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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 110
- 试验地点
- 1
- 主要终点
- Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
120 µg/kg of 3K3A-APC
3K3A-APC, q12h for up to 5 doses
干预措施: 3K3A-APC (Biological)
240 µg/kg of 3K3A-APC
3K3A-APC, q12h for up to 5 doses
干预措施: 3K3A-APC (Biological)
360 µg/kg of 3K3A-APC
3K3A-APC, q12h for up to 5 doses
干预措施: 3K3A-APC (Biological)
540 µg/kg of 3K3A-APC
3K3A-APC, q12h for up to 5 doses
干预措施: 3K3A-APC (Biological)
Placebo
Matching placebo, q12h for up to 5 doses
干预措施: Placebo (Drug)
结局指标
主要结局
Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol
时间窗: 48-hours following last dose
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.
次要结局
- PK of 3K3A-APC by Compartmental Analysis (Cmax)(Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI)
- Number of Participants With a Presence of Measurable Bleeds in the Brain (Hemorrhage and Microbleeds) as Determined by 1.5T MRI(Day 30)
- PK of 3K3A-APC by Compartmental Analysis (Clearance)(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)(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])(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)(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)(Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI)