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Giant Trial of NSAIDs to Generate Samples For Biomarker Studies; Perhaps Cox-2 PGx

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A huge clinical trial of three pain relievers may venture into investigating pharmacogenomic markers signaling a risk of adverse events related to a cox-2 inhibitor, and will definitely leave a large reservoir of biological samples that can be plumbed for years to uncover gene variants of response to these extremely popular class of drugs.

"In my view, everything's genetically related, but there's not a lot of evidence," Steven Nissen, medical director of the Cleveland Clinical Cardiovascular Coordinating Center told Pharmacogenomics Reporter last week. "We are in discussions now about whether to collect — at least on some patients in the study — genetic material, but that is complicated from a consent point of view, and we will discuss that very soon at the executive committee of the trial," he said.

The Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen or Naproxen (PRECISION) trial will begin in early 2006 and will examine 20,000 patients to determine the safest non-steroidal anti-inflammatory agent for those with heart disease or high risk for heart disease. Researchers at the Cleveland Clinic in Ohio will follow patients on ibuprofin, naproxen, and Pfizer's celecoxib (Celebrex) for at least two years to discover related incidences of myocardial infarction, cardiovascular death, and stroke. "This is the first dedicated cardiovascular outcome trial to be done with NSAIDs and cox-2 inhibitors," said Nissen.

The PRECISION trial will result in a bank of stored blood from all of its participants. "That's an extremely powerful approach, because when we get the outcome, other investigators can go back, and with small aliquots of blood can ask questions about biomarkers, about metabolism, and other questions that might help us explain the results," Nissen said. The trial's executive committee has control over the samples, and a separate committee has the responsibility for overseeing substudies.


"What we know is that [these drugs] work via the cycloxygenase system, and we know that there are polymorphisms of that system that do affect people."

Even if the trial's executive committee does not decide to investigate the pharmacogenomics of cox-2 inhibitors' adverse cardiovascular events, the drugs' molecular pathway holds several promising biomarker candidates. "What we know is that [these drugs] work via the cycloxygenase system, and we know that there are polymorphisms of that system that do affect people," Nissen said. "You've got two gene products, you've got two enzymes — thromboxane and prostacyclin — and the balance between those two is what's being affected by these drugs, and so it's not at all surprising to expect that there may be individual variations in the ratio of cox-1 to cox-2 activity, and the ratio of prostacycline to thromboxane production, and that would have a profound effect on how people respond to these drugs," he said.

High dosages are also a factor in cox-2 inhibitors' adverse events, and the enzyme CYP450 3A4 may cause patients to exhibit different serum levels of the drugs when given the same dose. "That's not proven, but what we're trying to do here is answer the clinical question," said Nissen. "But in the process of answering the clinical question, the question of 'why' will come up, and so this is a chance to do some very good probing of some of those relationships between metabolism and drug toxicity," he said.

Nissen also served on the US Food and Drug Administration panel that reviewed cardiovascular adverse events related to cox-2 inhibitors in February. That panel decided that cox-2 inhibitors Celebrex and Bextra should remain on the market, although data shows that higher doses of Celebrex are associated with increased cardiovascular risk. Merck voluntarily withdrew its cox-2 inhibitor Vioxx from the market last September, due to the drug's association with patient deaths related to cardiovascular conditions. "We put warnings on all drugs in the class because we don't know what's safe and what's not," Nissen said.

To maintain independence and "restore public confidence" in NSAIDs, the Pfizer-sponsored trial will be conducted at the Cleveland Clinic's Cardiovascular Coordinating Center and controlled by a nine-member executive committee that cannot accept any sort of reimbursement from industry, including honoraria and consulting fees, said Nissen.

After publishing the PRECISION trial's findings, along with those of substudies, the trial database will be put into the public domain. "No one's ever done that before — it's really quite unique," said Nissen.

— Chris Womack ([email protected])

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