Effects of Dual Cyclooxygenase-2 and Carbonic Anhydrase Inhibition
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.
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.
|Healthy Volunteers||Drug: CG100649 (2 mg) Drug: Celecoxib Drug: Placebo capsules Drug: Naproxen Drug: Acetazolamide Drug: CG100649 (8 mg)||Phase 1|
|Study Design:||Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|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)|
- 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. ]
- 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 ]
|Study Start Date:||October 2008|
|Study Completion Date:||July 2013|
|Primary Completion Date:||July 2013 (Final data collection date for primary outcome measure)|
CG100649, single oral dose of 2 mg
Drug: 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).
CG100649, single oral dose of 8 mg
Drug: 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).
Active Comparator: 3
Celecoxib, single oral dose of 200 mg
Celecoxib (Celebrex®) capsules: 200 mg; single oral administration (Part 1 and 3)
Other Name: Celebrex®
Active Comparator: 4
Naproxen, single oral dose of 500 mg
Naproxen (Naprosyn®) tablets: 500 mg, single oral administration (Part 3)
Other Name: Naprosyn®)
Active Comparator: 5
Acetazolamide, single oral dose of 250 mg
Acetazolamide (generic, immediate release) tablets: 250 mg, single oral administration (Part 3)
Other Name: generic Acetazolamide
Placebo Comparator: 6
Placebo, single oral administration
Drug: Placebo capsules
Placebo capsules: 198 mg silicified microcrystalline cellulose + 2 mg talc, multiple oral administrations (Part 1 and 3)
Other Name: silicified microcrystalline cellulose
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00780325
|United States, Pennsylvania|
|Institute for Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania School of Medicine|
|Philadelphia, Pennsylvania, United States, 19104|
|Principal Investigator:||Garret A FitzGerald, MD||Institute for Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania School of Medicine|
|Principal Investigator:||Carsten C Skarke, MD||Institute for Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania School of Medicine|
|Study Director:||William K Schmidt, PhD||CrystalGenomics, Inc.|