Variability in Response to Non-steroidal Anti-inflammatory Drugs
Information source: University of Pennsylvania
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Healthy
Intervention: Celecoxib (Drug); Naproxen (Drug); Placebo (Drug)
Phase: Phase 1
Status: Not yet recruiting
Sponsored by: University of Pennsylvania Official(s) and/or principal investigator(s): Garret A FitzGerald, MD, Principal Investigator, Affiliation: University of Pennsylvania, Institute for Translational Medicine and Therapeutics Tilo Grosser, MD, Principal Investigator, Affiliation: University of Pennsylvania, Institute for Translational Medicine and Therapeutics Katherine N Theken, PharmD, PhD, Principal Investigator, Affiliation: University of Pennsylvania, Institute for Translational Medicine and Therapeutics
Overall contact: Katherine N Theken, PharmD, PhD, Phone: 215-898-0255, Email: ktheken@mail.med.upenn.edu
Summary
This research study will evaluate inter-individual variability in the response to the
non-steroidal anti-inflammatory drugs (NSAIDs), celecoxib and naproxen, among healthy
adults. It will also investigate what factors, like age, sex, or genetic background, cause
this variability.
Clinical Details
Official title: A Double-blind, Placebo-controlled Investigation of Inter-individual Variability in Pharmacologic Response to Non-steroidal Anti-inflammatory Drugs
Study design: Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator)
Primary outcome: COX-1 and COX-2 activity
Secondary outcome: Celecoxib and naproxen plasma concentrationsAmbulatory blood pressure Renal function COX pathway gene expression Composition of the gut microbiome Whole blood transcriptomics Plasma proteomics Urinary and plasma metabolomics DNA sequencing Nutritional assessment composite
Detailed description:
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used for the treatment of
inflammatory pain. Pain is a highly subjective experience, and selecting an analgesic
regimen that provides optimal pain relief for a specific patient can be challenging.
Moreover, patients often express a preference for a particular NSAID, raising the
possibility that the efficacy in relieving pain is variable among individuals. However this
has never been studied systematically. The clinical decision-making process has been further
complicated by the recognition that NSAIDs cause serious thrombotic adverse events in some
patients (1). Elucidating the factors that influence an individual patient's risk of
cardiovascular complications and the likelihood of analgesic efficacy will enable clinicians
to prescribe NSAIDs rationally in order to maximize their therapeutic benefit while
minimizing the risk of adverse cardiovascular events.
NSAIDs are a chemically diverse class of therapeutic agents that exert their analgesic and
anti-inflammatory effects via inhibition of cyclooxygenase (COX)-1 and/or COX-2, enzymes
that catalyze the first committed step in prostaglandin (PG) synthesis. PGs produce a
diverse array of biologic effects via activation of prostanoid receptors, and play important
roles in a variety of pathologic and homeostatic processes (2). COX-2 is readily induced in
response to pro-inflammatory stimuli and has been considered the primary source of
inflammatory PGs. In contrast, the production of PGs with homeostatic functions, such as
gastric epithelium cytoprotection, has been ascribed to COX-1, which is constitutively
expressed in most tissues (2). Consequently, COX-2-selective NSAIDs, including rofecoxib,
valdecoxib, and celecoxib, were developed in order to retain the anti-inflammatory and
analgesic effects of inhibition of COX-2-derived PG formation, while avoiding the
gastrointestinal toxicity of traditional NSAIDs (i. e. aspirin, ibuprofen, naproxen, etc)
that inhibit both isoforms. Although fewer gastrointestinal complications were observed in
clinical trials, treatment with COX-2-selective NSAIDs increased the risk of serious
cardiovascular adverse events, including myocardial infarction, stroke, and heart failure
(1,3).
