John G. Fort

Video capsule endoscopy to prospectively assess small bowel injury with celecoxib, naproxen plus omeprazole, and placebo

BACKGROUND & AIMS Data indicate that cyclooxygenase-2-specific inhibitors cause less gastroduodenal mucosal damage than nonspecific NSAIDS, but their effects on the small bowel mucosa are less well recognized. In a multicenter, double-blind, placebo-controlled trial with video capsule endoscopy (VCE) we prospectively evaluated the incidence of small bowel injury in healthy subjects treated with celecoxib compared to naproxen plus omeprazole. METHODS We randomly assigned subjects with normal baseline VCEs to celecoxib 200 mg twice daily (n = 120), naproxen 500 mg twice daily plus omeprazole 20 mg once daily (n = 118), or placebo (n = 118) for 2 weeks. The primary end point was the mean number of small bowel mucosal breaks per subject. RESULTS Baseline VCE found small bowel lesions in 13.8% (57/413) of screened subjects, who became ineligible for randomization. The mean number of small bowel mucosal breaks per subject and the percentage of subjects with these mucosal breaks were 2.99 +/- 0.51, 55% for naproxen/omeprazole compared to 0.32 +/- 0.10, 16% for celecoxib and 0.11 +/- 0.04, 7% for placebo (P < .001, both comparisons). The magnitude of the difference between celecoxib and placebo was small but statistically significant (P = .04). CONCLUSIONS Among healthy subjects with lesion-free baseline VCEs, celecoxib was associated with significantly fewer small bowel mucosal breaks than naproxen plus omeprazole. This study also showed that the background incidence of small bowel lesions in healthy adults is not insignificant and should be considered in future trials with VCE.

Cyclooxygenase-2--specific inhibitors and cardiorenal function: a randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients.

BackgroundArthritis and hypertension are common comorbid conditions affecting elderly adults. Use of nonsteroidal anti-inflammatory drugs in patients treated with antihypertensive medication can lead to destabilization of blood pressure control and other cardiorenal events. The potential for similar interactions with cyclooxygenase-2–specific inhibitors has not been fully explored. The authors evaluated the cardiorenal safety of two new cyclooxygenase-2–specific inhibitors, celecoxib and rofecoxib. MethodsThis study was a 6-week, randomized, parallel-group, double-blind trial in patients with osteoarthritis who were ≥65 years of age and were taking antihypertensive agents. Patients received once-daily celecoxib 200 mg or rofecoxib 25 mg. The primary endpoints were the development of edema, changes in systolic blood pressure, and changes in diastolic blood pressure as measured at any time point in the study. Measurements occurred at baseline and after 1, 2, and 6 weeks of treatment. FindingsEight hundred ten patients received study medication (celecoxib, n = 411; rofecoxib, n = 399). Nearly twice as many rofecoxib-compared with celecoxib-treated patients experienced edema (9.5% vs. 4.9%, P = 0.014). Systolic blood pressure increased significantly in 17% of rofecoxib-compared with 11% of celecoxib-treated patients (P = 0.032) at any study time point. Diastolic blood pressure increased in 2.3% of rofecoxib-compared with 1.5% of celecoxib-treated patients (P = 0.44). At week 6, the change from baseline in mean systolic blood pressure was +2.6 mmHg for rofecoxib compared with −0.5 mmHg for celecoxib (P = 0.007). ConclusionsPatients taking antihypertensive therapy and receiving cyclooxygenase-2–specific inhibitors should be monitored for the development of cardiorenal events. Patients receiving celecoxib experienced less edema and less destabilization of blood pressure control compared with those receiving rofecoxib.

The rate of NSAID-induced endoscopic ulcers increases linearly but not exponentially with age: a pooled analysis of 12 randomised trials

The risk of major ulcer complications on treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is known to increase exponentially with age. However, in a pooled analysis of 12 trial arms, the incidence of endoscopic ulcers on treatment with NSAID was found to increase with age in a roughly linear fashion. Thus, it is concluded that increasing age is associated with both more frequent and more serious NSAID gastropathy.

COX-2 specific inhibitors in the management of osteoarthritis of the knee: a placebo-controlled, randomized, double-blind study.

