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PURPOSE We present 5-year results from CheckMate 227 Part 1, in which nivolumab plus ipilimumab improved overall survival (OS) versus chemotherapy in patients with metastatic non–small-cell lung cancer, regardless of tumor programmed death ligand 1 (PD-L1) status. METHODS Adults with stage IV/recurrent non–small-cell lung cancer without EGFR mutations or ALK alterations and with tumor PD-L1 ≥ 1% or < 1% (n = 1739) were randomly assigned. Patients with tumor PD-L1 ≥ 1% were randomly assigned to first-line nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. Patients with tumor PD-L1 < 1% were randomly assigned to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. End points included exploratory 5-year results for efficacy, safety, and quality of life. RESULTS At a minimum follow-up of 61.3 months, 5-year OS rates were 24% versus 14% for nivolumab plus ipilimumab versus chemotherapy (PD-L1 ≥ 1%) and 19% versus 7% (PD-L1 < 1%). The median duration of response was 24.5 versus 6.7 months (PD-L1 ≥ 1%) and 19.4 versus 4.8 months (PD-L1 < 1%). Among patients surviving 5 years, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) were off nivolumab plus ipilimumab without initiating subsequent systemic anticancer treatment by the 5-year time point. Survival benefit continued after nivolumab plus ipilimumab discontinuation because of treatment-related adverse events, with a 5-year OS rate of 39% (combined PD-L1 ≥ 1% and < 1% populations). Quality of life in 5-year survivors treated with nivolumab plus ipilimumab was similar to that in the general US population through the 5-year follow-up. No new safety signals were observed. CONCLUSION With all patients off immunotherapy treatment for ≥ 3 years, nivolumab plus ipilimumab increased 5-year survivorship versus chemotherapy, including long-term, durable clinical benefit regardless of tumor PD-L1 expression. These data support nivolumab plus ipilimumab as an effective first-line treatment for patients with metastatic non–small-cell lung cancer. [Media: see text]

Score reproducibility is an important measurement property of fit-for-purpose patient-reported outcome (PRO) measures. It is commonly assessed via test-retest reliability, and best evaluated with a stable participant sample, which can be challenging to identify in diseases with highly variable symptoms. To provide empirical evidence comparing the retrospective (patient global impression of change [PGIC]) and current state (patient global impression of severity [PGIS]) approaches to identifying a stable subgroup for test-retest analyses, 3 PRO Consortium working groups collected data using both items as anchor measures.The PGIS was completed on Day 1 and Day 8 + 3 for the depression and non-small cell lung cancer (NSCLC) studies, and daily for the asthma study and compared between Day 3 and 10. The PGIC was completed on the final day in each study. Scores were compared using an intraclass correlation coefficient (ICC) for participants who reported "no change" between timepoints for each anchor.ICCs using the PGIS "no change" group were higher for depression (0.84 vs. 0.74), nighttime asthma (0.95 vs. 0.53) and daytime asthma (0.86 vs. 0.68) compared to the PGIC "no change" group. ICCs were similar for NSCLC (PGIS: 0.87; PGIC: 0.85).When considering anchor measures to identify a stable subgroup for test-retest reliability analyses, current state anchors perform better than retrospective anchors. Researchers should carefully consider the type of anchor selected, the time period covered, and should ensure anchor content is consistent with the target measure concept, as well as inclusion of both current and retrospective anchor measures.

In the CheckMate 9ER trial, patients with advanced renal cell carcinoma who received first-line nivolumab plus cabozantinib had significantly better progression-free survival compared with those given sunitinib. In this study, we aimed to describe the patient-reported outcome (PRO) results from CheckMate 9ER.In this open-label, randomised, phase 3 trial done in 125 cancer centres, urology centres, and hospitals across 18 countries, patients aged 18 years or older with previously untreated advanced renal cell carcinoma with a clear-cell component, a Karnofsky performance status of 70% or more, and available tumour tissue were randomly assigned (1:1) via interactive response technology to nivolumab 240 mg intravenously every 2 weeks plus oral cabozantinib 40 mg per day, or oral sunitinib 50 mg per day monotherapy for 4 weeks in 6-week cycles. The primary endpoint of progression-free survival was reported previously. PROs were analysed as prespecified exploratory endpoints at common timepoints (at baseline and every 6 weeks) until week 115. Disease-related symptoms were evaluated using the 19-item Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19), and global health status was assessed with the three-level EQ-5D (EQ-5D-3L) visual analogue scale (VAS) and UK utility index. PRO analyses were done in the intention-to-treat population. Change from baseline was assessed using mixed-model repeated measures. A time-to-deterioration analysis was done for first and confirmed deterioration events. This study is registered with ClinicalTrials.gov, NCT03141177, and is closed to recruitment.Between Sept 11, 2017, and May 14, 2019, 323 patients were randomly assigned to nivolumab plus cabozantinib and 328 to sunitinib. Median follow-up was 23·5 months (IQR 21·0-26·5). At baseline, patients in both groups reported low symptom burden (FKSI-19 disease-related symptoms version 1 mean scores at baseline were 30·24 [SD 5·19] for the nivolumab plus cabozantinib group and 30·06 [5·03] for the sunitinib group). Change from baseline in PRO scores indicated that nivolumab plus cabozantinib was associated with more favourable outcomes versus sunitinib (treatment difference 2·38 [95% CI 1·20-3·56], nominal p0·0001, effect size 0·33 [95% CI 0·17-0·50] for FKSI-19 total score; 1·33 [0·84-1·83], nominal p0·0001, 0·45 [0·28-0·61] for FKSI-19 disease-related symptoms version 1; 3·48 [1·58-5·39], nominal p=0·0004, 0·30 [0·14-0·47] for EQ-5D-3L VAS; and 0·04 [0·01-0·07], nominal p=0·0036, 0·25 [0·08-0·41] for EQ-5D-3L UK utility index), reaching significance at most timepoints. Nivolumab plus cabozantinib was associated with decreased risk of clinically meaningful deterioration for FKSI-19 total score compared with sunitinib (first deterioration event hazard ratio 0·70 [95% CI 0·56-0·86], nominal p=0·0007; confirmed deterioration event 0·63 [0·50-0·80], nominal p=0·0001).PROs were maintained or improved with nivolumab plus cabozantinib versus sunitinib. Compared with sunitinib, nivolumab plus cabozantinib significantly delayed time to deterioration of patient-reported outcome scores. These results suggest a benefit for nivolumab plus cabozantinib compared with sunitinib in the treatment of patients with advanced renal cell carcinoma.Bristol Myers Squibb.

LBA9025 Background: In CheckMate 227 part 1 (NCT02477826), 1L NIVO + IPI demonstrated long-term, durable survival benefit vs platinum-doublet chemo in patients (pts) with metastatic NSCLC regardless of tumor programmed death ligand 1 (PD-L1) expression level. Here we present the longest reported follow-up (5 y) of a phase 3 trial of 1L combination immunotherapy in metastatic NSCLC. Methods: Adults with previously untreated stage IV or recurrent NSCLC, no known EGFR/ ALK alterations , and an ECOG performance status ≤ 1 were enrolled and stratified by histology. Pts with tumor PD-L1 ≥ 1% were randomized 1:1:1 to NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), NIVO (240 mg Q2W), or chemo. Pts with tumor PD-L1 < 1% were randomized 1:1:1 to NIVO + IPI, NIVO (360 mg Q3W) + chemo, or chemo. Pts were treated until progression, toxicity, or ≤ 2 y for immunotherapy. Assessments included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and a novel efficacy endpoint, treatment-free interval. Treatment-free interval was measured in pts who discontinued study therapy (for any reason including treatment completion) and was defined as the time from last study dose to start of subsequent systemic therapy or death, whichever occurred first. Results: Minimum follow-up was 61.3 mo (database lock, Feb 15, 2022). In pts with tumor PD-L1 ≥ 1% (N = 1189), continued long-term OS benefit was seen with NIVO + IPI vs chemo (HR, 0.77 [95% CI, 0.66–0.91]); 5-y OS rates were 24% (NIVO + IPI), 17% (NIVO), and 14% (chemo). OS benefit also continued in pts with tumor PD-L1 < 1% (N = 550) for NIVO + IPI vs chemo (HR, 0.65 [95% CI, 0.52–0.81]); 5-y OS rates were 19% (NIVO + IPI), 10% (NIVO + chemo), and 7% (chemo). Clinical benefit with NIVO + IPI vs chemo was observed across additional efficacy endpoints in the overall population and in pts alive at 5 y (table). PFS, ORR, and DOR with NIVO and NIVO + chemo will be presented. Among pts alive at 5 y in the NIVO + IPI group, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) remained treatment-free ≥ 3 y after discontinuing study therapy; median (range) duration of NIVO ± IPI therapy was 17.7 (0-25.5) mo (PD-L1 ≥ 1%) and 9.5 (0-25.1) mo (PD-L1 < 1%). No new safety signals were observed. Conclusions: With a 5-y minimum follow-up, NIVO + IPI continues to provide long-term, durable clinical benefit vs chemo in previously untreated pts with metastatic NSCLC, regardless of PD-L1 expression. NIVO + IPI led to increased 5-y survivorship; the majority of these pts were treatment-free for ≥ 3 y post-treatment discontinuation. Clinical trial information: NCT02477826. [Table: see text]

4502 Background: In CM 214, when compared to sunitinib (S), nivolumab plus ipilimumab (N+I) was associated with both clinical benefit and improved HRQoL as first-line treatment for intermediate/poor (I/P)-risk patients (pts). This analysis investigates the direct association between HRQoL and clinical outcomes in aRCC pts. Methods: I/P-risk population included 425 and 422 pts in the N+I and S arms, respectively. HRQoL was assessed using the FKSI-19 (Total Score and Disease Related Symptoms [DRS]). Three separate analyses (A, B, and C) were conducted. A: Changes in individual item scores from baseline to last assessment prior to progression were descriptively assessed. B: For each FKSI-19 score, multivariable Cox regression, adjusted for treatment and stratification factors, was used to evaluate the prognostic significance of baseline and time-dependent HRQoL scores in separate models. Hazard ratios (HR) were calculated based on the risk of death per improvement in HRQoL scores, defined using the clinically meaningful change threshold (5 points for FKSI-19 Total and 3 points for DRS). Pts with overall survival (OS) events were censored if their survival event was not within 12 weeks of the last available HRQoL assessment. C: The association between HRQoL change status (ie, improvement or maintenance vs. worsening from baseline in the FKSI-19 Total Score), irrespective of treatment arm, and OS was further assessed using a landmark analysis at the month 6 (mo-6) landmark. Additional landmark time points were explored in sensitivity analysis. Results: Items related to fatigue and perceived bother of the side-effects of treatment had the largest percentage of pts worsening prior to progression. In both baseline and time-dependent HRQoL analyses, OS was independently associated with both HRQoL measures. Higher (better) baseline scores were associated with significantly reduced risk of death (HR [95% CI] for FKSI-19 Total Score and DRS was 0.83 [0.80-0.87] and 0.80 [0.76-0.84], respectively). Every 5-point increase (improvement) in FKSI-19 Total Score and 3-point increase in DRS was associated with a 31% decreased risk of death ( P < 0.01). At mo-6, 301 pts showed improvement or maintenance in HRQoL. Pts with improved/stable HRQoL had a 52% reduction in risk of death compared to pts who had worsened (HR 0.48 [95% CI: 0.39-0.59]). Conclusions: Results demonstrate there is an association between HRQoL and clinical outcomes in CM 214. Baseline HRQoL scores are a potential predictor for survival in aRCC, and HRQoL changes are informative for pts’ expected survival. HRQoL change status at mo-6 was significantly and positively associated with subsequent survival. Thus, patient-reported outcomes may be useful for both describing pt experience in clinical trials and providing valuable clinical insights during routine practice. Clinical trial information: NCT02231749.

Introduction In CheckMate 227 (NCT02477826), patients with treatment-naive stage IV or recurrent NSCLC and 1% or greater tumor programmed death ligand 1 expression had significantly improved overall survival with nivolumab plus ipilimumab versus chemotherapy. We present the patient-reported outcomes (PROs). Methods Patients (N = 1189) were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy. PROs were exploratory. Changes in Lung Cancer Symptom Scale (LCSS) average symptom burden index, LCSS 3-item global index, EQ-5D visual analog scale (VAS), and EQ-5D utility index were analyzed descriptively. Mixed-effect model repeated measures and time-to-first deterioration and improvement analyses were conducted. Results PRO completion rates were generally greater than 80%. On-treatment improvements from baseline in LCSS measures of symptom burden and global health status with nivolumab plus ipilimumab generally met or exceeded the minimal important difference (smallest clinically meaningful change) from weeks 24 and 30, respectively; improvements with chemotherapy generally remained below the minimal important difference. Mean on-treatment EQ-5D VAS scores for both treatments approached the U.K. population norm at week 24, remaining so throughout the treatment period. Mixed-effect model repeated measures analyses revealed numerically greater improvements from baseline with nivolumab plus ipilimumab versus chemotherapy across LCSS average symptom burden index and 3-item global index, and EQ-5D VAS and utility index. Nivolumab plus ipilimumab had delayed time-to-first deterioration (hazard ratio [95% confidence interval] 0.74 [0.56 to 0.98]) and a trend for more rapid time-to-first improvement (1.24 [0.98 to 1.59]) versus chemotherapy. Conclusions Nivolumab plus ipilimumab revealed delayed deterioration and numerical improvement in symptoms and health-related quality of life versus chemotherapy in patients with advanced NSCLC and 1% or greater programmed death ligand 1 expression.

307 Background: Nivolumab + ipilimumab (N+I) demonstrated durable, long-term survival in the phase 3 CheckMate 214 trial as first-line treatment for intermediate/poor (I/P)-risk patients (pts) with aRCC. After a minimum follow-up of 5 years, N+I maintained superior overall survival and response benefits vs sunitinib (S) in both I/P-risk pts and across all randomized pts. We report the HRQoL results from the 5-year follow-up. Methods: Pts were randomized 1:1 to receive N 3 mg/kg + I 1 mg/kg every 3 weeks (wks) for 4 cycles followed by N 3 mg/kg every 2 wks or S 50 mg/d orally for 4 wks (6-wk cycle). HRQoL was assessed using the FKSI-19, FACT-G, and EQ-5D-3L instruments at baseline (BL) and on day 1 of wks 1 and 4 of the first 2 cycles, on day 1 of wks 1 and 5 of the next 2 cycles, and on day 1 of wk 1 of subsequent cycles. The analyses included mixed-model repeated measures (MMRM) for change from BL across 59 months (while on-treatment) and time to confirmed deterioration (TCD). Bother with treatment side effects (item GP5 in FKSI-19) was assessed using a generalized estimating equations model with response dichotomized as minimal bother (“not at all” or “a little bit”) vs notable bother (“somewhat”, “quite a bit”, and “very much”). Results: 1096 pts were randomized to N+I (I/P-risk: 425; favorable [F]-risk: 125) and S (I/P-risk: 422; F-risk: 124). In the overall and I/P-risk populations, N+I pts reported improved mean FKSI-19 total scores over time compared with a decline observed with S. Overall changes from BL through 59 months favored N+I over S with significant differences between arms observed for all outcomes (Table). Median TCD was significantly longer with N+I vs S for all FKSI-19 scores, as well as FACT-G total and physical domains for both populations ( P < 0.05). Pts in the N+I arm were 76% (odds ratio [95% CI]: 0.24 [0.16–0.35]) and 73% (0.27 [0.18–0.40]) less likely to be notably bothered by side effects than pts in the S arm in the total and I/P-risk populations, respectively. Conclusions: Pts reported HRQoL benefits with N+I vs S. Treatment with N+I showed a decreased risk of being bothered by treatment side effects and of experiencing clinically meaningful deterioration in HRQoL in contrast with S. These results suggest that the superior efficacy of N+I over S comes with the additional benefit of improved long-term HRQoL. Clinical trial information: NCT02231749. [Table: see text]

323 Background: In CheckMate 9ER, patients (pts) with aRCC were randomized 1:1 to nivolumab 240 mg IV Q2W + cabozantinib 40 mg PO QD (N+C; n = 323) or sunitinib (S) 50 mg PO (4 weeks of 6-week cycles; n = 328). As reported previously, at a median follow-up of 18.1 months, N+C led to superior progression-free and overall survival and more favorable HRQoL than S. We report results of HRQoL analyses for 32.9-months follow-up. Methods: Disease-related symptoms (DRS) were evaluated using the FKSI-19 instrument and HRQoL with the EQ-5D-3L visual analogue scale (VAS). Change from baseline (BL) was assessed using mixed-model repeated measures (MMRM), adjusting for baseline scores and stratification factors, and included all common timepoints (at BL and every 6 wks) through week 151. Time to deterioration analysis was conducted for first (TFD), confirmed (TCD) and definitive (TDD) deterioration events using Kaplan-Meier estimates and Cox proportional hazards models. Bother with treatment side effects (item GP5 in FKSI-19) was assessed using a generalized estimating equations model with response dichotomized as minimal bother (“not at all” or “a little bit”) vs notable bother (“somewhat”, “quite a bit”, and “very much”). HRQoL endpoints were exploratory and P-values are nominal and descriptive. Results: Group mean scores over time show that HRQoL was maintained or improved from BL with N+C while reductions were observed with S. Overall changes from BL though week 151 favored N+C with nominal significant differences between treatments observed for all scores except functional well-being (FWB; Table). Similarly, decreased risk of deterioration was observed with N+C vs S for all scores except FWB, irrespective of the deterioration definition used (TFD, TCD, TDD). Pts in N+C arm were 48% (odds ratio: 0.52 [95% CI, 0.35-0.77]) less likely to be notably bothered by side effects than pts in S arm. Conclusions: Pts continued to report improved HRQoL with N+C compared to S. Treatment with N+C reduced the risk of meaningful deterioration in HRQoL scores, regardless of the definition of deterioration and showed a decreased risk of being bothered by treatment side effects in contrast to S. These results suggest that the superior efficacy of N+C over S with the additional benefit of improved HRQoL is maintained with longer follow-up. Clinical trial information: NCT03141177. [Table: see text]

262 Background: This analysis evaluated HRQoL as exploratory endpoints in CheckMate 648, a randomized, open-label, global Phase 3 study, evaluating treatment with N+I, N+CT and CT alone in inoperable advanced, recurrent, or metastatic ESCC. Methods: The effects of N+I vs N+CT vs CT on HRQoL were assessed using the Functional Assessment of Cancer Therapy-Esophageal (FACT-E) (including the GP5 item to assess impact of side effects) and EQ-5D-3L. A mixed model for repeated measures was used to evaluate longitudinal changes from baseline (BL) and differences between treatment groups. Comparison of the risk of being bothered by the side effects of treatment was estimated for the GP5 using generalized estimating equation (GEE). Time to confirmed deterioration (TTCD) was assessed using Kaplan-Meier plots along with Cox proportional hazard models. Analyses were conducted on both the all-randomized population and the subset of patients with PD-L1 expression ≥1%. Results: 970 pts were randomized 1:1:1 to N+I (n=325), N+CT (n=321), or CT (n=324). 90% of pts completed both a BL and at least one on-treatment assessment and were included in the PRO analysis population. FACT-E (all randomized pts). Study showed similar BL scores across all 3 treatment groups. Changes from BL showed a trend towards better HRQoL for pts treated with N+I and N+CT compared to CT alone, however these results were not statistically significant. Patients treated with N+I had significantly decreased risk of experiencing bother associated with the side effects of treatment than patients treated with either N+CT or CT. TTCD analysis demonstrated delayed deterioration for pts treated with N+CT vs CT. Findings for PD-L1 ≥1% subpopulation were similar to all randomized pts. Conclusions: In pts with inoperable advanced, recurrent, or metastatic ESCC, HRQoL is maintained throughout treatment with N+I and N+CT. Trends towards better HRQoL and decreased risk of deterioration were observed with N+I and N+CT compared to CT alone. Clinical trial information: NCT03143153. [Table: see text]

Measurement development in hard-to-reach populations can pose methodological challenges. Item response theory (IRT) is a useful statistical tool, but often requires large samples. We describe the use of longitudinal IRT models as a pragmatic approach to instrument development when large samples are not feasible. The statistical foundations and practical benefits of longitudinal IRT models are briefly described. Results from a simulation study are reported to demonstrate the model’s ability to recover the generating measurement structure and parameters using a range of sample sizes, number of items, and number of time points. An example using early-phase clinical trial data in a rare condition demonstrates these methods in practice. Simulation study results demonstrate that the longitudinal IRT model’s ability to recover the generating parameters rests largely on the interaction between sample size and the number of time points. Overall, the model performs well even in small samples provided a sufficient number of time points are available. The clinical trial data example demonstrates that by using conditional, longitudinal IRT models researchers can obtain stable estimates of psychometric characteristics from samples typically considered too small for rigorous psychometric modeling. Capitalizing on repeated measurements, it is possible to estimate psychometric characteristics for an assessment even when sample size is small. This allows researchers to optimize study designs and have increased confidence in subsequent comparisons using scores obtained from such models. While there are limitations and caveats to consider when using these models, longitudinal IRT modeling may be especially beneficial when developing measures for rare conditions and diseases in difficult-to-reach populations.

The Patient Assessment for Low Back Pain–Symptoms is a newly developed patient-reported outcome instrument to assess specific symptoms of chronic low back pain for use in clinical trials and practice., We describe the mixed-methods (qualitative and quantitative) development and preliminary validation of the Patient Assessment for Low Back Pain–Symptoms (PAL-S), a patient-reported outcome measure for use in chronic low back pain (cLBP) clinical trials. Qualitative methods (concept elicitation and cognitive interviews) were used to identify and refine symptom concepts and quantitative methods (classical test theory and Rasch measurement theory) were used to evaluate item- and scale-level performance of the measure using an iterative approach. Patients with cLBP participated in concept elicitation interviews (N = 43), cognitive interviews (N = 38), and interview-based assessment of paper-to-electronic mode equivalence (N = 8). A web-based sample of patients with self-reported cLBP participated in quantitative studies to evaluate preliminary (N = 598) and revised (n = 401) drafts and a physician-diagnosed cohort of patients with cLBP (N = 45) participated in preliminary validation of the measure. The PAL-S contained 14 items describing symptoms (overall pain, sharp, prickling, sensitive, tender, radiating, shocking, shooting, burning, squeezing, muscle spasms, throbbing, aching, and stiffness). Item-level performance, scale structure, and scoring seemed to be appropriate. One-week test–retest reproducibility was acceptable (intraclass correlation coefficient 0.81 [95% confidence interval, 0.61-0.91]). Convergent validity was demonstrated with total score and MOS-36 Bodily Pain (Pearson correlation −0.79), Neuropathic Pain Symptom Inventory (0.73), Roland-Morris Disability Questionnaire (0.67), and MOS-36 Physical Functioning (−0.65). Individual item scores and total score discriminated between numeric rating scale tertile groups and painDETECT categories. Respondent interpretation of paper and electronic administration modes was equivalent. The PAL-S has demonstrated content validity and is potentially useful to assess treatment benefit in cLBP clinical trials.

167 Background: CheckMate 649 (NCT02872116) is a randomized, open label phase 3 study in first line (1L) treatment of pts with advanced GC/GEJC/EAC. Primary analysis results showed statistically significant improvement in overall survival (OS) for NIVO+chemo vs. chemo in all randomized pts. We present HRQOL results for these pts, included as an exploratory study objective. Methods: HRQOL was assessed using EQ-5D-3L (EQ-5D) and Functional Assessment of Cancer Therapy–Gastric Cancer (FACT-Ga). Assessments were performed at baseline (BL), every 6 weeks during treatment and during follow-up. Change from BL EQ-5D Visual Analog Scale (VAS), Utility Index (UI) and FACT-Ga scores were analyzed using mixed models. Time to first symptom deterioration (TTSD), time until definitive deterioration (TuDD), and time to improvement (TTI) were estimated with Kaplan-Meier estimators and stratified Cox models; deterioration/improvement was based on prespecified meaningful change thresholds. Results: 1581 pts were randomized to NIVO+chemo (n = 789) or chemo (n = 792). Among 1359 pts with BL and post-BL patient-reported outcomes (NIVO+chemo, n = 693; chemo, n = 666), BL scores for FACT-Ga total were similar between treatment groups. Least squares mean differences from BL favored NIVO+chemo at most visits for EQ-5D, FACT-Ga total, and Gastric Cancer Subscale (GaCS), and were comparable for other subscales (not shown). TTI generally favored NIVO+chemo (most HR > 1) but was not significantly different between arms. TTSD was longer in NIVO+chemo arm compared with chemo alone (all HRs < 1), except for Emotional Well-Being (WB); only GaCS and FACT-Ga total were significantly different between arms. TuDD showed statistically significant delays in deterioration (HR with CI < 1) for all scores expect Social WB. Conclusions: Compared with chemo alone, the addition of NIVO to chemo maintained HRQoL with a decreased risk of symptom deterioration in patients with previously untreated advanced or metastatic GC/GEJC/EAC. Together with improved OS, these data support NIVO+chemo as a new 1L standard treatment for GC/GEJC/EAC. Clinical trial information: NCT02872116. [Table: see text]

Objective To identify patient-reported outcome (PRO) instruments that assess chronic low back pain (cLBP) symptoms (specifically pain qualities) and/or impacts for potential use in cLBP clinical trials to demonstrate treatment benefit and support labeling claims. Design Literature review of existing PRO measures. Methods Publications detailing existing PRO measures for cLBP were identified, reviewed, and summarized. As recommended by the US Food & Drug Administration (FDA) PRO development guidance, standard measurement characteristics were reviewed, including development history, psychometric properties (validity and reliability), ability to detect change, and interpretation of observed changes. Results Thirteen instruments were selected and reviewed: Low Back Pain Bothersomeness Scale, Neuropathic Pain Symptom Inventory, PainDETECT, Pain Quality Assessment Scale Revised, Revised Short Form McGill Pain Questionnaire, Low Back Pain Impact Questionnaire, Oswestry Disability Index, Pain Disability Index, Roland-Morris Disability Questionnaire, Brief Pain Inventory and Brief Pain Inventory Short Form, Musculoskeletal Outcomes Data Evaluation and Management System Spine Module, Orebro Musculoskeletal Pain Questionnaire, and the West Haven-Yale Multidimensional Pain Inventory Interference Scale. The instruments varied in the aspects of pain and/or impacts that they assessed, and none of the instruments fulfilled all criteria for use in clinical trials to support labeling claims based on recommendations outlined in the FDA PRO guidance. Conclusions There is an unmet need for a validated PRO instrument to evaluate cLBP-related symptoms and impacts for use in clinical trials.

4066 Background: CheckMate 649 (NCT02872116) is a randomized, open label phase 3 study in first line (1L) GC/GEJC/EAC. Prespecified interim results showed statistically significant improvement in overall survival (OS) and progression-free survival (PFS) for N+C vs C in all randomized pts and pts whose tumors expressed programmed death-ligand 1 combined positive score (CPS) ≥ 5. We present interim HRQOL results for CPS ≥ 5 pts, included as exploratory in the study. Methods: HRQOL was assessed using EQ-5D-3L (EQ-5D) and Functional Assessment of Cancer Therapy–Gastric Cancer (FACT-Ga). Assessments were performed at baseline (BL), every 6 weeks during treatment, and during follow-up. Change from BL EQ-5D Visual Analog Scale (VAS), Utility Index (UI) and FACT-Ga scores were analyzed using mixed models. Time to first symptom deterioration (TTSD), time until definitive deterioration (TuDD), and time to improvement (TTI) were estimated with Kaplan-Meier estimators and stratified Cox models; deterioration/improvement was based on prespecified meaningful change thresholds. Results: 1,581 pts were randomized to N+C (n = 789) and C (n = 792); of those, 955 pts had CPS ≥ 5 (N+C [n = 473] and C [n = 482]). Among 821 pts with BL and post BL PROs (N+C [n = 421] and C [n = 400]), BL scores for FACT-Ga total were similar for N+C and C. Least-squares mean differences from BL favored N+C at most visits for EQ-5D and FACT-Ga total and GaCS, and were comparable for other FACT subscales (data not shown). TTI largely favored N+C (most hazard ratios (HR) > 1) but was not significantly different between treatments. For TTSD, pts treated with N+C had decreased risk of deterioration (HR < 1) in EQ-5D UI, FACT-Ga total, and GaCS. TuDD showed statistically significant delays in deterioration (HR with confidence intervals [CI] < 1) for all scores. Conclusions: Pts with 1L GC/GEJC/EAC experienced better HRQOL with N+C compared with C alone. Change from BL in EQ-5D and FACT-Ga total and GaCS favored N+C at most visits. N+C decreased deterioration risk compared to C with OS and PFS improvement, suggesting favorable benefits in 1L GC/GEJC/EAC pts with CPS ≥ 5. Clinical trial information: NCT02872116. [Table: see text]

285 Background: In the phase III, open-label CheckMate 9ER trial (NCT03141177), patients with aRCC were randomized 1:1 (stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk score, tumor programmed death ligand 1 expression, geographic region) to nivolumab 240 mg IV Q2W + cabozantinib 40 mg PO QD (N+C; n = 323) or sunitinib (S) 50 mg PO (4 weeks of 6-week cycles; n = 328) for first-line treatment until disease progression or unacceptable toxicity (max N treatment, 2 years). N+C met primary and secondary efficacy endpoints by significantly improving progression-free survival, overall survival, and objective response rate versus S in aRCC patients with a clear cell component. Here, we present in-depth health-related quality of life (HRQoL) patient-reported outcome (PRO) results, including overall between-group comparisons of treatment groups and time to confirmed deterioration (TCD). Methods: PROs in all randomized patients were an exploratory endpoint assessed using the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19) and EQ-5D-3L instruments. PRO assessments at baseline, common on-treatment scheduled visits, and common follow-up visits for both arms were analyzed. Changes from baseline were assessed using mixed-model repeated measures (MMRM), adjusting for baseline scores and stratification factors. TCD was calculated from Kaplan–Meier estimates and Cox proportional hazards models. Results: Median follow-up for overall survival was 18.1 months. PRO completion rates were > 90% at baseline, and ≥ 80% at all on-treatment assessments (≥ 10 patients) through week 91 in both arms. The overall least squares mean difference in change from baseline favored N+C over S in FKSI-19 (all domains) and in EQ-5D-3L. Patients treated with N+C experienced less treatment burden, with decreased risk of confirmed deterioration across most measurements versus S, including FKSI-19 total, disease-related symptoms (DRS), DRS-physical (DRS-P), DRS-emotional (DRS-E), functional well-being (FWB), and EQ-5D-3L visual analog scale (VAS) scores (Table). Conclusions: Patients reported statistically significant HRQoL benefits with N+C versus S. Treatment with N+C significantly reduced the risk of deterioration in HRQoL scores, including in disease-related symptoms of kidney cancer. These results suggest that the superior efficacy of N+C over S comes with the additional benefit of improved HRQoL. Clinical trial information: NCT03141177 . [Table: see text]

Established in 2008, the Patient-Reported Outcome (PRO) Consortium is a collaboration among the US Food and Drug Administration's Center for Drug Evaluation and Research, the Critical Path Institute, the pharmaceutical/biotechnology industry, and other stakeholders. The purpose of the consortium is to qualify PRO instruments through the Center for Drug Evaluation and Research's drug development tool qualification process for use as clinical trial endpoints to support drug approval and product labeling claims. The PRO Consortium has made notable progress toward collaborative development of PRO instruments in the following areas: asthma, mild cognitive impairment, depression, functional dyspepsia, irritable bowel syndrome, non-small cell lung cancer, and rheumatoid arthritis. This progress has come with considerable challenges, including navigating a new and evolving regulatory initiative, gaining consensus on key issues, and maintaining communication and engagement in a precompetitive environment. The purpose of this paper is to describe some of the challenges and lessons learned since the creation of the PRO Consortium in hopes that this information may provide direction and insight for similar collaborations.

The Patient Assessment for Low Back Pain–Impacts is a newly developed patient-reported outcome instrument to assess specific impacts of chronic low back pain for use in clinical trials and practice., We describe qualitative and quantitative development and preliminary validation of the Patient Assessment for Low Back Pain–Impacts (PAL-I), a patient-reported outcome measure for use in chronic low back pain (cLBP) clinical trials. Concept elicitation and cognitive interviews (qualitative methods) were used to identify and refine symptom concepts. Classical test theory and Rasch measurement theory (quantitative methods) were used to evaluate item-level and scale-level performance of the PAL-I using an iterative approach between qualitative and quantitative methods. Patients with cLBP participated in concept elicitation interviews (N = 43), cognitive interviews (N = 38), and assessment of paper-to-electronic format equivalence (N = 8). A web-based sample of self-reported patients with cLBP participated in quantitative studies to evaluate preliminary (N = 598) and revised (n = 401) drafts and patients with physician-diagnosed cLBP (N = 45) participated in preliminary validation of the PAL-I. The instrument contained 9 items describing cLBP impacts (walking, sitting, standing, lifting, sleep, social activities, travelling, climbing, and body movements). Item-level performance, scale structure, and scoring seemed to be appropriate. One-week test–retest reproducibility was acceptable (intraclass correlation coefficient 0.88 [95% confidence interval, 0.78-0.94]). Convergent validity was demonstrated with PAL-I total score and Roland-Morris Disability Questionnaire (Pearson correlation 0.82), MOS-36 Physical Functioning (−0.71), and MOS-36 Bodily Pain (−0.71). Individual item scores and total score discriminated between numeric rating scale tertile groups and painDETECT categories. Interpretation of paper and electronic administration modes was equivalent. The PAL-I demonstrated content validity and is potentially useful to assess treatment benefit in clinical trials of cLBP therapies.

Content valid, patient-reported outcome (PRO) measures of major depressive disorder (MDD) symptoms are needed to assess MDD treatment benefit. While a range of questionnaires are currently available to evaluate aspects of depression from the patient’s perspective, their comprehensiveness and qualitative development histories are unclear. The objective of this study was to describe the process and results of the preliminary qualitative development of a new symptom-based PRO measure intended to assess treatment benefit in MDD clinical trials. Qualitative interviews were conducted with adult MDD patients in the USA who recently experienced a major depressive episode. Experienced interviewers conducted concept elicitation (CE) and cognitive interviews using semi-structured interview guides. The CE interview guide was used to elicit spontaneous reports of symptom experiences along with probing to further explore and confirm concepts. The cognitive interview guide was developed to evaluate concept relevance, understandability, and structure of the draft items, and to facilitate further instrument refinement. Forty patients participated in the CE interviews. A total of 3022 symptom codes, representing 84 different concepts were derived from the transcripts. Data from the CE interviews were considered alongside existing literature and clinical expert opinion during an item-generation process, leading to development of a preliminary version of the Symptoms of Major Depressive Disorder Scale (SMDDS). Fifteen patients participated in three waves of cognitive interviews, during which the SMDDS was further refined. The SMDDS is a 35-item PRO measure intended for use as an endpoint in MDD clinical trials to support medical product labeling. The SMDDS uses a 7-day recall period and verbal rating scales. It was developed in accordance with the US Food and Drug Administration (FDA)’s PRO Guidance and best practices. Qualitative interviews have provided evidence for content validity. Future quantitative studies will confirm the SMDDS’s measurement properties and support FDA qualification.

INTRODUCTION Levomilnacipran extended-release (ER) is an FDA-approved serotonin norepinephrine reuptake inhibitor (SNRI) for treating major depressive disorder (MDD). SF-36v2 Health Survey outcomes from a Phase III, randomized, double-blind, placebo-controlled study (NCT00969709) were evaluated. METHODS Prospective and post hoc analyses of SF-36 Mental and Physical Component Summaries (MCS, PCS), and individual domains compared pooled levomilnacipran ER doses (40, 80, 120 mg/day) with placebo. Patients (18-65 years) had MDD, depressive episode ≥ 8 weeks, and Montgomery-Asberg Depression Rating Scale total score ≥ 30. SF-36 score changes from baseline to Week 8 were analyzed using ANCOVA and the observed cases approach (Intent-to-Treat [ITT] Population). Minimally important differences (MID) evaluated clinical relevance. RESULTS Baseline MCS scores reflected marked mental deficits in the ITT Population (levomilnacipran ER = 529; placebo = 175). MCS change at Week 8 was significantly greater for levomilnacipran ER than placebo (LSMD [SE] = 4.8 [1.5]; P = 0.0011); MID exceeded the 3-point threshold. Baseline PCS scores suggested minimal physical deficits; no between-group difference at Week 8 was noted. LSMD was nominally statistically significant (P < 0.05) for levomilnacipran ER versus placebo in 5 domains (General Health [2.44; P = 0.0010], Vitality [2.48; P = 0.0307], Social Functioning [3.25; P = 0.0097], Role-Emotional [3.38; P = 0.0078], Mental Health [4.34; P = 0.0005]); changes in Vitality, Social Functioning, and Mental Health exceeded MID. LIMITATIONS The trial was limited by short duration; analyses were post hoc and adjustments were not made for multiplicity. CONCLUSION Statistically significant and clinically meaningful improvement on the MCS and several individual domains suggest overall and dimensional improvement in health-related functioning for patients with MDD treated with levomilnacipran ER versus placebo.

