BackgroundIpratropium bromide/albuterol Respimat inhaler (CVT-R) was developed as an environmentally friendly alternative to ipratropium bromide/albuterol metered-dose inhaler (CVT-MDI), which uses a chlorofluorocarbon propellant.ObjectiveThe objective of this study was to evaluate patient satisfaction, device usage, and long-term safety of CVT-R compared to CVT-MDI, and to the simultaneous administration of ipratropium bromide hydrofluoroalkane (HFA; I) and albuterol HFA (A) metered-dose inhalers as dual monotherapies (I + A).DesignThis is a 48-week, open-label, randomized, active-controlled, parallel-group study (n = 470) comparing CVT-R to CVT-MDI and to I + A.ParticipantsPatients were at least 40 years of age, diagnosed with chronic obstructive pulmonary disease (COPD), and current or exsmokers.InterventionsPatients were randomized to receive: (1) CVT-R, one inhalation four times daily (QID); or (2) CVT-MDI, two inhalations QID; or (3) I + A two inhalations of each inhaler QID.Main measuresPatient Satisfaction and Preference Questionnaire (PASAPQ) performance score (primary endpoint) and adverse events.Key resultsPASAPQ performance score was significantly higher (CVT-R versus CVT-MDI, 9.6; and CVT-R versus I + A, 6.2; both P < 0.001) when using CVT-R compared to CVT-MDI or I + A at all visits starting from week 3, while CVT-MDI and I + A treatment groups were similar. Time to first COPD exacerbation was slightly longer in the CVT-R group compared to the other treatment groups, although it did not reach statistical significance (CVT-R versus CVT-MDI, P = 0.57; CVT-R versus I + A, P = 0.22). Rates of withdrawal and patient refusal to continue treatment were lower in CVT-R compared with CVT-MDI and I + A groups (CVT-R versus CVT-MDI, P = 0.09; CVT-R versus I + A, P = 0.005). The percentage of patients reporting adverse events and serious adverse events was similar across all three treatment groups.ConclusionCVT-R is an effective, environmentally friendly inhaler that provides patients with a high level of user satisfaction and may positively impact clinical outcomes while having no adverse impacts on patients using the device.

SUMMARY The log-rank test is widely used to compare two survival distributions in a randomized clinical trial, while partial likelihood (Cox, 1975) is the method of choice for making inference about the hazard ratio under the Cox (1972) proportional hazards model. The Wald 95% confidence interval of the hazard ratio may include the null value of 1 when the p-value of the log-rank test is less than 0.05. Peto et al. (1977) provided an estimator for the hazard ratio based on the log-rank statistic; the corresponding 95% confidence interval excludes the null value of 1 if and only if the p-value of the log-rank test is less than 0.05. However, Peto’s estimator is not consistent, and the corresponding confidence interval does not have correct coverage probability. In this paper, we construct the confidence interval by inverting the score test under the (possibly stratified) Cox model, and we modify the variance estimator such that the resulting score test for the null hypothesis of no treatment difference is identical to the log-rank test in the possible presence of ties. Like Peto’s method, the proposed confidence interval excludes the null value if and only if the log-rank test is significant. Unlike Peto’s method, however, this interval has correct coverage probability. An added benefit of the proposed confidence interval is that it tends to be more accurate and narrower than the Wald confidence interval. We demonstrate the advantages of the proposed method through extensive simulation studies and a colon cancer study.

TPS5599 Background: Locally advanced squamous cell cancer of the head and neck (SCCHN) is treated with curative intent, but recurrence and death are common. SCCHN frequently over-expresses EGFR (ErbB1). Co-expression of other HER family members such as HER2 (ErbB2) may contribute to resistance to EGFR inhibition, which is the only validated targeted therapy in SCCHN. Methods: The trial investigates if adjuvant afatanib, an irreversible ErbB family blocker, which has shown preclinical activity against all ErbB dimers including EGFR and HER2, reduces the risk of recurrence in high-risk patients who have no evidence of disease following platinum-based chemoradiation with or without neck dissection. Patients are eligible who have received definitive chemoradiation to a minimum of 66 Gy, with concurrent cisplatin (≥200 mg/m2) or carboplatin (≥AUC 9), for SCC of the oral cavity, oropharynx, or hypopharynx or larynx. Patients with base of tongue or tonsil cancer and ≤10 pack years of tobacco use, as well as those with nasopharynx, sinus or salivary gland cancer, are excluded. Adequate bone marrow, liver and kidney function is required. Prior therapy with investigational agents or EGFR inhibitors is not permitted. Randomization must take place within 16 weeks of the completion of chemoradiation with or without subsequent neck dissection. Patients are randomized 2:1 to afatinib 40 mg po qd or placebo, and treatment continues for 18 months in the absence of disease recurrence, second primary tumors, or intolerance to the study medication. Dose escalation to 50 mg qd is undertaken in patients with no side effects, and stepwise dose reduction to 30 or 20 mg po qd for diarrhea, skin toxicity or other adverse events is permitted. The primary endpoint is disease-free survival (DFS). The study is planned to accrue approximately 669 patients worldwide, with a 90% power to detect a hazard ratio of 0.72. Secondary endpoints are DFS at 2 years, overall survival, health-related quality of life, and safety.

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Problem statement:Relative risk has concrete meanings of comparing two groups and measuring the association between exposures and outcomes in medical and public health studies. Logbinomial model, using a log link function on binary outcomes, is straightforward to estimate risk ratios, whereas generates boundary problems. When the estimates are located near the boundary of constrained parameter space, common approaches or procedures using software such as R or SAS fail to converge. Approach: In this study we proposed a truncated algorithm to estimate relative risk using the log-binomial model. We used simulation studies on both single and multiple covariates models to investigate its performance and compare with other similar methods. Results: Our algorithm was shown to outperform other methods regarding precision, especially in high dimensional predictor space. Conclusion: The truncated IWLS method solves the slow convergence problem and provides valid estimates when previously proposed methods fail.