Efficacy and Safety Evaluation of 3K3A-APC in Ischemic Stroke (RHAPSODY-2)

A Phase 3 Study to Evaluate the Efficacy and Safety of 3K3A-APC in Combination with Tissue Plasminogen Activator, Mechanical Thrombectomy, or Both in Subjects with Moderate to Severe Acute Ischemic Stroke

The purpose of this study is to evaluate the efficacy and safety of intravenous doses of 3K3A-APC, a recombinant variant of human activated protein C (APC), in the treatment of acute ischemic stroke following treatment with thrombolysis, mechanical thrombectomy or both.

Study Overview

• Status: Withdrawn
• Conditions: Ischemic Stroke
• Intervention / Treatment: Biological: 3K3A-APC; Other: Placebo

Detailed Description

This multicenter, randomized, placebo-controlled, double-blind, Phase 3 study is being performed in coordination with StrokeNet to evaluate efficacy and safety of 3K3A-APC following administration of thrombolysis, mechanical thrombectomy, or both in subjects with moderate to severe acute ischemic stroke.

The study will be conducted in two phases. During a lead-in dose-finding phase, a maximum of 360 subjects will be randomized to 3K3A-APC or placebo using a Bayesian adaptive approach. Randomized subjects will receive 3K3A-APC or placebo every 12 hours for up to 5 doses (approximately 3 days) or until discharge from the hospital (whichever occurs first). The lead-in phase will transition to one selected 3K3A APC dose-and recruitment will continue-when a single dose proves superior to all other doses and safe.

The definitive phase will continue with the selected dose of 3K3A-APC from the lead-in phase. Randomization will be stratified on 4 variables. Lead-in patients who received the dose selected for the definitive phase will be included in the final data analysis.

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Acute ischemic stroke
• Able to receive thrombolysis, mechanical thrombectomy or both
• National Institutes of Health Stroke Scale (NIHSS) score of ≥ 5
• Signed informed consent
• Agreement to use effective birth control throughout the study

Exclusion Criteria:

• Neurologic deficit is non-disabling
• History of stroke or penetrating head injury within 90 days prior to enrollment
• History of previous or current diagnosis of intracranial hemorrhage
• Moyamoya disease, cerebral arteriovenous malformation, or known unsecured aneurysm requiring intervention during the acute study period
• Presence of tandem lesions suggesting a likely need for proximal artery stenting during the thrombectomy procedure that would mandate post-operative dual antiplatelet therapy
• Presence of other neurological or non-neurological co-morbidities, independently of the current stroke, that may lead to further deterioration in the subject's neurological status during the study period
• Prolonged prothrombin time (PT) or activated partial thromboplastin time (aPTT)
• Severe hypertension or hypotension
• Blood glucose concentration < 50 mg/dL
• Prior exposure to any exogenous form of a recombinant variant of human APC

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Matching placebo, q12h for up to 5 doses	Other: Placebo; Matching placebo, 0.9% sodium chloride in water, given at 100 mL IV infusion; Other Names: Matching Placebo
Active Comparator: 10mg of 3K3A-APC; 3K3A-APC, q12h for up to 5 doses	Biological: 3K3A-APC; 3K3A-APC, diluted in 0.9% sodium chloride in water, given at 100 mL IV infusion; Other Names: 3K3A-Activated Protein C
Active Comparator: 15mg of 3K3A-APC; 3K3A-APC, q12h for up to 5 doses	Biological: 3K3A-APC; 3K3A-APC, diluted in 0.9% sodium chloride in water, given at 100 mL IV infusion; Other Names: 3K3A-Activated Protein C
Active Comparator: 30mg of 3K3A-APC; 3K3A-APC, q12h for up to 5 doses	Biological: 3K3A-APC; 3K3A-APC, diluted in 0.9% sodium chloride in water, given at 100 mL IV infusion; Other Names: 3K3A-Activated Protein C

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the effect of 3K3A-APC on 90-day disability	Day 90 mRS scores will be compared between groups using ordinal (shift) analysis	Day 90 mRS

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the safety of 3K3A-APC	The percentage of subjects who experienced any treatment-related AE will be compared using a Fisher's exact test.	Baseline to Day 90

Collaborators and Investigators

• Sponsor: ZZ Biotech, LLC
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS); University of Southern California; University of South Carolina; University of Cincinnati
• Investigators: Principal Investigator: Patrick D Lyden, MD, University of Southern California

Publications and helpful links

Helpful Links

• ZZ Biotech Scientific References

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2024
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: July 29, 2022
• First Submitted That Met QC Criteria: July 29, 2022
• First Posted (Actual): August 2, 2022

Study Record Updates

• Last Update Posted (Actual): October 1, 2024
• Last Update Submitted That Met QC Criteria: September 26, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: Stroke; Ischemic Stroke; APC; 3K3A; 3K3A-APC; RHAPSODY; Activated protein C
• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Ischemia; Infarction; Brain Infarction; Stroke; Ischemic Stroke; Ischemia; Cerebral Infarction; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Protein C
• Other Study ID Numbers: ZZ-3K3A-301; UG3NS119199 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No