Hui Quan

Effect of Oral Alendronate on Bone Mineral Density and the Incidence of Fractures in Postmenopausal Osteoporosis

BACKGROUND Postmenopausal osteoporosis is a serious health problem, and additional treatments are needed. METHODS We studied the effects of oral alendronate, an aminobisphosphonate, on bone mineral density and the incidence of fractures and height loss in 994 women with postmenopausal osteoporosis. The women were treated with placebo or alendronate (5 or 10 mg daily for three years, or 20 mg for two years followed by 5 mg for one year); all the women received 500 mg of calcium daily. Bone mineral density was measured by dual-energy x-ray absorptiometry. The occurrence of new vertebral fractures and the progression of vertebral deformities were determined by an analysis of digitized radiographs, and loss of height was determined by sequential height measurements. RESULTS The women receiving alendronate had significant, progressive increases in bone mineral density at all skeletal sites, whereas those receiving placebo had decreases in bone mineral density. At three years, the mean (+/- SE) differences in bone mineral density between the women receiving 10 mg of alendronate daily and those receiving placebo were 8.8 +/- 0.4 percent in the spine, 5.9 +/- 0.5 percent in the femoral neck, 7.8 +/- 0.6 percent in the trochanter, and 2.5 +/- 0.3 percent in the total body (P < 0.001 for all comparisons). The 5-mg dose was less effective than the 10-mg dose, and the regimen of 20 mg followed by 5 mg was similar in efficacy to the 10-mg dose. Overall, treatment with alendronate was associated with a 48 percent reduction in the proportion of women with new vertebral fractures (3.2 percent, vs. 6.2 percent in the placebo group; P = 0.03), a decreased progression of vertebral deformities (33 percent, vs. 41 percent in the placebo group; P = 0.028), and a reduced loss of height (P = 0.005) and was well tolerated. CONCLUSIONS Daily treatment with alendronate progressively increases the bone mass in the spine, hip, and total body and reduces the incidence of vertebral fractures, the progression of vertebral deformities, and height loss in postmenopausal women with osteoporosis.

A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2–specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis

BACKGROUND & AIMS Prostaglandin production in the normal gastrointestinal tract, believed to be critical for mucosal integrity, is mediated by cyclooxygenase (COX)-1, whereas prostaglandin production at inflammatory sites seems to occur via induction of COX-2. We hypothesized that COX-2-specific inhibition with rofecoxib (25 mg once daily) in the treatment of patients with osteoarthritis would cause fewer gastroduodenal ulcers than an equally effective dose of ibuprofen (800 mg 3 times a day), a nonspecific COX inhibitor. METHODS A total of 742 osteoarthritis patients without ulcers on baseline endoscopy were randomly assigned to receive rofecoxib (25 or 50 mg once daily), ibuprofen (800 mg 3 times daily), or placebo. Endoscopy was repeated at 6, 12, and 24 weeks. At 16 weeks, by study design, 95% of the placebo group and 5% of the other groups were discontinued. RESULTS The cumulative incidence of gastroduodenal ulcers >/=3 mm with rofecoxib (25 or 50 mg once daily) was significantly (P < 0.001) lower than with ibuprofen and was statistically equivalent to placebo at week 12 (placebo, 9.9%; 25 mg rofecoxib, 4.1%; 50 mg rofecoxib, 7.3%; and ibuprofen, 27.7%). At 24 weeks, ulcer rates were 25 mg rofecoxib, 9. 6%; 50 mg rofecoxib, 14.7%; and ibuprofen, 45.8% (P < 0.001, ibuprofen vs. 25 and 50 mg rofecoxib). CONCLUSIONS Rofecoxib, at doses 2-4 times the dose demonstrated to relieve symptoms of osteoarthritis, caused significantly less gastroduodenal ulceration than ibuprofen, with ulcer rates comparable to placebo.

