Patient-reported outcomes in ZUMA-7, a phase 3 study of axicabtagene ciloleucel in second-line large B-cell lymphoma.

Here, we report the first comparative analysis of patient-reported outcomes (PROs) with chimeric antigen receptor T-cell therapy vs standard-of-care (SOC) therapy in second-line relapsed/refractory large B-cell lymphoma (R/R LBCL) from the pivotal randomized phase 3 ZUMA-7 study of axicabtagene ciloleucel (axi-cel) vs SOC. PRO instruments were administered at baseline, day 50, day 100, day 150, month 9, and every 3 months from randomization until 24 months or an event-free survival event. The quality of life (QoL) analysis set comprised patients with a baseline and ≥1 follow-up PRO completion. Prespecified hypotheses for Quality of Life Questionnaire-Core 30 (QLQ-C30) physical functioning, global health status/QoL, and EQ-5D-5L visual analog scale (VAS) were tested using mixed-effects models with repeated measures. Clinically meaningful changes were defined as 10 points for QLQ-C30 and 7 for EQ-5D-5L VAS. Among 359 patients, 296 (165 axi-cel, 131 SOC) met inclusion criteria for QoL analysis. At day 100, statistically significant and clinically meaningful differences in mean change of scores from baseline were observed favoring axi-cel over SOC for QLQ-C30 global health status/QoL (estimated difference 18.1 [95% confidence interval (CI), 12.3-23.9]), physical functioning (13.1 [95% CI, 8.0-18.2]), and EQ-5D-5L VAS (13.7 [95% CI, 8.5-18.8]; P < .0001 for all). At day 150, scores significantly favored axi-cel vs SOC for global health status/QoL (9.8 [95% CI, 2.6-17.0]; P = .0124) and EQ-5D-5L VAS (11.3 [95% CI, 5.4-17.1]; P = .0004). Axi-cel showed clinically meaningful improvements in QoL over SOC. Superior clinical outcomes and favorable patient experience with axi-cel should help inform treatment choices in second-line R/R LBCL. This trial was registered at www.clinicaltrials.gov as #NCT03391466.

A quality-adjusted survival time without symptoms or toxicities analysis of glasdegib plus low-dose cytarabine versus low-dose cytarabine as initial therapy for acute myeloid leukemia in patients who are not considered candidates for intensive chemotherapy.

BACKGROUND: In a randomized study, glasdegib (a hedgehog inhibitor) plus low-dose cytarabine (LDAC) significantly prolonged survival in comparison with LDAC in patients with acute myeloid leukemia (AML). A quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) approach was used to evaluate comparative quality-adjusted survival. METHODS: Overall survival was partitioned into the following: time with any treatment-emergent grade 3 or higher adverse events (TOX); time without symptoms of disease progression or toxicity (TWiST); and time after treatment discontinuation due to insufficient clinical response, relapse, or death time after progression (REL). Q-TWiST was calculated by multiplying the restricted mean time in each state by respective utilities and then summing up the utility-adjusted time. RESULTS: At 20 months of follow-up, the survival probabilities for the glasdegib-LDAC arm and the LDAC arm were 28.2% and 7.9%, respectively. Glasdegib-LDAC patients (n = 78), in comparison with LDAC patients (n = 38), had significantly longer mean TWiST (+3.4 months; 95% confidence interval [CI], 1.8-5.2 months) and TOX (+0.8 months; 95% CI, 0.1-1.6 months) and longer but nonsignificant REL (+0.3 months; 95% CI, -1.9 to 2.3 months). Q-TWiST was 4.0 months (95% CI, 2.1-5.8 months) longer with glasdegib plus LDAC, and this translated into a 75% relative improvement in quality-adjusted survival with respect to LDAC. Results were robust to the length of follow-up (6-24 months) and remained significant when all adverse events, regardless of grade, were included. CONCLUSIONS: These results suggest that most of the survival benefit from glasdegib plus LDAC versus LDAC alone is TWiST, and this represents added time in relatively "good" health. These results support the clinical value of glasdegib plus LDAC as initial therapy for AML in patients for whom intensive chemotherapy is not an option.

Quality-adjusted survival with combination nal-IRI+5-FU/LV vs 5-FU/LV alone in metastatic pancreatic cancer patients previously treated with gemcitabine-based therapy: a Q-TWiST analysis.

BACKGROUND: In the NAPOLI-1 Phase 3 trial, nal-IRI+5-fluorouracil and leucovorin (5-FU/LV) significantly improved median overall survival (6.1 vs 4.2 months, P=0.012) and progression-free survival (3.1 vs 1.5 months, P=0.0001) vs 5-FU/LV alone in metastatic pancreatic adenocarcinoma patients previously treated with gemcitabine-based therapy. This analysis evaluated between treatment differences in quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST). METHODS: Overall survival was partitioned into time with grade ⩾3 toxicity (TOX), disease progression (REL), and time without disease progression symptoms or grade ⩾3 toxicity (TWiST). Mean Q-TWiST was calculated by weighting time spent by a utility of 1.0 for TWiST and 0.5 for TOX and REL. In threshold analyses, utility for TOX and REL were varied from 0.0 to 1.0. RESULTS: Patients in nal-IRI+5-FU/LV (n=117) vs 5-FU/LV (n=119) had significantly more mean time in TWiST (3.4 vs 2.4 months) and TOX (1.0 vs 0.3 months) but similar REL (2.5 vs 2.7 months). In the base case, nal-IRI+5-FU/LV patients had 1.3 months (95% CI, 0.4-2.1; 5.1 vs 3.9) greater Q-TWiST (threshold analyses range: 0.9-1.6 months). CONCLUSIONS: Within NAPOLI-1, nal-IRI+5-FU/LV resulted in statistically significant and clinically meaningful gains in quality-adjusted survival vs 5-FU/LV alone.

Impact of pulmonary exacerbations and lung function on generic health-related quality of life in patients with cystic fibrosis.

BACKGROUND: The analysis aimed to examine the impact of pulmonary exacerbations (PEs) and lung function on generic measures of HRQL in patients with cystic fibrosis (CF) using trial-based data. METHODS: In a 48-week randomized, placebo-controlled study of ivacaftor in patients ≥12 years with CF and a G551D-CFTR mutation the relationship between PEs, PE-related hospitalizations and percent predicted forced expiratory volume in one second (ppFEV1) with EQ-5D measures (index and visual analog scale [VAS]) was examined in post-hoc analyses. Multivariate mixed-effects models were employed to describe the association of PEs, PE-related hospitalizations, and ppFEV1 on EQ-5D measures. RESULTS: One hundred sixty one patients (age: mean 25.5 [SD 9.5] years; baseline ppFEV1: 63.6 [16.4]) contributed 1,214 observations (ppFEV1: no lung dysfunction [n = 157], mild [n = 419], moderate [n = 572], severe [n = 66]). Problems were most frequently reported on pain/discomfort, anxiety/depression, and usual activities EQ-5D items. The mean (SE) EQ-5D index nominally decreased (worsened) with worsening severity of lung dysfunction (P = 0.070): 0.931 (0.023); mild: 0.923 (0.021); moderate: 0.904 (0.018); severe: 0.870 (0.020). 146 PEs were experienced by 72 patients, including 52 PEs (35.6 %) that required hospitalization. Mean EQ-5D index and VAS scores were lowest (worst) within 1 week (before or after PE start) for PEs requiring hospitalization. Pulmonary exacerbations, PE-related hospitalizations, and ppFEV1 were significant predictors of EQ-5D index and VAS. CONCLUSIONS: In a clinical study of patients with CF (≥12 years of age and a G551D-CFTR mutation), PEs, primarily those requiring hospitalization, were associated with low EQ-5D index and VAS scores. The impact of ppFEV1 was relatively smaller. Reducing PEs, in particular those requiring hospitalization, would likely improve HRQL among these patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00909532 ; URL: clinicaltrials.gov, May 26, 2009.

A European chart review study on early rheumatoid arthritis treatment patterns, clinical outcomes, and healthcare utilization.

This retrospective medical chart review aimed to provide a current, real-world overview of biologic usage in patients with rheumatoid arthritis (RA) in Germany, Spain, and the UK, and estimate clinical and healthcare utilization outcomes associated with early versus late treatment. Adults (≥18 years) with a confirmed RA diagnosis between January 2008 and December 2010, who received biologic treatment for ≥3 months and had ≥12 months of follow-up were included. Early treatment was receipt of biologic agent ≤1 year after RA diagnosis. Outcomes included 28-joint disease activity score (DAS28) reduction of ≥1.2 from biologic start and remission (DAS28 < 2.6). Time to outcome was evaluated using Kaplan-Meier curves and log-rank tests. Of 328 patients enrolled (Germany [n = 111], Spain [n = 106], UK [n = 111]), 58.2 % received early biologic (Germany: 55.0 %, UK: 55.9 %, Spain: 64.2 %; p = 0.321). First-line biologics were more frequent in Spain (26.4 %) and Germany (19.8 %) versus the UK (7.2 %; p < 0.001). Late-treated patients were hospitalized more often than early-treated patients (10.5 vs 2.9 % [p = 0.006] for 9.0 vs 5.4 mean inpatient days [p = 0.408]). DAS28 was 5.1 at biologic initiation (n = 310); 73.5 % of patients had a DAS28 decrease of ≥1.2 and 44.5 % achieved remission. More patients had DAS28 decrease of ≥1.2 (79.2 vs 65.9 %; p = 0.009) and remission (51.1 vs 35.6 %; p = 0.007) with early versus late treatment, with a significant difference in Kaplan-Meier curves when indexing on time since diagnosis (p < 0.001) and biologic start (p = 0.024). In RA patients receiving biologic therapy, over half received biologic therapy early. Early initiation was associated with improved clinical outcomes and reduced hospitalization rates versus late treatment.

Impact of acute bleeding on daily activities of patients with congenital hemophilia with inhibitors and their caregivers and families: observations from the Dosing Observational Study in Hemophilia (DOSE).

