Sample Size Reestimation in Stochastic Curtailment Tests With Time-to-Events Outcome in the Case of Nonproportional Hazards Utilizing Two Weibull Distributions With Unknown Shape Parameters.

Stochastic curtailment tests for Phase II two-arm trials with time-to-event end points are traditionally performed using the log-rank test. Recent advances in designing time-to-event trials have utilized the Weibull distribution with a known shape parameter estimated from historical studies. As sample size calculations depend on the value of this shape parameter, these methods either cannot be used or likely underperform/overperform when the natural variation around the point estimate is ignored. We demonstrate that when the magnitude of the Weibull shape parameters changes, unblinded interim information on the shape of the survival curves can be useful to enrich the final analysis for reestimation of the sample size. For such scenarios, we propose two Bayesian solutions to estimate the natural variations of the Weibull shape parameter. We implement these approaches under the framework of the newly proposed relative time method that allows nonproportional hazards and nonproportional time. We also demonstrate the sample size reestimation for the relative time method using three different approaches (internal pilot study approach, conditional power, and predictive power approach) at the interim stage of the trial. We demonstrate our methods using a hypothetical example and provide insights regarding the practical constraints for the proposed methods.

Group sequential design for time-to-event outcome with non-proportional hazards using the concept of relative time utilizing two different Weibull distributions.

A group sequential design allows investigators to sequentially monitor efficacy and safety as part of interim testing in phase III trials. Literature is well developed in the case of continuous and binary outcomes, however, in case of trials with a time-to-event outcome, popular methods of sample size calculation often assume proportional hazards. In situations where the proportional hazards assumption is inappropriate as indicated by historical data, these popular methods are very restrictive. In this paper, a novel simulation-based group sequential design is proposed for a two-arm randomized phase III clinical trial with a survival endpoint for the non-proportional hazards scenario. By assuming that the survival times for each treatment arm follow two different Weibull distributions, the proposed method utilizes the concept of Relative Time to calculate the efficacy and safety boundaries at selected interim testing points. The test statistic used to generate these boundaries is asymptotically normal, allowing p-value calculation at each boundary. Many design features specific to time-to-event data can be incorporated with ease. Additionally, the proposed method allows the flexibility of having the accelerated failure time model and the proportional hazards model as constrained special cases. Real life applications are discussed demonstrating the practicality of the proposed method.

P2Y12 Inhibitors Refill Gap Predicts Death in Medicare Beneficiaries on Chronic Dialysis.

Introduction: Oral P2Y12 inhibitors (P2Y12-I) are commonly used antiplatelet drugs in patients with end-stage kidney disease (ESKD) on chronic dialysis. Although gaps in prescription refills are quite common in patients with ESKD, it remains unclear whether P2Y12-I prescription refill patterns are associated with adverse clinical outcomes. Methods: We used the United States Renal Data System (USRDS) registry for patients with ESKD to capture new P2Y12-I prescriptions from 2011 to 2015. The primary exposure was prescription refill patterns and the primary outcome was all-cause death. Results: Among the 31,243 patients with new P2Y12-I prescription, median age was 64 years; 54% were male; and 39% were Caucasian, 37% African American, and 18% Hispanic. We observed 3 P2Y12-I refill patterns as follows: continuous users (45.1%), noncontinuous users (3.6%), and users with ≥30 days refill gap (51.4%). Prescription refill pattern with ≥30 days refill gap (vs. continuous use) was associated with all-cause death (adjusted hazard ratio [HR]: 1.18; 95% confidence interval [CI]: 1.13-1.23). Age and race were the most important risk factors associated with prescription refill pattern. African Americans (vs. Caucasians) were more likely to demonstrate ≥30 days refill gap, (adjusted odds ratio [OR]: 1.43; 95% CI: 1.36-1.51). In addition, younger patients (vs. older) were more likely to demonstrate ≥30 day refill gap (adjusted OR/decade: 0.9; 95% CI: 0.89-0.92). Conclusion: Nonadherence to P2Y12-I prescriptions is quite common, and disproportionately affects minorities. Younger individuals with ESKD are independently associated with a higher risk of death. The odds of having a refill gap are decreasing for older patients who are more compliant than younger patients. Future studies should investigate whether phenotyping subgroups of patients with ESKD based on prescription refill patterns can help in improving adverse clinical outcomes.