The risk of thrombotic events associated with the use of NSAIDs, particularly those
selective for COX-2, is mediated via suppression of COX-2-derived prostacyclin formation in
endothelial and vascular smooth muscle cells (4,5). Prostacyclin possesses potent
anti-thrombotic and vasodilatory effects, and thus acts as a general inhibitor of platelet
activation in vivo (2). Traditional NSAIDs also inhibit COX-2 in the vasculature, but the
associated risk of thrombosis is mitigated to some extent by inhibition of formation of
thromboxane A2 (TxA2), a COX-1-derived PG released by activated platelets that promotes
platelet activation and aggregation (1,3). Thus, the risk of thrombosis for a particular
NSAID is dependent upon its relative selectivity for COX-2 over COX-1 (3,6). In addition to
their effects on vascular PG production, all NSAIDs inhibit renal PG formation, resulting in
sodium retention and hypertension, which may further augment cardiovascular risk (1,3,7).
Currently, it is recommended that NSAIDs be avoided or used only for a limited duration in
patients classified as high cardiovascular risk (8). These recommendations are supported by
studies demonstrating that even short-term NSAID use increased the incidence of
cardiovascular events in patients undergoing coronary artery bypass grafting (9,10) and
following a myocardial infarction (11,12). However, long-term treatment with COX-2-selective
NSAIDs also increased the incidence of cardiovascular events in patients considered to be at
low baseline risk (13,14), consistent with risk transformation due to atherogenesis and
indicating traditional cardiovascular risk factors alone are not sufficient to guide
therapeutic decisions. Thus, additional studies are necessary to define comprehensively the
factors that modify the cardiovascular risk of NSAID use and facilitate the progressive
personalization of NSAID therapy.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- Adult men and women greater than 18 years of age who are non-smokers and in good
health based on medical history, physical examination, vital signs, and laboratory
tests. Volunteers with adequately controlled hypertension and hyperlipidemia (total
cholesterol of ≤270 mg/dL) may participate in the study.
Exclusion Criteria:
- Female subjects who are pregnant or nursing a child.
- Subjects who have received an investigational drug or used an experimental medical
device within 30 days prior to screening, or who gave a blood donation of ≥ one pint
within 8 weeks prior to screening.
- Subjects with any coagulation, bleeding or blood disorders.
- Subjects who are sensitive or allergic to celecoxib (Celebrex) or naproxen (Naprosyn)
or their components.
- Subjects who are sensitive or allergic to aspirin or other NSAIDs.
- Subjects with documented history of any gastrointestinal disorders, including
bleeding ulcers.
- History of significant cardiovascular disease (including stroke or TIA), renal,
hepatic, respiratory (except infections which longer > 6 months prior to screening),
immune, endocrine, hematopoietic disorder or neurological disorders.
- History of cancer within the last 5 years (except for cutaneous basal cell or
squamous cell cancer resolved by excision, or carcinoma in situ of the cervix
adequately treated).
- Has taken any prescription medication other than hormone replacement therapy
(including males taking testosterone as a hormone replacement to treat a documented
low testosterone level), thyroid replacement hormones, anti-hyperlipidemic agents, or
anti-hypertensive medications. Individuals taking other/additional chronic stable
medications can be considered on a case-by-case basis for inclusion in the study if
agreed upon by judgment of the investigators.
- Has taken NSAIDs or anti-secretory agents (proton pump inhibitors or H2 receptor
antagonists) within 14 days prior to study drug administration
- Has ever taken the any anti-platelet or anti-coagulant agents
- Used dietary or herbal supplements containing salicylates, Vitamin E, fish oil, or
any other herbal supplements, within 14 days of study drug administration.
- Subjects with any abnormal laboratory value or physical finding that according to the
investigator may interfere with interpretation of the study results, be indicative of
an underlying disease state, or compromise the safety of a potential subject.
- Subjects who have had a history of drug or alcohol abuse within the last 6 months.
- Subjects who are unwilling to provide a blood sample for genetic analyses and
creation of a lymphoblastoid cell line.
Locations and Contacts
Katherine N Theken, PharmD, PhD, Phone: 215-898-0255, Email: ktheken@mail.med.upenn.edu Additional Information
Starting date: September 2015
Last updated: July 16, 2015
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