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

ZZ Biotech

Status and phase: Completed; Phase 2

Conditions: Ischemic Stroke

Treatments: Biological: 3K3A-APC; Drug: Placebo

Study type: Interventional

Funder types: Other; Industry; NIH

Identifiers

NCT02222714

ZZ-3K3A-201 (NN104)

U01NS077179-01 (U.S. NIH Grant/Contract)

U01NS077352 (U.S. NIH Grant/Contract)

1U01NS088312-01 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 110 patients

Sex: All

Ages: 18 to 90 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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110 participants in 5 patient groups, including a placebo group

120 µg/kg of 3K3A-APC

Active Comparator group

Description:

3K3A-APC, q12h for up to 5 doses

Treatment:

Biological: 3K3A-APC

240 µg/kg of 3K3A-APC

Active Comparator group

Description:

3K3A-APC, q12h for up to 5 doses

Treatment:

Biological: 3K3A-APC

360 µg/kg of 3K3A-APC

Active Comparator group

Description:

3K3A-APC, q12h for up to 5 doses

Treatment:

Biological: 3K3A-APC

540 µg/kg of 3K3A-APC

Active Comparator group

Description:

3K3A-APC, q12h for up to 5 doses

Treatment:

Biological: 3K3A-APC

Placebo

Placebo Comparator group

Description:

Matching placebo, q12h for up to 5 doses

Treatment:

Drug: Placebo