Healthy VolunteersPhase 1NCT00780325

Effects of Dual Cyclooxygenase-2 and Carbonic Anhydrase Inhibition

A Phase 1 study testing CG100649 (2 mg), Celecoxib and Naproxen in people with Healthy Volunteers, run by University of Pennsylvania at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

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Trial summary

Cyclooxygenase-2 (COX-2) inhibitors have become a common analgesic treatment option for patients with arthritis. However, long-term treatment has been associated with increased cardiovascular risk. With the past withdrawals and rejections of approval for COX-2 inhibitors the treatment options are now very limited. Read more about this study

Who is it for?: Ages 18 to 60 yearsHealthy volunteers can take part
Conditions the study is for: Healthy Volunteers
What is being tested?: CG100649 (2 mg), Celecoxib and Naproxen
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 26 participants
Where: 1 siteUnited States
Study dates: Oct 2008to Jul 2013
Phase: Phase 1
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 18 to 60 years
All sexes
Healthy volunteers accepted
Adult

Who may be able to join

Age 18-60 years old, able and willing to provide written informed consent to participate in the study;
Subjects must be in generally good health as determined by pre-study medical history, physical examination, clinical laboratory tests and 12-lead electrocardiogram (ECG);
Body mass index (BMI) 19-32 kg/m2;
Normal blood pressure (BP) [systolic BP 90-140 mmHg, diastolic BP 50-90 mmHg] and heart rate (HR) [resting HR 45-90 bpm] without medication;
Clinical chemistry profile including electrolytes, alkaline phosphatase (ALK), lactate dehydrogenase (LDH), creatine phosphokinase (CPK), creatinine, and urea must be within the normal range without medication; screening liver enzymes may be up to 1.5x normal range; screening CPK must be within 2x normal range without medication;
Urinalysis including urinary creatinine must be within normal limits (trace findings and minor deviations are acceptable per the clinical decision of the Principal Investigator);

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Subjects must be non-smokers and non-drinkers or willing to abstain from smoking, alcohol, caffeine and high-fat foods for the duration of study;
Subjects must be able to read, understand and follow the study instructions;
Subjects and their sexual partners must agree to use double barrier contraception during the study period and for 2 months afterward or provide proof of surgical sterility. Double barrier contraception may include, but is not limited to, using a male condom with spermicide; having a female sexual partner who agrees to use an IUD with spermicide, a female condom with spermicide, a diaphragm with spermicide, a cervical cap with spermicide; or having a sterile sexual partner. Female subjects must be non-pregnant, non-lactating, and either postmenopausal for at least 1 year, surgically sterile for at least 3 months, or willing to use double barrier contraception from 28 days prior to study enrollment and/or their last confirmed menstrual period (whichever is longer) until 2 months after final clinic visit. For all females, the pregnancy test result must be negative at Screening;
Subjects must tolerate the insertion of an intravenous line of the size ≥ 20 gauge for the drug administration study days.

Who cannot join

Use of any non-study medication(s) including low dose aspirin for cardiovascular prophylaxis within 2 weeks prior and 2 weeks after receipt of each dose of study drug;
Use of chemotherapy agents or history of cancer, other than non-metastatic skin cancer that has been completely excised, within five (5) years prior to the screening visit;
History of bacterial or viral infection requiring treatment with antibiotics or antivirals within 3 months of study;
Presence or history of peripheral edema within the past 5 years;
History of congestive heart failure;
Use of drugs which are P450 3A4 inducers or inhibitors within the past 30 days (e.g. alprazolam, chlorpheniramine, cimetidine, fluoxetine, haloperidol, ketoconazole, itraconazole, erythromycin, clarithromycin, sildenafil, simvastatin, St. John's Wort);

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Use of prescribed systemic or topical medications or any dietary aids or foods that are known to modulate drug metabolizing enzymes (e.g. grapefruit juice) within 14 days of dose administration;
Difficulty in swallowing oral medications;
History of seizure disorder;
Serious psychosocial co-morbidities;
Cognitive or psychiatric disorders, or any other condition that could interfere with compliance with study procedures and/or confinement in a clinical study unit for 2 days or longer;
History of drug or alcohol abuse within one year prior to screening;
Use of any other investigational drug within 1 month prior to enrollment;
Use of any prescription drugs within 1 month prior to enrollment;
Use of over the counter medication excluding routine vitamins, but including mega-dose vitamin therapy, within one week of enrollment;
Donation and/or receipt of any blood or blood products within 3 months prior to enrollment;
Active gastrointestinal, renal, hepatic, or coagulant disorder within 1 month prior to enrollment;
Esophageal or gastroduodenal ulceration within 1 month prior to enrollment;
Hypersensitivity to NSAIDs, sulfonamides, COX-2 inhibitors, or carbonic anhydrase inhibitors;
Known allergy or hypersensitivity to sulfa drugs;
Family history of significant cardiac disease (i.e. sudden death in first degree relative; myocardial infarction prior to 50 years old);
Occult blood in stool (fecal occult blood test).

