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Variability in Response to Non-steroidal Anti-inflammatory Drugs

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ClinicalTrials.gov Identifier: NCT02502006
Recruitment Status : Recruiting
First Posted : July 17, 2015
Last Update Posted : August 5, 2019
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
University of Pennsylvania

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.

Condition or disease Intervention/treatment Phase
Healthy Drug: Celecoxib Drug: Naproxen Drug: Placebo Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 288 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Other
Official Title: A Double-blind, Placebo-controlled Investigation of Inter-individual Variability in Pharmacologic Response to Non-steroidal Anti-inflammatory Drugs
Study Start Date : November 2015
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : September 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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.
Drug: Celecoxib
Other Name: Celebrex

Drug: Naproxen
Other Name: Naprosyn

Drug: Placebo
Experimental: 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.
Drug: Celecoxib
Other Name: Celebrex

Drug: Naproxen
Other Name: Naprosyn

Drug: Placebo



Primary Outcome Measures :
  1. COX-1 and COX-2 activity [ Time Frame: up to 12-hours ]
    COX-1 and COX-2 activity will be measured ex vivo using a whole blood assay and in vivo by quantifying concentrations of prostaglandin metabolites in urine.


Secondary Outcome Measures :
  1. Celecoxib and naproxen plasma concentrations [ Time Frame: up to 12-hours ]
    Assessed by measuring the amount of celecoxib and naproxen present in plasma

  2. Ambulatory blood pressure [ Time Frame: 24 hours ]
    Blood pressure will be measured over 24 hours using an automatic ambulatory blood pressure monitor.

  3. Renal function [ Time Frame: 12 hours during each treatment phase ]
    Assessed by glomerular filtration rate, sodium and potassium excretion, aldosterone, and creatinine in 12-hour urine, as well as renin, creatinine, urea nitrogen in serum.

  4. COX pathway gene expression [ Time Frame: 1 day ]
    mRNA levels will be measured in lymphoblastoid cell lines derived from peripheral blood mononuclear cells

  5. Composition of the gut microbiome [ Time Frame: 1 day ]
    Assessed by evaluating the microbes present in a stool sample

  6. Whole blood transcriptomics [ Time Frame: Baseline and 4 hours after taking study medication during each treatment phase ]
    Assessed by evaluating gene expression in a blood sample

  7. Plasma proteomics [ Time Frame: Baseline and 4 hours after taking study medication during each treatment phase ]
    Assessed by measuring levels of proteins in plasma

  8. Urinary and plasma metabolomics [ Time Frame: Baseline and 4 hours after taking study medication during each treatment phase ]
    Assessed by measuring levels of metabolites in urine and plasma

  9. DNA sequencing [ Time Frame: 1 day ]
    Assessment of genetic variation

  10. Nutritional assessment composite [ Time Frame: up to 3 days ]
    3-day food records, 24-hour dietary recalls, and concentrations/ratios of major n-3/n-6 PUFAs in red blood cell membranes



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02502006


Contacts
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Contact: Katherine N Theken, PharmD, PhD 215-573-9592 ktheken@pennmedicine.upenn.edu
Contact: LaVenia Banas, RN 215-662-4652 banas@pennmedicine.upenn.edu

Locations
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United States, Pennsylvania
Institute for Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania School of Medicine Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Katherine N Theken, PharmD, PhD    215-573-9592    ktheken@pennmedicine.upenn.edu   
Contact: LaVenia Banas, RN    215-662-4652    banas@pennmedicine.upenn.edu   
Sponsors and Collaborators
University of Pennsylvania
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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Principal Investigator: Garret A FitzGerald, MD University of Pennsylvania, Institute for Translational Medicine and Therapeutics
Principal Investigator: Tilo Grosser, MD University of Pennsylvania, Institute for Translational Medicine and Therapeutics
Principal Investigator: Katherine N Theken, PharmD, PhD University of Pennsylvania, Institute for Translational Medicine and Therapeutics
Principal Investigator: Carsten Skarke, MD University of Pennsylvania, Institute for Translational Medicine and Therapeutics

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Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT02502006    
Other Study ID Numbers: 820715
5U54HL117798 ( U.S. NIH Grant/Contract )
First Posted: July 17, 2015    Key Record Dates
Last Update Posted: August 5, 2019
Last Verified: August 2019
Keywords provided by University of Pennsylvania:
Non-steroidal Anti-inflammatory Drugs
Healthy volunteers
Celecoxib
Naproxen
Prostaglandin
Cyclooxygenase
Additional relevant MeSH terms:
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Celecoxib
Naproxen
Anti-Inflammatory Agents, Non-Steroidal
Anti-Inflammatory Agents
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Antirheumatic Agents
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Gout Suppressants