PPI and Clopidogrel Response

• Sponsor: University of Florida (Other)
• Overall Status: Completed
• CT.gov ID: NCT01170533
• Collaborator: Bristol-Myers Squibb (Industry), Sanofi (Industry)
• Enrollment: 20
• Location: 1
• Arms: 2
• Duration (Months): 17
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

Clopidogrel, in combination with aspirin, is currently the recommended treatment for secondary prevention of ischemic events in high-risk patients and for prevention of coronary artery stent thrombosis. Patients receiving aspirin and clopidogrel are frequently treated with proton pump inhibitors, such as omeprazole or pantoprazole, in order to prevent the risk of gastrointestinal bleeding, accorded to guidelines. An interaction between proton pump inhibitors and clopidogrel has been suggested, which may lead to a decrease of clopidogrel effects. It remains unclear whether this interaction between PPIs and clopidogrel might be a class effect or if this may be affected by timing regimen.

The objectives of this two-phase investigation are:

1. to compare clopidogrel platelet inhibitory effects when taken at the same time versus separated at least 8 hours from omeprazole administration.

2. to compare clopidogrel-induced inhibitory effects when taken at the same time versus staggered at least 8 hours from pantoprazole administration.

Condition or Disease	Intervention/Treatment	Phase
Drug Interaction	Drug: omeprazole and pantoprazole	Phase 1

Detailed Description

Clopidogrel, in combination with aspirin, is currently the recommended treatment for secondary prevention of ischemic events in high-risk patients and for prevention of coronary artery stent thrombosis. Patients receiving aspirin and clopidogrel are frequently treated with proton pump inhibitors, such as omeprazole or pantoprazole, in order to prevent the risk of gastrointestinal bleeding, accorded to guidelines. An interaction between proton pump inhibitors and clopidogrel has been suggested, which may lead to a decrease of clopidogrel effects. It remains unclear whether this interaction between PPIs and clopidogrel might be a class effect or if this may be affected by timing regimen. The objectives of this two-phase investigation are: 1. to compare clopidogrel platelet inhibitory effects when taken at the same time versus separated at least 8 hours from omeprazole administration. 2. to compare clopidogrel-induced inhibitory effects when taken at the same time versus staggered at least 8 hours from pantoprazole administration. The clopidogrel dose will be a 600mg loading dose followed by a 75mg daily maintenance dose, starting the next day for 7 days. Omeprazole will be used at a daily dose of 40mg and pantoprazole at 80mg.

The proposed study will have a prospective, randomized, cross-over design. Subjects are randomized in a 1:1 fashion to take PPI concomitantly (CONC regimen) or staggered by 8-12 hours (STAG regimen) for one-week on a background of clopidogrel therapy. In particular, in the CONC regimen both drugs were taken in the morning, while in the STAG regimen clopidogrel was taken in the morning and omeprazole in the evening. After a 2-4 week washout period, subjects crossed-over treatment regimen. After completing these two treatment phases, subjects underwent another washout period of 2-4 weeks and were treated for 1 week with clopidogrel alone, without receiving omeprazole therapy (CLOP regimen). The sequence with the PPI pantoprazole will have the same prospective, randomized, cross-over design as the omeprazole sequence. A CLOP regimen in the absence of pantoprazole will be collected before entering randomization phase with adequate wash-out period.

Blood sampling for platelet function assessments were performed at all three phases of the study at the following time points: a) baseline, b) 24 hours after LD (before intake of study medication), and c) 7 days (24 hours after the last MD).

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Official Title: Effects of PPI Therapy on Clopidogrel-Induced Antiplatelet Effects: A Randomized Study
• Study Start Date: Mar 1, 2009
• Actual Primary Completion Date: Aug 1, 2010
• Actual Study Completion Date: Aug 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Omeprazole prospective, open-label, two-sequence, three-period, randomized crossover study	Drug: omeprazole and pantoprazole; The clopidogrel dose will be a 600mg loading dose followed by a 75mg daily maintenance dose, starting the next day for 7 days. Omeprazole will be used at a daily dose of 40mg and pantoprazole at 80mg.
Active Comparator: Pantoprazole prospective, open-label, two-sequence, three-period, randomized crossover study	Drug: omeprazole and pantoprazole; The clopidogrel dose will be a 600mg loading dose followed by a 75mg daily maintenance dose, starting the next day for 7 days. Omeprazole will be used at a daily dose of 40mg and pantoprazole at 80mg.

