Population-based study of disease trajectory after radical treatment for high-risk prostate cancer.

OBJECTIVES: To investigate long-term disease trajectories among men with high-risk localized or locally advanced prostate cancer (HRLPC) treated with radical radiotherapy (RT) or radical prostatectomy (RP). MATERIAL AND METHODS: Men diagnosed with HRLPC in 2006-2020, who received primary RT or RP, were identified from the Prostate Cancer data Base Sweden (PCBaSe) 5.0. Follow-up ended on 30 June 2021. Treatment trajectories and risk of death from prostate cancer (PCa) or other causes were assessed by competing risk analyses using cumulative incidence for each event. RESULTS: In total, 8317 men received RT and 4923 men underwent RP. The median (interquartile range) follow-up was 6.2 (3.6-9.5) years. After RT, the 10-year risk of PCa-related death was 0.13 (95% confidence interval [CI] 0.12-0.14) and the risk of death from all causes was 0.32 (95% CI 0.31-0.34). After RP, the 10-year risk of PCa-related death was 0.09 (95% CI 0.08-0.10) and the risk of death from all causes was 0.19 (95% CI 0.18-0.21). The 10-year risks of androgen deprivation therapy (ADT) as secondary treatment were 0.42 (95% CI 0.41-0.44) and 0.21 (95% CI 0.20-0.23) after RT and RP, respectively. Among men who received ADT as secondary treatment, the risk of PCa-related death at 10 years after initiation of ADT was 0.33 (95% CI 030-0.36) after RT and 0.27 (95% CI 0.24-0.30) after RP. CONCLUSION: Approximately one in 10 men with HRLPC who received primary RT or RP had died from PCa 10 years after diagnosis. Approximately one in three men who received secondary ADT, an indication of PCa progression, died from PCa 10 years after the start of ADT. Early identification and aggressive treatment of men with high risk of progression after radical treatment are warranted.

A US real-world study of treatment patterns and outcomes in localized or locally advanced prostate cancer patients.

PURPOSE: Men with localized or locally advanced prostate cancer (LPC/LAPC) are at risk of progression after radiotherapy (RT) or radical prostatectomy (RP). Using real-world data, we evaluated patient characteristics, treatment patterns, and outcomes in LPC/LAPC. METHODS: Optum claims and electronic health records (EHR) data from January 2010 to December 2021 were queried for men with LPC/LAPC who received primary RT, RP, or androgen deprivation therapy alone within 180 days after diagnosis. Survival outcomes were analyzed using descriptive statistics and Kaplan-Meier curves. Real-world overall survival (rwOS) was compared in patients with and without evidence of disease (i.e., disease recurrence, metastasis, diagnosis of castration-resistant PC) at defined time points. RESULTS: 61,772 and 62,361 men in claims and EHR cohorts met the inclusion criteria. Median follow-up was 719 and 901 days, respectively. Most men received primary RT (51.0% claims, 35.0% EHR) or RP (39.4% claims, 53.8% EHR). Survival was greatest among men treated with RP, followed by RT. Adjusted for age and comorbidity, rwOS was shorter among men with evidence of disease within 1, 3, 4, and 5 years after primary treatment than those without at the same time points. CONCLUSION: Real-world claims and EHR data show that survival among men with LPC/LAPC differs by primary treatment and time point of disease recurrence thereafter. Poor outcomes in men with LPC/LAPC who progress early indicate an unmet medical need for more effective primary treatment. If validated for surrogacy, no evidence of disease at specific time points could represent an intermediate efficacy endpoint in future trials.

Teclistamab versus real-world physician's choice of therapy in triple-class exposed relapsed/refractory multiple myeloma.

Aim: We compared the effectiveness of teclistamab versus real-world physician's choice of therapy (RWPC) in triple-class exposed relapsed/refractory multiple myeloma. Materials & methods: MajesTEC-1 eligibility criteria were applied to the RWPC cohort. Baseline covariate imbalances were adjusted using inverse probability of treatment weighting. Overall survival, progression-free survival and time to next treatment were compared. Results: After inverse probability of treatment weighting, baseline characteristics were similar between cohorts (teclistamab, n = 165; RWPC, n = 364 [766 observations]). Teclistamab treated patients had numerically better overall survival (hazard ratio [HR]: 0.82 [95% CI: 0.59-1.14]; p = 0.233) and significantly greater progression-free survival (HR: 0.43 [0.33-0.56]; p < 0.0001) and time to next treatment (HR: 0.36 [0.27-0.49]; p < 0.0001) versus the RWPC cohort. Conclusion: Teclistamab offered clinical benefit over RWPC in triple-class exposed relapsed/refractory multiple myeloma.

Comparative Efficacy of Teclistamab Versus Physician's Choice of Therapy in the Long-term Follow-up of APOLLO, POLLUX, CASTOR, and EQUULEUS Clinical Trials in Patients With Triple-class Exposed Relapsed or Refractory Multiple Myeloma.

BACKGROUND: The efficacy and safety of teclistamab in patients with RRMM who received ≥3 prior lines of therapy and were triple-class exposed (TCE) are being evaluated in the single-arm, multicohort, phase I/II MajesTEC-1 trial (NCT04557098). We evaluated the comparative effectiveness of teclistamab versus physician's choice (PC) of therapy in TCE RRMM patients. METHODS: Individual patient-level data from MajesTEC-1 patients who received teclistamab (1.5 mg/kg weekly; clinical cutoff March 16, 2022) were included. An external control arm was created from patients in long-term follow-up of 4 clinical trials of daratumumab who were treated with PC therapy after discontinuation of trial treatments. In the primary analysis, inverse probability of treatment weighting was used to adjust for imbalances in 9 baseline covariates. A fully adjusted model included 5 additional prognostic factors. Outcomes included overall response rate (ORR), very good partial response or better (≥VGPR) rate, overall survival (OS), progression-free survival (PFS), and time to next treatment (TTNT). RESULTS: After adjustment, baseline characteristics were balanced between cohorts. In the primary analysis, outcomes were significantly improved with teclistamab versus PC: ORR (OR [95% CI] 4.81 [3.04-7.72]; P < .0001); ≥VGPR rate (OR, 12.07 [6.91-22.11]; P < .0001); OS (HR, 0.54 [0.40-0.73]; P < .0001); PFS (HR, 0.59 [0.46-0.78]; P = .0001); and TTNT (HR, 0.32 [0.24-0.42]; P < .0001). Results of the fully adjusted model were consistent with the primary analysis. CONCLUSION: Teclistamab showed significantly improved effectiveness versus PC on all outcomes, highlighting its clinical benefit in patients with TCE RRMM and limited treatment options.

Guselkumab demonstrated an independent treatment effect in reducing fatigue after adjustment for clinical response-results from two phase 3 clinical trials of 1120 patients with active psoriatic arthritis.

BACKGROUND: The interleukin-23p19-subunit inhibitor guselkumab effectively treats signs and symptoms of psoriatic arthritis (PsA). We evaluated the effect of guselkumab on fatigue. METHODS: Across two phase 3 trials of guselkumab (DISCOVER-1, DISCOVER-2), patients with active PsA despite standard therapy were randomized to subcutaneous injections of guselkumab 100 mg every 4 weeks (Q4W, N = 373); guselkumab 100 mg at week 0, week 4, and then Q8W (N = 375); or placebo (N = 372) through week 24, after which patients in the placebo group crossed over to guselkumab Q4W. Fatigue was measured as a secondary endpoint using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue instrument (range 0-52, higher scores indicate less fatigue). Least-squares mean changes in FACIT-Fatigue scores were compared between treatments using a mixed-effect model for repeated measures. Mediation analysis was used to adjust for indirect effects on fatigue deriving from improvement in other outcomes, including ≥20% improvement in American College of Rheumatology criteria (ACR20; prespecified), minimal disease activity (MDA; post hoc), or C-reactive protein (CRP; post hoc). RESULTS: Baseline mean (SD) FACIT-Fatigue scores in DISCOVER-1 (N = 381) and DISCOVER-2 (N = 739), ranging from 29.1 (9.5) to 31.4 (10.1), indicated substantial levels of fatigue relative to the United States general population (43.6 [9.4]). Across studies, mean improvements, and proportions of patients with ≥4-point improvements, in FACIT-Fatigue scores at week 24 with guselkumab Q4W and Q8W (5.6-7.6 and 54-63%, respectively) were larger vs placebo (2.2-3.6 and 35-46%). Improvement in FACIT-Fatigue scores with guselkumab was sustained from week 24 to week 52, with moderate-to-large effect sizes (Cohen's d = 0.52-0.81 at week 24; 0.66-0.91 at week 52). Mediation analyses demonstrated that substantial proportions of the effects of guselkumab vs placebo on fatigue were direct effect, after adjusting for achievement of ACR20 (Q4W 69-70%, Q8W 12-36% direct effect) or MDA (72-92% across dosing regimens) response or for change in serum CRP concentrations (82-88% across dosing regimens). CONCLUSIONS: In patients with active PsA, guselkumab 100 mg Q4W or Q8W led to clinically meaningful and sustained improvements in fatigue through 1 year. A substantial portion of the improvement in FACIT-Fatigue scores induced by guselkumab was independent of effects on the achievement of other select outcomes. TRIAL REGISTRATION: Name of the registry: ClinicalTrials.gov Trial registrations: DISCOVER-1, NCT03162796; DISCOVER-2, NCT03158285 Date of registration: DISCOVER-1, May 22, 2017; DISCOVER-2, May 18, 2017 URLs of the trial registry record: DISCOVER-1, https://clinicaltrials.gov/ct2/show/NCT03162796?term=NCT03162796&draw=1&rank=1 DISCOVER-2, https://clinicaltrials.gov/ct2/show/NCT03158285?term=NCT03158285&draw=2&rank=1.

Treatment Response With Esketamine Nasal Spray Plus an Oral Antidepressant in Patients With Treatment-Resistant Depression Without Evidence of Early Response: A Pooled Post Hoc Analysis of the TRANSFORM Studies.

Objective: To evaluate response to esketamine nasal spray plus an oral antidepressant (ESK + AD) at day 28 in patients with major depressive disorder (DSM-5) and treatment-resistant depression (TRD) who did not meet response criteria within the first week of treatment.Methods: The current study is a pooled post hoc analysis of two phase 3, double-blind, active-controlled studies, conducted between August 2015 and February 2018, comparing ESK + AD with an oral antidepressant plus placebo (AD + PBO). Early treatment response was defined as a ≥ 50% decrease in Montgomery-Åsberg Depression Rating Scale total score at day 2 or days 2 and 8. Response rates at day 28 were determined among those not meeting early response criteria.Results: 518 patients in the analysis had day 28 observations (ESK + AD, n = 310; AD + PBO, n = 208). A greater percentage of patients treated with ESK + AD versus AD + PBO met response criteria beginning at day 2 (17.3% [55/318] vs 9.4% [19/203]) and at all subsequent timepoints, including day 28 (58.7% [182/310] vs 45.2% [94/208]). In day 2 nonresponders, 54.9% vs 44.3% (ESK + AD vs AD + PBO, respectively) achieved response at day 28 (P < .01). Similarly, among day 2 and 8 nonresponders, 52.1% vs 42.4% achieved response by day 28 (P = .01). In nonresponders at day 2 and at days 2 and 8, the odds ratio for a response at day 28 was 1.61 (95% CI, 1.09-2.40) with ESK + AD versus 1.56 (95% CI, 1.04-2.35) with AD + PBO.Conclusions: Patients with TRD without a demonstrated response within the first week of treatment may still derive benefit from a full 4-week induction course of esketamine nasal spray.Trial Registration: ClinicalTrials.gov identifiers NCT02417064 and NCT02418585.

Opioid Use in Patients With Inflammatory Bowel Disease.

Background: Data on opioid use in patients with inflammatory bowel disease and the relationship between disease, opioid use, and healthcare resource utilization are needed. Methods: This analysis of real-world data from IBM Watson Health Commercial Claims and Encounters Database included patients with the first claim of inflammatory bowel disease (IBD) between 2007 and 2014. Results: Opioid use was higher in patients with IBD than in the matched non-IBD cohort. Adjusted for age, gender, and Charlson Comorbidity Index score, inpatient and emergency room visits risk was higher in opioid users than non-users in both IBD cohorts. Conclusions: Opioid use could be a potential surrogate for inadequate disease control manifested by increased inpatient and emergency room visit risks. These results suggest a need exists for better disease management and the development of an outcomes measurement tool for IBD pain.

Reliability, validity and responsiveness of E-RS:COPD in patients with spirometric asthma-COPD overlap.

