Arginine Supplementation to Improve Cardiovascular and Endothelial Function After NSAID Treatment

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Healthy

Intervention / Treatment
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* Drug: Celecoxib
* Other: Placebo
* Other: L-arginine + placebo
* Other: L-arginine + celecoxib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Healthy male volunteers will be blinded and randomized to 7 days' treatment with celecoxib (200mg bd) or placebo.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Celecoxib<br>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<br>* Two 200 mg capsules per day (400 mg/day) for 7 days<br>* Other names: Celebrex;Other: L-arginine + celecoxib<br>* 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<br>|
| Placebo Comparator: Placebo<br>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<br>* 2 capsules/day for 7 days<br>Other: L-arginine + placebo<br>* L-arginine = Five capsules of 2 mg per day (10 mg/day) for 7 days Placebo = 2 capsules/day for 7 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endothelial function | Measured using EndoPAT | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sitting blood pressure | Participants will record their blood pressure daily using a home monitoring device. | 7 days | 
| Cardiovascular Biomarkers | Measured using mass spectrometry | 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endothelial function, COX-2, Celecoxib, biomarker, NSAID