Trial locations and contacts

1 site in 1 country.

United States1 site

Institute for Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania School of Medicine
Philadelphia, Pennsylvania, 19104

Other trials in United States

About this study

Official title: A Single Center, Double-blind, Placebo-controlled Phase I Single-dose Cross-over Study in Healthy Subjects to Investigate the Inhibitory Effect of CG100649, Celecoxib, Naproxen, and Acetazolamide on the Activity of Cyclooxygenases (COX-1, COX-2) and Carbonic Anhydrases (CA-I, CA-II)

This translates for example to about 10 million osteoarthritis patients in the US who cannot receive COX-2 inhibitors because of concomitant hypertension. And this exemplifies the unmet medical need to develop and offer safe treatment options for this particular patient population.

This trial investigates pharmacodynamic aspects of CG100649 which is being developed as a novel COX-2 inhibitor. Preclinical data show a dual mechanism of action, which consists of the inhibition of the two enzymes COX-2 and carbonic anhydrase-I/-II (CA-I/II) and through which the cardiovascular risk of COX-2 inhibition might be attenuated.

Read the detailed description

Part 1 and 2 (staged analysis): Single dose of study drugs [celecoxib, placebo] followed by 3 days of blood draws as Period I; then after a wash-out phase, single dose of study drugs [CG100649 2mg and 8mg, celecoxib 200mg, placebo], followed by blood draws on 6 days and bi-weekly urine collections for 8 weeks.

Part 3: Five-way cross-over of single doses of study drugs with a CG100649 single dose level as determined by part 1 and 2, celecoxib 200mg, naproxen 500mg, acetazolamide 250mg and placebo.

Conditions: Healthy Volunteers
Being tested: CG100649 (2 mg), Celecoxib, Placebo capsules, Naproxen, Acetazolamide
Keywords: Cyclooxygenase-2, Carbonic anhydrase, Eicosanoids, Healthy volunteers

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

CG100649 (2 mg)Drug
CG100649 capsules: 2 mg, single oral administration (Part 1); CG100649 capsules: dose to be determined, single oral administration (the single CG100649 dose level used in Part 3 will be determined by part 1 and 2).
CelecoxibDrug
Also called Celebrex®
Celecoxib (Celebrex®) capsules: 200 mg; single oral administration (Part 1 and 3)
Placebo capsulesDrug
Also called silicified microcrystalline cellulose
Placebo capsules: 198 mg silicified microcrystalline cellulose + 2 mg talc, multiple oral administrations (Part 1 and 3)
NaproxenDrug
Also called Naprosyn®)
Naproxen (Naprosyn®) tablets: 500 mg, single oral administration (Part 3)
AcetazolamideDrug
Also called generic Acetazolamide
Acetazolamide (generic, immediate release) tablets: 250 mg, single oral administration (Part 3)
CG100649 (8 mg)Drug
CG100649 capsules: 8 mg, single oral administration (Part 1); CG100649 capsules: dose to be determined, single oral administration (the single CG100649 dose level used in Part 3 will be determined by part 1 and 2).

Study groups in NCT00780325
Study group	Role	What they receive
1	Experimental	CG100649, single oral dose of 2 mg Receives: Drug: CG100649 (2 mg)
2	Experimental	CG100649, single oral dose of 8 mg Receives: Drug: CG100649 (8 mg)
3	Active comparator	Celecoxib, single oral dose of 200 mg Receives: Drug: Celecoxib
4	Active comparator	Naproxen, single oral dose of 500 mg Receives: Drug: Naproxen
5	Active comparator	Acetazolamide, single oral dose of 250 mg Receives: Drug: Acetazolamide
6	Placebo comparator	Placebo, single oral administration Receives: Drug: Placebo capsules

What is being measured

The primary outcome is the main question the study is designed to answer.

Study compound-induced changes on the TxB2 formation in plasma and the formation of prostacyclin metabolite (PGI-M) in urine (Part 1)
Measured: Hours and days
Study compound-induced changes on urinary eicosanoid metabolites (Part 2)
Measured: Hours and days.
The study compound's biochemical selectivity for COX-2 (Part 3)
Measured: Hours and days.