OBJECTIVES: There is limited understanding of the effects of bleeding episodes on the daily lives of patients with congenital hemophilia with inhibitors and their caregivers. This analysis of the Dosing Observational Study in Hemophilia examined the impact of acute bleeding episodes on work, school, and family activities. METHODS: Patients and caregivers participated in a diary study for 90 or more days or until patients experienced four bleeding episodes. All bleed treatments, interference with daily activities, and quality-of-life assessments were captured in daily records. Patients and caregivers reported planned workdays or school days eligible to be "lost" so as to differentiate from days lost because of disability or nonworking status, weekends, and vacations. RESULTS: Diaries were completed for 39 patients (18 adults and 21 children). Bleeding episodes that continued for 3 or more days (16.4%) accounted for most of the major changes to family plans. For the 38 patients with bleeding episodes, 47% of 491 bleed days fell on planned workdays or school days; the remainder fell on weekends, holidays, or nonworkdays or non-school days and therefore did not count as "lost days." Patients reported a loss of productivity on a greater percentage of eligible bleed days than did caregivers (3.9% vs. 0.8%, respectively). Patients and caregivers reported 13.5%/9.3% fully missed and 3.5%/7.6% partially missed days. CONCLUSIONS: This study demonstrated that in hemophilia with inhibitors, bleeding episodes interfere with the daily activities of patients and their caregivers. Furthermore, documenting only lost days underestimated the impact of bleeding episodes because of the high percentage of days without planned work or school.

Influence of real-world characteristics on outcomes for patients with methicillin-resistant Staphylococcal skin and soft tissue infections: a multi-country medical chart review in Europe.

BACKGROUND: Patient-related (demographic/disease) and treatment-related (drug/clinician/hospital) characteristics were evaluated as potential predictors of healthcare resource use and opportunities for early switch (ES) from intravenous (IV)-to-oral methicillin-resistant Staphylococcus aureus (MRSA)-active antibiotic therapy and early hospital discharge (ED). METHODS: This retrospective observational medical chart study analyzed patients (across 12 European countries) with microbiologically confirmed MRSA complicated skin and soft tissue infections (cSSTI), ≥3 days of IV anti-MRSA antibiotics during hospitalization (July 1, 2010-June 30, 2011), and discharged alive by July 31, 2011. Logistic/linear regression models evaluated characteristics potentially associated with actual resource use (length of IV therapy, length of hospital stay [LOS], IV-to-oral antibiotic switch), and ES and ED (using literature-based and expert-verified criteria) outcomes. RESULTS: 1542 patients (mean ± SD age 60.8 ± 16.5 years; 61.5% males) were assessed with 81.0% hospitalized for MRSA cSSTI as the primary reason. Several patient demographic, infection, complication, treatment, and hospital characteristics were predictive of length of IV therapy, LOS, IV-to-oral antibiotic switch, or ES and ED opportunities. Outcomes and ES and ED opportunities varied across countries. Length of IV therapy and LOS (r = 0.66, p < 0.0001) and eligibilities for ES and ED (r = 0.44, p < 0.0001) showed relatively strong correlations. IV-to-oral antibiotic switch patients had significantly shorter length of IV therapy (-5.19 days, p < 0.001) and non-significantly shorter LOS (-1.86 days, p > 0.05). Certain patient and treatment characteristics were associated with increased odds of ES (healthcare-associated/ hospital-acquired infection) and ED (patient living arrangements, healthcare-associated/ hospital-acquired infection, initiating MRSA-active treatment 1-2 days post cSSTI index date, existing ED protocol), while other factors decreased the odds of ES (no documented MRSA culture, ≥4 days from admission to cSSTI index date, IV-to-oral switch, IV line infection) and ED (dementia, no documented MRSA culture, initiating MRSA-active treatment ≥3 days post cSSTI index date, existing ES protocol). CONCLUSIONS: Practice patterns and opportunity for further ES and ED were affected by several infection, treatment, hospital, and geographical characteristics, which should be considered in identifying ES and ED opportunities and designing interventions for MRSA cSSTI to reduce IV days and LOS while maintaining the quality of care.

Mealtime-related dosing directions for proton-pump inhibitors in gastroesophageal reflux disease: physician knowledge, patient adherence.

OBJECTIVE To describe physicians' knowledge, patients' adherence, and perceptions of both regarding mealtime-related dosing directions for proton-pump inhibitors (PPIs). DESIGN Chart review and survey of patients and physicians. SETTING United States, with data collected between January and July 2011. PARTICIPANTS Patients being treated for gastroesophageal reflux disease (GERD) with PPIs and their prescribing physicians. MAIN OUTCOME MEASURES Patient- and physician-reported perception of PPI mealtime-related directions as important/inconvenient (seven-point Likert scale; 7 = very important/very inconvenient); physician-reported knowledge of PPI mealtime-related dosing directions based on whether the agent is labeled to be taken 30-60 minutes before eating (DIR-esomeprazole magnesium [Nexium-AstraZeneca], lansoprazole, and omeprazole) or labeled to be taken regardless of meals (NoDIR-dexlansoprazole [Dexilant-Takeda], rabeprazole, and pantoprazole); and patient-reported PPI mealtime-related directions received and adherence to directions. RESULTS Physicians (n = 262) recruited 501 patients who had been prescribed PPIs (262 DIR/239 NoDIR; mean age 51 years, 37% men, 56% nonerosive GERD [29% undocumented]). Across PPIs, physicians frequently reported incorrect directions or "did not know directions" (29% for esomeprazole to 69% for pantoprazole). While 98% of patients reported receiving directions from their physicians and 55% from their pharmacists, only 65% of DIR patients and 18% of NoDIR received directions consistent with product labeling. Physicians perceived greater inconvenience than patients (4.4 vs. 1.6, P < 0.001) and greater importance (5.2 vs. 4.5, P < 0.001) of mealtime-related directions. Overall, 81% of patients reported taking their PPI as directed. CONCLUSION While this patient cohort was adherent to directions given, physicians' directions were often inconsistent with product labeling. Understanding physician and patient knowledge gaps may be critical to ensuring patients receive appropriate directions, improving patient adherence to specific dosing instructions, attaining positive therapy outcomes, and identifying opportunities for pharmacist-led interventions.

