Clinical trial NCT04110275: Injection of Recombinant Human Tissue-type Plasminogen Activator Derivative for Acute Pulmonary Embolism(rPA)
Official title: A Phase II Clinical Study to Evaluate the Efficacy and Safety of Thrombolytic Therapy With Recombinant Human Tissue-type Plasminogen Activator Derivative for Acute Pulmonary Embolism
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Acute Pulmonary Embolism
Keywords: Acute Pulmonary Embolism
Lead sponsor: Angde Biotech Pharmaceutical Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2019-10-01
Enrollment: 174
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this trial is to compare the efficacy and safety of Recombinant Human Tissue-Type Plasminogen Activator Derivative(rPA) and Recombinant Tissue-Type Plasminogen Activator(rt-PA) for the treatment of acute pulmonary embolism.

This trial includes two stages, the first stage is to study the dosage of administration of the test drug(rPA), the second is to compare the efficacy and safety of rPA and rt-PA. Both of the two stages are randomized, open and parallel controlled.

Detailed description: This trial is a multicenter, randomized, open and parallel controlled project designed for patients with acute pulmonary embolism requiring thrombolysis after anticoagulant therapy in high-risk and middle-high risk populations.

For the first stage: Subjects who are qualified for the screening criteria according to the inclusion and exclusion criteria will be randomly assigned to low-dose test drugs, high-dose test drugs or reference drugs for thrombolytic therapy at a ratio of 1:1:1.

For the second stage: Subjects who are qualified for the screening criteria according to the inclusion and exclusion criteria will be randomly assigned to rPA(test group)or rt-PA(control group) for thrombolytic therapy at a ratio of 1:1.

Eligibility criteria: Inclusion Criteria:

* Patients with high-risk acute pulmonary embolism: the main manifestations are shock and hypotension.Systemic systolic blood pressure \<90 millimetre of mercury (mmHg) (1mmHg=0.133kPa), or a decrease from the base value ≥40 millimetre of mercury for more than 15min.
* Patients with moderate to high-risk acute pulmonary embolism who have worsened anticoagulant therapy require thrombolytic therapy:

(Patients with moderate to high-risk acute pulmonary embolism: Right ventricular dysfunction (RVD) and elevated cardiac biomarkers coexist.)

1. RVD diagnostic criteria: imaging evidence including echocardiography or CT:1) Ultrasound examination is consistent with the following performance: 1. right ventricular dilatation (right ventricular end-diastolic diameter / left ventricular end-diastolic diameter \> 1.0 or 0.9); 2. right ventricular free wall movement amplitude decreased; 3. tricuspid regurgitation speed increased; 4. tricuspid annulus systolic displacement decreased (\<17mm); 2) Computed Tomographic Pulmonary Angiography examination meets the following conditions: right ventricular dilatation (right ventricular end-diastolic diameter / left ventricular end-diastolic diameter \> 1.0 or 0.9) found at the four-chamber heart level;
2. Cardiac biological markers including N terminal pro B type natriuretic peptide (NT-proBNP/BNP) and troponin elevation;

Diagnostic criteria for worsening after anticoagulant therapy in patients with moderate to high risk acute pulmonary embolism:

Hemodynamic deterioration (defined as meeting at least one of the following conditions: 1. requires cardiopulmonary resuscitation; 2. systemic systolic blood pressure \<90 mmHg (1 mmHg = 0.133 kPa), or a decrease in basal value ≥ 40 mmHg for more than 15 min, or with terminal Low organ perfusion (limb cold or urine volume \<30 ml/hr, or mental confusion); 3. need to infuse a booster drug (except dopamine \<5 μg/kg/min) to maintain adequate tissue perfusion and systolic blood pressure \> 90 mmHg ;

* The time from onset to the time of thrombolysis is ≤ 14 days;
* Male patients must agree to take effective contraceptive measures during treatment and at least 28 days after the end of the trial, and do not donate sperm during this period; women of childbearing age must be negative within the first 72 hours of randomization, and agree to adopt effective contraceptive measures during treatment and at least 28 days afterwards the last treatment.
* Voluntary signing of written informed consent form.

