Low-Dose Tenecteplase in Covid-19 Patients With Acute Pulmonary Embolism: A Randomized, Double-Blind, Placebo-Controlled Trial
试验速览
- 阶段
- 4 期
- 状态
- 终止
- 入组人数
- 2
- 试验地点
- 1
- 主要终点
- Percent Improvement in Shock Index (Defined as Heart Rate Divided by Systolic Blood Pressure) 6 Hours After the TNK/Placebo Bolus.
研究概览
简要总结
- There is a knowledge gap associated with the management of patients with COVID-19 lung injury and a laboratory picture compatible with disseminated intravascular coagulation (DIC). Clinical data to date support that COVID-19 is associated with a prothrombotic state that is not simply explained by an influx of more critically ill individuals.
- These patients suffer from severe respiratory failure; hypoxemia and ventilator dependence are the primary concerns; ARDS with respiratory failure is frequently the cause of death. Macroscopic and probable microvascular thromboembolic events are a major concern in this population.
- When DIC is associated with COVID-19, it predicts a very poor prognosis.
- This study will evaluate the clinical efficacy and safety of low-dose IV bolus tenecteplase (TNK) together with anticoagulation compared with control patients on therapeutic anticoagulation alone in hospitalized adults diagnosed with COVID-19 and acute intermediate-risk PE.
- Prospective, multicenter, randomized two-arm trial enrolling consecutive patients who meet enrollment criteria.
- The study will generate evidence that low-dose TNK together with anticoagulation is beneficial in these patients
详细描述
This is a prospective, double-blind, placebo-controlled study randomizing patients with acute intermediate-risk PE who meet enrollment criteria in a 2:1 manner into intervention (TNK) versus placebo arms, respectively. There will be up to 6 sites. After 18 patients are enrolled, a safety assessment will be performed by an independent Data and Safety Monitoring Board, and if a safety issue arises, it will be considered and discussed among the investigators. The planned sample size is 45 patients (30 treatment and 15 control). Subjects will be assessed daily while hospitalized. Subjects discharged from the hospital will be asked to attend study visits at Days 14 and 30 (telephone / telemedicine, clinic or inpatient ward).
The overall objective of the study is to evaluate the clinical efficacy and safety of IV bolus tenecteplase (TNK) and therapeutic anticoagulation compared with placebo and therapeutic anticoagulation in hospitalized adults diagnosed with COVID-19 infection and acute intermediate-risk PE.
Written informed consent for participation in the study must be obtained before performing any study-related procedures (including screening evaluations). Informed Consent Forms for enrolled patients and for patients who are not subsequently enrolled will be maintained at the study site.
After informed consent is obtained, screening assessment will be completed to confirm a patient's eligibility for participation in the study. The screening visit will include medical history, physical exam and vital signs. Standard of care (SOC). labs will be reviewed. These may include INR, aPTT, PT (if patient is currently taking an anticoagulant), CBC with diff, comprehensive chemistry panel, D-dimer and Ferritin. The results of the SARS-CoV-2 will be documented. If subject is in child-bearing age and a pregnancy test was not done for SOC, a urine pregnancy test will be performed. Electrocadiogram and CTA will be reviewed.
If the patient is determined to be eligible, the study site will obtain the patient's medical record number/unique patient identification number, and treatment assignment to either interventional (TNK) or placebo will be randomly determined. Patients will be allocated to the interventional versus placebo arms in a 2:1 manner as per a computer-generated randomization schedule using permuted blocks of random sizes. The block sizes will not be disclosed to ensure concealment. A total of 30 TNK subjects versus 15 placebo controls will be enrolled.
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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or non-pregnant female adult ≥18 years of age, but < 75 years of age at time of enrollment.
- •Laboratory-confirmed SARS-CoV-2 infection as determined by PCR, or other commercial or public health assay in any specimen < 28 days prior to randomization, OR person under investigation (PUI) of COVID-19 with pulmonary infiltrates and elevated ferritin and CRP level.
- •Acute intermediate-risk pulmonary embolism defined as:
- •Presence of acute pulmonary embolism confirmed by diagnostic imaging (computed tomographic angiography, ventilation-perfusion scan, or invasive pulmonary angiography) AND
- •Presence of clot burden with at least one lobar artery involved OR bilateral with at least segmental branches OR unilateral clot in at least multiple segmental branches.
- •Subject (or legally authorized representative) provides written informed consent prior to the performance of any study procedures.