Secondary outcomes (2)

Study compound-induced changes on the urinary metabolites PGE-M and TxB-M; on the cyclooxygenase-2 dependent PGE2 production in ex vivo LPS-stimulated monocytes and on the carbonic anhydrase-I and II function; Biochemical selectivity for COX-2 (Part 1)
Measured: Hours and days
Inhibition of carbonic anhydrase and relationship to drug concentrations; Study compound-induced changes on serum TxB2, on PGE2 formation in LPS-stimulated monocytes, on PGI-M, PGE-M, TxB-M and PGD-M levels and on platelet aggregation (Part 3)
Measured: Hours and days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Oct 2008Jul 2013

First posted27 Oct 2008 (estimated)
Study startOct 2008
Primary completionJul 2013
Study completionJul 2013

Why it stopped: A total of three parts were planned for this study. The sponsor funded only Part 1, so that neither Part 2 nor Part 3 of this study has been conducted.

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (2)Papers the sponsor has linked to this study.
Other trials for Healthy VolunteersStudies of the same condition, open and under way.
More trials run by University of PennsylvaniaThe sponsor's other registered studies.
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: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 26 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00780325
Sponsor's protocol ID: 807821
Status last verified: Feb 2014
First submitted: 24 Oct 2008
Last updated: 6 Feb 2014
Results posted: No
Data monitoring committee: No

Publications

Skarke C, Alamuddin N, Lawson JA, Cen L, Propert KJ, Fitzgerald GA. Comparative impact on prostanoid biosynthesis of celecoxib and the novel nonsteroidal anti-inflammatory drug CG100649. Clin Pharmacol Ther. 2012 Jun;91(6):986-93. doi: 10.1038/clpt.2012.3. Epub 2012 Jan 25.
PubMed 22278334
Hirankarn S, Barrett JS, Alamuddin N, FitzGerald GA, Skarke C. GCG100649, A Novel Cyclooxygenase-2 Inhibitor, Exhibits a Drug Disposition Profile in Healthy Volunteers Compatible With High Affinity to Carbonic Anhydrase-I/II: Preliminary Dose-Exposure Relationships to Define Clinical Development Strategies. Clin Pharmacol Drug Dev. 2013 Oct;2(4):379-86. doi: 10.1002/cpdd.47. Epub 2013 Jul 25.
PubMed 27121942

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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Study at a glance

From the registry record, last updated by the sponsor on 6 Feb 2014. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Single Center, Double-blind, Placebo-controlled Phase I Single-dose Cross-over Study in Healthy Subjects to Investigate the Inhibitory Effect of CG100649, Celecoxib, Naproxen, and Acetazolamide on the Activity of Cyclooxygenases (COX-1, COX-2) and Carbonic Anhydrases (CA-I, CA-II)
ClinicalTrials.gov ID: NCT00780325
Acronym / sponsor ID: 807821
Conditions: Healthy Volunteers
Keywords: Cyclooxygenase-2, Carbonic anhydrase, Eicosanoids, Healthy volunteers
Phase: Phase 1
Study type: Interventional
Recruitment status: TerminatedReason stopped: A total of three parts were planned for this study. The sponsor funded only Part 1, so that neither Part 2 nor Part 3 of this study has been conducted.
Enrolment: 26 participants (actual)
Lead sponsor: University of PennsylvaniaUniversity, hospital or other
Collaborators: CrystalGenomics, Inc.
Study start: Oct 2008
Primary completion: Jul 2013 (actual)
Study completion: Jul 2013 (actual)
First posted: 27 Oct 2008 (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.

Detailed description

Part 3: Five-way cross-over of single doses of study drugs with a CG100649 single dose level as determined by part 1 and 2, celecoxib 200mg, naproxen 500mg, acetazolamide 250mg and placebo.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 6

Arm	Type	Receives
1	Experimental	Drug: CG100649 (2 mg)CG100649, single oral dose of 2 mg
2	Experimental	Drug: CG100649 (8 mg)CG100649, single oral dose of 8 mg
3	Active comparator	Drug: CelecoxibCelecoxib, single oral dose of 200 mg
4	Active comparator	Drug: NaproxenNaproxen, single oral dose of 500 mg
5	Active comparator	Drug: AcetazolamideAcetazolamide, single oral dose of 250 mg
6	Placebo comparator	Drug: Placebo capsulesPlacebo, single oral administration

Who may qualify

Ages: 18 to 60 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult

Key inclusion criteria (10 listed)

Age 18-60 years old, able and willing to provide written informed consent to participate in the study;
Subjects must be in generally good health as determined by pre-study medical history, physical examination, clinical laboratory tests and 12-lead electrocardiogram (ECG);
Body mass index (BMI) 19-32 kg/m2;
Normal blood pressure (BP) [systolic BP 90-140 mmHg, diastolic BP 50-90 mmHg] and heart rate (HR) [resting HR 45-90 bpm] without medication;
Clinical chemistry profile including electrolytes, alkaline phosphatase (ALK), lactate dehydrogenase (LDH), creatine phosphokinase (CPK), creatinine, and urea must be within the normal range without medication; screening liver enzymes may be up to 1.5x normal range; screening CPK must be within 2x normal range without medication;

