OsteoarthritisNCT01279395
Anti-inflammatory Agents and Cholesterol Metabolism
An observational study of Osteoarthritis, run by Winthrop University Hospital at 1 site in United States.
Trial summary
We hypothesize that administration of anti-inflammatory medications such as celecoxib, naprosyn and diclofenac will cause changes in the blood plasma and white blood cells of patients such that they will be less able to efficiently process cholesterol. Read more about this study
- Who is it for?
- Ages 40 to 70 years
- Conditions the study is for
- Osteoarthritis
- How many people
- 3 participants
- Where
- 1 siteUnited States
- Study dates
- Nov 2010to 18 Jan 2018
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Patients age 40-70 who fulfill the ACR criteria for a diagnosis of primary osteoarthritis are considered
Who may be able to join
- Age 40-70, osteoarthritis, male or female
Who cannot join
- other known autoimmune or inflammatory rheumatic conditions, renal disease, current or recent (>1 month) corticosteroid or statin treatment, contraindications to medication (i.e. those taking oral anticoagulants, e.g. warfarin), those pregnant or trying to become pregnant or breastfeeding. Participants will not have consumed any medications containing aspirin or other NSAIDs for at least 2 weeks before the trial.
Trial locations and contacts
1 site in 1 country.
United States1 site
Winthrop University Hospital
Mineola, New York, 11501
About this study
Official title: Impact of Anti-inflammatory Agents on Cholesterol Metabolism and Atherogenic Potency of Patient Plasma
We hypothesize that administration of anti-inflammatory medications such as celecoxib, naprosyn and diclofenac will cause changes in the blood plasma and white blood cells of patients such that they will be less able to efficiently process cholesterol.
Read the detailed description
Drugs that inhibit cyclooxygenase (COX) are frequently administered to relieve pain and inflammation, but have been associated with cardiovascular (CV) toxicity and an elevated risk of acute myocardial infarction. We have demonstrated that drugs that inhibit the COX-2 isoform act to interfere with cellular cholesterol movement by suppressing expression of proteins that facilitate efflux of cholesterol as well as by enhancing expression of scavenger receptors that mediate cholesterol uptake. We further showed that in cultured THP-1 human macrophages, COX-2 inhibition with drugs (celecoxib, NS398) or by COX-2 RNA silencing leads to foam cell transformation, a critical component of atherogenesis. Thus, COX-2 inhibitors act in a pro-atherogenic fashion on a series of genes which we have named the "Cholesterol Metabolic Signature." Alterations in this signature may contribute to heightened risk of development of atherosclerotic CV disease associated with prolonged use of this drug class. COX enzyme activity supports cholesterol homeostasis through catalysis of prostaglandin (PG) production, and we have shown in vitro that specific subsets of these PGs (PGD2 or PGE2) are sufficient to maintain balance. The aims of this project is: In an observational study of persons with pharmacologic COX-2 selective inhibition (celecoxib) or COX-1/2 inhibition (naproxen, diclofenac), document treatment effects on the Cholesterol Metabolic Signature in isolated subject mononuclear cells and in naïve THP-1 monocytes/macrophages exposed to subject plasma. This will allow detection of variations in degree of pro-atherogenic response of the Cholesterol Metabolic Signature to COX inhibition within human patients that may be associated with a higher likelihood of developing CV sequelae. Understanding the nature of the association between COX inhibition and cholesterol metabolism, and the extent to which they may promote atherosclerotic CV disease, is of critical importance in developing analgesic and anti-inflammatory medications with a more favorable risk profile. The knowledge gained may also improve clinical decision-making by identifying subsets of patients most vulnerable to adverse CV effects of COX inhibition.
- Conditions
- Osteoarthritis
- Keywords
- atherosclerosis, cholesterol, cyclooxygenase, gene expression, lipid metabolism
- Medical subject headings
- Osteoarthritis, Atherosclerosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| naproxen | Patients age 40-70 who fulfill the American College of Rheumatology (ACR) criteria for a diagnosis of primary osteoarthritis are considered eligible. This group has been prescribed naproxen (1000 mg/day) for a minimum of two weeks. | |
| diclofenac | Patients age 40-70 who fulfill the ACR criteria for a diagnosis of primary osteoarthritis. The group consists of patients who have been prescribed diclofenac (150 mg/day)for a minimum of two weeks. | |
| celecoxib | Patients age 40-70 who fulfill the ACR criteria for a diagnosis of primary osteoarthritis are considered eligible. This group has been prescribed celecoxib (200 mg/day) for a minimum of two weeks. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Difference in expression of the cholesterol-metabolizing enzyme cytochrome P450 cholesterol 27-hydroxylase in peripheral blood mononuclear cells (PBMC) before and after treatment with naprosyn, celecoxib or diclofenac.