- •In the Investigator's judgement, patient has the ability to comply with the study protocol, and understands and agrees to comply with planned TNK bolus versus placebo.
排除标准
- •Anticipated transfer to another hospital (which is not a study site) within 72 hours
- •Allergy or contraindications to TNK
- •Contraindications to systemic anticoagulation
- •Active bleeding
- •Known significant bleeding risk (although recent exposure to aspirin or any other antiplatelet therapy is not an exclusion criterion). While there is no specific hemoglobin cut-off value for enrollment, Investigators will gauge the severity / stability of the Hgb and exclude patients deemed inappropriate.
- •Major GI or GU bleed within the past 3 weeks
- •History of hemorrhagic stroke
- •History of acute ischemic stroke in the last 90 days
- •High-risk (massive) acute PE (PE associated with hypotension (systolic BP < 90 mmHg for > 15 min).
- •PE associated with syncope and any degree of head trauma
- •PE meeting criteria for intermediate-risk PE and thus for enrollment, but with clinical evidence of deterioration such that the Investigator deems the patient not appropriate for enrollment.
- •Administration of thrombolytic agent within the previous 7 days
- •Pulmonary thrombectomy within the previous 30 days
- •Uncontrolled hypertension defined as systolic blood pressure >180 mm Hg and/or diastolic blood pressure >110 mm Hg at randomization
- •Severe ARDS (P/F ratio < 100)
- •Platelet count lower than 80,000/mm3
- •Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency; recent oral anticoagulant therapy with INR >1.7
- •Arterial puncture at a non-compressible site within the past 5 days
- •Prior brain surgery
- •Severe trauma in the prior 2 weeks
- •Major surgery in the prior 2 weeks
- •Brain malignancy / metastases, brain tumor in past 5 years
- •Brain AVM or ruptured aneurysm at any time
- •Acute myocardial infarction or history of myocardial infarction within the past 3 weeks or cardiac arrest during hospitalization
- •Cardiac tamponade
- •Lumbar puncture with in past 7 days
- •Known abdominal or thoracic aneurysm
- •Acute or chronic renal failure requiring dialysis
- •Chronic liver failure (acutely elevated liver function tests not an exclusion criterion)
- •Bacterial endocarditis at time of study entry
- •Seizure during pre-hospital course or during hospitalization for COVID-19
- •Currently on ECMO
- •Pregnancy, lactation or parturition within the previous 30 days
- •Patients, in whom, in the opinion of the Investigator, are critically ill from concomitant comorbid cardiopulmonary disease, and unlikely to benefit.
- •Any other condition that the Investigator felt would place the patient at increased risk if the investigational therapy were initiated
- •Previous enrollment in this study
研究组 & 干预措施
Low-dose TNKase and Standard of Care Anticoagulation
- TNKase (0.25 mg/kg) bolus Other names: Tenecteplase, TNK
- Standard of care anticoagulation (heparin or enoxaparin)
干预措施: TNKase (Drug)
Low-dose TNKase and Standard of Care Anticoagulation
- TNKase (0.25 mg/kg) bolus Other names: Tenecteplase, TNK
- Standard of care anticoagulation (heparin or enoxaparin)
干预措施: Enoxaparin (Drug)
Placebo and and Standard of Care Anticoagulation
- Placebo bolus (intravenous syringe identical to that of TNK )
- Standard of care anticoagulation (heparin or enoxaparin)
干预措施: Placebo (Drug)
Placebo and and Standard of Care Anticoagulation
- Placebo bolus (intravenous syringe identical to that of TNK )
- Standard of care anticoagulation (heparin or enoxaparin)
干预措施: Enoxaparin (Drug)
结局指标
主要结局
Percent Improvement in Shock Index (Defined as Heart Rate Divided by Systolic Blood Pressure) 6 Hours After the TNK/Placebo Bolus.
时间窗: 6 hours post TNK/placebo infusion
For example, a patient may start with a heart rate of 100 beats/min and systolic blood pressure of 100 mm Hg (shock index = 1) and after therapy there may be an improvement where the heart rate is 90 beats/min, with systolic blood pressure of 110 mm Hg (shock index of 0.81), an improvement of 19%. A normal shock index is between 0.5 and 0.7 in healthy patients.
次要结局
- 1. Clinical Status at 24 Hours After Administration of TNK / Placebo Based Upon 7-point Scale.(24 +/- 6 hours post TNK/placebo infusion.)
研究者
Victor Tapson, MD
Professor of Medicine
Cedars-Sinai Medical Center