Official Title: “A Phase 1, Randomized, Open-Label, 2-Period, Crossover Design Study to Assess the Effects of Multiple Oral Doses of Dexlansoprazole, Lansoprazole, Omeprazole or Esomeprazole on the Steady-State Pharmacokinetics and Pharmacodynamics of Clopidogrel in Healthy Subjects”

The purpose of this study is to assess the potential effect and safety of multiple oral doses of dexlansoprazole, lansoprazole, omeprazole or esomeprazole, once daily (QD), on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel and to asses the safety of multiple doses of clopidogrel in healthy subjects.

Study Type: Interventional

Study Design: Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Open Label

Study Primary Completion Date: June 2010

This is a Phase 1, randomized, open-label, single-center, multiple-dose, 2-period, crossover study to assess the effects of multiple oral doses of dexlansoprazole, lansoprazole, omeprazole or esomeprazole on the steady-state pharmacokinetics (PK) and pharmacodynamics of clopidogrel in healthy subjects.

Subjects will be randomized equally into eight regimen sequence groups, 20 subjects each.

Subjects who are randomized to Sequence Groups 1 and 2, 3 and 4, 5 and 6 and 7 and 8 are called PPI Groups 1, 2, 3, and 4, respectively. Each sequence group will consist of 2 regimens. Sequence Groups 1, 3, 5 and 7 will dose Regimen A (75 mg clopidogrel) for Days 1-9 of Period 1 and then will cross over to one of the following 4 regimens for Days 1-9 of Period 2: Regimen B (75 mg clopidogrel + 30 mg lansoprazole), Regimen C (75 mg clopidogrel + 60 mg dexlansoprazole), Regimen D (75 mg clopidogrel + 80 mg omeprazole), or Regimen E (75 mg clopidogrel + 40 mg esomeprazole). Sequence Groups 2, 4, 6 and 8 will begin with either Regimen B, C, D or E for Period 1 and will then cross over to Regimen A for Period 2.

On Day 9 of each period, blood samples will be collected at predose and for 24 hours postdose to measure plasma concentrations of the active metabolite of clopidogrel. Platelet function will be assessed daily prior to the dose of clopidogrel on Days 7-9 and 24-hours post Day 9 dose in each period. There will be a washout interval of 10 to 14 days between the last dose of study drug in Period 1 and the first dose of study drug in Period 2.

Study subjects will be confined to the study center for 10 consecutive nights in Period 1, followed by a 10- to 14-day washout interval and confined for an additional 10 consecutive nights in Period 2.

Intervention(s) in this Clinical Trial

• Drug: Clopidogrel
  • Clopidogrel 75 mg, tablets, orally, once daily days 1-9.
• Drug: Clopidogrel and Lansoprazole
  • Clopidogrel 75 mg, tablets, orally, once daily and Lansoprazole 30 mg, capsules, orally, once daily days 1-9.
• Drug: Clopidogrel and Dexlansoprazole
  • Clopidogrel 75 mg, tablets, orally, once daily and Dexlansoprazole 60 mg, capsules, orally, once daily days 1-9.
• Drug: Clopidogrel and Omeprazole
  • Clopidogrel 75 mg, tablets, orally, once daily and Omeprazole 80 mg, capsules, orally, once daily days 1-9.
• Drug: Clopidogrel and Esomeprazole
  • Clopidogrel 75 mg, tablets, orally, once daily and Esomeprazole 40 mg, capsules, orally, once daily days 1-9.

Arms, Groups and Cohorts in this Clinical Trial

• Other: Regimen A
  • Clopidogrel 75 mg QD
• Other: Regimen B
  • Clopidogrel 75 mg QD and Lansoprazole 30 mg QD
• Other: Regimen C
  • Clopidogrel 75 mg QD and Dexlansoprazole 60 mg QD
• Other: Regimen D
  • Clopidogrel 75 mg QD and Omeprazole 80 mg QD
• Other: Regimen E
  • Clopidogrel 75 mg QD and Esomeprazole 40 mg QD

Primary Measures

• Pharmacokinetic parameter peak plasma concentration (Cmax) of clopidogrel's active metabolite.
  • Time Frame: Day 9 of each period
    Safety Issue?: No
• Pharmacokinetic parameter area under the plasma concentration versus time curve (AUC) from time 0 to time of the last quantifiable concentration (AUC[0-tlqc]) of clopidogrel's active metabolite.
  • Time Frame: Day 9 of each period
    Safety Issue?: No
• Pharmacodynamic parameter Platelet Reactivity Index (PRI) from vasodilator-stimulated phosphoprotein (VASP) phosphorylation state (flow cytometry).
  • Time Frame: 24-hour post Day 9 dose in each period.
    Safety Issue?: No
• Pharmacodynamic parameter Maximum Platelet Aggregation (MPA) from aggregometry (turbidimetric) with 5 and 20 µM ADP.
  • Time Frame: 24-hour post Day 9 dose in each period.
    Safety Issue?: No

Inclusion Criteria:

