Novel α2-Antiplasmin Inactivation for Lysis of Intravascular Thrombi (NAIL-IT) Trial

Study Overview
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Brief Summary
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Phase II trial of TS23

Detailed Description
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Evaluation of safety and thrombolytic effect of ascending doses of TS23 in subjects with intermediate-risk (sub-massive) acute pulmonary embolism (PE)

Official Title
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Evaluation of the Safety and Thrombolytic Effects of Ascending Doses of TS23 in Subjects With Intermediate-Risk (Sub-Massive) Acute Pulmonary Embolism

Conditions
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Pulmonary Embolism

Intervention / Treatment
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* Drug: TS23
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects, age >18 years; PE involving a segmental or more proximal pulmonary artery confirmed by CTPA scan and with an onset of symptoms not more than 5 days prior to diagnosis; Subject is hemodynamically stable with a systolic blood pressure (SBP) >90 mm Hg; Subject has evidence of RV dysfunction as indicated by a right ventricular-to-left ventricular (RV/LV) diameter ratio > 0.9 on CTPA scan (measuring the minor axis of the right and left ventricle in the transverse plane), prior to the initiation of study drug administration. Exclusion Criteria: Subjects for whom thrombolytic therapy or thrombectomy is planned; or subjects with history of administration of thrombolytic agents within the previous 4 days; Subjects receiving ≥ 48 hours of therapeutic doses of heparin or low molecular weight heparin (LMWH) or other anticoagulant therapy immediately prior to randomization; Subjects with contraindications to SOC therapies such as unfractionated heparin or LMWH or oral anticoagulant, or any of the excipients (including study drug excipients); Subjects who are considered at very high risk of bleeding: Known coagulation disorder with history of pathologic bleeding tendencies Subjects with prior intracranial hemorrhage, known arteriovenous malformation or aneurysm of the brain, or evidence of active bleeding; Subjects with a history of major surgery, clinically significant head trauma (in the opinion of the Principal Investigator), or stroke in the past 3 months prior to randomization; Subjects with uncontrolled hypertension defined as SBP ≥180 mm Hg and/or diastolic BP (DBP) ≥110 mm Hg at randomization Subjects requiring concomitant dual antiplatelet therapy Subjects with Creatinine Clearance (CrCL) < 30 mL/min or serum creatinine ≥ 2.5 mg/dL; Subjects with hemoglobin < 8.0 g/dL; Subjects with a platelet count < 100,000/µL; Subjects with acute or persistent hepatitis or diagnosed active liver disease or with elevation of liver enzymes: Alanine transaminase (ALT) or aspartate transaminase (AST) ≥ 3 x upper limit of normal (ULN); Subjects with known history of testing positive for Hepatitis B antigen or Hepatitis C antibody; Subjects with known history of testing positive for the human immunodeficiency virus (HIV); Subjects with life-expectancy < 6 months; Female subjects of child bearing potential with a positive pregnancy test or who are lactating, or unwilling to use highly effective methods of contraception. Highly effective methods of birth control include combination hormonal therapy (estrogen and progresterone), contraceptives administered orally, intravaginally or transdermally, progesterone-only contraceptives administered orally, by injection or implantation, use of an intrauterine device (IUD), intrauterine hormone- releasing system (IUS), bilateral tubal occlusion, partner vasectomy or sexual abstinence; Subjects currently participating in another investigational study or who have participated in an investigational drug study within 30 days (or longer depending on the half-life of the investigational drug; should allow at least five half-life of the investigational drug) prior to randomization.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo + standard of care (SOC) anticoagulation | Drug: Placebo<br>* Placebo<br>|
| Experimental: Low dose TS23<br>TS23 low dose + SOC anticoagulation | Drug: TS23<br>* Monoclonal antibody to a2-antiplasmin<br>|
| Experimental: Intermediate dose TS23<br>TS23 medium dose + SOC anticoagulation | Drug: TS23<br>* Monoclonal antibody to a2-antiplasmin<br>|
| Experimental: Higher dose TS23<br>TS23 highest dose + SOC anticoagulation | Drug: TS23<br>* Monoclonal antibody to a2-antiplasmin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RV/LV | Ratio of the right to left ventricle dimensions on CT perfusion angiogram (CTPA) | 48 hours after treatment | 
| Safety- Bleeding | Frequency of major or clinically significant bleeding | within 7 days of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Thrombus dissolution | Change in modified Miller Score | 48 hours after treatment |