COX-2 specific inhibitors have demonstrated significant safety advantages and comparable efficacy in osteoarthritis (OA) compared with conventional nonsteroidal anti-inflammatory drugs (NSAIDs), but no direct comparative trials between COX-2 specific inhibitors have been published. In this double-blind, placebo-controlled, parallel group, multicenter study, 182 patients (≥40 years old) with OA of the knee were randomly assigned to treatment with celecoxib 200 mg q.d. (n = 63), rofecoxib 25 mg q.d. (n = 59), or placebo (n = 60) for 6 weeks. Arthritis assessments were performed at baseline and Weeks 3 and 6, or at early termination. At Week 6, celecoxib and rofecoxib treatment resulted in similar mean changes from baseline (p > 0.55) in arthritis pain visual analogue scale, patients global assessment, and total score for WOMAC; all changes were superior to placebo (p < 0.05). In the patients global assessment of arthritis pain at Week 6, 79% of celecoxib-treated and 78% of rofecoxib-treated patients improved by ≥1 grade, compared with 50% of placebo patients (celecoxib, p = 0.025; rofecoxib, p = 0.020). Adverse event incidences were similar among the active comparators; however, celecoxib-treated patients had significantly fewer adverse gastrointestinal symptoms compared with rofecoxib-treated patients, which suggests that celecoxib may have a better gastrointestinal tolerability profile than rofecoxib at these doses. Adverse events that prompted withdrawal occurred in fewer than 7% of patients, and the overall incidences were similar between the active agents. Once-daily doses of celecoxib 200 mg and rofecoxib 25 mg offer comparable efficacy and are an effective alternative to conventional NSAIDs in the management of OA.

Fixed-dose combination of enteric-coated naproxen and immediate-release esomeprazole has comparable efficacy to celecoxib for knee osteoarthritis: two randomized trials

Abstract Objective: To demonstrate that a fixed-dose combination of enteric-coated naproxen 500 mg and immediate-release esomeprazole magnesium 20 mg has comparable efficacy to celecoxib for knee osteoarthritis. Research design and methods: Two randomized, double-blind, parallel-group, placebo-controlled, multicenter phase III studies (PN400-307 and PN400-309) enrolled patients aged ≥50 years with symptomatic knee osteoarthritis. Following an osteoarthritis flare, patients received naproxen/esomeprazole magnesium twice daily, celecoxib 200 mg once daily, or placebo for 12 weeks. Clinical trial registration: NCT00664560 and NCT00665431. Main outcome measures: Three co-primary efficacy endpoints were mean change from baseline to week 12 in Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain and function subscales, and Patient Global Assessment of osteoarthritis using a visual analog scale (PGA-VAS). Results: In Study 307, 619 patients were randomized and 614 treated. In Study 309, 615 patients were randomized and 610 treated. Both naproxen/esomeprazole magnesium and celecoxib were associated with improvements (least squares mean change from baseline to week 12) in WOMAC pain (Study 307: −42.0 and −41.8, respectively; Study 309: −44.2 and −42.9, respectively), WOMAC function (Study 307: −36.4 and −36.3, respectively; Study 309: −38.9 and −36.8, respectively), and PGA-VAS (Study 307: 21.2 and 21.6, respectively; Study 309: 29.0 and 25.6, respectively). A prespecified non-inferiority margin of 10 mm between naproxen/esomeprazole magnesium and celecoxib was satisfied for each co-primary endpoint at week 12 in both studies. Significant improvements were observed with naproxen/esomeprazole magnesium versus placebo in both studies (p < 0.05). Celecoxib was significantly different from placebo in Study 307 (p < 0.05); however, the improvements were not significant in Study 309. Acetaminophen use and patient expectation of receiving active treatment (80% probability) may have contributed to a high placebo response observed. Conclusions: Naproxen/esomeprazole magnesium has comparable efficacy to celecoxib for the management of pain associated with osteoarthritis of the knee over 12 weeks.

A fixed-dose combination of naproxen and esomeprazole magnesium has comparable upper gastrointestinal tolerability to celecoxib in patients with osteoarthritis of the knee: Results from two randomized, parallel-group, placebo-controlled trials