Continued Posttrial Benefits of Buprenorphine Extended Release: RECOVER Study Findings.

BACKGROUND: This analysis describes participants' opioid use disorder (OUD) outcomes for 18 months after discontinuing extended-release buprenorphine injection (BUP-XR, SUBLOCADE). METHODS: The RECOVER (Remission From Chronic Opioid Use: Studying Environmental and Socioeconomic Factors on Recovery) study recruited participants from BUP-XR clinical trials (NCT02357901, NCT025100142, and NCT02896296) to assess whether there were sustained benefits after leaving the trial. Abstinence from opioids and from all illicit substances (excluding medical cannabis), health-related quality of life, depression, and employment were measured after BUP-XR discontinuation and change in outcomes assessed at 6, 12, and 18 months. Results were analyzed within the full cohort and by duration of BUP-XR treatment (0-2 months, 3-5 months, 6-11 months, 12 months, or 13-18 months) with and without inverse probability weights adjusting for differences in baseline characteristics. RESULTS: Of 533 participants, 529 were assessed over the 18-month study period. Further posttrial pharmacotherapy was reported by 33% of participants. At RECOVER baseline, longer BUP-XR was associated with higher abstinence (0-2 months BUP-XR [n = 116]: 38.8%; 3-5 months BUP-XR [n = 61]: 41.0%; 6-11 months BUP-XR [n = 86]: 68.6%; 12 months BUP-XR [n = 135]: 71.9%; 18 months BUP-XR [n = 131]: 88.2%) and greater 12-Item Short Form Health Survey mental component scores. Over 60% of participants had stable or improved outcomes at 6, 12, and 18 months assessments. Overall 47% of participants self-reported sustained opioid abstinence for the full 18-month follow-up, with greater sustained abstinence associated with longer BUP-XR treatment duration. A sensitivity analysis, removing patients receiving medications for OUD, yielded similar results. CONCLUSIONS: Participants from BUP-XR clinical trials who continued into RECOVER maintained or improved on numerous outcomes over 18 months, demonstrating the long-term positive impact of OUD pharmacotherapy.

Quality-Adjusted Time without Symptoms or Toxicity: Analysis of Axicabtagene Ciloleucel versus Standard of Care in Patients with Relapsed/Refractory Large B Cell Lymphoma.

The quality-adjusted time without symptoms or toxicity (Q-TWiST) methodology provides a comprehensive framework for treatment comparison that partitions survival time into distinct health states reflecting both treatment toxicity and disease progression. ZUMA-7 (ClinicalTrials.gov identifier NCT03391466), a phase 3 randomized open-label multicenter study, was conducted to evaluate the efficacy of axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor T cell therapy, compared with standard of care (SOC) involving platinum-based salvage chemotherapy with autologous stem cell transplantation (ASCT) consolidation as a second-line treatment for relapsed/refractory (R/R) large B cell lymphoma (LBCL), and met its primary endpoint of improved event-free survival (EFS). We aimed to use the Q-TWiST method to compare the quality-adjusted survival of R/R LBCL patients treated with axi-cel and those treated with SOC who were enrolled in ZUMA-7. The preplanned analysis of overall survival (OS) was partitioned into 3 mutually exclusive health states: time with grade ≥3 adverse events before the event as defined in the EFS analysis (TOX), time without severe toxicity before the event (TWiST), and time after the event (REL). Q-TWiST was computed as a weighted sum of mean TOX, TWiST, and REL values multiplied by state-specific quality of life (QoL) utility scores. Q-TWiST was evaluated in the intention-to-treat cohort at median follow-up. A relative Q-TWiST gain of 10% was deemed "clinically important" and a gain of ≥15% was deemed "clearly clinically important" based on established categorization. Sensitivity analyses with follow-up ranging from 3 months to the maximum follow-up and subgroup analyses by age and R/R status were explored. At a median follow-up of 23.5 months, the axi-cel cohort showed a significantly longer time without severe toxicity compared with the SOC cohort, with a mean TWiST duration of 11.18 months versus 5.39 months, respectively. The mean TOX was 1.16 months versus .74 months, and mean REL was 6.02 months versus 10.66 months. Quality-adjusted survival was significantly longer with axi-cel by 3.7 months (95% CI, 2.3 to 5.2 months), representing a relative gain of 21.9%. This was reflected across all subgroups, with estimated Q-TWiST gains of 3.1 months (95% CI, 1.5 to 4.9 months) for patients age <65 years, 5.2 months (95% CI, 2.4 to 7.9 months) for those age ≥65 years, 3.2 months (95% CI, 1.4 to 4.9 months) for those with primary refractory disease, 9.1 months (95% CI, 3.9 to months 13.5) for those who relapsed within 6 months, and 4.1 months (95% CI, 1.1 to 7.1 months) for those who relapsed between 6 and 12 months. The Q-TWiST gain for axi-cel also was statistically significant across follow-up durations, increasing from .2 month (95% CI, .1 to .3 month) at a 3-month follow-up to 4.9 months (95% CI, 2.4 to 7.8 months) at the maximum follow-up of 37.7 months. Axi-cel was associated with a statistically significant and "clearly clinically important" gain in quality-adjusted survival, regardless of the relative decline in QoL associated with treatment toxicity, disease progression, or additional cancer treatment. This finding adds to the existing evidence supporting a benefit for axi-cel as a second-line treatment for patients with R/R LBCL.