Outcome Measures

Primary Outcome Measures

1. Platelet Function as Assessed by the P2Y12 Reactivity Index [1 week]

   P2Y12 reactivity index which will be assessed by flow cytometry determination of vasodilator-stimulated phosphoprotein (VASP).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy volunteers aged between 18 and 75 years

Exclusion Criteria:

1. Known allergies to clopidogrel or omeprazole.

2. Blood dyscrasia or bleeding diathesis.

3. Recent antiplatelet treatment (< 30 days) with a glycoprotein IIb/IIIa antagonist, thienopyridine (ticlopidine, clopidogrel), cilostazol or dipyridamole.

4. Treatment with other medications that may interfere with the CYP system (ketoconazole, itraconazole, diltiazem, erythromycin, clarithromycin, fluvoxamine, fluoxetine, nefazodone, or sertraline).

5. Platelet count <100x106/microL.

6. Diabetes mellitus

7. History of coronary artery disease, gastrointestinal bleed, gastroesophageal reflux disease (GERD), cerebrovascular event or any active malignancy.

8. Active bleeding or hemodynamic instability.

9. Serum creatinine >2mg/dL.

10. Baseline ALT >2.5 times the upper limit of normal.

11. Pregnant females.

12. Patients taking omeprazole or any H2 antagonist or proton pump inhibitors

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Florida	Jacksonville	Florida	United States	32209

Sponsors and Collaborators

• University of Florida
• Bristol-Myers Squibb
• Sanofi

Investigators

• Principal Investigator: Dominick J Angiolillo, MD, PhD, University of Florida

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT01170533
• Other Study ID Numbers: UFJ 2009-2
• First Posted: Jul 27, 2010
• Last Update Posted: Mar 6, 2012
• Last Verified: Mar 1, 2012

• Keywords provided by University of Florida: proton pump inhibitor; clopidogrel; platelet function
• Additional relevant MeSH terms: Omeprazole; Pantoprazole

Study Results

Participant Flow

Pre-assignment Detail	The proposed study will have a prospective, randomized, cross-over design.

Arm/Group Title	Omeprazole	Pantoprazole
Arm/Group Description	This was a prospective, open-label, two-sequence, three-period, randomized crossover study conducted in non-medicated healthy male subjects between the ages of 18 and 65 years. Subjects were randomized in a 1:1 fashion to take a PPI (omeprazole) concomitantly (CONC) or staggered (STAG) by 8-12 hours for one-week on a background of clopidogrel therapy. In particular, in the CONC regimen both drugs were taken in the morning, while in the STAG regimen clopidogrel was taken in the morning and the PPI (omeprazole)in the evening. After a 2-4 week washout period, subjects crossed-over treatment regimen. After completing these two treatment phases, subjects underwent another washout period of 2-4 weeks and were treated for 1 week with clopidogrel alone, without receiving PPI therapy (CLOP regimen).	This was a prospective, open-label, two-sequence, three-period, randomized crossover study conducted in non-medicated healthy male subjects between the ages of 18 and 65 years. Subjects were randomized in a 1:1 fashion to take a PPI (pantoprazole) concomitantly (CONC) or staggered (STAG) by 8-12 hours for one-week on a background of clopidogrel therapy. In particular, in the CONC regimen both drugs were taken in the morning, while in the STAG regimen clopidogrel was taken in the morning and the PPI in the evening. After a 2-4 week washout period, subjects crossed-over treatment regimen. After completing these two treatment phases, subjects underwent another washout period of 2-4 weeks and were treated for 1 week with clopidogrel alone, without receiving PPI (pantoprazole) therapy (CLOP regimen).
Period Title: Omeprazole Cross-over
STARTED	20	0
COMPLETED	20	0
NOT COMPLETED	0	0
Period Title: Omeprazole Cross-over
STARTED	0	20
COMPLETED	0	20
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	This was a prospective, open-label, two-sequence, three-period, randomized crossover study conducted in non-medicated healthy male subjects between the ages of 18 and 65 years. Subjects were randomized in a 1:1 fashion to take a PPI concomitantly (CONC) or staggered (STAG) by 8-12 hours for one-week on a background of clopidogrel therapy. In particular, in the CONC regimen both drugs were taken in the morning, while in the STAG regimen clopidogrel was taken in the morning and the PPI in the evening. After a 2-4 week washout period, subjects crossed-over treatment regimen. After completing these two treatment phases, subjects underwent another washout period of 2-4 weeks and were treated for 1 week with clopidogrel alone, without receiving PPI therapy (CLOP regimen). The PPI could be omeprazole (first phase) or pantoprazole (second phase).
Overall Participants	25
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	25 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Omeprazole cross-over n=20	34 (6)
Pantoprazole cross-over n=20	33 (5)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	25 100%
Region of Enrollment (participants) [Number]
United States	25 100%