Comparison of the effect of rofecoxib (a cyclooxygenase 2 inhibitor), ibuprofen, and placebo on the gastroduodenal mucosa of patients with osteoarthritis: A randomized, double‐blind, placebo‐controlled trial

OBJECTIVE This randomized, double-blind study tested the hypothesis that rofecoxib, a drug that specifically inhibits cyclooxygenase 2, would cause fewer gastroduodenal ulcers than ibuprofen (in a multicenter trial), and its side effects would be equivalent to those of placebo (in a prespecified analysis combining the results with another trial of identical design). METHODS Seven hundred seventy-five patients with osteoarthritis were randomized to receive rofecoxib at a dosage of 25 mg or 50 mg once daily, ibuprofen 800 mg 3 times daily, or placebo. Gastroduodenal ulceration was assessed by endoscopy at 6, 12, and (for active treatment) 24 weeks. The primary and secondary end points were the incidence of gastroduodenal ulcers at 12 and 24 weeks, respectively. RESULTS Ulcers were significantly less common (P < 0.001) following treatment with rofecoxib (25 mg or 50 mg) than with ibuprofen after 12 weeks (5.3% and 8.8% versus 29.2%, respectively) or 24 weeks (9.9% and 12.4% versus 46.8%, respectively). In the combined analysis, the 12-week ulcer incidence with 25 mg rofecoxib (4.7%) and with placebo (7.3%) satisfied prespecified criteria for equivalence. CONCLUSION At 2-4 times the therapeutically effective dose, rofecoxib caused fewer endoscopically detected ulcers than did ibuprofen. Rofecoxib at a dose of 25 mg (the highest dose recommended for osteoarthritis) satisfied prespecified criteria for equivalence to placebo.

The upper GI safety and tolerability of oral alendronate at a dose of 70 milligrams once weekly: a placebo-controlled endoscopy study

OBJECTIVE:Alendronate (10 mg daily) has been shown in long term clinical trials to be an effective treatment for postmenopausal osteoporosis. A weekly dosing regimen of alendronate is preferred by both patients and physicians, as it has the potential to provide greater convenience and enhance compliance. In a 1-yr clinical trial, alendronate (70 mg once weekly) was equally efficacious and at least as well tolerated as the 10-mg daily dose in the treatment of postmenopausal osteoporosis, despite the higher unit dosage required. We conducted a randomized, double blind, placebo- and active-controlled endoscopy study to confirm the results of this clinical trial. We hypothesized that mean endoscopic gastric erosion scores would be similar in subjects receiving alendronate (70 mg once weekly) and those receiving a placebo.METHODS:Two hundred seventy-seven subjects (90 men and 187 women) were randomized to one of three treatment groups: 1) alendronate (70 mg once weekly) for 10 wk (N = 126), 2) placebo (once weekly) for 10 wk (N = 126), or 3) placebo (once weekly) for 10 wk followed by aspirin (650 mg q.i.d.) for the last week as the positive control (N = 25). Esophagogastroduodenoscopy was performed 5 to 7 days after the last dose of alendronate or matching placebo.RESULTS:The mean gastric erosion scores (Lanza scale) were similar in subjects given alendronate (70 mg once weekly) and those given a placebo (0.32 vs 0.35, respectively; 95% CI for difference =− 0.22–0.16, p = 0.75), whereas scores in both groups were significantly lower than in those given aspirin (3.09; p < 0.001). Endoscopic gastroduodenal ulcers occurred in no alendronate (0%), two placebo (1.7%), and five aspirin (23.8%) subjects. The mean erosion scores in the esophagus and duodenum of alendronate and placebo subjects were also similar. The incidences of upper GI symptoms were similar in the alendronate and placebo subjects and did not suggest a relationship with endoscopic lesions.CONCLUSIONS:Alendronate (70 mg once weekly) was not associated with any increase in endoscopic lesions in the upper GI tract relative to a placebo.

Influence of risk factors on endoscopic and clinical ulcers in patients taking rofecoxib or ibuprofen in two randomized controlled trials.

Highly selective inhibitors of the inducible cyclooxygenase‐2 enzyme (coxibs) have been associated with less gastrotoxicity than nonselective NSAIDs in clinical studies.