PBMC are isolated directly from patient blood by Ficoll hypaque gradient centrifugation. Total RNA is obtained (TriZol) from PBMC. 27-hydroxylase message is quantitated by quantitative real-time polymerase chain reaction (QRT-PCR) using specific primers.
Measured: 2 weeks
Secondary outcomes (1)
Difference in expression of cholesterol 27-hydroxylase in naive THP-1 human macrophages incubated in plasma from patients obtained before and after treatment with naprosyn, diclofenac or celecoxib.
Comparison of abundance of the cholesterol-metabolizing enzyme cytochrome P450 cholesterol 27-hydroxylase in the THP-1 human monocyte/macrophage cell line incubated in plasma taken from the same patient before and after treatment with naprosyn, celecoxib or diclofenac. 27-hydroxylase message is quantitated by QRT-PCR and protein by immunoblot.
Measured: 2 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Jan 2011 (estimated)
- Study startNov 2010
- Primary completion18 Jan 2018
- Study completion18 Jan 2018
Why it stopped: Could not recruit adequate number of subjectsa
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for OsteoarthritisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 3 participants (actual)
Sponsor and investigators
- Lead sponsor
- Winthrop University Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Allison B. Reiss, MD, Winthrop University Hospital
- Investigators
- Allison B Reiss, MD, Principal investigator, Winthrop University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01279395
- Sponsor's protocol ID
- 151973-1
- Status last verified
- Aug 2019
- First submitted
- 14 Jan 2011
- Last updated
- 16 Aug 2019
- Results posted
- No
- Data monitoring committee
- No
Publications
Anwar K, Voloshyna I, Littlefield MJ, Carsons SE, Wirkowski PA, Jaber NL, Sohn A, Eapen S, Reiss AB. COX-2 inhibition and inhibition of cytosolic phospholipase A2 increase CD36 expression and foam cell formation in THP-1 cells. Lipids. 2011 Feb;46(2):131-42. doi: 10.1007/s11745-010-3502-4. Epub 2010 Dec 22.
PubMed 21181286Reiss AB, Anwar F, Chan ES, Anwar K. Disruption of cholesterol efflux by coxib medications and inflammatory processes: link to increased cardiovascular risk. J Investig Med. 2009 Aug;57(6):695-702. doi: 10.2310/JIM.0b013e31819ec3c7.
PubMed 19289972Chan ES, Zhang H, Fernandez P, Edelman SD, Pillinger MH, Ragolia L, Palaia T, Carsons S, Reiss AB. Effect of cyclooxygenase inhibition on cholesterol efflux proteins and atheromatous foam cell transformation in THP-1 human macrophages: a possible mechanism for increased cardiovascular risk. Arthritis Res Ther. 2007;9(1):R4. doi: 10.1186/ar2109.
PubMed 17244362
Study at a glance
From the registry record, last updated by the sponsor on 16 Aug 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Impact of Anti-inflammatory Agents on Cholesterol Metabolism and Atherogenic Potency of Patient Plasma
- ClinicalTrials.gov ID
- NCT01279395
- Acronym / sponsor ID
- 151973-1
- Conditions
- Osteoarthritis
- Keywords
- atherosclerosis, cholesterol, cyclooxygenase, gene expression, lipid metabolism
- Study type
- Observational
- Recruitment status
- TerminatedReason stopped: Could not recruit adequate number of subjectsa
- Enrolment
- 3 participants (actual)
- Lead sponsor
- Winthrop University HospitalUniversity, hospital or other
- Study start
- Nov 2010
- Primary completion
- 18 Jan 2018 (actual)
- Study completion
- 18 Jan 2018 (actual)
- First posted
- 19 Jan 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
We hypothesize that administration of anti-inflammatory medications such as celecoxib, naprosyn and diclofenac will cause changes in the blood plasma and white blood cells of patients such that they will be less able to efficiently process cholesterol.
