Lipidomics Screening of Celecoxib in ex Vivo Human Whole Blood Assay - Part B

• ClinicalTrials.gov Identifier: NCT02413203
• Recruitment Status: Completed
• First Posted: April 9, 2015
• Results First Posted: May 30, 2017
• Last Update Posted: May 30, 2017
• Sponsor: University of Pennsylvania
• Collaborator: Eli Lilly and Company
• Information provided by (Responsible Party): University of Pennsylvania

Study Description

Brief Summary:

Cardiovascular complications of NSAIDs, selective for inhibition of COX-2, stimulated interest in microsomal prostaglandin E synthase-1 (mPGES-1) as an alternative drug target. Global deletion of mPGES-1 in mice suppresses prostaglandin (PG) E2 and augments PGI2 by PGH2 substrate rediversion. Unlike COX-2 inhibition or gene deletion, mPGES-1 deletion does not cause a predisposition to thrombogenesis and hypertension. However, cell-specific deletion of mPGES-1 reveals that the predominant substrate rediversion product among the prostaglandins varies by cell type, complicating drug development. The research team has developed an ultra performance liquid chromatography/ tandem mass spectrometry (UPLC-MS/MS) technique that allows the quantification of a wide range of lipids beyond the prostaglandin pathway (leukotrienes, anandamide and the 2-arachidonylglycerol cascades).

This study is designed to examine different pathway interventions from the arachidonic acid cascade by anti-inflammatory compounds (with a focus on mPGES-1 inhibition) in whole human blood in vitro (Part A) and ex vivo (Part B). In Part B, healthy volunteers will be asked to take a single, therapeutic dose of celecoxib and blood and urine samples will be collected before and after drug administration. Collected blood will be stimulated ex vivo, and lipids and their metabolites will be measured in blood and urine, respectively. The investigators expect that lipid profile from ex vivo hWBA done on celecoxib-treated subjects will recapitulate findings from the in vitro hWBA received with celecoxib-treated human blood (Part A).

Condition or disease	Intervention/treatment	Phase
Healthy	Drug: Celecoxib; Drug: Placebo	Not Applicable

  Show Detailed Description

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Screening
• Official Title: A Randomized, Double-blinded, Placebo-controlled Study Investigating the Pharmacological Response to Celecoxib Using ex Vivo Human Whole-blood Assay (hWBA) and Broad-spectrum Lipidomics Analysis
• Study Start Date: March 2015
• Actual Primary Completion Date: November 2015
• Actual Study Completion Date: November 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: Celecoxib; Oral administration of a single pill of celecoxib (200 mg). Celecoxib pills will be over-encapsulated to match the placebo.	Drug: Celecoxib; Blood and urine collections before and 3 hours after celecoxib administration.; Other Name: Celebrex
Placebo Comparator: Placebo; Oral administration of a single placebo pill.	Drug: Placebo; Blood and urine collections before and 3 hours after placebo administration.

Outcome Measures

Primary Outcome Measures :

1. Quantification of Plasma Lipids in the Whole Blood: Prostaglandin E2 (PGE2) [ Time Frame: A single visit of around 4 hours ]
   PGE2 in blood taken from celecoxib-treated subjects and stimulated ex vivo with LPS was compared to similarly treated blood from placebo group. Plasma PGE2 was normalized to sample volume (ng/ml) and expressed as a percentage of subject's pre-dose control using the formula: percentage of pre-dose control = (Cpost-dose/Cpre-dose) × 100%, where C represents PGE2 concentration in ng/ml.
2. Quantification of Plasma Lipids in the Whole Blood: Prostaglandin F2a (PGF2a) [ Time Frame: A single visit of around 4 hours ]
   PGF2a in blood taken from celecoxib-treated subjects and stimulated ex vivo with LPS was compared to similarly treated blood from placebo group. Plasma PGF2a was normalized to sample volume (ng/ml) and expressed as a percentage of subject's pre-dose control using the formula: percentage of pre-dose control = (Cpost-dose/Cpre-dose) × 100%, where C represents PGF2a concentration in ng/ml.
3. Quantification of Plasma Lipids in the Whole Blood: Thromboxane B2 (TxB2) [ Time Frame: A single visit of around 4 hours ]
   TxB2 in blood taken from celecoxib-treated subjects and stimulated ex vivo with LPS was compared to similarly treated blood from placebo group. Plasma TxB2 was normalized to sample volume (ng/ml) and expressed as a percentage of subject's pre-dose control using the formula: percentage of pre-dose control = (Cpost-dose/Cpre-dose) × 100%, where C represents TxB2 concentration in ng/ml.
4. Quantification of Plasma Lipids in the Whole Blood: 15-Hydroxyeicosatetraenoic Acid (15-HETE) [ Time Frame: A single visit of around 4 hours ]
   15-HETE in blood taken from celecoxib-treated subjects and stimulated ex vivo with LPS was compared to similarly treated blood from placebo group. Plasma 15-HETE was normalized to sample volume (ng/ml) and expressed as a percentage of subject's pre-dose control using the formula: percentage of pre-dose control = (Cpost-dose/Cpre-dose) × 100%, where C represents 15-HETE concentration in ng/ml.

