A Randomized Phase 1 Dose-Escalation Study of Subcutaneously(SC) Administered RUC-4
| Status: | Recruiting |
|---|---|
| Conditions: | Peripheral Vascular Disease, Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - 75 |
| Updated: | 3/7/2019 |
| Start Date: | February 18, 2019 |
| End Date: | January 2020 |
| Contact: | Robert S Hillman, PhD |
| Email: | rhillman@celecor.com |
| Phone: | 8587779750 |
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
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 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).
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.
required to achieve 80% or more inhibition of the initial slope of platelet aggregation to 20
µM ADP 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).
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.
Part 1 Dose Escalation:
Drug: RUC-4 0.05 mg/kg (Cohort 1) Drug: RUC-4 0.1 mg/kg (Cohort 2) Drug: RUC-4 0.3 mg/kg
(Cohort 3) Drug: RUC-4 (Cohorts 4-7 doses to be defined) Drug: Placebo (Cohorts 1-7)
Part 2 Dose Escalation Drug: RUC-4 (Cohort 1-7 doses to be defined) Placebo (Cohorts 1-7)
Part 2 Dose Expansion Drug: RUC-4 (dose to be defined, up to 2 Cohorts) Drug: Placebo (up to
2 Cohorts)
Drug: RUC-4 0.05 mg/kg (Cohort 1) Drug: RUC-4 0.1 mg/kg (Cohort 2) Drug: RUC-4 0.3 mg/kg
(Cohort 3) Drug: RUC-4 (Cohorts 4-7 doses to be defined) Drug: Placebo (Cohorts 1-7)
Part 2 Dose Escalation Drug: RUC-4 (Cohort 1-7 doses to be defined) Placebo (Cohorts 1-7)
Part 2 Dose Expansion Drug: RUC-4 (dose to be defined, up to 2 Cohorts) Drug: Placebo (up to
2 Cohorts)
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 200,000/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
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