Detailed description
Drugs that inhibit cyclooxygenase (COX) are frequently administered to relieve pain and inflammation, but have been associated with cardiovascular (CV) toxicity and an elevated risk of acute myocardial infarction. We have demonstrated that drugs that inhibit the COX-2 isoform act to interfere with cellular cholesterol movement by suppressing expression of proteins that facilitate efflux of cholesterol as well as by enhancing expression of scavenger receptors that mediate cholesterol uptake. We further showed that in cultured THP-1 human macrophages, COX-2 inhibition with drugs (celecoxib, NS398) or by COX-2 RNA silencing leads to foam cell transformation, a critical component of atherogenesis. Thus, COX-2 inhibitors act in a pro-atherogenic fashion on a series of genes which we have named the "Cholesterol Metabolic Signature." Alterations in this signature may contribute to heightened risk of development of atherosclerotic CV disease associated with prolonged use of this drug class. COX enzyme activity supports cholesterol homeostasis through catalysis of prostaglandin (PG) production, and we have shown in vitro that specific subsets of these PGs (PGD2 or PGE2) are sufficient to maintain balance. The aims of this project is: In an observational study of persons with pharmacologic COX-2 selective inhibition (celecoxib) or COX-1/2 inhibition (naproxen, diclofenac), document treatment effects on the Cholesterol Metabolic Signature in isolated subject mononuclear cells and in naïve THP-1 monocytes/macrophages exposed to subject plasma. This will allow detection of variations in degree of pro-atherogenic response of the Cholesterol Metabolic Signature to COX inhibition within human patients that may be associated with a higher likelihood of developing CV sequelae. Understanding the nature of the association between COX inhibition and cholesterol metabolism, and the extent to which they may promote atherosclerotic CV disease, is of critical importance in developing analgesic and anti-inflammatory medications with a more favorable risk profile. The knowledge gained may also improve clinical decision-making by identifying subsets of patients most vulnerable to adverse CV effects of COX inhibition.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| naproxen | – | –Patients age 40-70 who fulfill the American College of Rheumatology (ACR) criteria for a diagnosis of primary osteoarthritis are considered eligible. This group has been prescribed naproxen (1000 mg/day) for a minimum of two weeks. |
| diclofenac | – | –Patients age 40-70 who fulfill the ACR criteria for a diagnosis of primary osteoarthritis. The group consists of patients who have been prescribed diclofenac (150 mg/day)for a minimum of two weeks. |
| celecoxib | – | –Patients age 40-70 who fulfill the ACR criteria for a diagnosis of primary osteoarthritis are considered eligible. This group has been prescribed celecoxib (200 mg/day) for a minimum of two weeks. |
Who may qualify
- Ages
- 40 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Patients age 40-70 who fulfill the ACR criteria for a diagnosis of primary osteoarthritis are considered
Key inclusion criteria (1 listed)
- Age 40-70, osteoarthritis, male or female
Key exclusion criteria (1 listed)
- other known autoimmune or inflammatory rheumatic conditions, renal disease, current or recent (>1 month) corticosteroid or statin treatment, contraindications to medication (i.e. those taking oral anticoagulants, e.g. warfarin), those pregnant or trying to become pregnant or breastfeeding. Participants will not have consumed any medications containing aspirin or other NSAIDs for at least 2 weeks before the trial.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Difference in expression of the cholesterol-metabolizing enzyme cytochrome P450 cholesterol 27-hydroxylase in peripheral blood mononuclear cells (PBMC) before and after treatment with naprosyn, celecoxib or diclofenac.
Time frame: 2 weeks
PBMC are isolated directly from patient blood by Ficoll hypaque gradient centrifugation. Total RNA is obtained (TriZol) from PBMC. 27-hydroxylase message is quantitated by quantitative real-time polymerase chain reaction (QRT-PCR) using specific primers.
1 secondary outcome
Difference in expression of cholesterol 27-hydroxylase in naive THP-1 human macrophages incubated in plasma from patients obtained before and after treatment with naprosyn, diclofenac or celecoxib.
Time frame: 2 weeks
Results and safety
The study was stopped early (reason given: Could not recruit adequate number of subjectsa). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Aug 2019.
- Background: PubMed 21181286Anwar K, Voloshyna I, Littlefield MJ, Carsons SE, Wirkowski PA, Jaber NL, Sohn A, Eapen S, Reiss AB. COX-2 inhibition and inhibition of cytosolic phospholipase A2 increase CD36 expression and foam cell formation in THP-1 cells. Lipids. 2011 Feb;46(2):131-42. doi: 10.1007/s11745-010-3502-4. Epub 2010 Dec 22.
- Background: PubMed 19289972Reiss AB, Anwar F, Chan ES, Anwar K. Disruption of cholesterol efflux by coxib medications and inflammatory processes: link to increased cardiovascular risk. J Investig Med. 2009 Aug;57(6):695-702. doi: 10.2310/JIM.0b013e31819ec3c7.
- Background: PubMed 17244362Chan ES, Zhang H, Fernandez P, Edelman SD, Pillinger MH, Ragolia L, Palaia T, Carsons S, Reiss AB. Effect of cyclooxygenase inhibition on cholesterol efflux proteins and atheromatous foam cell transformation in THP-1 human macrophages: a possible mechanism for increased cardiovascular risk. Arthritis Res Ther. 2007;9(1):R4. doi: 10.1186/ar2109.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Allison B Reiss, MD principal investigator
Winthrop University Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Osteoarthritis, run by Winthrop University Hospital at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 16 Aug 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was stopped early (reason given: Could not recruit adequate number of subjectsa). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Difference in expression of the cholesterol-metabolizing enzyme cytochrome P450 cholesterol 27-hydroxylase in peripheral blood mononuclear cells (PBMC) before and after treatment with naprosyn, celecoxib or diclofenac. (time frame: 2 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01279395, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Aug 2019.