Abstract Background. Non-steroidal anti-inflammatory drugs are associated with poor upper gastrointestinal (UGI) tolerability and increased ulcer risk, but patient adherence to gastroprotective co-therapy is frequently inadequate. A fixed-dose combination of enteric-coated naproxen 500 mg and immediate-release esomeprazole magnesium 20 mg was evaluated: efficacy is reported by Hochberg et al. (Curr Med Res Opin 2011;27:1243–53); tolerability findings are reported here. Patients and methods. In two 12-week double-blind, placebo-controlled, multicenter, phase III studies (PN400-307 and PN400-309), patients aged ≥ 50 years with symptomatic knee osteoarthritis randomly (2:2:1) received naproxen/esomeprazole magnesium BID, celecoxib 200 mg QD, or placebo. Tolerability end-points included: modified Severity of Dyspepsia Assessment (mSODA); heartburn severity; and UGI adverse events (AEs). Results. Overall, 619 (PN400-307) and 615 (PN400-309) patients were randomized; mSODA scores improved (baseline to week 12) in each group, with no significant treatment differences between naproxen/esomeprazole magnesium and celecoxib (95% CIs: PN400-307: –0.4, 1.9; PN400-309: –1.8, 0.6). Naproxen/esomeprazole magnesium-treated patients reported significantly more heartburn-free days versus celecoxib (95% CIs: PN400-307: 2.1, 12.7; PN400-309: 2.5, 13.4). UGI AE incidence (PN400-307: 17.3%; PN400-309: 20.3%) was similar between treatment groups. UGI AEs resulted in few discontinuations (< 4%, either study). Conclusions. Naproxen/esomeprazole magnesium has comparable UGI tolerability to celecoxib in patients with osteoarthritis.

Long-term safety of naproxen and esomeprazole magnesium fixed-dose combination: phase III study in patients at risk for NSAID-associated gastric ulcers

Abstract Objective: To evaluate long-term safety of enteric-coated naproxen 500 mg and immediate-release esomeprazole magnesium 20 mg fixed-dose combination (FDC) in patients at risk of NSAID-associated upper gastrointestinal (UGI) ulcers. Research design and methods: In this open-label, multicenter, phase III study, Helicobacter pylori-negative patients aged ≥50 years or 18–49 years with history of uncomplicated ulcer within the past 5 years, who had osteoarthritis, rheumatoid arthritis, or other condition requiring daily NSAIDs for ≥12 months received naproxen/esomeprazole twice daily for 12 months. Clinical trial registration: NCT00527904. Main outcome measures: Adverse events (AEs), vital signs, physical examination, and laboratory tests. Subgroup analyses included age and low-dose aspirin (LDA) use. Predefined NSAID-associated UGI and cardiovascular AEs were analyzed. Results: Of 239 patients treated (safety population), 135 completed ≥348 treatment days (12-month completers). AE incidence was approximately 70%; dyspepsia, constipation, upper respiratory tract infection, nausea, back pain, and contusion were most frequent (≥5% patients, either population). Treatment-related AEs occurred in 28.0% and 23.7% of patients in the safety and 12-month completer populations, respectively; 18.8% of patients withdrew due to AEs (safety population). Few serious AEs and no deaths occurred. In the safety population, AE incidence was 71.4% and 76.9% in patients aged <65 years (n = 161) and ≥65 years (n = 78), respectively, and 67.6% and 75.8% in LDA users (n = 74) and non-users (n = 165), respectively. Predefined UGI and cardiovascular AEs were observed in 18.8% and 6.3% of patients, respectively, in the safety population, and 16.3% and 5.2%, respectively, in 12-month completers. Dyspepsia and hypertension were most common. Additional assessments showed no unexpected findings. Conclusions: Based on these outcome measures, long-term treatment with FDC naproxen/esomeprazole is not associated with any new safety issues, including predefined UGI and cardiovascular AEs, in patients requiring NSAID therapy who are at risk of UGI complications.

PA32540 (a coordinated-delivery tablet of enteric-coated aspirin 325 mg and immediate-release omeprazole 40 mg) versus enteric-coated aspirin 325 mg alone in subjects at risk for aspirin-associated gastric ulcers: Results of two 6-month, phase 3 studies

BACKGROUND Discontinuations and/or interruptions in aspirin therapy for secondary cardioprotection due to upper gastrointestinal (UGI) complications or symptoms have been shown to increase the risk for subsequent cardiovascular events. PA32540 is a coordinated-delivery, combination tablet consisting of enteric-coated aspirin (EC-ASA) 325 mg and immediate-release (IR) omeprazole 40 mg. METHODS Two identically-designed, 6-month, randomized, double-blind trials evaluated PA32540 vs. EC-ASA 325 mg in a secondary cardiovascular disease prevention population taking aspirin 325 mg daily for ≥3 months and at risk for ASA-associated gastric ulcers (GUs). The combined study population was 1049 subjects (524 randomized to PA32540, 525 to EC-ASA 325 mg). The primary endpoint was the occurrence of endoscopically-determined gastric ulceration over 6 months. Safety outcomes included the rates of major adverse cardiovascular events (MACE) and UGI symptoms. RESULTS Significantly fewer PA32540-treated subjects (3.2%) developed endoscopic GUs vs. EC-ASA 325 mg-treated subjects (8.6%) (P < .001). Overall occurrence of MACE was low (2.1%), with no significant differences between treatments in types or incidence of MACE. PA32540-treated subjects had significantly fewer UGI symptoms (P < .001) and significantly fewer discontinuations due to pre-specified UGI adverse events (1.5% vs. 8.2%, respectively; P < .001). CONCLUSIONS PA32540 reduced the incidence of endoscopic GUs compared to EC-ASA 325 mg, but with a similar cardiovascular event profile. Due to fewer UGI symptoms, continuation on aspirin therapy was greater in the PA32540 treatment arm.

