Probability of Response in the First Sixteen Weeks After Starting Biologics: An Analysis of Juvenile Idiopathic Arthritis Biologics Trials.

OBJECTIVES: Most juvenile idiopathic arthritis (JIA) biologic disease-modifying antirheumatic drugs (bDMARDs) trials used an open-label run-in period followed by randomized medication withdrawal. We used data from the run-in period of 4 bDMARD trials to 1) delineate early response trajectory to bDMARDs and 2) identify predictors of early response. METHODS: Data from the first 16 weeks of 4 bDMARD trials were used. The primary outcome was the American College of Rheumatology (ACR) Pediatric 50 (Pedi 50) response criteria: clinically significant response defined as ACR Pedi 50 or greater. The secondary outcome was the clinical Juvenile Arthritis Disease Activity Score in 10 joints (cJADAS10) minimal disease activity state. Response transition rates and predictors were modeled using an inhomogeneous Markov multistate model. RESULTS: Five hundred thirty-two participants (70% receiving methotrexate, 41% prednisone) were included. By month 4, the probability of attaining ACR Pedi 50 or greater was 0.698. If ACR Pedi 50 or more was not achieved by month 1, the probability of achieving it by month 4 was 0.60. If ACR Pedi 50 or more was not achieved by month 3, the probability of achieving this by month 4 was 0.31. Age at diagnosis, disease duration, baseline rheumatoid factor, and active joint counts predicted ACR and cJADAS state transitions, adjusted for concomitant treatment. CONCLUSIONS: No response ACR Pedi 50 or more by month 1 after treatment was associated with a 0.60 probability of responding by month 4, but not responding by month 3 was associated with a 0.31 probability of response by month 4. Baseline disease duration, rheumatoid factor, and active joint counts predicted early treatment response (ACR and cJADAS10 states).

Latent classes of early response trajectories to biologics initiation in juvenile idiopathic arthritis: an analysis of four trials.

AIMS: 1) To delineate latent classes of treatment response to biologics in juvenile idiopathic arthritis (JIA) patients in the first 16 weeks after initiation. 2) To identify predictors of early disease response. METHODS: The study population was drawn from four biologics trials in polyarticular course JIA: Etanercept 2000, Abatacept 2008, TRial of Early Aggressive Therapy (TREAT) 2012 and Tocilizumab 2014. The outcome was active joint counts (AJC). Semiparametric latent class trajectory analysis was applied to identify latent classes of response to treatment; AJC was transformed for this modelling. We tested baseline disease and treatment characteristics for their abilities to predict class membership of response. RESULTS: There were 480 participants, 74% females. At baseline, 26% were rheumatoid factor positive. 67% were on methotrexate at enrollment. Three latent class solution provided the best fit. Baseline AJC was the sole best predictor of class membership. Participants classified by their highest membership probabilities into high baseline AJC (> 30) and slow response (26.5%), low baseline AJC (< 10), early and sustained response (29.7%), and moderate baseline AJC progressive response (43.8%). Participants were classified into the latent classes with a mean class membership posterior probability of 0.97. Those on methotrexate at baseline were less likely to belong to high baseline AJC class. CONCLUSIONS: Three latent classes of responses were detectable in the first 16 weeks of biologics therapy. Those with the highest baseline AJC demonstrated very slow response in this window and were less likely to be on concomitant methotrexate. TRIALS REGISTRATION: TREAT 2012 (NCT NCT00443430 ) (Wallace et. al, Arthritis Rheum 64:2012-21, 2012), tocilizumab trial 2014 ( NCT00988221 ), abatacept trial 2008 ( NCT00095173 ). Etanercept 2000 from Amgen does not have a trial registration number.

Quantifying the extent of visit irregularity in longitudinal data.

The timings of visits in observational longitudinal data may depend on the study outcome, and this can result in bias if ignored. Assessing the extent of visit irregularity is important because it can help determine whether visits can be treated as repeated measures or as irregular data. We propose plotting the mean proportions of individuals with 0 visits per bin against the mean proportions of individuals with >1 visit per bin as bin width is varied and using the area under the curve (AUC) to assess the extent of irregularity. The AUC is a single score which can be used to quantify the extent of irregularity and assess how closely visits resemble repeated measures. Simulation results confirm that the AUC increases with increasing irregularity while being invariant to sample size and the number of scheduled measurement occasions. A demonstration of the AUC was performed on the TARGet Kids! study which enrolls healthy children aged 0-5 years with the aim of investigating the relationship between early life exposures and later health problems. The quality of statistical analyses can be improved by using the AUC as a guide to select the appropriate analytic outcome approach and minimize the potential for biased results.