Effect of acute bleeding on daily quality of life assessments in patients with congenital hemophilia with inhibitors and their families: observations from the dosing observational study in hemophilia.

INTRODUCTION: Quality-of-life (QOL) assessments in frequently bleeding patients with congenital hemophilia with inhibitors and their families are confounded by preexisting arthropathy and family circumstances. Periodic QOL assessments typically made on nonbleed days may not provide complete reflections of the burden on patients/families. AIM: To evaluate the impact of bleeding episodes on patients/caregivers/families and the association between monthly QOL scores and patients' average diary experiences. METHODS: Frequently bleeding inhibitor patients (≥four bleeds in 3 months), or their caregivers, provided daily assessment of EuroQol five-dimensional questionnaire and EuroQol five-dimensional questionnaire visual analogue scale, pain (11-point Likert scale), and family anxiety/stress/activity change over 3 to 6 months. QOL scores were stratified by bleed/nonbleed days. RESULTS: Patient QOL assessments were recorded by 37 of the 39 enrolled patients/caregivers (3771 of 3777 eligible dairy days, 472 bleed/3299 nonbleed days). Median (range) diary duration was 91 (66-180) days, with 8.2% (0%-72.2%) bleed days. Mean health scores were significantly worse on bleed days than on nonbleed days (P < 0.0001 for all): EuroQol five-dimensional questionnaire index, 0.66 versus 0.82; visual analogue scale health, 69.7 versus 77.4; and pain score, 4.1 versus 1.8. Bleed days also had higher (P < 0.001) proportions of days with abnormalities in family anxiety/stress (42% vs. 30%) and family activity changes (34% vs. 21%). CONCLUSIONS: Assessing the impact of hemophilia with inhibitors on patient/family QOL typically includes periodic (likely nonbleed day) evaluations reflecting baseline abnormalities. Daily assessment, however, indicated that frequent acute bleeds impair QOL beyond patient's nonbleed day baseline. New approaches are required to assess the cumulative impact of frequent acute bleeds on patients and their families.

Psychometric Validation of the EQ-5D-3L in Patients with Nontuberculous Mycobacterial (NTM) Lung Disease Caused by Mycobacterium avium Complex (MAC).

PURPOSE: This analysis evaluated the psychometric properties of the EQ-5D-3L among patients with Mycobacterium avium complex lung disease (MAC-LD). METHODS: Data from the Phase III CONVERT trial were analyzed. Study measures including the EQ-5D-3L, St. George's Respiratory Questionnaire (SGRQ), the 6-minute walk test (6MWT), and percent predicted forced expiratory volume in 1 second (ppFEV1) were collected at baseline, month 3 (M3), month 4 (M4; only 6MWT), and month 6 (M6). Item characteristics and validity were evaluated at baseline. Test-retest reliability was assessed using intraclass correlation coefficients (ICC) and a weighted kappa statistic among a subgroup of stable patients. Validity was tested by evaluating correlations of the EQ-5D-3L index/visual analogue scale (VAS) scores with SGRQ and 6MWT and comparing mean index/VAS scores across known groups defined using 6MWT and ppFEV1. Responsiveness of the EQ-5D-3L was assessed using 6MWT, SGRQ, ppFEV1, and culture conversion as anchors. RESULTS: The index score was subject to ceiling effects, with 32.6% of patients reporting perfect health at baseline. ICCs for the index (0.80) and VAS (0.85) scores and weighted kappas for the domains (0.5-0.72) indicated adequate test-retest reliability. Correlations between the index/VAS scores and related domains of the SGRQ and 6MWT were as hypothesized (0.31-0.62), and the mean index/VAS scores were significantly different between the 6MWT and ppFEV1 known groups (p<0.05), supporting the validity of the EQ-5D-3L. No evidence was found supporting the responsiveness of the EQ-5D-3L to changes in any of the anchors. CONCLUSION: EQ-5D-3L exhibited evidence of validity and reliability but poor responsiveness to clinically meaningful changes in patients with MAC-LD.

Costs and Cost Drivers Associated with Non-Small-Cell Lung Cancer Patients Who Received Two or More Lines of Therapy in Europe.