BACKGROUND: The Evaluating Respiratory Symptoms in Chronic Obstructive Pulmonary Disease (E-RS:COPD) is a patient-reported diary that assesses respiratory symptoms in stable COPD. METHODS: This post hoc analysis of a randomized, double-blind, parallel-arm trial (GSK ID: 200699; NCT02164539) assessed the structure, reliability, validity and responsiveness of the E-RS, and a separate wheeze item, for use in patients with a primary diagnosis of asthma or COPD, but with spirometric characteristics of both (fixed airflow obstruction and reversibility to salbutamol; a subset of patients referred to as spirometric asthma-COPD overlap [ACO]; N = 338). RESULTS: Factor analysis demonstrated that E-RS included Cough and Sputum, Chest Symptoms, and Breathlessness domains, with a Total score suitable for quantifying overall respiratory symptoms (comparative fit index: 0.9), consistent with the structure shown in COPD. The wheeze item did not fit the model. Total and domain scores were internally consistent (Cronbach's alpha: 0.7-0.9) and reproducible (intra-class correlations > 0.7). Moderate correlations between RS-Total and RS-Breathlessness scores were observed with St George's Respiratory Questionnaire (SGRQ) Total and Activity domain scores at baseline (r = 0.43 and r = 0.48, respectively). E-RS scores were sensitive to change when a patient global impression of change and SGRQ change scores were used to define responders, with changes of ≥ - 1.4 in RS-Total score interpreted as clinically meaningful. CONCLUSIONS: E-RS:COPD scores were reliable, valid and responsive in this sample, suggesting the measure may be suitable for evaluating the severity of respiratory symptoms and the effects of treatment in patients with asthma and COPD that exhibit spirometric characteristics of both fixed airflow obstruction and reversibility. Further study of this instrument and wheeze in new samples of patients with ACO is warranted.

Long-Term Impact of Belimumab on Health-Related Quality of Life and Fatigue in Patients With Systemic Lupus Erythematosus: Six Years of Treatment.

OBJECTIVE: To report long-term health-related quality of life (HRQoL) and fatigue outcomes in patients with systemic lupus erythematosus (SLE) receiving belimumab. METHODS: Patients with SLE who completed the Study of Belimumab in Subjects with SLE 76-week trial (BLISS-76) were enrolled in this continuation study (BEL112233 [ClinicalTrials.gov identifier: NCT00724867]). The belimumab groups continued to receive the same dose (1 mg/kg or 10 mg/kg) intravenously. After March 2011, all patients received belimumab 10 mg/kg every 28 days plus standard therapy. The placebo group switched to belimumab 10 mg/kg. HRQoL and fatigue assessments included the Short Form 36 (SF-36) health survey and the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue subscale. Post hoc subgroup analyses (BEL206350) assessed clinical characteristics associated with improved HRQoL and fatigue. RESULTS: Of the 268 patients enrolled, 140 completed the study. Patients receiving long-term belimumab treatment reported continued improvements in HRQoL and fatigue. At study year 6, the mean ± SD SF-36 physical component summary (PCS) score and the mental component summary (MCS) score increased from 37.0 ± 9.9 at baseline to 41.7 ± 10.0 (mean ± SD change 4.8 ± 9.4) and from 44.3 ± 11.3 to 47.0 ± 11.6 (mean ± SD change 2.7 ± 11.3) for the PCS and MCS, respectively, exceeding the minimum clinically important difference (MCID) for improvement (2.5 units). The mean ± SD FACIT-Fatigue score exceeded the MCID of 4 at study years 1-5; at study year 6, the mean ± SD change was 3.7 ± 11.8. Statistically significant associations were observed between parent trial treatment groups and change from baseline in PCS, MCS, and FACIT-Fatigue scores (P < 0.01). CONCLUSION: Long-term control of SLE disease activity with belimumab plus standard therapy translates into meaningful improvements in patient-reported fatigue and HRQoL.

Humanistic outcomes in treatment resistant depression: a secondary analysis of the STAR*D study.

BACKGROUND: In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, a third of patients did not achieve remission or adequate response after two treatment trials, fulfilling requirements for treatment resistant depression (TRD). The present study is a secondary analysis of the STAR*D data conducted to compare the humanistic outcomes in patients with TRD and non-TRD MDD. METHODS: Patients with major depressive disorder who entered level 3 of the STAR*D were included in the TRD group, while patients who responded to treatment and entered follow-up from level 1 or 2 were included in the non-TRD group. The first visit in level 1 was used for baseline assessments. The time-point of assessments for comparison was the first visit in level 3 for TRD patients (median day: 141), and the visit closest to 141 ± 60 days from baseline for non-TRD patients. Outcomes were assessed by the 12-item Short Form Health Survey (SF12), 16-item Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), Work and Social Adjustment Scale (WSAS), and Work Productivity and Activity Impairment scale (WPAI). Scores were compared in a linear model with adjustment for covariates including age, gender, and depression severity measured by the 17-item Hamilton Rating Scale for Depression (HDRS17) and Quick Inventory of Depressive Symptomatology (QIDS). RESULTS: A total of 2467 (TRD: 377; non-TRD: 2090) patients were studied. TRD patients were slightly older (mean age 44 vs 42 years), had a higher proportion of men (49% vs 37%, p < .0001), and baseline depression severity (HDRS17: 24.4 vs 22.0, p < .0001) vs non-TRD patients. During follow-up, TRD patients had lower health-related quality of life (HRQOL) scores on mental (30 vs 45.7) and physical components (47.7 vs 48.9) of the SF12, and lower Q-LES-Q scores (43.6 vs 63.7), greater functional and work impairments and productivity loss vs non-TRD patients (all p < 0.05). CONCLUSION: Patients with TRD had worse HRQOL, work productivity, and social functioning than the non-TRD patients.