Efficacy, Safety, and Pharmacodynamic Effects of the Bruton's Tyrosine Kinase Inhibitor Fenebrutinib (GDC-0853) in Systemic Lupus Erythematosus: Results of a Phase II, Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: Fenebrutinib (GDC-0853) is a noncovalent, oral, and highly selective inhibitor of Bruton's tyrosine kinase (BTK). The efficacy, safety, and pharmacodynamics of fenebrutinib in systemic lupus erythematosus (SLE) were assessed in this phase II, multicenter, randomized, placebo-controlled study. METHODS: Patients who had moderately to severely active SLE while receiving background standard therapy were randomized to receive placebo, fenebrutinib 150 mg once daily, or fenebrutinib 200 mg twice daily. Glucocorticoid taper was recommended from weeks 0 to 12 and from weeks 24 to 36. The primary end point was the SLE Responder Index 4 (SRI-4) response at week 48. RESULTS: Patients (n = 260) were enrolled from 44 sites in 12 countries, with the majority from Latin America, the US, and Western Europe. The SRI-4 response rates at week 48 were 51% for fenebrutinib 150 mg once daily (P = 0.37 versus placebo), 52% for fenebrutinib 200 mg twice daily (P = 0.34 versus placebo), and 44% for placebo. British Isles Lupus Assessment Group-based Combined Lupus Assessment response rates at week 48 were 53% for fenebrutinib 150 mg once daily (P = 0.086 versus placebo), 42% for fenebrutinib 200 mg twice daily (P = 0.879 versus placebo), and 41% for placebo. Safety results were similar across all arms, although serious adverse events were more frequent with fenebrutinib 200 mg twice daily. By week 48, patients treated with fenebrutinib had reduced levels of a BTK-dependent plasmablast RNA signature, anti-double-stranded DNA autoantibodies, total IgG, and IgM, as well as increased complement C4 levels, all relative to placebo. CONCLUSION: While fenebrutinib had an acceptable safety profile, the primary end point, SRI-4 response, was not met despite evidence of strong pathway inhibition.

Summarizing the extent of visit irregularity in longitudinal data.

BACKGROUND: Observational longitudinal data often feature irregular, informative visit times. We propose descriptive measures to quantify the extent of irregularity to select an appropriate analytic outcome approach. METHODS: We divided the study period into bins and calculated the mean proportions of individuals with 0, 1, and > 1 visits per bin. Perfect repeated measures features everyone with 1 visit per bin. Missingness leads to individuals with 0 visits per bin while irregularity leads to individuals with > 1 visit per bin. We applied these methods to: 1) the TARGet Kids! study, which invites participation at ages 2, 4, 6, 9, 12, 15, 18, 24 months, and 2) the childhood-onset Systemic Lupus Erythematosus (cSLE) study which recommended at least 1 visit every 6 months. RESULTS: The mean proportions of 0 and > 1 visits per bin were above 0.67 and below 0.03 respectively in the TARGet Kids! study, suggesting repeated measures with missingness. For the cSLE study, bin widths of 6 months yielded mean proportions of 1 and > 1 visits per bin of 0.39, suggesting irregular visits. CONCLUSIONS: Our methods describe the extent of irregularity and help distinguish between protocol-driven visits and irregular visits. This is an important step in choosing an analytic strategy for the outcome.

Cancer survivorship and opioid prescribing rates: A population-based matched cohort study among individuals with and without a history of cancer.