PURPOSE: Advanced non-small-cell lung cancer (aNSCLC; stage IIIB/IV) presents a substantial clinical burden to society; reliable estimates of its economic burden are lacking. Therefore, this study aimed to quantify real-world health care resource utilization (HCRU) and costs of patients with squamous (SQ) and non-SQ (NSQ) aNSCLC who received two or more lines of treatment (2L+) in Europe, and to describe cost-predictors. METHODS: The LENS (Leading the Evaluation of Non-squamous and Squamous NSCLC) retrospective chart review study collected data from 2L+ patients with aNSCLC diagnosed between 07/2009 and 08/2011 (wave 1) or 07/2010 and 09/2012 (wave 2) in France, Germany, Italy, Spain, England, the Netherlands, and Sweden. Patients were followed from diagnosis through most recent visit/death. A weighted average of country-specific unit costs (2018 Euro) was applied to systemic anti-cancer therapy usage and HCRU (hospital/emergency department visit, surgery, radiotherapy, ancillary care, biomarker testing) to determine the total cost from aNSCLC diagnosis to death. Generalized linear models (gamma distribution, log link) were used to assess clinical and demographic predictors. RESULTS: Of 973 2L+ aNSCLC patients, median overall survival (OS) was 1.5 years from advanced diagnosis (range: 0.2-5.3; median OS: 1.4 [SQ], 1.6 [NSQ]), 79.0% died during follow-up. Weighted mean total per-patient costs were €21,273, ranging from €17,761 (England) to €30,854 (Sweden), and €15,446 (SQ) to €26,477 (NSQ). Systemic drug costs comprised 77.4% of total costs. Insurance status, presence of epidermal growth factor receptor (EGFR) mutation, SQ histology, age, alcohol abuse, and year of diagnosis were significant predictors for lower total costs per patient-month, Eastern Cooperative Oncology Group performance status (ECOG PS) ≥1 and country for higher costs. CONCLUSION: In the era pre-immunotherapy, HCRU and costs were substantial in aNSCLC 2L+ patients, with most of the costs accrued prior to start of 2L. NSQ patients incurred significantly higher total costs than SQ patients in all participating countries.

Effects of monthly buprenorphine extended-release injections on patient-centered outcomes: A long-term study.

INTRODUCTION: The physical, social, psychological, and economic burden of opioid use disorder (OUD) is substantial. As of the year 2019, the predominant focus of OUD research was outcomes such as retention and abstinence. We report herein the effects of extended-release buprenorphine (BUP-XR), the first FDA-approved subcutaneously injected, monthly treatment for OUD, on patient-centered outcomes. MATERIALS AND METHODS: Patient-centered outcomes were collected during an open-label safety study of participants with OUD (NCT# 02510014) evaluating BUP-XR. Measures collected during the study included the EQ-5D-5L, SF-36v2, Treatment Effectiveness Assessment (TEA), Addiction Severity Index-Lite (ASI-Lite), employment/insurance status questionnaire, and Medication Satisfaction Questionnaire (MSQ). Changes from baseline to end of study week 49 were analyzed using mixed models for repeated measures. "Baseline" was defined as the value collected prior to the first BUP-XR injection. Results presented are for those participants who initiated treatment on BUP-XR during the open-label study and were eligible to receive up to 12 injections. RESULTS: Four hundred twelve participants were included in analyses; 206 participants discontinued BUP-XR prematurely. Mean EQ-5D-5L scores remained stable from baseline to end of study. Statistically significant improvements from baseline to end of study were noted for the SF-36v2 mental component summary score (difference = 5.0, 95%CI: 3.5-6.5) and 7 of 8 domain scores (P < .05 for all comparisons); the SF-36v2 physical component summary remained stable from baseline to end of study. The TEA total score (difference = 9.3 points, 95%CI: 8.0-10.5) and 4 of 4 domain scores (difference = 2-3 points per domain) significantly improved from baseline to end of study. Significant improvements (P < .05 for all comparisons) on the ASI-Lite were seen for all problem areas except alcohol use from baseline to end of study. Employment rate increased 7% whereas health insurance status remained stable from baseline to end of study. Medication satisfaction measured using the MSQ was >88% at end of study. CONCLUSIONS: Treatment with BUP-XR monthly injections for up to 12 months in this cohort of treatment-seeking individuals with OUD led to positive PCOs and high treatment satisfaction, which correspond to personal recovery.

Early switch/early discharge opportunities for hospitalized patients with methicillin resistant Staphylococcus aureus complicated skin and soft tissue infections: Saudi Arabia and United Arab Emirates.

OBJECTIVES: To describe opportunities for early switch (ES) from intravenous (IV) to oral (PO) antibiotics and early discharge (ED) of patients hospitalized in the Kingdom of Saudi Arabia (KSA) and the United Arab Emirates (UAE) with methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft tissue infections (cSSTIs). METHODS: This retrospective medical chart review study enrolled physicians from 16 KSA and UAE sites to collect data for 107 MRSA cSSTI patients. RESULTS: Actual length of MRSA-active treatment was 13.3±9.3 mean days in KSA and 11.2±3.9 mean days in UAE, with a mean of 11.8±9.3 days of MRSA-targeted IV therapy in KSA and 10.7±4.3 days in UAE. 12.5% in KSA met ES criteria and potentially could have discontinued IV therapy 4.0±2.9 days sooner; 44.0% in UAE could have discontinued 6.6±3.6 days sooner. Patients were hospitalized for a mean 28.6±45.0 days in KSA and 13.1±5.9 days in UAE. 25.0% in KSA and 48.0% in UAE met ED criteria and potentially could have been discharged 6.1±8.0 days earlier in KSA and 7.9±5.0 days earlier in UAE. CONCLUSIONS: A significant proportion of patients hospitalized for MRSA cSSTI could be eligible for ES or ED opportunities, resulting in potential for reductions in IV and bed days.