The impact of long-term systemic glucocorticoid use in severe asthma: A UK retrospective cohort analysis.

OBJECTIVE: Systemic glucocorticoids (SGCs) are a treatment option for severe asthma but are associated with the development of adverse events (AEs). Evidence on the extent of SGC use and the relationship between SGC dose and AE risk in severe asthma is limited. METHODS: Patients with severe asthma (Global Initiative for Asthma step 4/5), with no SGC use during the <6-12 months before severe asthma determination (index date) were identified in the UK-based Clinical Practice Research Datalink database (2004-2012). Patients were assessed for SGC exposure and an incident diagnosis of an SGC-related AE (cataracts, diabetes, myocardial infarction [MI], osteoporosis, peptic ulcer or stroke) during the 8-year observation phase. The dose-related risk of an SGC-related AE was determined using AE-specific Cox proportional hazards models. RESULTS: Overall, 75% of 60,418 patients identified with severe asthma received SGC during the 8-year follow-up, with the majority receiving an average of >0-≤2.5 mg/day. The risk of diabetes (hazard ratio [HR]:1.20 [95% confidence interval (CI): 1.11, 1.30]), MI (HR: 1.25 [95% CI: 1.09, 1.43]) and osteoporosis (HR: 1.64 [95% CI: 1.51, 1.78]) was increased at low SGC doses (0-2.5 mg/day), with further risk increases at doses >2.5 mg/day versus no SGC use. Compared with no SGC use, SGC increased the risk of peptic ulcer in a non-dose-dependent manner, but the risk of stroke was unchanged. CONCLUSIONS: Most patients with severe asthma are exposed to SGC, which increases SGC-related AE risk. This suggests that SGC exposure should be minimized as recommended by asthma treatment guidelines.

The Burden of Illness Related to Chronic Obstructive Pulmonary Disease Exacerbations in Québec, Canada.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) prevalence in Canada has risen over time. COPD-related exacerbations contribute to the increased health care utilization (HCU) in this population. This study investigated the impact of exacerbations on COPD-related HCU. METHODS: This retrospective observational cohort study used patient data from the Québec provincial health insurance databases. Eligible patients with a new HCU claim with a diagnostic billing for COPD during 2001-2010 were followed until March 31, 2011. Exacerbation rates and time to first exacerbation were assessed. Unadjusted analyses and multivariable models compared the rate of HCU by exacerbation classification (any [moderate/severe], moderate, or severe). RESULTS: The exacerbation event rate in patients with an exacerbation was 34.3 events/100 patient-years (22.7 for moderate exacerbations and 11.6 for severe exacerbations). Median time to first exacerbation of any classification was 37 months. In unadjusted analyses, COPD-related HCU significantly increased with exacerbation severity. In the multivariable, HCU rates were significantly higher after exacerbation versus before exacerbation (p < 0.01) for patients with an exacerbation or moderate exacerbations. For severe exacerbations, general practitioner, respiratory specialist, emergency room, and hospital visits were significantly higher after exacerbation versus before exacerbation (p < 0.001). CONCLUSIONS: Exacerbations were associated with increased HCU, which was more pronounced for patients with severe exacerbations. Interventions to reduce the risk of exacerbations in patients with COPD may reduce disease burden.

Burden of systemic glucocorticoid-related complications in severe asthma.

OBJECTIVES: Although systemic glucocorticoids (SGCs) are efficacious, their chronic use is associated with a range of complications. Yet limited data are available about the risks following chronic use in patients with severe asthma, who are at risk of long-term SGC-related complications. This study was carried out to investigate the risks of developing SGC-related complications, and to quantify the associated healthcare resource utilization and costs for patients with severe asthma in the United States. METHODS: This was a longitudinal, open-cohort, observational study. Medicaid claims data (1997-2013) for patients ≥12 years old with ≥2 asthma diagnoses were used. A total of 26,987 SGC non-users were identified for inclusion in the study, alongside 3628 SGC users with ≥6 months' continuous SGC use. RESULTS: Multivariate generalized estimating equation models were used to estimate the adjusted risk of developing SGC-related complications, and to quantify the associated healthcare resource utilization and costs. This analysis compared SGC users with SGC non-users, and found that SGC users had an increased likelihood of developing complications. A significant dose-response relationship was demonstrated between chronic SGC use and risk of developing any complications (odds ratios for low, medium, and high SGC exposure were 2.03 [p = .0511], 2.85 [p < .0001], and 3.64 [p < .0001], respectively, vs. SGC non-users). The increased likelihood of SGC-related complications translated into estimated annual healthcare costs for SGC users of $2712 to $8560 above those of SGC non-users. A key limitation of this study is the disparity in age between the SGC users and the SGC non-users; however, age was included as a confounding factor in the analysis. CONCLUSIONS: These findings confirm the risk associated with chronic use of SGCs, irrespective of dose level, and highlight the need for new SGC-sparing treatment strategies for patients with severe asthma.