Secondary Outcome Measures :

1. Urinary Lipid Metabolites: PGE2 Metabolite (PGE-M) [ Time Frame: A single visit of around 4 hours ]
   Effect of celecoxib on systemic PGE2 was assessed by comparing urine PGE-M in celecoxib vs placebo-treated groups. Urine data are reported as a percentage of the volunteer's own pre-dose control using the formula: percentage of pre-dose control = (Cpost-dose/Cpre-dose) × 100%, where C represents metabolite concentration in ng/mg creatinine.
2. Celecoxib Plasma Concentration [ Time Frame: A single visit of around 4 hours ]
   Celecoxib plasma concentration will be measured in drug-treated and placebo groups by UPLC-MS/MS, and will be expressed as amount of the drug per volume of plasma (ng/ml). At Tmax of 3 hours after a single oral dose of celecoxib of 200 mg, drug plasma concentration should correspond to the maximum plasma concentration or Cmax.
3. Urinary Lipid Metabolites: PGI2 Metabolite (PGI-M) [ Time Frame: A single visit of around 4 hours ]
   Effect of celecoxib on systemic PGI2 was assessed by comparing urine PGI-M in celecoxib vs placebo-treated groups. Urine data are reported as a percentage of the volunteer's own pre-dose control using the formula: percentage of pre-dose control = (Cpost-dose/Cpre-dose) × 100%, where C represents metabolite concentration in ng/mg creatinine.
4. Urinary Lipid Metabolites: TxB2 Metabolite (Tx-M) [ Time Frame: A single visit of around 4 hours ]
   Effect of celecoxib on systemic TxB2 was assessed by comparing urine Tx-M in celecoxib vs placebo-treated groups. Urine data are reported as a percentage of the volunteer's own pre-dose control using the formula: percentage of pre-dose control = (Cpost-dose/Cpre-dose) × 100%, where C represents metabolite concentration in ng/mg creatinine.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 50 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Age between 18 - 50
• Volunteers must be in good health as based on medical history
• All volunteers must be non-smoking and non-pregnant

Exclusion Criteria:

• Subjects with any medical condition, which 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 (cancer or history of significant cardiovascular disease (including stroke or TIA), renal, hepatic, gastrointestinal, respiratory, endocrine, metabolic, hematopoietic, or neurological disorders).
• Subjects who have received an experimental drug within 30 days prior to the study
• Subjects who have taken medications at least two weeks prior to the study. Subjects using hormonal birth control, however, will not be an exclusionary criterion.
• Subjects who have taken aspirin or aspirin containing products for at least two weeks prior to the study.
• Subjects who are sensitive or allergic to celecoxib (Celebrex) or its components
• Subjects who have taken any formulation of celecoxib including but not limited to Celebrex, Celebra, Onsenal for at least two weeks prior to the start of the study and throughout the study
• Subjects who have taken acetaminophen, NSAIDs, COX-2 inhibitors (OTC or prescription) for at least two weeks prior to the study.
• Subjects who are consuming any type of tobacco product(s).
• Subjects who consume high doses of antioxidant vitamins daily (vitamin C> 1000mg, Vitamin E> 400IU, Beta Carotene> 1000IU, Vitamin A> 5000IU, Selenium> 200mcg, Folic Acid> 1mg) for the two weeks prior to the start of the study and throughout the study.
• Subjects who consume alcohol, caffeine or high fat food 24 hours prior to the study.

Contacts and Locations

Locations

United States, Pennsylvania

The Clinical Translational Research Center (CTRC) at the Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

Sponsors and Collaborators

University of Pennsylvania

Eli Lilly and Company

Investigators

• Principal Investigator: Garret FitzGerald, MD; University of Pennsylvania, Institute for Translationals Medicine and Therapeutics

More Information

• Responsible Party: University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT02413203 History of Changes
• Other Study ID Numbers: 818658-Part B
• First Posted: April 9, 2015
• Results First Posted: May 30, 2017
• Last Update Posted: May 30, 2017
• Last Verified: April 2017

Keywords provided by University of Pennsylvania:

lipidomics; ex vivo human whole blood assay; celecoxib; selective COX-2 inhibitor

Additional relevant MeSH terms:

Celecoxib; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action