Clinical trial NCT02222714: Safety Evaluation of 3K3A-APC in Ischemic Stroke
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ischemic Stroke
Keywords: ischemic stroke
stroke
APC
3K3A
3K3A-APC
activated protein C
RHAPSODY
Lead sponsor: ZZ Biotech, LLC
Sponsor class: INDUSTRY
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
name: Cedars-Sinai Medical Center
name: Massachusetts General Hospital
name: University of Iowa
First posted: 2014-08-21
Enrollment: 110
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol
timeFrame: 48-hours following last dose
Secondary outcomes:
measure: Number of Participants With a Presence of Measurable Bleeds in the Brain (Hemorrhage and Microbleeds) as Determined by 1.5T MRI
timeFrame: Day 30
measure: PK of 3K3A-APC by Compartmental Analysis (Clearance)
timeFrame: Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI
measure: PK of 3K3A-APC by Compartmental Analysis (Volume of Distribution)
timeFrame: Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI
measure: PK of 3K3A-APC by Compartmental Analysis (Cmax)
timeFrame: Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI
measure: PK of 3K3A-APC by Compartmental Analysis (AUC[0-inf])
timeFrame: Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI
measure: PK of 3K3A-APC by Compartmental Analysis (λz)
timeFrame: Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI
measure: PK of 3K3A-APC by Compartmental Analysis (Half-life)
timeFrame: Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Stroke Center
state: California
city: Chicago
country: United States
facility: Stroke Center
state: Illinois
city: Kansas City
country: United States
facility: Stroke Center
state: Kansas
city: Boston
country: United States
facility: Stroke Center
state: Massachusetts
city: Saint Louis
country: United States
facility: Stroke Center
state: Missouri
city: Buffalo
country: United States
facility: Stroke Center
state: New York
city: New York
country: United States
facility: Stroke Center
state: New York
city: Rochester
country: United States
facility: Stroke Center
state: New York
city: Cincinnati
country: United States
facility: Stroke Center
state: Ohio
city: Columbus
country: United States
facility: Stroke Center
state: Ohio
city: Pittsburgh
country: United States
facility: Stroke Center
state: Pennsylvania
city: Nashville
country: United States
facility: Stroke Center
state: Tennessee
city: Dallas
country: United States
facility: Stroke Center
state: Texas
city: Salt Lake City
country: United States
facility: Stroke Center
state: Utah
city: Charlottesville
country: United States
facility: Stroke Center
state: Virginia
Study officials:
affiliation: Cedars-Sinai Medical Center
name: Patrick D. Lyden, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.