Recovery From Opioid Use Disorder (OUD) After Monthly Long-acting Buprenorphine Treatment: 12-Month Longitudinal Outcomes From RECOVER, an Observational Study.

OBJECTIVES: While evidence has mounted regarding the short-term effectiveness of pharmacotherapy for opioid use disorder (OUD), little is known about longer-term psychosocial, economic, and health outcomes. We report herein 12-month outcomes for an observational study enrolling participants who had previously taken part in a long-acting buprenorphine subcutaneous injection (BUP-XR) trial for moderate to severe OUD. METHODS: The RECOVER (Remission from Chronic Opioid Use: Studying Environmental and SocioEconomic Factors on Recovery; NCT03604861) study enrolled participants from 35 US community-based sites. Self-reported sustained opioid abstinence over 12 months and self-reported past-week abstinence at 3-, 6-, 9-, and 12-month visits were assessed. Multiple regression models assessed the association of BUP-XR duration with abstinence, controlling for potential confounders. Withdrawal, pain, health-related quality of life, depression, and employment at RECOVER baseline and 12-month visits were also compared to values collected before treatment in the BUP-XR trial. RESULTS: Of 533 RECOVER participants, 425 completed the 12-month visit (average age 42 years; 66% male); 50.8% self-reported sustained 12-month and 68.0% past-week opioid abstinence. In multiple regressions, participants receiving 12-month versus ≤2-month BUP-XR treatment duration had significantly higher likelihood of sustained opioid abstinence (75.3% vs 24.1%; P = 0.001), with similar results for past-week self-reported abstinence over time. During RECOVER, participants had fewer withdrawal symptoms, lower pain, positive health-related quality of life, minimal depression, and higher employment versus pre-trial visit. CONCLUSIONS: RECOVER participants reported positive outcomes over the 12-month observational period, including high opioid abstinence and stable or improved humanistic outcomes. These findings provide insights into the long-term impact of pharmacotherapy in OUD recovery.

A Quality-adjusted Time Without Symptoms or Toxicity (Q-TWiST) Analysis of Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma (aRCC).

BACKGROUND: This analysis compared quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) between nivolumab and everolimus among previously treated patients with advanced renal cell carcinoma enrolled in the phase III CheckMate 025 trial (NCT01668784). MATERIALS AND METHODS: At 45-month follow-up, overall survival (OS) was partitioned into 3 health states: TWiST, time with grade ≥ 3 toxicity (TOX), and time after progression (REL). Mean Q-TWiST was determined by multiplying each state's duration with its utility (TWiST, 1.0; TOX, 0.5; REL, 0.5). Relative Q-TWiST gains (calculated as Q-TWiST difference divided by everolimus OS) of ≥ 10% were predefined as clinically important. Immuno-oncology-specific sensitivity analyses considered 4 alternative progression definitions: Tumor size increase ≥ 25% from nadir; treatment discontinuation; ≥ 2-point reduction from baseline in Functional Assessment of Cancer Therapy-Kidney Symptom Index Disease-Related Symptoms scores; and a composite definition. A scenario incorporating grade ≥ 2 toxicities was tested. RESULTS: Compared with everolimus, nivolumab was associated with a significant Q-TWiST improvement of 3.3 months (P < .001). In all sensitivity analyses, nivolumab was associated with Q-TWiST gains (relative gain %) ranging from 3.3 months (14.4%) to 4.8 months (20.9%). CONCLUSIONS: Nivolumab is associated with a statistically significant and clinically meaningful gain in quality-adjusted OS versus everolimus among previously treated patients with advanced renal cell carcinoma.

Patient-centered Outcomes in Participants of a Buprenorphine Monthly Depot (BUP-XR) Double-blind, Placebo-controlled, Multicenter, Phase 3 Study.

