Clinical trial NCT04765644: Arginine Supplementation to Improve Cardiovascular and Endothelial Function After NSAID Treatment
Official title: Arginine Supplementation to Improve Cardiovascular and Endothelial Function After NSAID Treatment (ASCENT)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Healthy
Keywords: NSAID
Endothelial function
COX-2
Celecoxib
biomarker
Lead sponsor: Imperial College London
Sponsor class: OTHER
First posted: 2021-02-21
Enrollment: 44
Sex: MALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Healthy male volunteers will be blinded and randomized to 7 days' treatment with celecoxib (200mg bd) or placebo.
Primary purpose: BASIC_SCIENCE

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Log Reactive Hyperaemic Index
timeFrame: Baseline and 7 days
measure: Augmentation Index
timeFrame: Baseline and 7 days
Secondary outcomes:
measure: Blood Pressure
timeFrame: Baseline and 7 Days
measure: Increase/Decrease of Cardiovascular Biomarkers From Baseline
timeFrame: Baseline and 7 days
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Imperial College Clinical Research Facility
Study officials:
affiliation: Imperial College London
name: Jane Mitchell, Professor
role: STUDY_DIRECTOR
References:
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.
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-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.
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. No abstract available.
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.
citation: 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.