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

Influence of Rabeprazole on the Magnitude of the Antiplatelet Action of Clopidogrel. A Prospective, placebo-and Active Treatment-controlled, Open Label, Randomized 3-way Cross Over Study in Healthy Subjects

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Treatment A - rabeprazole; Drug: Treatment B - omeprazole; Other: Treatment C - placebo

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 46 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo group	Other: Treatment C - placebo; placebo once daily for 7 days, in combination with 75 mg clopidogrel once daily for 7 days, oral dosing
Experimental: Treatment group; patients received clopidogrel 75 mg with rabeprazole 20 mg, omeprazole 20 mg, or placebo in a crossover manner	Drug: Treatment A - rabeprazole; 20 mg rabeprazole sodium once daily for 7 days, in combination with 75 mg clopidogrel once daily for 7 days, oral dosing; Drug: Treatment B - omeprazole; 20 mg omeprazole once daily for 7 days, in combination with 75 mg clopidogrel once daily for 7 days, oral dosing

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The effect of rabeprazole and placebo on inhibition of platelet function after 7 daily standard 75 mg doses of clopidogrel in healthy male volunteers.	Day 7 of period 1, 2 or 3

Secondary Outcome Measures

Outcome Measure	Time Frame
The difference in inhibiting the activity of clopidogrel after the administration of rabeprazole compared to placebo	Measurement at day 7 of period 1, 2 or 3
The difference in inhibiting the activity of clopidogrel after the administration of omeprazole compared to placebo	measurement at day 7 of period 1, 2, or 3
The difference in inhibiting the activity of clopidogrel after the administration of rabeprazole compared to omeprazole.	measurement at day 7 of period 1, 2, or 3

Collaborators and Investigators

• Sponsor: Janssen Cilag S.A.S.
• Investigators: Study Director: Janssen-Cilag S.A.S. Clinical Trial, Janssen Cilag S.A.S.

Publications and helpful links

Helpful Links

• Influence of rabeprazole on the magnitude of the antiplatelet action of clopidogrel. A prospective, placebo and active treatment-controlled, open-label, randomized 3-way cross over study in healthy subjects

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): March 1, 2010
• Study Completion (Actual): March 1, 2010

Study Registration Dates

• First Submitted: October 2, 2009
• First Submitted That Met QC Criteria: October 2, 2009
• First Posted (Estimate): October 5, 2009

Study Record Updates

• Last Update Posted (Estimate): September 21, 2012
• Last Update Submitted That Met QC Criteria: September 19, 2012
• Last Verified: September 1, 2012

More Information

Terms related to this study

• Keywords: Clopidogrel; Drug-Drug interaction; Rabeprazol; Omeprazol; Pharmacodynamic Study
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Rabeprazole; Omeprazole
• Other Study ID Numbers: CR016333; RABGRD1008 (Other Identifier: Janssen-Cilag International NV); 2009-014756-29 (EudraCT Number)