A Randomized Phase 1 Dose-Escalation Study of Subcutaneously(SC) Administered RUC-4

Study Overview
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Brief Summary
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This study is designed to assess tolerability of the weight-adjusted dose of RUC-4 (mg/kg) required to achieve 80% or more inhibition of the initial slope of platelet aggregation to 20 µM ADP by Light Transmission Aggregometry (LTA) within 15 minutes of SC administration of RUC-4 with return toward baseline values within 4 hours in healthy volunteers and subjects on aspirin with stable coronary artery disease (CAD). In the Dose Expansion Part, VerifyNow PRUTest will be used to measure platelet aggregation in addition to LTA. Since the goal of RUC-4 therapy is to achieve maximal antiplatelet therapy as rapidly as possible, first the tolerability of the weight-adjusted dose (mg/kg) that inhibits ADP-induced platelet aggregation by 80% or more in 5 of 6 healthy volunteers will be identified. A similar dose escalation will be subsequently performed in subjects with CAD who are taking aspirin. To facilitate administration using a single weight-adjusted (mg/kg) dose for a defined group of subjects weighing between 55 and 120 kg, the study will also evaluate the safety and biologic effect on platelet aggregation of the weight adjusted (mg/kg) dose when administered to subjects with weights at either end of this range.

Detailed Description
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Part 1 Dose Escalation: Drug: RUC-4 0.05 mg/kg (Cohort 1) Drug: RUC-4 0.075 mg/kg (Cohort 2) Drug: Placebo (Cohorts 1-2) Part 2 Dose Escalation Drug: RUC-4 (Cohort 1-3 doses to be defined) Placebo (Cohorts 1-3) Part 2 Dose Expansion Drug: RUC-4 (dose to be defined, 1 Cohort) Drug: Placebo (1Cohort)

Official Title
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A Randomized Phase 1 Dose-Escalation Study in Healthy Volunteers and Subjects on Aspirin With Stable Coronary Artery Disease to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneous RUC-4

Conditions
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Coronary Disease

Intervention / Treatment
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* Drug: RUC-4 Compound


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria (all subjects) weight between 55-120 kg, inclusive, and BMI between 18-38 kg/m2 females must be non-pregnant, non-lactating, and of non-childbearing potential. good general health as determined by no acute illness and no clinically significant abnormal findings on medical history, clinical laboratory test results, vital signs, or physical examination platelet count of 150,000/uL to 400,000/uL and mean platelet volume (MPV) within the normal range Subjects with stable CAD, defined as history of documented myocardial infarction (MI) or angina, or evidence of CAD derived from cardiac stress test, or imaging (calcium score [greater than 100 or abnormal for age], angiography, computerized tomography, or magnetic resonance image); absence of angina, or presence of angina with no change in frequency, duration, precipitating causes or ease of relief for at least 60 days, and no ECG or biomarker evidence of myocardial damage in past 60 days blood pressure control achieved with 4 or fewer anti-hypertensive medications on a stable regimen of aspirin at a dose of 81 to 325 mg/day Main exclusion criteria (all subjects): history of prior stroke or clinically significant cardiovascular (e.g., unstable angina, New York Heart Association [NYHA] class II, II or IV heart failure), dermatologic, endocrine, gastrointestinal (GI), hematologic, infectious, metabolic, neurologic, psychologic, or pulmonary disorder or any other condition, including active cancer that in the opinion of the PI would jeopardize the safety of the subject or impact the validity of the study results history of upper or lower GI bleeding requiring intervention or treatment within 12 months of Screening or endoscopic evidence of active peptic ulcer disease within 6 months of Screening bleeding score > 3 on the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool coagulation abnormality, bleeding disorder, or history of documented prior hemorrhagic or thrombotic stroke whole blood donation and/or diagnostic blood evaluation exceeding 500 mL within 8 weeks of Screening surgical procedure, major injury, or dental procedure with high risk of bleeding within 30 days of Screening alcohol consumption of >210 mL of alcohol per week within 6 months of Screening, or alcohol detected in urine at Screening marijuana use within the past 3 months, or history/presence of substance abuse febrile illness within 14 days of Screening use of metformin within 7 days of Screening use of herbal or nutritional supplements/medicines within 7 days of Screening participation in another investigational product or device study within 30 days of Screening or during the study Presence of HIV antibody, HCV antibody, or HbsAg in serum at Screening employee of the Sponsor or The Lindner Center staff member directly affiliated with the study, or their immediate family member defined as spouse, parent, child, or sibling abnormal platelet aggregation or in vitro inhibition of platelet aggregation pattern by RUC-4 receiving or have received in the past 30 days an anticoagulant or fibrinolytic agent a cardiac pacemaker history of allergy to any of the ingredients in the RUC-4 or placebo formulation Healthy Subjects only: medication known to have an impact on platelet function within 30 days of Screening. abnormally low response to arachidonic acid-induced platelet aggregation screening ECG abnormality that is interpreted by the PI to be clinically significant Stable CAD subjects only: medication known to have an impact on platelet function, with the exception of aspirin, within 30 days of Screening. ->4 anti-hypertensive medications required to achieve blood pressure control incomplete inhibition of arachidonic acid-induced platelet aggregation acute changes on ECG