Key exclusion criteria (22 listed)

Use of any non-study medication(s) including low dose aspirin for cardiovascular prophylaxis within 2 weeks prior and 2 weeks after receipt of each dose of study drug;
Use of chemotherapy agents or history of cancer, other than non-metastatic skin cancer that has been completely excised, within five (5) years prior to the screening visit;
History of bacterial or viral infection requiring treatment with antibiotics or antivirals within 3 months of study;
Presence or history of peripheral edema within the past 5 years;
History of congestive heart failure;

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
CG100649 (2 mg)CG100649 capsules: 2 mg, single oral administration (Part 1); CG100649 capsules: dose to be determined, single oral administration (the single CG100649 dose level used in Part 3 will be determined by part 1 and 2).	Drug	1
CelecoxibAlso: Celebrex®Celecoxib (Celebrex®) capsules: 200 mg; single oral administration (Part 1 and 3)	Drug	3
Placebo capsulesAlso: silicified microcrystalline cellulosePlacebo capsules: 198 mg silicified microcrystalline cellulose + 2 mg talc, multiple oral administrations (Part 1 and 3)	Drug	6
NaproxenAlso: Naprosyn®)Naproxen (Naprosyn®) tablets: 500 mg, single oral administration (Part 3)	Drug	4
AcetazolamideAlso: generic AcetazolamideAcetazolamide (generic, immediate release) tablets: 250 mg, single oral administration (Part 3)	Drug	5
CG100649 (8 mg)CG100649 capsules: 8 mg, single oral administration (Part 1); CG100649 capsules: dose to be determined, single oral administration (the single CG100649 dose level used in Part 3 will be determined by part 1 and 2).	Drug	2

Primary outcome

Study compound-induced changes on the TxB2 formation in plasma and the formation of prostacyclin metabolite (PGI-M) in urine (Part 1)
Time frame: Hours and days
Study compound-induced changes on urinary eicosanoid metabolites (Part 2)
Time frame: Hours and days.
The study compound's biochemical selectivity for COX-2 (Part 3)
Time frame: Hours and days.

2 secondary outcomes

Study compound-induced changes on the urinary metabolites PGE-M and TxB-M; on the cyclooxygenase-2 dependent PGE2 production in ex vivo LPS-stimulated monocytes and on the carbonic anhydrase-I and II function; Biochemical selectivity for COX-2 (Part 1)
Time frame: Hours and days
Inhibition of carbonic anhydrase and relationship to drug concentrations; Study compound-induced changes on serum TxB2, on PGE2 formation in LPS-stimulated monocytes, on PGI-M, PGE-M, TxB-M and PGD-M levels and on platelet aggregation (Part 3)
Time frame: Hours and days

Results and safety

The study was stopped early (reason given: A total of three parts were planned for this study. The sponsor funded only Part 1, so that neither Part 2 nor Part 3 of this study has been conducted.). Results are not available in the source record.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 6 Feb 2014.
Results publication: PubMed 22278334Skarke C, Alamuddin N, Lawson JA, Cen L, Propert KJ, Fitzgerald GA. Comparative impact on prostanoid biosynthesis of celecoxib and the novel nonsteroidal anti-inflammatory drug CG100649. Clin Pharmacol Ther. 2012 Jun;91(6):986-93. doi: 10.1038/clpt.2012.3. Epub 2012 Jan 25.
Results publication: PubMed 27121942Hirankarn S, Barrett JS, Alamuddin N, FitzGerald GA, Skarke C. GCG100649, A Novel Cyclooxygenase-2 Inhibitor, Exhibits a Drug Disposition Profile in Healthy Volunteers Compatible With High Affinity to Carbonic Anhydrase-I/II: Preliminary Dose-Exposure Relationships to Define Clinical Development Strategies. Clin Pharmacol Drug Dev. 2013 Oct;2(4):379-86. doi: 10.1002/cpdd.47. Epub 2013 Jul 25.

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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.

Garret A FitzGerald, MD principal investigator

Institute for Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania School of Medicine

Carsten C Skarke, MD principal investigator

Institute for Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania School of Medicine

William K Schmidt, PhD study director

CrystalGenomics, Inc.

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing CG100649 (2 mg), Celecoxib and Naproxen in people with Healthy Volunteers, run by University of Pennsylvania 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 10 inclusion and 22 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 6 Feb 2014. 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. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

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?

Study compound-induced changes on the TxB2 formation in plasma and the formation of prostacyclin metabolite (PGI-M) in urine (Part 1) (time frame: Hours and days). The study lists 3 primary outcomes in all. 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 NCT00780325, which also lists 2 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 6 Feb 2014.