Safety Evaluation of 3K3A-APC in Ischemic Stroke

Ischemic Stroke Clinical Trial

— RHAPSODY  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02222714
• Other study ID #: ZZ-3K3A-201 (NN104)
• Secondary ID: 1U01NS088312-01U
• Status: Completed
• Phase: Phase 2
• Start date: October 2014
• Est. completion date: June 29, 2017

Study information

• Verified date: October 2018
• Source: ZZ Biotech, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 110
• Est. completion date: June 29, 2017
• Est. primary completion date: April 18, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

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

Related Conditions & MeSH terms

• Cerebral Infarction
• Ischemia
• Ischemic Stroke
• Stroke

Intervention

Biological:
• 3K3A-APC
3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion

Drug:
• Placebo
Matching placebo, 0.9% sodium chloride in water, given as 100 mL IV infusion

Locations

Country	Name	City	State
United States	Stroke Center	Boston	Massachusetts
United States	Stroke Center	Buffalo	New York
United States	Stroke Center	Charlottesville	Virginia
United States	Stroke Center	Chicago	Illinois
United States	Stroke Center	Cincinnati	Ohio
United States	Stroke Center	Columbus	Ohio
United States	Stroke Center	Dallas	Texas
United States	Stroke Center	Kansas City	Kansas
United States	Stroke Center	Los Angeles	California
United States	Stroke Center	Nashville	Tennessee
United States	Stroke Center	New York	New York
United States	Stroke Center	Pittsburgh	Pennsylvania
United States	Stroke Center	Rochester	New York
United States	Stroke Center	Saint Louis	Missouri
United States	Stroke Center	Salt Lake City	Utah

Sponsors (5)

Lead Sponsor	Collaborator
ZZ Biotech, LLC	Cedars-Sinai Medical Center, Massachusetts General Hospital, National Institute of Neurological Disorders and Stroke (NINDS), University of Iowa

Country where clinical trial is conducted

United States, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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), ?z, 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
Secondary	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), ?z, 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
Secondary	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), ?z, 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
Secondary	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), ?z, 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
Secondary	PK of 3K3A-APC by Compartmental Analysis (?z)	Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), ?z, 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
Secondary	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), ?z, 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

External Links

•   ZZ Biotech Scientific References