Dose-Response Relationship Between Long-Term Systemic Corticosteroid Use and Related Complications in Patients with Severe Asthma.

BACKGROUND: Systemic corticosteroids are a leading cause of drug-related complications, yet little has been done to quantify the dose-response relationship between systemic corticosteroid exposure and complications in patients with severe asthma. OBJECTIVES: To (a) evaluate the risk of developing systemic corticosteroid-related complications by corticosteroid exposure in severe asthma and (b) quantify the associated health care resource utilization and costs. METHODS: This is a retrospective study using administrative claims data from a large commercial database between 2003 and 2014. Multivariate generalized estimating equation models were used to compare corticosteroid-related complications in patients continuously exposed to at least 5 mg of prednisone or equivalent for ≥ 6 months with a 1:1 ratio of propensity score-matched patients with asthma who did not use corticosteroids. RESULTS: A total of 12,697 corticosteroid users and as many matched nonusers were identified. The odds of developing associated complications increased significantly in a dose-dependent manner with systemic corticosteroid exposure: odds ratios were 2.50, 2.95, and 3.32 (P values <0.05) for low (defined as < 5 mg/day), medium (≥ 5-10 mg/day), and high (>10 mg/day) exposure, respectively, relative to no exposure. Health care resource utilization increased significantly with levels of systemic corticosteroid exposure. Hence, incidence rate ratios for inpatient visits with low, medium, and high exposure relative to none were estimated to be 1.86, 2.40, and 3.37, respectively (P < 0.05). CONCLUSIONS: A significant dose-response relationship was found between the long-term use of systemic corticosteroids and the risk of developing systemic corticosteroid-related complications in patients with severe asthma, resulting in increased burden and costs on the health care system that intensified with systemic corticosteroid exposure. DISCLOSURES: Funding for this study was provided by GlaxoSmithKline, Study number H0-15-15930, to Analysis Group for the conduct of this study. Lefebvre, Duh, and Gozalo are employees of Analysis Group, a contract research organization that has received research grants from GlaxoSmithKline. Robitaille was employed by Analysis Group at the time of this study. Yancey, Forshag, Lin, and Albers are employees of GlaxoSmithKline and own company stock. Dalal and Ortega were employed by GlaxoSmithKline at the time of this study. Lefebvre had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Additionally, all listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. Study concept and design were contributed by Dalal, Duh, Albers, Yancey, Ortega, Forshag, and Lefebvre. Data acquisition was by Dalal, Gozalo, Robitaille, Forshag, and Lefebvre and was analyzed and interpreted by Dalal, Gozalo, Robitaille, Albers, Yancey, Ortega, Forshag, and Lefebvre. The manuscript was drafted and approved by Dalal, Duh, Gozalo, Robitaille, Albers, Yancey, Ortega, Forshag, Lin, and Lefebvre.

Use of ICS/LABA on Asthma Exacerbation Risk in Patients Within a Medical Group.

