A multicenter, randomized, placebo-controlled, double-blinded, Phase 3 study to evaluate the efficacy and safety of 3K3A-APC, a recombinant variant of human activated protein C, in combination with tissue plasminogen activator, mechanical thrombectomy, or both, in subjects with moderate to severe acute ischemic stroke
Trial Summary:
This is a multicenter, randomized, placebo-controlled, double-blind, Phase 3 study, performed in coordination with StrokeNet to evaluate the efficacy and safety of 3K3A‑APC following administration of thrombolysis, mechanical thrombectomy, or both, in subjects with moderate to severe acute ischemic stroke. Subjects will be considered for the study if they are eligible for thrombolysis administration, mechanical thrombectomy, or both, for acute ischemic stroke with National Institutes of Health Stroke Scale (NIHSS) score ≥5.
The study will be conducted at approximately 60 United States (US) sites and approximately 40 non-US sites.
Trial Design and Outcomes:
The study will be conducted in 2 phases: the lead-in dose-finding phase and the definitive phase.
During the lead-in dose-finding phase, a maximum of 360 subjects will be randomized to 3K3A-APC (10, 15, or 30 mg) or placebo using a Bayesian adaptive approach.
Randomized subjects will receive 3K3A-APC or placebo (control) every 12 hours for 5 doses (approximately 3 days) or until discharge from the hospital (whichever occurs first).
Subjects will be monitored through Day 7/Discharge and on Days 30, 60 (phone/virtual), and 90.
The lead-in phase will transition to 1 selected 3K3A‑APC dose and recruitment will continue when a single dose proves superior to control, as measured by the proportion of intracerebral bleeding or death. If more than 1 dose proves superior to control, the lower dose will advance to the next phase. The entire study will stop if no dose proves superior to control during the lead-in phase.
The definitive phase will continue with the 1 selected dose of 3K3A-APC from the lead‑in phase. Approximately 1040 subjects will be randomized during the definitive phase. Subjects from the lead-in phase who receive the dose selected for the definitive phase will be included in the final data analysis.
Objectives/Endpoints/Analyses
| Primary: | Objectives | Endpoints | Analyses |
| - Lead-in phase: | To evaluate the effect of 3K3A-APC on bleed-free survival at Day 30 | Intracerebral bleeding (any blood detected on SWI‑MRI) or death at 30days after ischemic stroke | Bayesian adaptive analysis of posterior probabilities that the proportion of bleeding or death for best dose is lower than control |
| - Definitive phase: | To evaluate the effect of 3K3A-APC on 90‑day disability | Day90 mRS | Day 90 mRS scores will be compared between groups using Bayesian ordinal (shift) analysis |
Protocol Synopsis: View
Study Sponsor and Lead Investigator:
Patrick D. Lyden, MD, FAAN, FAHA, University of Southern California
Other Collaborators:
ZZ Biotech LLC
The National Institute of Neurological Disorders and Stroke (NINDS) - 1U01NS100699-01A1
NIH StrokeNet National Coordinating Center at the University of Cincinnati
NIH StrokeNet National Data Management Center at Medical University of South Carolina
US FDA IND#: 103,728
ClincalTrials.gov identifier: NCT05484154