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

A Multi-center, Phase 2 Study Using a Continual Reassessment Method to Determine the Safety and Tolerability of 3K3A-APC in Combination With tPA, Mechanical Thrombectomy or Both in Moderate to Severe Acute Ischemic Stroke

The purpose of this study was to evaluate the safety, pharmacokinetics (PK) and preliminary efficacy of multiple ascending intravenous doses of 3K3A-APC, a Recombinant Variant of Human activated protein C (APC), in in the treatment of acute ischemic stroke following treatment with recombinant tissue plasminogen activator (tPA), mechanical thrombectomy or both.

Study Overview

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

Detailed Description

This was a multicenter, prospective, randomized, controlled, double-blinded Phase 2 study intended to evaluate the safety, PK and preliminary efficacy of 3K3A-APC following treatment with tPA, mechanical thrombectomy or both in subjects with moderate to severe acute ischemic stroke.

Approximately 115 subjects were to be randomized, which included the planned 88 subjects in groups of 4 subjects to either 3K3A-APC or placebo (in a 3:1 ratio) and the additional placebo subjects who were enrolled during safety review pauses. This study used a modified version of the continual reassessment method (CRM) in order to establish a maximum tolerated dose (MTD).

Eligible subjects received 3K3A-APC or placebo every 12 hours for up to 5 doses (approximately 3 days), or until discharge from the hospital, whichever occurred first. Subjects were monitored for safety evaluations through Day 7 (or discharge, if earlier) and were expected to be seen on Day 7, 14, 30, and 90 for safety and outcome evaluations.

• Study Type: Interventional
• Enrollment (Actual): 110
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90048
      • Stroke Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Stroke Center
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Stroke Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Stroke Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Stroke Center
  • New York
    • Buffalo, New York, United States, 14209
      • Stroke Center
    • New York, New York, United States, 10032
      • Stroke Center
    • Rochester, New York, United States, 14642
      • Stroke Center
  • Ohio
    • Cincinnati, Ohio, United States, 45208
      • Stroke Center
    • Columbus, Ohio, United States, 43210
      • Stroke Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Stroke Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Stroke Center
  • Texas
    • Dallas, Texas, United States, 75390
      • Stroke Center
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Stroke Center
  • Virginia
    • Charlottesville, Virginia, United States, 22904
      • Stroke Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 88 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Acute ischemic stroke
• Able to receive IV tPA, mechanical thrombectomy or both
• National Institutes of Health Stroke Scale (NIHSS) score of ≥ 5
• Signed informed consent
• Mechanical thrombectomy subjects only: onset time to arterial puncture time < 6 hours

Exclusion Criteria:

• History of stroke or penetrating head injury within 90 days prior to enrollment
• History of previous or current diagnosis of intracranial hemorrhage that represents a potential for re-hemorrhage if subjected to thrombolytic therapy or mechanical thrombectomy
• Moyamoya disease, cerebral arterio-venous malformation (AVM), known unsecured aneurysm requiring intervention during the acute study period
• Presence of other neurological or non-neurological co-morbidities that may lead, independently of the current stroke, to further deterioration in the subject's neurological status during the trial period
• Presence of premorbid neurological deficits and functional limitations assessed by a retrospective Modified Rankin Scale (mRS) score of ≥ 2
• Mechanical thrombectomy subjects only: baseline non-contrast CT scan revealing a large core occlusion as defined by local protocol
• Prolonged prothrombin time (PT) or activated partial thromboplastin time (aPTT)
• Severe hypertension or hypotension
• Glomerular filtration rate (GFR) <35 mL/min
• Blood glucose concentration < 50 mg/dL
• Prior exposure to any exogenous form of APC

