 [2.3-10.4]; P<0.001). Gross recruitment was 0.11 patients per site month versus 0.43 patients per site per month, respectively, before and after the amendment.

Conclusions: It is feasible to include IAT in a neuroprotectant trial for acute ischemic stroke. Criteria are presented for including such patients in a manner that is consistent with published evidence for IAT while still preserving the ability to test the role of the putative neuroprotectant.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714.

Keywords: activated protein C; clinical trial; neuroprotective agents; thrombectomy; thrombolysis.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Brain Ischemia / drug therapy
  • Brain Ischemia / therapy*
  • Clinical Protocols*
  • Clinical Trials as Topic / standards*
  • Double-Blind Method
  • Humans
  • Mechanical Thrombolysis
  • Neuroprotective Agents / administration & dosage
  • Neuroprotective Agents / adverse effects
  • Neuroprotective Agents / pharmacology*
  • Patient Selection*
  • Protein C / administration & dosage
  • Protein C / adverse effects
  • Protein C / pharmacology*
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / adverse effects
  • Recombinant Proteins / pharmacology*
  • Stroke / drug therapy
  • Stroke / therapy*
  • Thrombolytic Therapy

Substances

  • 3K3A-APC protein
  • Neuroprotective Agents
  • Protein C
  • Recombinant Proteins

Associated data

  • ClinicalTrials.gov/NCT02222714