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Cohort 1<br>Cohort 1: 0.05 mg/kg RUC-4/placebo 7 subjects will be enrolled: 6 subjects will receive a single subcutaneous dose of RUC-4 and 1 subject will receive matched placebo. | Drug: RUC-4 Compound<br>* single subcutaneous administration of RUC-4<br>|
| Experimental: Part 1 Cohort 2<br>Cohort 2: 0.075 mg/kg RUC-4/placebo 7 subjects will be enrolled: 6 subjects will receive a single subcutaneous dose of RUC-4 and 1 subject will receive matched placebo. | Drug: RUC-4 Compound<br>* single subcutaneous administration of RUC-4<br>|
| Experimental: Part 2 Cohort 1<br>Cohort 1: initial dose to be selected by the Safety Review Committee (SRC) after completion of Part 1 (the same initial dose used in Part 1 or one of the previously studied higher doses that is lower than the overall RUC-4 BED) 7 subjects will be enrolled: 6 subjects will receive a single subcutaneous dose of RUC-4 and 1 subject will receive matched placebo. | Drug: RUC-4 Compound<br>* single subcutaneous administration of RUC-4<br>|
| Experimental: Part 2 Cohorts 2-3<br>7 subjects (6 receiving RUC-4, 1 receiving placebo) will be enrolled in each dose cohort, with a safety evaluation performed after 2 subjects in a dose cohort receive RUC 4 and at the completion of dosing for all subjects in the dose cohort. Dose escalation to be determined by the SRC charter and will continue until identification of the overall RUC-4 BED or MTD | Drug: RUC-4 Compound<br>* single subcutaneous administration of RUC-4<br>|
| Experimental: Part 2 Dose Expansion Cohort 1<br>14 subjects will receive a selected dose of RUC-4 based on SRC review of dose escalation data. In the expansion cohort, 7 subjects weighing 55 to 65 kg and 7 subjects weighing 100 to 120 kg will be enrolled; 12 subjects will receive a single subcutaneous dose of RUC-4 and 2 will receive matched placebo | Drug: RUC-4 Compound<br>* single subcutaneous administration of RUC-4<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Platelet Inhibition | inhibition of platelet aggregation | 5 minutes | 
| Platelet inhibition | inhibition of platelet aggregation | 15 min | 
| Platelet inhibition | inhibition of platelet aggregation | 30 min | 
| Platelet inhibition | inhibition of platelet aggregation | 60 min | 
| Platelet inhibition | inhibition of platelet aggregation | 90 min | 
| Platelet inhibition | inhibition of platelet aggregation | 120 min | 
| Platelet inhibition | inhibition of platelet aggregation | 189 min | 
| Platelet inhibition | inhibition of platelet aggregation | 240 min | 
| Platelet Inhibition | inhibition of platelet aggregation | 360 min | 
| Platelet Inhibition | inhibition of platelet aggregation | 24 hours |