BACKGROUND: Little is known about opioid prescribing among individuals who have survived cancer. Our aim is to examine a predominantly socio-economically disadvantaged population for differences in opioid prescribing rates among cancer survivors compared with matched controls without a prior diagnosis of cancer. METHODS: This was a retrospective population-wide matched cohort study. Starting in 2010, individuals residing in Ontario, Canada, who were 18 to 64 years of age and at least 5 years past their cancer diagnosis were matched to controls without a prior cancer diagnosis based on sex and calendar year of birth. Follow-up was terminated at any indication of cancer recurrence, second malignancy, or new cancer diagnosis. To examine the association between survivorship and the rate of opioid prescriptions, an Andersen-Gill recurrent event regression model was implemented, adjusting for numerous individual-level characteristics and also accounting for the matched design. RESULTS: The rate of opioid prescribing was 1.22 times higher among survivors than among their corresponding matched controls (adjusted relative rate, 1.22; 95% CI, 1.11-1.34). Individuals from lower income quintiles who were younger, were from rural neighborhoods, and had more comorbidities had significantly higher prescribing rates. Sex was not associated with prescribing rates. This increased rate of opioid prescribing was also seen among survivors who were 10 or more years past their cancer diagnosis (compared with their controls). CONCLUSION: This study demonstrates substantially higher opioid prescribing rates among cancer survivors, even long after attaining survivorship. This raises concerns about the diagnosis and management of chronic pain problems among survivors stemming from their cancer diagnosis or treatment. Cancer 2017;123:4286-4293. © 2017 American Cancer Society.

Trends and Outcomes of Patent Ductus Arteriosus Treatment in Very Preterm Infants in Canada.

Objective To assess trends in patent ductus arteriosus (PDA) management and examine concurrent changes in neonatal mortality and morbidities. Methods This retrospective observational study examined infants born at 23 to 32 weeks' gestational age with PDA and admitted to a neonatal unit during 2006 to 2012. Multivariable logistic regression assessed trends in yearly PDA treatment rates and compared a composite outcome of mortality or any severe morbidity (bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, or necrotizing enterocolitis) between and within time periods and PDA treatments. Results Study subjects included 5,824 preterm neonates with clinical/echocardiographic PDA diagnosis. During 2006 to 2012, conservative management increased (14-38%), whereas pharmacotherapy-only (58-49%), surgical ligation-only (7.1-2.5%), and both pharmacotherapy and surgical ligation (21-10%) decreased (p-values <0.01). From 2006 to 2008 and 2009 to 2012, the composite outcome decreased for infants managed conservatively (AOR = 0.70, 95% CI 0.52-0.92), with no changes detected for pharmacotherapy and/or ligation. Lower composite outcome after conservative management versus pharmacotherapy-only during 2009 to 2012 (AOR = 0.61, 95% CI 0.51-0.74), but not during 2006 to 2008 reflect significant effect modification by time period. Conclusion In Canada, during 2006 to 2012, conservative PDA management increased while pharmacotherapy and/or surgical ligation decreased. Lower composite outcome was detected during later years after increases in conservative management; however, bias due to unmeasured confounders remains possible.

Trends in unintentional injury mortality in Canadian children 1950-2009 and association with selected population-level interventions.

OBJECTIVES: To examine unintentional injury mortality rates in children (0-19 years) in Canada from 1950 to 2009 against national population-level injury prevention interventions. METHODS: Injury mortality rates were age and sex adjusted. Changes in trend and level of mortality rates were assessed at pre-specified intervention periods using segmented linear regression analyses for interrupted time series. Maximum likelihood estimation was used with a second order autoregressive error process. RESULTS: From 1950 to 2009, the overall unintentional injury mortality rate decreased by 86%. Males had consistently higher mortality rates compared to females; however, the standardized rate ratio decreased from 2.37:1 in 1950 to 1.97:1 in 2009. Substantial declines in choking/suffocation deaths were noted in children less than 1 year of age, predominantly during the period 1970-1988 when the Hazardous Products Act and Crib Regulations were implemented. For burns, significant changes in slope were noted comparing 1972-1994 to pre-1971 (introduction of the Hazardous Products Act - Flammability Regulations), where the greatest decline was noted in children ages 1-4 years (Est. = -0.03, 95% CI = -0.02, -0.04). For 15-19 year olds, there was a 408% increase in motor vehicle collision-related mortality rates between 1950 and 1971; however a significant change in slope was noted during the period 1978-1985, compared to 1972-1977 (Est. = -0.10, 95% CI = -0.20, -0.007) across all age groups. CONCLUSION: While this study is not a cause and effect analysis, there is a strong association with implementation of safety campaigns and legislative changes related to child safety and a dramatic decline in childhood fatalities related to injury.