The purpose of this study is to assess the potential for lansoprazole, dexlansoprazole,
omeprazole or esomeprazole to affect the steady state pharmacokinetics and pharmacodynamics
of clopidogrel, and to asses the safety of multiple doses of clopidogrel in combination with
lansoprazole, dexlansoprazole, omeprazole or esomeprazole.
Each of the four PPI treatment groups will consist of 2 sequence groups (Sequence Group1 and
Sequence Group 2) and each sequence group will consist of 2 regimens. Sequence Group 1 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 + 40 mg omeprazole), or Regimen E (75 mg clopidogrel + 40 mg esomeprazole).
Sequence Group 2 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 clopidogrel's active metabolite. Platelet
activation 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 is no washout interval between Period 1 and Period 2.
Inclusion Criteria:
- Is capable of understanding and complying with protocol requirements.
- The subject or the subject's legally acceptable representative signs a written,
informed consent form prior to the initiation of any study procedures.
- Weighs at least 50 kg and has a body mass index (BMI) between 18 and 30 kg/m2,
inclusive, at the Screening and Check-in (Day - 1 of Period 1) Visits.
- Female participants cannot not be nursing, must have a negative serum pregnancy test
at Check-in (Day 1 of Period 1), and must meet 1 of the criteria 1) or 2) below:
1. Be of non-childbearing potential (therefore birth control methods are not
required) by meeting 1 of the following criteria:
- Be postmenopausal, for the purposes of this study defined as:
greater than 40 years of age and amenorrhea for greater than 1 year and a
Follicle-stimulating hormone (FSH) level greater than 40 IU/L .
- Have had a hysterectomy and/or bilateral oophorectomy.
2. Be of childbearing potential and have a negative serum human chorionic
gonadotropin (hCG) pregnancy test during screening and a negative serum
pregnancy test at Check-in (Day - 1 of Period 1) and be using 1 of the following
methods of birth control:
- Continuously practice abstinence during the Screening Period and throughout
the duration of the study and for 30 days after the last dose of study
drug. If abstinence is discontinued during this period, an acceptable
alternative method of contraception as defined in protocol must be used.
- Barrier contraception (condom with spermicide, with or without cap or
diaphragm) or intrauterine device during the Screening Period and agreement
to use throughout the duration of the study and for 30 days after the last
dose of study drug. Condoms without spermicide and diaphragm without
spermicide and male condom are not acceptable methods of barrier
contraception.
- Bilateral tubal ligation if performed a minimum of 90 days prior to Day 1
of Period 1.
- At the Screening and Check-in (Day -1 of Period 1) Visits, must have an estimated
creatinine clearance (CLcr) greater than or equal 80 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 (including but not limited to cigarettes,
pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) 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.
- If male, the subject intends to impregnate others or donate sperm during the course
of this study or for 1 month thereafter.
- Subject, in the opinion of the investigator, is unlikely to comply with the protocol
or is unsuitable for any other reason.
Takeda Study Registration Call Center, Phone: 800-778-2860, Email: medicalinformation@tpna.com
