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Background: Pain is a common symptom of hemophilia that may adversely affect patients’ quality of life (QoL). Previous post hoc analyses of prophylaxis with recombinant factor IX Fc fusion protein (rFIXFc) have been published for adults and adolescents, demonstrating improvements in health-related QoL (HRQoL) when assessed by the haemophilia-specific QoL (HaemAQoL) questionnaire. Objective: To describe in depth the evolution of QoL, pain- and activity-related domains and questions for pediatric, adolescent, and adult patients with hemophilia B treated with rFIXFc prophylaxis. Design: A post hoc analysis of data from a series of clinical trials. Methods: This post hoc , long-term analysis assessed patient-reported outcomes (PROs) from the Kids B-LONG (NCT01440946: pediatric) and B-LONG (NCT01027364: adults and adolescents) parent studies and the B-YOND (NCT01425723: all age groups) extension study. Results: Ninety-two adult and adolescent patients that started in the B-LONG study were assessed, with a median (range) duration of follow-up of 58.9 (0.0–78.4) months. The Haem-A-QoL total score was significantly reduced from baseline by 4.45 ( p ⩽ 0.01), as were the subdomains ‘physical health’ (9.10; p = 0.001), ‘sports and leisure’ (11.25; p ⩽ 0.01), ‘treatment’ (2.69; p = 0.05), and ‘view of self’ (5.81; p = 0.002). Thirty pediatric patients that started in the Kids B-LONG study were assessed, with a median (min–max) duration of follow-up of 36.7 (9.0–59.9) months. The high level of satisfaction demonstrated by the PROs at baseline was maintained. Conclusion: rFIXFc prophylaxis reduced perceived pain and increased levels of physical activity with sustained, long-term improvements in QoL in adult and adolescent patients with hemophilia B and maintained high QoL scores in pediatric patients.

Background: Pain, a common symptom of hemophilia, begins early in life primarily due to joint bleeding. Recurrent bleeding adversely affects patients’ pain-related physical functioning, which can negatively impact their quality of life (QoL). Objective: Post hoc analysis of data from the A-LONG study (NCT01181128), to assess change over time in pain-related QoL in patients with severe hemophilia A treated prophylactically with recombinant factor VIII Fc fusion protein (rFVIIIFc). Methods: Patients who completed Haem-A-QoL (17–65 years) and EQ-5D-3L (⩾12–65 years) questionnaires at baseline (BL) and end of study (EoS). Individual-level changes were assessed using three pain-related items of the Haem-A-QoL ‘Physical Health’ domain and the pain/discomfort item of EQ-5D-3L. Distributions of responses (EoS versus BL) were compared using McNemar’s test. Results: A significantly greater proportion of patients reported they did not experience painful swellings ( n = 87; 66% versus 46%, p < 0.01) or pain in their joints ( n = 89; 42% versus 27%; p < 0.05) at EoS versus BL. The proportion of patients who did not find it painful to move numerically increased at EoS versus BL ( n = 86; 47% versus 38%; p = NS). A significantly greater proportion of patients reported no pain/discomfort at EoS versus BL ( n = 116; 45% versus 34%; p < 0.05). Conclusion: This study reports the effect of FVIII prophylaxis on patient-reported measures of pain over time in patients with severe hemophilia A. The results of this post hoc analysis showed improvements in pain from BL to EoS in patients receiving rFVIIIFc individualized prophylaxis indicating effective pain management, a key component of patient care.

PurposeObservational studies using routinely collected data are faced with a number of potential shortcomings that can bias their results. Many methods rely on controlling for measured and unmeasured confounders. In this work, we investigate the use of instrumental variables (IV) and quasi-trial analysis to control for unmeasured confounders in the context of a study based on the retrospective Epidemiological Strategy and Medical Economics (ESME) database, which compared overall survival (OS) with paclitaxel plus bevacizumab or paclitaxel alone as first-line treatment in patients with HER2-negative metastatic breast cancer (MBC).Patients and methodsCausal interpretations and estimates can be made from observation data using IV and quasi-trial analysis. Quasi-trial analysis has the same conceptual basis as IV, however, instead of using IV in the analysis, a "superficial" or "pseudo" randomized trial is used in a Cox model. For instance, in a multicenter trial, instead of using the treatment variable, quasi-trial analysis can consider the treatment preference in each center, which can be informative, and then comparisons of results between centers or clinicians can be informative.ResultsIn the original analysis, the OS adjusted for major factors was significantly longer with paclitaxel and bevacizumab than with paclitaxel alone. Using the center-treatment preference as an instrument yielded to concordant results. For the quasi-trial analysis, a Cox model was used, adjusted on all factors initially used. The results consolidate those obtained with a conventional multivariate Cox model.ConclusionUnmeasured confounding is a major concern in observational studies, and IV or quasi-trial analysis can be helpful to complement analysis of studies of this nature.

BackgroundIn oncology, the aim of dose-finding phase I studies is to find the maximum tolerated dose for further studies. The use of combinations of two or more agents is increasing. Several dose-finding designs have been proposed for this situation. Numerous publications have however pointed out the complexity of evaluating therapies in combination due to difficulties in choosing between different designs for an actual trial, as well as complications related to their implementation and application in practice.MethodsIn this work, we propose R functions for Wang and Ivanova's approach. These functions compute the dose for the next patients enrolled and provide a simulation study in order to calibrate the design before it is applied and to assess the performance of the design in different scenarios of dose-toxicity relationships. This choice of the method was supported by a simulation study which the aim was to compare two designs in the context of an actual phase I trial: i) in 2005, Wang and Ivanova developed an empirical three-parameter model-based method in Bayesian inference, ii) in 2008, Yuan and Yin proposed a simple, adaptive two-dimensional dose-finding design. In particular, they converted the two-dimensional dose-finding trial to a series of one-dimensional dose-finding sub-trials by setting the dose of one drug at a fixed level. The performance assessment of Wang's design was then compared with those of designs presented in the paper by Hirakawa et al. (2015) in their simulation context.Results and conclusionIt is recommended to assess the performances of the designs in the context of the clinical trial before beginning the trial. The two-dimensional dose-finding design proposed by Wang and Ivanova is a comprehensive approach that yields good performances. The two R functions that we propose can facilitate the use of this design in practice.