Appraisal of MDCO-157 and Plavix® Pharmacokinetics and Pharmacodynamics in Healthy Volunteers With an Evaluation

Study Overview
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Brief Summary
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Following a first, dose ascending study that enrolled 144 normal healthy volunteers (NHVs), this study, to be conducted in approximately 36 NHVs, will provide pertinent information in determining the dose-response of MDCO-157 for platelet aggregation inhibition and P2Y12 receptor inhibition effects and in selection of doses that match the antiplatelet effects of 300 mg PLAVIX® ®. The study will also provide additional data for pharmacokinetics (PK), safety and tolerability of single doses of MDCO-157.

Official Title
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Appraisal of MDCO-157 and Plavix® Pharmacokinetics and Pharmacodynamics in Healthy Volunteers With an Open-label, Randomized, Cross-over Evaluation: The AMPHORE Study

Conditions
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Pharmacokinetics and Pharmacodynamics in Healthy Volunteers

Intervention / Treatment
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* Drug: MDCO-157
* Drug: PLAVIX


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Healthy males or females 18 to 45 years of age, inclusive. Provide written informed consent for genetic testing and written informed consent for the study before initiation of any study related procedures Affiliated to the French social security system Screening and baseline Fridericia's correction (QTcF) interval < 450 msec and baseline heart rate between 50 and 100 bpm (inclusive) Exclusion Criteria: Known or suspected hypersensitivity or allergy to clopidogrel, Captisol, PLAVIX® , or its excipients Body mass index <20 or > 30 kg/m² Inability to communicate with the investigator or comply with study related procedures, or high likelihood of being lost to follow up Known or suspected pregnancy or lactating female Medical history, physical examination including 12-lead ECG or laboratory evaluation conducted at the screening visit with results indicative of any disease or condition which might compromise the hematologic, cardiovascular, pulmonary, renal, gastrointestinal, hepatic, or central nervous system; or other conditions that may interfere with the absorption, distribution, metabolism or excretion of study drug, or would place the subject at increased risk Tobacco product use within the last 6 months prior to dosing Platelet count < 150,000/µL A personal or family history of coagulation or bleeding disorders or reasonable suspicion of vascular malformations Active pathological bleeding such as peptic ulcer or intracranial hemorrhage Positive screen for Hepatitis B (Hepatitis B Surface Antigen HBsAg), Hepatitis C (Hepatitis C Antibody), or HIV (anti-HIV 1/2) Received an investigational drug within a period of 30 days or 5 half-lives, whichever is longer, prior to enrollment in the study Use of aspirin, other non-steroidal anti-inflammatory drugs, CYP3A4 inhibitors (ketoconazole), CYP2C19 inhibitors (eg, omeprazole) or other drugs known to affect platelet function or coagulation within 14 days prior to receiving study drug (MDCO-157 or oral clopidogrel) Grapefruit within 10 days prior to receiving study drug (MDCO-157 or PLAVIX®) Use of any over-the-counter medication, including herbal products, within 7 days prior to administration of study drug (MDCO-157 or PLAVIX®), except for up to 2 grams of acetaminophen per day for up to 3 days for pain control

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 75mg MDCO-157<br>iv | Drug: MDCO-157<br>* intravenous administration<br>|
| Active Comparator: 150mg MDCO-157<br>iv | Drug: MDCO-157<br>* intravenous administration<br>|
| Active Comparator: 300mg MDCO-157<br>iv | Drug: MDCO-157<br>* intravenous administration<br>|
| Active Comparator: 300mg PLAVIX<br>oral | Drug: PLAVIX<br>* oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Response of MDCO-157 (3 doses) compared to Plavix 300 mg | To evaluate the dose-response of MDCO-157 (at 3 doses) compared to Plavix (300 mg), using Emax and AUEC with VASP, over 24 hours: Maximum effect of P2Y12 receptor inhibition (Emax) using VASP (flow cytometry) Area under the effect of P2Y12 receptor inhibition time curve (AUEC) using VASP (flow cytometry) | 24 hr | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) of MDCO-157 and its metabolites | To determine the pharmacokinetic (PK) of MDCO-157, including clopidogrel, clopidogrel carboxylic acid, and clopidogrel H4 thiol active metabolite in plasma | 24 hrs | 
| Safety and tolerability | To assess the safety and tolerability of single doses of MDCO 157 (75 mg, 150mg and 300mg) as measured by assessment of AEs and SAEs. | 48 hrs post each treatment period | 
| Dose response of MDCO-157 as assessed by LTA |  | 24 hours | 
| Dose response of MDCO-157 as assess by VerifyNow P2Y12 assay |  | 24 hours |