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)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 26
- 试验地点
- 1
- 主要终点
- Study compound-induced changes on the TxB2 formation in plasma and the formation of prostacyclin metabolite (PGI-M) in urine (Part 1)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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);
- •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.
排除标准
- •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);
- •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).
研究组 & 干预措施
1
CG100649, single oral dose of 2 mg
干预措施: CG100649 (2 mg) (Drug)
2
CG100649, single oral dose of 8 mg
干预措施: CG100649 (8 mg) (Drug)
3
Celecoxib, single oral dose of 200 mg
干预措施: Celecoxib (Drug)
4
Naproxen, single oral dose of 500 mg
干预措施: Naproxen (Drug)
5
Acetazolamide, single oral dose of 250 mg
干预措施: Acetazolamide (Drug)
6
Placebo, single oral administration
干预措施: Placebo capsules (Drug)
结局指标
主要结局
Study compound-induced changes on the TxB2 formation in plasma and the formation of prostacyclin metabolite (PGI-M) in urine (Part 1)
时间窗: Hours and days
Study compound-induced changes on urinary eicosanoid metabolites (Part 2)
时间窗: Hours and days.
The study compound's biochemical selectivity for COX-2 (Part 3)
时间窗: Hours and days.
次要结局
- 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)(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)(Hours and days)
研究者
Carsten Skarke
MD
University of Pennsylvania