BACKGROUND: Asthma medication ratio (AMR) ≥ 0.5 has been shown to predict asthma exacerbations. This study explores the impact of increasing or decreasing inhaled corticosteroid/long-acting beta-agonist (ICS/LABA) use over a 7-year period on achieving an AMR of ≥ 0.5. OBJECTIVES: To (a) assess the impact of increasing use of ICS/LABAs on changes in a modified AMR (mAMR) and (b) examine asthma risk over time as measured by an mAMR over a 7-year period, adjusting for differences in baseline characteristics. METHODS: This is a retrospective, observational study using pharmacy and medical claims from a medical group from January 1, 2003, to December 31, 2010. All patients with ≥ 1 asthma diagnosis (ICD-9-CM, 493.xx) with ≥ 1 inhaled asthma medication dispensed in each year of eligibility were included. The mAMR = total ICS controllers dispensed/(total ICS controllers dispensed + albuterol dispensed). The proportion of ICS/LABA use was determined as the number of ICS/LABA canisters dispensed/(total of ICS/LABA + ICS dispensed). Generalized linear mixed models were used to assess the effect of incremental change in ICS/LABA use on mAMR over 7 years, adjusting for differences in resource utilization, time, and asthma medication use.  RESULTS: Nine hundred ninety patients (mean age [± SD] 34.7 years [± 18.2], 61.7% female) met all criteria. Overall, mean mAMR increased over time, while mean albuterol use decreased over time. Adjusting for covariates, we found that a 10% increase in ICS/LABA use was associated with a 9% increase (adjusted OR = 1.09, 95% CI = 1.06-1.12) in the likelihood of achieving an mAMR ≥ 0.5, while a 50% increase in ICS/LABA use was associated with a 53% increase (OR = 1.53, 95% CI = 1.31-1.80) in the likelihood of achieving an mAMR ≥ 0.5. CONCLUSIONS: Increase in ICS/LABA use over time in a population of asthma patients was significantly associated with a higher likelihood of achieving an mAMR ≥ 0.5.

Acute and chronic systemic corticosteroid-related complications in patients with severe asthma.

BACKGROUND: Many patients with severe asthma require maintenance treatment with systemic corticosteroids (SCSs) to control daily symptoms and prevent serious acute exacerbations, but chronic SCS use is associated with complications. OBJECTIVE: We sought to evaluate the risk of SCS-related complications by SCS exposure and quantify the associated health care costs and resource use in patients with severe asthma. METHODS: We performed a longitudinal, open-cohort, observational study using health insurance claims data (1997-2013: Medicaid) from Florida, Iowa, Kansas, Missouri, Mississippi, and New Jersey. Eligible patients were 12 years old or older with 2 or more asthma diagnoses and had more than 6 months of continuous SCS use. An open-cohort approach was used to classify patients' follow-up into low, medium, and high SCS exposure (≤ 6, >6-12, and >12 mg/d, respectively). Multivariate generalized estimating equation models were used to estimate the adjusted risk of SCS-related complications for patients with medium and high exposure compared with patients with low exposure and quantify the resulting health care resource use and costs. RESULTS: The study included 3628 patients (mean age, 57.6 years; 68% female). Patients with medium and high SCS exposure had significantly higher risks of SCS-related complications, including infections and cardiovascular, metabolic, psychiatric, ocular, gastrointestinal, and bone-related complications (odds ratio, 1.23-2.12 by complication; P < .05 for all but one) versus those with low (reference group) SCS exposure. Medium and high SCS exposure were also associated with significantly more emergency department visits (incidence rate ratios, 1.31 [P = .0004] and 1.78 [P < .0001]) and inpatient visits (incidence rate ratios, 1.25 [P < .0001] and 1.59 [P < .0001]) versus low SCS exposure. CONCLUSIONS: A significant dose-response relationship was demonstrated between chronic SCS use and risk of SCS-related complications in patients with severe asthma. Effective SCS-sparing strategies might reduce the burden associated with SCS-related complications in patients with severe asthma.

A proposed modification to Hy's law and Edish criteria in oncology clinical trials using aggregated historical data.

PURPOSE: Identifying drug-induced liver injury is a critical task in drug development and postapproval real-world care. Severe liver injury is identified by the liver chemistry threshold of alanine aminotransferase (ALT) >3× upper limit of normal (ULN) and bilirubin >2× ULN, termed Hy's law by the Food and Drug Administration. These thresholds require discontinuation of the causative drug and are seldom exceeded in most patient populations. However, because maintenance of therapy is critical in the treatment of advanced cancer, customized thresholds may be useful in oncology patient populations, particularly for those with baseline liver chemistries elevations. METHODS: Liver chemistry data from 31 aggregated oncology clinical trials were modeled through a truncated robust multivariate outlier detection (TRMOD) method to develop the decision boundary or threshold for examining liver injury in oncology clinical trials. RESULTS: The boundary of TRMOD identified outliers with an ALT limit 5.0× ULN and total bilirubin limit 2.7× ULN. In addition, TRMOD was applied to the aggregated oncology data to examine fold-baseline ALT and total bilirubin, revealing limits of ALT 6.9× baseline and bilirubin 6.5× baseline. Similar ALT and bilirubin threshold limits were observed for oncology patients both with and without liver metastases. CONCLUSIONS: These higher liver chemistry thresholds examining fold-ULN and fold-baseline data may be valuable in identifying potential severe liver injury and detecting liver safety signals of clinical concern in oncology clinical trials and postapproval settings while helping to avoid premature discontinuation of curative therapy.