Pharmacokinetics and Relative Bioavailability of a Fixed‐Dose Combination of Enteric‐Coated Naproxen and Non‐Enteric‐Coated Esomeprazole Magnesium

This randomized, 4‐way crossover study assessed the single‐dose pharmacokinetics and relative bioavailability of naproxen and esomeprazole after administration of a fixed‐dose combination tablet of enteric‐coated (EC) naproxen 500 mg and non‐EC esomeprazole magnesium 20 mg (NAP/ESO tablet). Equivalent doses of an EC naproxen tablet plus an EC esomeprazole magnesium capsule taken concomitantly, an EC naproxen tablet alone, or an EC esomeprazole magnesium capsule alone were used as comparators. Forty healthy adults were randomized to receive 4 study treatments with a washout interval ≥12 days. Naproxen plasma profiles were similar between the NAP/ESO tablet and EC naproxen, although median tmax was longest for the NAP/ESO tablet (5.3 vs 3.5–4.0 hours). Naproxen Cmax, AUC0‐∞, and AUC0‐t showed bioequivalence between naproxen formulations. The NAP/ESO tablet produced much shorter esomeprazole tmax than the EC esomeprazole formulation (0.45 vs 2.5 hours). Esomeprazole Cmax and AUCs were comparable between the EC esomeprazole formulation administered with or without EC naproxen but were lower with the NAP/ESO tablet. In conclusion, there are no pharmacokinetic drug interactions between naproxen and esomeprazole. The NAP/ESO tablet is bioequivalent to EC naproxen, and as expected, the bioavailability of non‐EC esomeprazole from the NAP/ESO tablet is lower than the EC esomeprazole formulation.

Onset and durability of pain relief in knee osteoarthritis: Pooled results from two placebo trials of naproxen/esomeprazole combination and celecoxib.

Abstract Objective. To further characterize time-to-first pain relief, effect size, correlations between various outcome measures and durability of relief for single-tablet naproxen 500 mg/esomeprazole 20 mg (NAP/ESO) given twice daily and celecoxib (CEL) (200 mg) given once daily versus placebo in knee osteoarthritis (OA). Methods. Unpublished data from two double-blind, double-dummy, placebo-controlled trials in which patients aged ≥50 years with knee OA were randomized to NAP/ESO (n = 487), CEL (n = 486) or placebo (n = 246) were pooled (NCT00664560 and NCT00665431). Acute response endpoints: 1) Time to first significant pain response, 2) Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain subscale and 3) American Pain Society Patient Outcome Questionnaire (APS-POQ) scores. Sustainability endpoints: 1) Routine Assessment of Patient Index Data (RAPID3) and 2) WOMAC Stiffness, Pain and Total scores; and Patient Global Assessment (PGA) at 6 and 12 weeks. Effect sizes for all measures were calculated. Rescue pain medication use also was analyzed, as was the correlation of WOMAC to RAPID3. Results. NAP/ESO produced statistically significant decreases in WOMAC Pain on Days 2–7 and at Weeks 6 and 12 (all p < 0.05); most APS-POQ pain assessments with NAP/ESO were significantly improved on Days 2–7 compared with placebo (all p < 0.05). A good or excellent response occurred in a median of 6 days. RAPID3 and WOMAC total/stiffness/function/PGA scores decreased significantly at Weeks 6 and 12 (all p < 0.05). Placebo-adjusted WOMAC pain effect sizes were 0.44, 0.34 and 0.25 at Day 7, week 6 and week 12, respectively. RAPID3 to WOMAC total and WOMAC pain to RAPID3: Pain scores were highly correlated at 6 and 12 weeks (correlation coefficients >0.80). No significant differences in overall responses were found between CEL and NAP/ESO. Conclusion. Naproxen/esomeprazole produced a significant absolute moderate early pain response, which was maintained for 12 weeks. RAPID3 was found to be highly correlated with the typical OA measure (WOMAC) and might be a useful clinical tool for measuring NSAID response. NCT00664560: https://clinicaltrials.gov/ct2/show/NCT00664560, NCT00665431: https://www.clinicaltrials.gov/ct2/show/NCT00665431.