• Weighs at least 50 kg and has a body mass index (BMI) between 18 and 30 kg/m2, inclusive, at Screening and Check-in (Day -1 of Period 1) Visits.
• Must be a CYP2C19 extensive metabolizer (wt/wt).
• Female participants of childbearing potential cannot be nursing, must have a negative serum pregnancy test at Check-in (Day 1 of Period 1), and use barrier contraception, or continuously practice abstinence throughout the duration of the study and for 30 days after the last dose of study drug.
• At the Screening and Check-in (Day -1 of Period 1) Visits, must have an estimated creatinine clearance (CLcr) greater than or equal 90 mL/minute as determined from the Cockcroft-Gault formula.
• Is in good health as determined by a physician based upon medical history, electrocardiogram, and physical examination findings at the Screening and Check-in (Day -1 of Period 1) Visits.
• Participant's clinical laboratory evaluations (including hematology, clinical chemistry [fasted for a least 8 hours], and urinalysis) at the Screening and Check-in (Day -1 of Period 1) Visits are within the reference range for the testing laboratory or are deemed not clinically significant by the investigator and TGRD Medical
• Monitor.
• Participant's urine drug screen for selected substances of abuse is negative at the Screening and Check-in (Day -1 of Period 1) Visits.

Exclusion Criteria:

• Has consumed products containing Seville oranges (sour), grapefruit or grapefruit juice within 14 days prior to the first dose of study drug or is unwilling to agree to abstain from products containing Seville oranges (sour), grapefruit or grapefruit juice while participating in the study.
• Has current or recent (within 6 months) gastrointestinal disease, a history of malabsorption, esophageal reflux, gastric bleeding or peptic ulcer disease, frequent (more than once per week) occurrence of heartburn, or any surgical intervention (eg, cholecystectomy), which would be expected to influence the absorption of drugs.
• Has a history of drug abuse or a history of alcohol abuse within 1 year prior to the Screening Visit or is unwilling to agree to abstain from alcohol and drugs throughout the study.
• Is currently participating in another investigational study or has received any investigational compound within 30 days prior to the Check-in (Day -1 of Period 1) Visit.
• Has received any known hepatic or renal clearance altering agents (eg, erythromycin, cimetidine, barbiturates, phenothiazines, fluvoxamine, etc.) within 28 days prior to first dose of study drug.
• Has a history or clinical manifestations of significant metabolic, hematologic, pulmonary, cardiovascular, gastrointestinal, neurologic, hepatic, renal, urologic, immunologic, or psychiatric disorder as determined by the investigator which may impact the ability of the subject to participate or potentially confound the trial results.
• Has a history of hypersensitivity or allergies to any drug or food or any excipients of clopidogrel, lansoprazole, dexlansoprazole, omeprazole, esomeprazole or other drug with the same mechanism of action or related compounds.
• Has had an acute, clinically significant illness within 30 days prior to the first dose of study drug.
• Has a systolic blood pressure greater than 140 mm Hg or has a diastolic blood pressure greater than 90 mm Hg at Screening or Check-in (Day -1 of Period 1).
• Has a positive test result for hepatitis B surface antigen (HBsAg) or antibody to hepatitis C virus (anti-HCV) at Screening, or a known history of infection with the human immunodeficiency virus (HIV).
• Has a Day -1 laboratory value assessed by the principal investigator and sponsor medical monitor as clinically significant underlying disease or condition that may prevent the subject from entering the study.
• Has an alanine aminotransferase, aspartate aminotransferase or Total Bilirubin level that exceeds the upper limit of normal at the Screening or Check-in (Day -1 of Period 1) Visits.
• Has used nicotine-containing products within 6 weeks prior to Check-in (Day -1 of Period 1) Visit, or has a positive cotinine screen at the Screening or Check-in (Day 1 of Period 1) Visits or anticipates an inability to abstain from these products for the duration of the study.
• With the exception of acetaminophen, has taken any excluded medication, supplements or food products listed in the Excluded Dietary Items and Medications table.
• Has donated blood products (such as plasma) within 30 days, or has donated whole blood or had a significant blood loss (500 mL) within 56 days of the first dose of study drug
• Has a positive test result for caffeine at the Check-in (Day -1 of Period 1) Visit.
• Has a history of cancer, except basal cell carcinoma, which has not been in remission for at least 5 years prior to the first dose of study drug.
• Has received clopidogrel or any PPIs or histamine2-receptor antagonists within 28 days of screening.
• Subject, in the opinion of the investigator, is unlikely to comply with the protocol or is unsuitable for any other reason.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 55 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: Takeda Global Research & Development Center, Inc.

Overall Clinical Trial Officials and Contacts

Medical Director Clinical Science Study Director Takeda Global Research & Development Center, Inc.  

Information obtained from ClinicalTrials.gov on September 02, 2010

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00942175

Study ID Number: TAK-390MR_101

ClinicalTrials.gov Identifier: NCT00942175

Health Authority: United States: Food and Drug Administration

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