Influence of Rabeprazole on the Magnitude of the Antiplatelet Action of Clopidogrel (CLARA)

Janssen (J&J Innovative Medicine)

Status and phase

Completed

Phase 1

Conditions

Healthy

Treatments

Drug: Treatment A - rabeprazole

Drug: Treatment B - omeprazole

Other: Treatment C - placebo

Study type

Interventional

Funder types

Industry

Identifiers

NCT00989300

CR016333

RABGRD1008 (Other Identifier)

2009-014756-29 (EudraCT Number)

Details and patient eligibility

About

The purpose of this study is to assess, whether the administration of a proton pump inhibitor, Rabeprazole, has a negative effect on the activity of a concomitantly administered blood thinner drug. Proton pump inhibitors (PPI's) are prescribed for patients with gastric problems to reduce the gastric acid secretion. The blood thinner drug, Clopidogrel, administered in this trial is approved for the treatment of mild heart attacks; it works by preventing blood platelets from sticking together to form clots that would restrict blood flow. Previous trials have shown that the proton pump inhibitor omeprazole interacts with the blood thinning drug clopidogrel to reduce the active form of clopidogrel, thereby preventing the drug's blood thinning effect. In this trial, the effect of two different proton pump inhibitors, namely rabeprazole and omeprazole on the activity of the blood thinner drug clopidogrel will be assessed and compared to the effect of placebo on the activity of the blood thinner drug clopidogrel. This will be done in three sequential periods and each of the patients enrolled into this trial will be asked to participate in three different periods, during which clopidogrel with either rabeprazol, or omeprazol, or placebo will be administered daily.

Full description

In this open-label trial (investigators and patients know, what medication is administered), participants will in the course of three different periods, receive three different combinations of study drugs, namely either clopidogrel combined with rabeprazole, or clopidogrel combined with omeprazole or clopidogrel combined with placebo. Each of these treatment periods will last 7 days and will be interrupted by 2 to 3 weeks without any medication. The goal is to recruit a total of 36 healthy volunteers for all three periods. Clopidogrel is a blood thinner drug that acts on the platelet cell membrane. By this mechanism, clopidogrel inhibits the platelets aggregation. Clopidogrel is a prodrug, meaning that it is orally administrated as an inactive drug and must be activated through several biochemical steps to acquire its antiplatelet properties. This process takes place in the liver and implies a complex enzymatic system. A part of this enzymatic system, called cytochrome 2C19 (CYP2C19) has an important role in the metabolism of the clopidogrel and of other drugs. One of the drugs, which is also metabolized through this system is the proton pump inhibitor (PPI) omeprazole. If omeprazole is given concomitantly with clopidogrel, the metabolism of clopidogrel is inhibited and as a consequence, the therapeutic activity of clopidogrel is reduced. The aim of this study is to investigate whether the proton pump inhibitor rabeprazole, whose metabolism is much less dependent on CYP2C19, interferes less with clopidogrel bioactivation and could thus be proposed as an alternative to other PPIs to patients taking clopidogrel. To confirm that rabeprazole has no clinically relevant effect on the metabolism of clopidogrel, one session is performed with placebo tablets in combination with clopidogrel. Each patient will receive 2 types of study drug during 3 separate periods; either one tablet clopidogrel (75 mg) combined with rabeprazole, or clopidogrel (75 mg) combined with omeprazole or clopidogrel (75 mg) combined with placebo. Each of these treatment periods will last 7 days and will be interrupted by 2 to 3 weeks without any medication.

Enrollment

39 patients

Sex

Male

Ages

18 to 50 years old

Volunteers

Accepts Healthy Volunteers

Inclusion criteria

Healthy Volunteer in good health as determined by a medical history, physical examination including vital signs, and clinical laboratory test results
Body Mass Index between 18 and 30 kg/m2 (inclusive) and body weight not less than 50 kg
Non smoker or smokes <5 cigarettes /day, at least 6 months before first study drug
ECG, blood pressure in normal range (blood pressure measured after the subject is sitting for 5 minutes, between 90 and 140 mm Hg systolic (inclusive) and no higher than 90 mmHg diastolic)

Exclusion criteria

Personal or family history of coagulation or bleeding disorders
Use of known inhibitors or inducers of CYP2C19 and CYP3A, including grape fruit juice intake
Use of any prescription or non prescription medication (including vitamins and herbal supplements), except for paracetamol (acetaminophen) within 14 days prior to screening
Known hypersensitivity to clopidogrel, rabeprazole, its excipients, omeprazole or substituted benzimidazoles
Current clinically significant medical illness or history of clinically significant medical illness
History of, or reason to believe a volunteer has a history of drug or alcohol abuse within the past 5 years