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

• Sponsor: Imperial College London (Other)
• Overall Status: Completed
• CT.gov ID: NCT04765644
• Collaborator: (none)
• Enrollment: 44
• Location: 1
• Arms: 2
• Actual Duration (Months): 7.5
• Patients Per Site Per Month: 5.9

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Celecoxib; Other: Placebo; Other: L-arginine + placebo; Other: L-arginine + celecoxib	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Healthy male volunteers will be blinded and randomized to 7 days' treatment with celecoxib (200mg bd) or placebo.Healthy male volunteers will be blinded and randomized to 7 days' treatment with celecoxib (200mg bd) or placebo.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Arginine Supplementation to Improve Cardiovascular and Endothelial Function After NSAID Treatment (ASCENT)
• Actual Study Start Date: Jun 10, 2021
• Actual Primary Completion Date: Jan 24, 2022
• Actual Study Completion Date: Jan 24, 2022

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Endothelial function [7 days]

   Measured using EndoPAT

Secondary Outcome Measures

1. Sitting blood pressure [7 days]

   Participants will record their blood pressure daily using a home monitoring device.

2. Cardiovascular Biomarkers [7 days]

   Measured using mass spectrometry

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 40 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Imperial College Clinical Research Facility	London		United Kingdom	w12 0HS

Sponsors and Collaborators

• Imperial College London

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

• Ahmetaj-Shala B, Kirkby NS, Knowles R, Al'Yamani M, Mazi S, Wang Z, Tucker AT, Mackenzie L, Armstrong PC, Nüsing 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.
• 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-κB 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.
• 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.
• 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.
• 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. Review.

• Responsible Party: Imperial College London
• ClinicalTrials.gov Identifier: NCT04765644
• Other Study ID Numbers: 18IC4757
• First Posted: Feb 21, 2021
• Last Update Posted: Feb 2, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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
• Keywords provided by Imperial College London: NSAID; Endothelial function; COX-2; Celecoxib; biomarker
• Additional relevant MeSH terms: Celecoxib

Study Results

No Results Posted as of Feb 2, 2022