Arginine Supplementation to Improve Cardiovascular and Endothelial Function After NSAID Treatment

Healthy Clinical Trial

— ASCENT  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04765644
• Other study ID #: 18IC4757
• Status: Completed
• Phase: Phase 4
• Start date: June 10, 2021
• Est. completion date: January 24, 2022

Study information

• Verified date: February 2022
• Source: Imperial College London
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 44
• Est. completion date: January 24, 2022
• Est. primary completion date: January 24, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 40 Years

Eligibility

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

Related Conditions & MeSH terms

• Healthy

Intervention

Drug:
• Celecoxib
Two 200 mg capsules per day (400 mg/day) for 7 days

Other:
• Placebo
2 capsules/day for 7 days
• 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
• 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

Locations

Country	Name	City	State
United Kingdom	Imperial College Clinical Research Facility	London

Sponsors (1)

Lead Sponsor	Collaborator
Imperial College London

Country where clinical trial is conducted

United Kingdom, 

References & Publications (5)

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. — View Citation

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-?B 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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Endothelial function	Measured using EndoPAT	7 days
Secondary	Sitting blood pressure	Participants will record their blood pressure daily using a home monitoring device.	7 days
Secondary	Cardiovascular Biomarkers	Measured using mass spectrometry	7 days