Assessment of Consistency of Treatment Effects in Multiregional Clinical Trials

Multiregional clinical trials (MRCTs) present great opportunities but also challenges to the trial community. To address the challenges and fully realize the opportunities, a PhRMA MRCT Cross-Functional Key Issue Team (KIT) was formed in 2008. One of the work streams within the KIT particularly focuses on the assessment of consistency of treatment effects across regions. As the main objective of this work stream, this research explores a number of definitions for consistency assessments. We address the issues primarily for superiority trials with continuous endpoints, then extend briefly to noninferiority trials, random effect models, binary endpoints, and survival endpoints. Computations and simulations are used to study the properties of the proposed definitions, particularly the power for showing consistency. To illustrate applications of the methods, we use a trial example with a continuous endpoint. We discuss considerations for trial design as well as for data analysis. The consistency assessment relies heavily on the definition of regions and the number of regions. We recommend working with health authorities to define region in a manner that is sensible from a practical interpretation standpoint and also makes region consistency assessment a feasible undertaking.

Assessing consistent treatment effect in a multi-regional clinical trial: a systematic review†

A key issue in multi-regional clinical trials (MRCTs) is how to assess the consistency of treatment effect across regions, although there is no a priori reason to believe that the treatment effect should vary across the regions. In this article, we define the research question as an assessment of overall consistency across all regions for which all regions are considered equally important. This is different from the region/country-specific analyses (e.g. US vs Non-US), which are frequently requested by local regulatory agencies and usually performed for multiple agencies. We provide a systematic review of methods that may potentially be used for assessing consistency across regions, including commonly used quantitative/qualitative interaction tests, Japanese Pharmaceutical Medical Device Agency (PMDA) Methods 1 & 2, and those proposed for different purposes (e.g. bridging studies, meta-analysis, and vaccine lot consistency, among others). These methods are classified into three groups: global methods, multivariate quantitative methods, and multivariate qualitative methods. A case study is used to illustrate these methods. We also provide recommendations on how to choose appropriate methods and incorporate them in the study design.

Empirical shrinkage estimator for consistency assessment of treatment effects in multi-regional clinical trials.

Multi-regional clinical trials have been widely used for efficient global new drug developments. Both a fixed-effect model and a random-effect model can be used for trial design and data analysis of a multi-regional clinical trial. In this paper, we first compare these two models in terms of the required sample size, type I error rate control, and the interpretability of trial results. We then apply the empirical shrinkage estimation approach based on the random-effect model to two criteria of consistency assessment of treatment effects across regions. As demonstrated in our computations, compared with the sample estimator, the shrinkage estimator of the treatment effect of an individual region borrowing information from the other regions is much closer to the estimator of the overall treatment effect, has smaller variability, and therefore provides much higher probability for demonstrating consistency. We use a multinational trial example with time to event endpoint to illustrate the application of the method.

Consistency of Treatment Effect across Regions in Multiregional Clinical Trials, Part 2: Monitoring, Reporting, and Interpretation

The degree of consistency of treatment effects seen across regions within a multiregional clinical trial has important implications for all stakeholders. It can affect the ability of the trial results to be interpreted by the scientific community in an unambiguous manner and can have important ramifications for regulatory decision making. This article is part of a PhRMA teams effort to provide perspective and recommendations on this issue. A companion article from the same team focuses on relevant design considerations, while in this article the focus is on monitoring considerations specific to multiregional trials, on how the final trial results should be presented, and on thought processes that are relevant to how signals of inconsistency should be investigated and interpreted.

Consistency of Treatment Effect across Regions in Multiregional Clinical Trials, Part 1: Design Considerations

Assessment of consistency of treatment effect across regions is often a key issue in a multiregional clinical trial (MRCT) because of differences in intrinsic and extrinsic factors. Careful consideration of consistency assessment of treatment effect across regions is necessary at the design stage. This article is part 1 of a cross-industry PhRMA teams effort to provide perspective and recommendations on the issue of regional consistency, with primary focus on design considerations. We argue that given the premise of an MRCT that there is no or limited regional variation, choices of appropriate consistency criteria for assessing regional consistency need to reflect this a priori belief and should not add an additional burden of proving regional consistency in addition to meeting the primary study objectives. The total sample size of the MRCT should be mainly driven by the primary objectives and hypotheses. Appropriate sample size partitioning and distribution across regions may be considered to achieve a target “assurance probability” based upon predefined consistency criteria such as modified PMDA (Pharmaceutical and Medical Devices Agency) methods. Prespecification and documentation of the plan for regional assessment in the protocol are important for interpreting the results. We also encourage communication with health authorities, and acknowledge negotiation may be necessary to reach an agreement, especially when there are region or country-specific interests.