Variability in Response to Non-steroidal Anti-inflammatory Drugs

NCT ID: NCT02502006

Last Updated: 2023-12-13

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 16 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-11-30
• Study Completion Date: 2022-09-30

Brief 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.

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.

Conditions

Healthy

Keywords

Non-steroidal Anti-inflammatory Drugs; Healthy volunteers; Celecoxib; Naproxen; Prostaglandin; Cyclooxygenase

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: OTHER
• Blinding Strategy: DOUBLE

Study Groups

High Dose

During each treatment phase, subjects will receive celecoxib (200 mg by mouth twice daily), naproxen (500 mg by mouth twice daily), or placebo (twice daily) for 7 days. Subjects will be instructed to take the study medications twice a day (at approximately 8 AM and 8 PM) on an empty stomach with a full glass of water.

Group Type: EXPERIMENTAL

Celecoxib

Intervention Type: DRUG

Naproxen

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

Low dose

During each treatment phase, subjects will receive celecoxib (100 mg by mouth twice daily), naproxen (250 mg by mouth twice daily), or placebo (twice daily) for 7 days. Subjects will be instructed to take the study medications twice a day (at approximately 8 AM and 8 PM) on an empty stomach with a full glass of water.

Group Type: EXPERIMENTAL

Celecoxib

Intervention Type: DRUG

Naproxen

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

Interventions

Celecoxib

Intervention Type: DRUG

Naproxen

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

Other Intervention Names

Celebrex; Naprosyn

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

University of Pennsylvania

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Garret A FitzGerald, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania, Institute for Translational Medicine and Therapeutics

Tilo Grosser, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania, Institute for Translational Medicine and Therapeutics

Katherine N Theken, PharmD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania, Institute for Translational Medicine and Therapeutics

Carsten Skarke, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania, Institute for Translational Medicine and Therapeutics

Locations

Institute for Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania School of Medicine

Philadelphia, Pennsylvania, United States

Countries

United States

References

Theken KN, Ghosh S, Skarke C, Fries S, Lahens NF, Sarantopoulou D, Grant GR, FitzGerald GA, Grosser T. Degree of Cyclooxygenase-2 Inhibition Modulates Blood Pressure Response to Celecoxib and Naproxen. medRxiv [Preprint]. 2024 May 31:2024.05.30.24308244. doi: 10.1101/2024.05.30.24308244.

Reference Type: DERIVED

PMID: 38854091 (View on PubMed)

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Other Identifiers

5U54HL117798

Identifier Type: NIH

Identifier Source: secondary_id

View Link

820715

Identifier Type: -

Identifier Source: org_study_id