Pain and Health-Related Quality of Life in Autosomal Dominant Polycystic Kidney Disease: Results from a National Patient-Powered Registry.

Rationale & Objective: Autosomal dominant polycystic kidney disease (ADPKD) affects health-related quality of life (HRQoL) including pain, discomfort, fatigue, emotional distress, and impaired mobility. Stakeholders prioritized kidney cyst-related pain as an important core outcome domain in clinical trials, leading to the development of disease-specific assessment tools. Study Design: The ADPKD Registry is hosted online with multiple disease-specific patient-reported outcomes modules to characterize the patient experience in the United States. Setting & Participants: The ADPKD Registry allows consented participants access to a Core Questionnaire that includes demographics, comorbid conditions, current symptoms, and kidney function. Participants complete subsequent modules on a 3-month schedule, including 2 validated HRQoL tools, the ADPKD-Pain and Discomfort Scale (ADPKD-PDS), the ADPKD Impact Scale (ADPKD-IS) and a Healthcare Access and Utilization module. Exposures: Patient-reported latest estimated glomerular filtration rate or creatinine used to calculate stage of chronic kidney disease. Outcomes: Health-related quality of life, measured using validated ADPKD-specific tools; access to polycystic kidney disease-specific health care. Analytical Approach: For the 2 HRQoL tools, scores were calculated for physical, emotional, and fatigue domains; pain severity; and pain interference (based on the licensed user manuals). Associations to health care access were also assessed. Results: By July 2022, 1,086 individuals with ADPKD completed at least 1 of the HRQoL modules, and 319 completed 4 over a year. Participants were an average age of 53. In total, 71% were women, and 91% were White, with all chronic kidney disease (CKD) stages represented. In total, 2.5% reported being treated with dialysis, and 23% had a kidney transplant. CKD stage 4/5 participants reported the most dull kidney pain, whereas sharp kidney pain was evenly distributed across early CKD stages. Dull kidney pain had an impact on sleep regardless of CKD stage. There was a strong positive correlation between the ADPKD-PDS and ADPKD-IS. Patients with a neutral or positive HRQoL were less likely to have been denied access to imaging or other care. Limitations: Currently, all the information collected is patient reported without health record validation of clinical variables. Conclusions: Use of the HRQoL tools in the ADPKD Registry provided a broad cross-sectional assessment in the United States and provided granular information on the burden of pain across the CKD spectrum in ADPKD. The ADPKD Registry allowed assessment of ADPKD impact in a community that experiences decline in health and kidney function over decades.

The Autosomal Dominant Polycystic Kidney Disease Registry is a longitudinal, patient-powered research tool created with the goal to better understand the impacts of ADPKD on affected individuals in the United States. Here, we analyze pain and other health-related quality of life outcomes in 1,086 individuals using validated tools and comment on the utility of these tools for future use in clinical trials and observational studies. We found that sharp pain, dull pain, fullness discomfort, and other related impacts affected individuals across the disease spectrum, although some participants reported more dull pain in later stages (CKD stages 4 and 5). Future analysis of these trends over time will be valuable in understanding how to assess and address the burden of pain in autosomal dominant polycystic kidney disease.

Clinical and biomarker results from a phase II trial of combined cabozantinib and durvalumab in patients with chemotherapy-refractory colorectal cancer (CRC): CAMILLA CRC cohort.

CAMILLA is a basket trial (NCT03539822) evaluating cabozantinib plus the ICI durvalumab in chemorefractory gastrointestinal cancer. Herein, are the phase II colorectal cohort results. 29 patients were evaluable. 100% had confirmed pMMR/MSS tumors. Primary endpoint was met with ORR of 27.6% (95% CI 12.7-47.2%). Secondary endpoints of 4-month PFS rate was 44.83% (95% CI 26.5-64.3%); and median OS was 9.1 months (95% CI 5.8-20.2). Grade≥3 TRAE occurred in 39%. In post-hoc analysis of patients with RAS wild type tumors, ORR was 50% and median PFS and OS were 6.3 and 21.5 months respectively. Exploratory spatial transcriptomic profiling of pretreatment tumors showed upregulation of VEGF and MET signaling, increased extracellular matrix activity and preexisting anti-tumor immune responses coexisting with immune suppressive features like T cell migration barriers in responders versus non-responders. Cabozantinib plus durvalumab demonstrated anti-tumor activity, manageable toxicity, and have led to the activation of the phase III STELLAR-303 trial.