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 120 µg/kg 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 as 100 mL IV infusion; Other Names: 3K3A-Activated Protein C
Active Comparator: 240 µg/kg 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 as 100 mL IV infusion; Other Names: 3K3A-Activated Protein C
Active Comparator: 360 µg/kg 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 as 100 mL IV infusion; Other Names: 3K3A-Activated Protein C
Active Comparator: 540 µg/kg 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 as 100 mL IV infusion; Other Names: 3K3A-Activated Protein C
Placebo Comparator: Placebo; Matching placebo, q12h for up to 5 doses	Drug: Placebo; Matching placebo, 0.9% sodium chloride in water, given as 100 mL IV infusion; Other Names: Matching Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	Specific AEs in the study were defined in the protocol to be dose-limiting toxicity events. Any given patient was adjudicated in a binary way to either have had a DLT or not to have had a DLT.	48-hours following last dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With a Presence of Measurable Bleeds in the Brain (Hemorrhage and Microbleeds) as Determined by 1.5T MRI	MRI examination to include-at minimum-T1 and T2 weighted images, as well as diffusion weighted imaging (DWI) and susceptibility weighted imaging (SWI) sequences. Post-tPA microbleeds-defined as hypointensities less than 5mm in diameter seen on SWI-will be counted as tPA-related only if found within the ischemic territory. All other areas of hypointensity on SWI larger than 5mm diameter will be counted as tPA-related regardless of the territory in which they are found. All treated subjects (regardless of dose) will be compared to all placebo subjects using a Pearson chi-square test.	Day 30
PK of 3K3A-APC by Compartmental Analysis (Clearance)	Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.	Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI
PK of 3K3A-APC by Compartmental Analysis (Volume of Distribution)	Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.	Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI
PK of 3K3A-APC by Compartmental Analysis (Cmax)	Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.	Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI
PK of 3K3A-APC by Compartmental Analysis (AUC[0-inf])	Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.	Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI
PK of 3K3A-APC by Compartmental Analysis (λz)	Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.	Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI
PK of 3K3A-APC by Compartmental Analysis (Half-life)	Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.	Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI

Collaborators and Investigators

• Sponsor: ZZ Biotech, LLC
• Collaborators: Massachusetts General Hospital; National Institute of Neurological Disorders and Stroke (NINDS); University of Iowa; Cedars-Sinai Medical Center
• Investigators: Principal Investigator: Patrick D. Lyden, MD, Cedars-Sinai Medical Center

Publications and helpful links

General Publications

• Lyden P, Levy H, Weymer S, Pryor K, Kramer W, Griffin JH, Davis TP, Zlokovic B. Phase 1 safety, tolerability and pharmacokinetics of 3K3A-APC in healthy adult volunteers. Curr Pharm Des. 2013;19(42):7479-85. doi: 10.2174/1381612819666131230131454.
• Lyden P, Pryor KE, Coffey CS, Cudkowicz M, Conwit R, Jadhav A, Sawyer RN Jr, Claassen J, Adeoye O, Song S, Hannon P, Rost NS, Hinduja A, Torbey M, Lee JM, Benesch C, Rippee M, Rymer M, Froehler MT, Clarke Haley E, Johnson M, Yankey J, Magee K, Qidwai J, Levy H, Mark Haacke E, Fawaz M, Davis TP, Toga AW, Griffin JH, Zlokovic BV; NeuroNEXT Clinical Trials Network NN104 Investigators. Final Results of the RHAPSODY Trial: A Multi-Center, Phase 2 Trial Using a Continual Reassessment Method to Determine the Safety and Tolerability of 3K3A-APC, A Recombinant Variant of Human Activated Protein C, in Combination with Tissue Plasminogen Activator, Mechanical Thrombectomy or both in Moderate to Severe Acute Ischemic Stroke. Ann Neurol. 2019 Jan;85(1):125-136. doi: 10.1002/ana.25383. Epub 2019 Jan 7.
• Lyden P, Weymer S, Coffey C, Cudkowicz M, Berg S, O'Brien S, Fisher M, Haley EC, Khatri P, Saver J, Levine S, Levy H, Rymer M, Wechsler L, Jadhav A, McNeil E, Waddy S, Pryor K. 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.

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Actual): April 18, 2017
• Study Completion (Actual): June 29, 2017

Study Registration Dates

• First Submitted: August 18, 2014
• First Submitted That Met QC Criteria: August 19, 2014
• First Posted (Estimate): August 21, 2014

Study Record Updates

• Last Update Posted (Actual): November 8, 2018
• Last Update Submitted That Met QC Criteria: October 10, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: stroke; ischemic stroke; APC; 3K3A; 3K3A-APC; activated protein C; RHAPSODY
• 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-201 (NN104); U01NS077179-01 (U.S. NIH Grant/Contract); U01NS077352 (U.S. NIH Grant/Contract); 1U01NS088312-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No