Exclusion Criteria:

* a history of hemorrhagic stroke or unexplained stroke;
* Ischemic stroke or transient ischemic attack within 3 months;
* Central nervous system damage or tumor;
* Surgery and trauma of the brain or spine within 2 months;
* Active internal bleeding within 1 month (such as gastrointestinal bleeding, hemoptysis, blood in the stool, etc.);
* High risk of bleeding: evidence or history of bleeding disorders, bleeding tendency, bleeding constitution or coagulopathy;
* oral anticoagulant (can be randomized after a certain period of time, such as oral rivaroxaban can be randomized after 1 day of elution, oral warfarin can be performed at International Normalized Ratio \<2.0 random);
* 1 week after pregnancy or delivery;
* vascular puncture of the site that cannot be oppressed;
* Cardiopulmonary resuscitation within 10 days;
* Hypertension that is difficult to control (systolic blood pressure \> 180 mmHg and / or diastolic blood pressure ≥ 110 mmHg);
* Liver function is grade C of Child-Pugh ;
* Infective endocarditis;
* History of aneurysms or arteriovenous malformations, or suspected aortic dissection;
* Cardiac thrombosis;
* Diabetes with hemorrhagic retinopathy or other hemorrhagic eye diseases;
* Laboratory inspection:Platelets (PLT) \<90×109/L;Alanine aminotransferase (ALT) \> 2.5 × ULN, aspartate aminotransferase (AST) \> 2.5 ×Upper Limit of Normal (ULN);Endogenous creatinine clearance (Ccr) ≤ 50ml/min (calculated according to the Cockcroft-Gault formula);Alkaline phosphatase (ALP) \> 2.0 × ULN;
* Severe cardiac insufficiency occurred in the past 6 months, New York Heart Association Heart Function Rating (NYHA classification) ≥ III;
* Participate in other clinical trials within 1 month prior to enrollment;
* Known or suspected hypersensitivity to plasminogen activator, or allergic to contrast agents, or drugs administered during the trial;
* People with mental disorders;
* Accompanied by other serious diseases that may prevent them from entering or affecting their survival, such as cancer or AIDS;
* Any disease or condition that is not suitable for intravenous thrombolysis;
* Other diseases or conditions that the investigator believes are not suitable for the trial.

Primary outcomes:
measure: the opening rate of thrombus
timeFrame: 48 hours (Day 3)after injection
Secondary outcomes:
measure: Mortality and recurrence rate
timeFrame: within 7 days after injection
measure: The incidence rates of endpoint events
timeFrame: within 30 days after injection
measure: the ratio of right ventricular end-diastolic diameter/left ventricular end-diastolic diameter
timeFrame: Day 2 (24h), Day 3 (48h), Day 7, Day 30 after injection
measure: The ratio of N terminal pro B type natriuretic peptide/B-type natriuretic peptide
timeFrame: Day 2 (24h), Day 3 (48h), Day 7, Day 30 after injection
measure: Thrombotic load
timeFrame: Day 3（48h）、Day 30 after injection
measure: the opening rate of thrombus
timeFrame: Day 30 after injection
measure: the occurrence rate of adverse event
timeFrame: through study completion, an average of 1.5 year
measure: blood pressure
timeFrame: through study completion, an average of 1.5 year
measure: life signs
timeFrame: through study completion, an average of 1.5 year
measure: pulse
timeFrame: through study completion, an average of 1.5 year
measure: Hemoglobin
timeFrame: through study completion, an average of 1.5 year
measure: red blood cell
timeFrame: through study completion, an average of 1.5 year
measure: white blood cell
timeFrame: through study completion, an average of 1.5 year
measure: platelet
timeFrame: through study completion, an average of 1.5 year
Other outcomes:
Locations:
Study officials:
affiliation: China-Japan Friendship Hospital
name: zhenguo Zhai, Doctor
role: PRINCIPAL_INVESTIGATOR
References: