Arginine Supplementation to Improve Cardiovascular and Endothelial Function After NSAID Treatment (ASCENT)

Arginine Supplementation to Improve Cardiovascular and Endothelial Function After NSAID Treatment (ASCENT)

A single centre, placebo controlled, blinded (participant, investigator, outcome assessor) trial to evaluate the effects of COX-2 inhibition with celecoxib on endothelial function in healthy male volunteers.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Celecoxib; Other: L-arginine + celecoxib; Other: Placebo; Other: L-arginine + placebo

Detailed Description

Primary Objective: To perform a systemic analysis of how COX-2 inhibition by celecoxib affects vascular function and 'omic biomarkers including those associated with the COX-2/prostacyclin/ADMA axis in healthy male volunteers

Secondary Objective: To investigate how this is altered by L-arginine supplementation

Methods: A single centre, double blind, placebo controlled trial will be carried out in healthy male volunteers between 18 and 40 years of age. In phase 1, participants will be blinded and randomised to receive either Celecoxib 200mgBD for 7 days or placebo. The primary endpoint is endothelial function measured by EndoPAT. In Phase 2, the same participants will receive either Celecoxib 200mgBD for 7 days + 10g L-arginine supplementation or placebo + 10g L-arginine supplementation to see if L-arginine can reverse any endothelial dysfunction caused by Celecoxib. Secondary outcomes will include measurement of 'omic biomarkers.

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 4

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, w12 0HS
    • Imperial College Clinical Research Facility

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• No abnormal findings on medical history, screening physical examination, hematology, biochemistry, urinalysis (including specific gravity), and vital signs (sitting blood pressure, sitting pulse rate, sitting respiratory rate and body temperature) within 2 weeks of commencement of the study.
• Normal fasting lipid profile
• Non-smoking
• Clear venous access in upper limbs
• BMI: 18-30
• No history or signs of drug abuse
• No other medication 4 weeks before or during the study
• Informed written consent

Exclusion Criteria:

• Any history of allergy to NSAIDS or arginine
• Significant medical conditions
• Pulse rate <50 bpm
• Sitting systolic blood pressure <80 or >160 mmHg
• Sitting diastolic pressure <60 or >100 mmHg
• Baseline endothelial dysfunction (as defined by EndoPAT; LnRHI <0.51)
• Participation in other clinical study 8 weeks before or during the study
• Donation of blood 8 weeks before or during the study
• Those on medication that cannot be discontinued

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Celecoxib; Phase 1: Twenty volunteers will receive celecoxib 200 mg, 2 times/day (total 400 mg/day) for 7 days. At this point, the study team will perform an interim analysis of the data. If our primary endpoint is not achieved we may revise our endpoints and/or if additional power is required, we may recruit up to an additional n=20 volunteers per group. This analysis may also serve as a stop-go checkpoint for continuation of the second phase of the study. If we do not see any effects of celecoxib on endothelial or cardiovascular function, we will not proceed to phase 2. If we do see a negative effect, we will proceed to phase 2. In phase 2 participants will be re-invited to the study site following a 4-8 week washout period. Participants will then receive either treatment with placebo + 10g L-arginine supplementation (20 participants) or celecoxib + 10g arginine supplementation (20 participants) for a total of 7 days	Drug: Celecoxib; Two 200 mg capsules per day (400 mg/day) for 7 days; Other Names: Celebrex; Other: L-arginine + celecoxib; L-arginine = Five capsules of 2 mg per day (10 mg/day) Celecoxib = Two 200 mg capsules per day (400 mg/day) for 7 days
Placebo Comparator: Placebo; Phase 1: Twenty volunteers will receive a placebo capsule, 2 times/day (total 400 mg/day) for 7 days. At this point, the study team will perform an interim analysis of the data. If our primary endpoint is not achieved we may revise our endpoints and/or if additional power is required, we may recruit up to an additional n=20 volunteers per group. This analysis may also serve as a stop-go checkpoint for continuation of the second phase of the study. If we do not see any effects of celecoxib on endothelial or cardiovascular function, we will not proceed to phase 2. If we do see a negative effect, we will proceed to phase 2. In phase 2 participants will be re-invited to the study site following a 4-8 week washout period. Participants will then receive either treatment with placebo + 10g L-arginine supplementation (20 participants) or celecoxib + 10g arginine supplementation (20 participants) for a total of 7 days	Other: Placebo; 2 capsules/day for 7 days; Other: L-arginine + placebo; L-arginine = Five capsules of 2 mg per day (10 mg/day) for 7 days Placebo = 2 capsules/day for 7 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Log Reactive Hyperaemic Index	Measured using the EndoPAT 2000 device (which is an FDA approved medical device). Data are issued by the equipment as: LnRHI (Log Reactive hyperaemic index), a reduction from the individual participant baseline value indicates endothelial dysfunction	Baseline and 7 days
Augmentation Index	Measured using the EndoPAT 2000 device (which is an FDA approved medical device) at baseline and at 7 days. Data are issued by the equipment. Augmentation index (which is a surrogate for vascular stiffness). An increase indicates an increase in vascular stiffness.	Baseline and 7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood Pressure	Participants will record their blood pressure daily using a home monitoring device at rest on day 1 (baseline) and day 7. Reported as change in systolic blood pressure (delta) from baseline.	Baseline and 7 Days
Increase/Decrease of Cardiovascular Biomarkers From Baseline	Measured using mass spectrometry on serum samples collected at baseline and at 7 days.	Baseline and 7 days

Collaborators and Investigators

• Sponsor: Imperial College London
• Investigators: Study Director: Jane Mitchell, Professor, Imperial College London

Publications and helpful links

General Publications

• Kirkby NS, Zaiss AK, Urquhart P, Jiao J, Austin PJ, Al-Yamani M, Lundberg MH, MacKenzie LS, Warner TD, Nicolaou A, Herschman HR, Mitchell JA. LC-MS/MS confirms that COX-1 drives vascular prostacyclin whilst gene expression pattern reveals non-vascular sites of COX-2 expression. PLoS One. 2013 Jul 9;8(7):e69524. doi: 10.1371/journal.pone.0069524. Print 2013.
• Kirkby NS, Chan MV, Zaiss AK, Garcia-Vaz E, Jiao J, Berglund LM, Verdu EF, Ahmetaj-Shala B, Wallace JL, Herschman HR, Gomez MF, Mitchell JA. Systematic study of constitutive cyclooxygenase-2 expression: Role of NF-kappaB and NFAT transcriptional pathways. Proc Natl Acad Sci U S A. 2016 Jan 12;113(2):434-9. doi: 10.1073/pnas.1517642113. Epub 2015 Dec 28.
• Warner TD, Mitchell JA. COX-2 selectivity alone does not define the cardiovascular risks associated with non-steroidal anti-inflammatory drugs. Lancet. 2008 Jan 19;371(9608):270-3. doi: 10.1016/S0140-6736(08)60137-3. No abstract available.
• Kirkby NS, Lundberg MH, Chan MV, Vojnovic I, Solomon AB, Emerson M, Mitchell JA, Warner TD. Blockade of the purinergic P2Y12 receptor greatly increases the platelet inhibitory actions of nitric oxide. Proc Natl Acad Sci U S A. 2013 Sep 24;110(39):15782-7. doi: 10.1073/pnas.1218880110. Epub 2013 Sep 3.
• Ahmetaj-Shala B, Kirkby NS, Knowles R, Al'Yamani M, Mazi S, Wang Z, Tucker AT, Mackenzie L, Armstrong PC, Nusing RM, Tomlinson JA, Warner TD, Leiper J, Mitchell JA. Evidence that links loss of cyclooxygenase-2 with increased asymmetric dimethylarginine: novel explanation of cardiovascular side effects associated with anti-inflammatory drugs. Circulation. 2015 Feb 17;131(7):633-42. doi: 10.1161/CIRCULATIONAHA.114.011591. Epub 2014 Dec 9.

Study record dates

Study Major Dates

• Study Start (Actual): June 10, 2021
• Primary Completion (Actual): January 24, 2022
• Study Completion (Actual): January 24, 2022

Study Registration Dates

• First Submitted: February 17, 2021
• First Submitted That Met QC Criteria: February 19, 2021
• First Posted (Actual): February 21, 2021

Study Record Updates

• Last Update Posted (Actual): April 17, 2026
• Last Update Submitted That Met QC Criteria: March 27, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Celecoxib; biomarker; Endothelial function; NSAID; COX-2
• Additional Relevant MeSH Terms: Amino Acids, Peptides, and Proteins; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Amides; Amino Acids; Benzene Derivatives; Amino Acids, Basic; Amino Acids, Diamino; Amino Acids, Essential; Benzenesulfonamides; Sulfonamides; Sulfones; Pyrazoles; Celecoxib; Arginine
• Other Study ID Numbers: 18IC4757

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No