Truncated robust distance for clinical laboratory safety data monitoring and assessment.

Laboratory safety data are routinely collected in clinical studies for safety monitoring and assessment. We have developed a truncated robust multivariate outlier detection method for identifying subjects with clinically relevant abnormal laboratory measurements. The proposed method can be applied to historical clinical data to establish a multivariate decision boundary that can then be used for future clinical trial laboratory safety data monitoring and assessment. Simulations demonstrate that the proposed method has the ability to detect relevant outliers while automatically excluding irrelevant outliers. Two examples from actual clinical studies are used to illustrate the use of this method for identifying clinically relevant outliers.

Predicting breast cancer chemotherapeutic response using a novel tool for microarray data analysis.

We developed a novel tool for microarray data analysis that can parsimoniously discover highly predictive genes by finding the optimal trade off between fold change and t-test p value through rigorous cross validation. In addition to find a small set of highly predictive genes, the tool also has a procedure that recursively discovers and removes predictive genes from the dataset until no such genes can be found. We applied our tool to a public breast cancer dataset with the goal to discover genes that can predict patient’s response to a preoperative chemotherapy. The results show that estrogen receptor (ER) gene is the most important gene to predict chemotherapeutic response and no gene signatures can add much clinical benefit for the whole patient population. We further identified a clinically homogenous subgroup of patients (ER-negative, PR-negative and HER2-negative) whose response to the chemotherapy can be reasonably predicted. Many of the discovered predictive markers for this subgroup of patients were successfully validated using a blinded validation set.

Validation of multivariate outlier detection analyses used to identify potential drug-induced liver injury in clinical trial populations.

BACKGROUND: Potential severe liver injury is identified in clinical trials by ALT >3 × upper limits of normal (ULN) and total bilirubin >2 × ULN, and termed 'Hy's Law' by the US FDA. However, there is limited evidence or validation of these thresholds in clinical trial populations. Using liver chemistry data from clinical trials, decision boundaries were built empirically with truncated robust multivariate outlier detection (TRMOD), in a statistically robust manner, and then compared with these fixed thresholds. Additionally, as the analysis of liver chemistry change from baseline has been recently suggested for the identification of liver signals, fold-baseline data was also assessed. OBJECTIVE: The aim of the study was to examine and validate the performance of fixed and empirically derived thresholds for severe liver injury in generally healthy clinical trial populations (i.e. populations without underlying renal, haematological or liver disease). METHODS: Using phase II-IV clinical trial data, ALT and total bilirubin data were analysed using outlier detection methods to compare with empirically derived and fixed thresholds of the FDA's Hy's Law limits, which were then assessed graphically with the FDA's evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) assessing fold-ULN, as well as a modified eDISH (mDISH) to assess fold-baseline liver chemistries. Data from 28 phase II-IV clinical trials conducted by GlaxoSmithKline were aggregated and analysed by the TRMOD algorithm to create decision boundaries. The data consisted of 18 672 predominantly female subjects with a mean age of 44 years and without known liver disease. RESULTS: Among generally healthy clinical trial subjects, the empirically-derived TRMOD boundaries were approximately equivalent to 'Hy's Law'. TRMOD boundaries for identifying outliers were an ALT limit of 3.4 × ULN and a bilirubin limit of 2.1 × ULN, compared with the FDA's 'Hy's Law' of 3 × ULN and bilirubin 2 × ULN. Inter-laboratory data variations were observed across the 28 studies, and were diminished by use of baseline-corrected data. By applying TRMOD to baseline-corrected data, these boundaries became ALT limit of 3.8 × baseline and bilirubin limit of 4.8 × baseline. Cumulative incidence plots of liver signals identified over time were examined. TRMOD analyses identified normative boundaries and outliers that provide comparative data to detect liver signals in similar trial populations. CONCLUSIONS: TRMOD liver chemistry analyses of clinical trial data in generally healthy subjects have confirmed the FDA's Hy's Law threshold as a robust means of detecting liver safety outliers. TRMOD evaluation of liver chemistry data, by both fold-ULN and fold-baseline, provides complementary analyses and valuable normative data for comparison in similar patient populations. No liver signal is present when new clinical trial data from similar patient populations lies within these normative boundaries. Use of baseline-corrected data diminishes inter-laboratory variation and may be more sensitive to possible drug effects. We suggest examining liver chemistries using graphical depictions of both ULN-corrected data (eDISH) and baseline-corrected data (mDISH), as complementary methods.