OBJECTIVE: Opioid use disorder (OUD) is associated with physical, social, psychological, and economic burden. This analysis assessed the effects of RBP-6000, referred to as BUP-XR (extended-release buprenorphine), a subcutaneously injected, monthly buprenorphine treatment for OUD compared with placebo on patient-centered outcomes measuring meaningful life changes. METHODS: Patient-centered outcomes were collected in a 24-week, phase 3, placebo-controlled study assessing the efficacy, safety, and tolerability of BUP-XR 300/300 mg (6 × 300 mg) and 300/100 mg (2 × 300 mg followed by 4 × 100 mg) injections in treatment-seeking participants with moderate-to-severe OUD. Measures included the EQ-5D-5L, SF-36v2, Medication Satisfaction Questionnaire, employment/insurance status, and healthcare resource utilization (HCRU). Changes from baseline to end of study were compared across treatment arms, using mixed models for repeated measures. RESULTS: Participants receiving BUP-XR (n = 389) versus placebo (n = 98) had significantly greater changes from baseline on the EQ-5D-5L index (300/300 mg: difference = 0.0636, P = 0.003), EQ-5D-5L visual analog scale (300/300 mg: difference = 5.9, P = 0.017; 300/100 mg: difference = 7.7, P = 0.002), and SF-36v2 physical component summary score (300/300 mg: difference = 3.8, P < 0.001; 300/100 mg: difference = 3.2, P = 0.002). Satisfaction was significantly higher for participants receiving BUP-XR 300/300 mg (88%, P < 0.001) and 300/100 mg (88%, P < 0.001) than placebo (46%). Employment and percentage of insured participants increased by 10.8% and 4.1% with BUP-XR 300/300 mg and 10.0% and 4.7% with 300/100 mg but decreased by 12.6% and 8.4% with placebo. Participants receiving BUP-XR compared with placebo had significantly fewer hospital days per person-year observed. CONCLUSIONS: These results show the feasibility of measuring patient-centered life changes in substance use disorder clinical studies. Participants receiving up to 6 monthly injections of BUP-XR, compared with placebo, reported better health, increased medication satisfaction, increased employment, and decreased healthcare utilization.

Measuring recovery in opioid use disorder: clinical utility and psychometric properties of the Treatment Effectiveness Assessment.

Purpose: The Treatment Effectiveness Assessment (TEA) is a patient-centered instrument for evaluating treatment progress and recovery from substance use disorders, including opioid use disorder (OUD). We assessed the TEA's reliability and validity and determined minimal clinically important differences (MIDs) in participants with moderate to severe OUD. Patients and methods: The TEA measures change in four single-item domains (substance use, health, lifestyle, community involvement) from treatment initiation across the duration of a treatment program. Self-reported responses range from 1 ("none or not much") to 10 ("much better") with items summed to a total score ranging from 4-40. We assessed floor and ceiling effects, internal consistency, test-retest reliability, known-groups validity (ANOVA stratified by current health status [36-Item Short Form Health Survey item 1]), convergent/divergent validity, and MIDs using data from a phase 3, open-label clinical trial of buprenorphine extended-release monthly injection for subcutaneous use (BUP-XR). Participants with OUD completed the TEA at screening and before monthly injections for up to 12 months. Results: Among 410 participants (mean age 38 years; 64% male), the mean baseline (pre-injection 1) TEA total score was 25.4 (SD 9.7), with <10% of participants at the measure floor and 10%-20% at the ceiling across domains. Internal consistency was high (Cronbach's α=0.90), with marginal test-retest reliability (intraclass correlation coefficient =0.69). Mean TEA total score consistently increased from baseline (n=410; mean 25.4 [SD 9.7]) to end of study (n=337; 35.0 [6.7]) and differentiated between current health status groups (P<0.001); it was weakly correlated with other measures of health-related quality of life/severity. MIDs ranged from 5-8 for the TEA total score across anchor- and distribution-based approaches. Conclusion: The TEA exhibited acceptable reliability and validity in a cohort of participants with moderate to severe OUD treated with BUP-XR. Given its brevity and psychometric properties, the TEA is a promising tool for use in clinical practice and research.

Patient-reported outcomes in schizophrenia patients treated with once-monthly extended-release risperidone in a long-term clinical study.

PURPOSE: RBP-7000 (PERSERIS™) is a once-monthly subcutaneous extended-release risperidone formulation approved by the United States Food and Drug Administration for the treatment of schizophrenia in adults. The objective of this study was to describe the long-term impact of RBP-7000 on health-related quality of life (HRQoL), subjective well-being, treatment satisfaction and medication preference in patients with schizophrenia. PATIENTS AND METHODS: HRQoL was derived from a 52-week multicentre Phase III single-arm open-label outpatient study that assessed the safety and efficacy of RBP-7000 (120 mg) in patients with schizophrenia. HRQoL was measured using the EuroQol EQ-5D-5L and Short-Form Survey SF-36 version 2; well-being using the Subjective Well-being Under Neuroleptic Treatment - Short Version (SWN-S); satisfaction using the Medication Satisfaction Questionnaire and medication preference using the Preference of Medication questionnaire. RESULTS: Of 482 participants at baseline, 234 remained through the end of study (EOS; week 52). Mean HRQoL and well-being scores remained stable between baseline (EQ-5D-5L index: 0.83; SF-36v2 Physical Component Score: 50; SF-36v2 Mental Component Score: 46; total SWN-S score: 89) and EOS (EQ-5D-5L index: 0.86; SF-36v2 Physical Component Score: 49; SF-36v2 Mental Component Score: 47; total SWN-S score: 90). The proportion of participants reporting satisfaction increased between week 4 (66%) and EOS (81%), with a similar trend for the preference of RBP-7000 over previous treatment (week 4: 66%; EOS: 72%). Sensitivity analyses suggested a minor effect of dropout on characterization of change over time in patient-reported outcomes (PRO) measures. CONCLUSION: Study participants attained mean HRQoL scores near that of the general US population. Over two-thirds reported high satisfaction with and preference for RBP-7000 across the study period. Additional research is needed to confirm whether these PRO translate into improved outcomes such as adherence and ultimately fewer relapses in patients with schizophrenia.