Outcome Measures

1. Primary Outcome

Title	Platelet Function as Assessed by the P2Y12 Reactivity Index
Description	P2Y12 reactivity index which will be assessed by flow cytometry determination of vasodilator-stimulated phosphoprotein (VASP).
Time Frame	1 week

Outcome Measure Data

Analysis Population Description

A sample size of 18 patients was required to be able to detect a 10% absolute difference in PRI between both regimens with 80% power and 2-sided significance level of 0.05, assuming a 15% standard deviation for the difference between regimens.

Arm/Group Title	Omeprazole Concomitant	Omeprazole Staggered	Pantoprazole Concomitant	Pantoprazole Staggered	Clopidogrel Only (Omeprazole Phase)	Clopidogrel Only (Pantoprazole Phase)
Arm/Group Description	Participants took omeprazole with clopidogrel concomitantly	Participants took omeprazole with clopidogrel staggered	Participants took pantoprazole with clopidogrel concomitantly	Participants took pantoprazole with clopidogrel staggered	Participants took clopidogrel only	Participants took clopidogrel only
Measure Participants	20	20	20	20	20	20
Least Squares Mean (Standard Error) [Percentage of platelet reactivity index]	56.1 (3.5)	61.6 (3.4)	56 (3.9)	61 (3.9)	48.8 (3.4)	61.0 (3.9)

Adverse Events

Arm/Group Title	Omeprazole		Pantoprazole
Arm/Group Description	This was a prospective, open-label, two-sequence, three-period, randomized crossover study conducted in non-medicated healthy male subjects between the ages of 18 and 65 years. Subjects were randomized in a 1:1 fashion to take a PPI (omeprazole) concomitantly (CONC) or staggered (STAG) by 8-12 hours for one-week on a background of clopidogrel therapy. In particular, in the CONC regimen both drugs were taken in the morning, while in the STAG regimen clopidogrel was taken in the morning and the PPI (omeprazole)in the evening. After a 2-4 week washout period, subjects crossed-over treatment regimen. After completing these two treatment phases, subjects underwent another washout period of 2-4 weeks and were treated for 1 week with clopidogrel alone, without receiving PPI therapy (CLOP regimen).		This was a prospective, open-label, two-sequence, three-period, randomized crossover study conducted in non-medicated healthy male subjects between the ages of 18 and 65 years. Subjects were randomized in a 1:1 fashion to take a PPI (pantoprazole) concomitantly (CONC) or staggered (STAG) by 8-12 hours for one-week on a background of clopidogrel therapy. In particular, in the CONC regimen both drugs were taken in the morning, while in the STAG regimen clopidogrel was taken in the morning and the PPI in the evening. After a 2-4 week washout period, subjects crossed-over treatment regimen. After completing these two treatment phases, subjects underwent another washout period of 2-4 weeks and were treated for 1 week with clopidogrel alone, without receiving PPI (pantoprazole) therapy (CLOP regimen).
All Cause Mortality
	Omeprazole		Pantoprazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Omeprazole		Pantoprazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Omeprazole		Pantoprazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.