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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Celecoxib | Active Comparator | 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 |
|
| Placebo | Placebo Comparator | 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 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Celecoxib | Drug | Two 200 mg capsules per day (400 mg/day) for 7 days |
|
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
Male Volunteers
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| Name | Affiliation | Role |
|---|---|---|
| Jane Mitchell, Professor | Imperial College London | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Imperial College Clinical Research Facility | London | w12 0HS | United Kingdom |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23874970 | Background | 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. | |
| 26712011 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Celecoxib | 22 participants were randomised and allocated to the celecoxib arm (200mg capsule taken orally twice a day for 7 days. Of these 2 participants withdrew from the study before the second study visit. In the final analysis there were 20 participants in the celecoxib arm. |
| FG001 | Placebo | 22 participants were randomised and allocated to the placebo arm (identical capsule to celecoxib containing placebo, 1 capsule taken orally twice daily for 7 days). Of these 2 participants were withdrawn from the study due to concomitant viral infection during the study week. In the final analysis there were 20 participants in the Placebo arm. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Celecoxib | Celecoxib |
| BG001 | Placebo | Placebo |
| BG002 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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 | Data presented as mean change from baseline (delta) | Posted | Mean | Standard Deviation | LnRHI (Log Reactive hyperaemic index) | Baseline and 7 days |
|
7 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Celecoxib | Celecoxib 200mg capsule taken orally twice a day for 7 days | 0 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Ricky Vaja | Imperial College London | 020 7589 5111 | r.vaja@imperial.ac.uk |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Dec 17, 2021 | Dec 7, 2023 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D000068579 | Celecoxib |
| D001120 | Arginine |
| ID | Term |
|---|---|
| D000096926 | Benzenesulfonamides |
| D013449 | Sulfonamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
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Healthy male volunteers will be blinded and randomized to 7 days' treatment with celecoxib (200mg bd) or placebo.
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| Placebo | Other | 2 capsules/day for 7 days |
|
| L-arginine + placebo | Other | 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 | Other | 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 |
|
Measured using mass spectrometry on serum samples collected at baseline and at 7 days. |
| Baseline and 7 days |
| 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. |
| 18207021 | Background | 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. |
| 24003163 | Background | 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. |
| 25492024 | Background | 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. |
| Total |
Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
|
|
| Primary | 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. | Posted | Mean | Standard Deviation | Augmentation Index | Baseline and 7 days |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | mmHg | Baseline and 7 Days |
|
|
|
| Secondary | Increase/Decrease of Cardiovascular Biomarkers From Baseline | Measured using mass spectrometry on serum samples collected at baseline and at 7 days. | Posted | Dec 2024 | Number | Analytes significant after FDR | Baseline and 7 days |
|
|
|
| 20 |
| 0 |
| 20 |
| 0 |
| 20 |
| EG001 | Placebo | Identical capsule to celecoxib containing placebo, 1 capsule taken orally twice daily for 7 days | 0 | 20 | 0 | 20 | 0 | 20 |
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| D001555 |
| Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |
| D011720 | Pyrazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D024361 | Amino Acids, Basic |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| D000599 | Amino Acids, Diamino |
| D000601 | Amino Acids, Essential |