483 Background: SOR is approved as 1L therapy for pts with aHCC, but there is still an unmet need to help improve or maintain HRQoL. This phase 3 study compared HRQoL of NIVO vs SOR as 1L therapy in pts with aHCC as an exploratory endpoint. Methods: FACT-Hep was administered cycle 1, day 1 and every other cycle. The effect of NIVO vs SOR on HRQoL using FACT-Hep was assessed via repeated measures mixed models (MMRM). Kaplan–Meier curves and Cox proportional-hazards models determined between-treatment differences in time to first and time until definitive deterioration (TTD/TUDD) based on prespecified thresholds for minimally important differences. The GP5 item from FACT-Hep was used to assess the burden associated with treatment side effects. Results: 743 pts with aHCC were randomized to NIVO (n = 371) or SOR (n = 372). Median OS was 16.4 mo for NIVO, 14.7 mo for SOR (HR 0.85 [95% CI 0.72–1.02]; P = 0.0752). ORR was 15% for NIVO, 7% for SOR (OR 2.41 [95% CI 1.48–3.92]). HRQoL scores were completed at baseline by 94.6% and 92.5% of participants, respectively, and were similar (FACT-Hep total: NIVO 140.7 [SD 21.5] and SOR 140. 6 [SD 19.1]. Questionnaire compliance rates exceeded 70% at most visits. MMRM analyses yielded clinically meaningful and statistically significant least squares means differences favoring NIVO on FACT-Hep total (10.1 [95% CI 7.3–13.0]), physical well-being (PWB; 2.0 [95% CI 1.4–2.6]), and functional well-being (FWB; 2.5 [95% CI 1.7–3.2]) scores. No sub-scales favored sorafenib. TTD was significantly delayed in NIVO for FACT-Hep total (HR 0.62 [95% CI 0.51–0.74]), PWB (HR 0.62 [95% CI 0.52–0.74]), FWB (HR 0.73 [95% CI 0.61–0.88]), and hepatobiliary cancer subscale (HR 0.57 [95% CI 0.48–0.69]). TUDD results were consistent with TTD. A greater proportion of NIVO pts did not experience increased burden of side effects (50%–67.7%) compared with SOR (26.8%–45%) based on the GP5 item. Conclusions: These patient-reported findings demonstrate that pts taking NIVO had superior HRQoL and reduced side effect burden, further supporting clinical data showing a treatment benefit for 1L NIVO in aHCC. Clinical trial information: NCT02576509.

BACKGROUND & OBJECTIVE Objectives The Pain Assessment in Low Back Pain Symptoms (PAL-S) is a Patient Reported Outcome (PRO) instrument being developed to assess the key symptoms of chronic low back pain (cLBP). Qualitative development included both concept elicitation and cognitive interviews. As part of the ongoing development of the instrument, we further evaluated and refined the PAL-S using a mixed methods approach. Methods Adults self-reporting a clinical diagnosis of cLBP were recruited from an existing US-based commercial survey panel to participate in a pilot quantitative study. Qualifying participants completed a web-based survey consisting of the 14-item PAL-S and items assessing clinical, treatment, and demographic characteristics. Study data was analyzed to assess itemand scale-level performance of the PAL-S using Rasch Measurement Theory analyses. Following analysis and modification, two waves of cognitive interviews were conducted to evaluate respondent understanding of the revised PAL-S. Results The dataset included 598 respondents (mean age: 55.5±12.6; 67.9% female; 88.0% white; and 54.0% married) who had cLBP for mean of 15.2±11.5 years. The Rasch analyses item threshold maps showed only two items having ordered thresholds, suggesting that respondents experienced increased difficulty distinguishing between options at the lower levels of the 0-10 scale. Simulations collapsing the responses to a best-fit 4-point response scale resulted in improved ordering of thresholds, suggesting a more optimal response option structure. Based on these findings, the numeric response scale of the PAL-S items was replaced with a 4-point verbal rating scale incorporating response choices such as not at all, slight, moderate, and severe. Findings from eight cognitive interviews confirmed patient comprehension and relevance of the revised instrument. Conclusion The mixed-methods approach proved valuable to the ongoing development of the PAL-S, as Rasch analyses identified a need for refinement of the response scale. The measurement properties of the revised PAL-S will be evaluated in additional web-based and clinic-based quantitative studies. Although a number of patient-reported outcome (PRO) instruments are available in low back pain (LBP), none of them were developed based on the most recent FDA PRO Guidance (2009) and would not be acceptable to the FDA to support labeling claims. Consequently, Forest Research Institute and partner Grunenthal in collaboration with experts have developed the Pain Assessment for Lower Back-Symptoms (PAL-S) instrument. The PAL-S was developed using state of the science best practices and in accordance with the FDA PRO Guidance (2009) to ensure evidence of content validity and measurement appropriate to support a labeling claim using PRO data. The early development work to create the PALS has included: • Completion of systematic reviews of the LBP literature and existing PRO instruments • The formation of an expert panel of clinical and methodological experts to provide advice during the development process • The completion of forty-three qualitative concept elicitation interviews conducted to identify the LBP-related concepts that are most important and relevant to the patients’ experience • A formal item-generation process in which evidence from the concept elicitation interviews, systematic literature reviews, and expert input was used to develop the content of the PAL-S • Four waves of qualitative cognitive interviews with patients with LBP to evaluate and refine the draft instruments This process has resulted in a 14-item developmental version ready for further quantitative testing. The primary aim is to collect initial quantitative data to further evaluate the performance of the PAL-S as appropriate PRO measures for use as endpoints in clinical studies of low back pain. The information gathered in this study will be used in the process of instrument refinement (item response theory, item reduction and/or modification), assessment of measurement characteristics, and finalization of the scoring approach to support the use of the PAL-S in subsequent studies.

To evaluate the effectiveness and costs of linaclotide (Linzess) versus lubiprostone (Amitiza) in the treatment of adult patients with chronic idiopathic constipation (CIC).A decision-tree model using model inputs derived from published literature, linaclotide phase 3 trial data, and a physician survey.Measures of treatment efficacy were selected based on comparability between trial data, with posthoc analyses of linaclotide required to ensure comparability with available lubiprostone data. Response to therapy was defined as (1) having one of the best two satisfaction answers of a 5-point global treatment satisfaction scale at Week 4 or (2) having a weekly spontaneous bowel movement (SBM) frequency 4 at Week 4. Patients who do not respond to therapy are assumed to accrue costs associated with a treatment failure. Model time horizon is aligned with the lubiprostone clinical trial duration of 4 weeks. Model outputs include response rates, quality-adjusted life-years (QALYs) and direct costs.Linaclotide was associated with lower per-patient costs vs lubiprostone for both definitions of response ($946 vs $1,015 for global assessment and $727 vs $737 for SBM frequency). When treatment response was based on a global assessment of treatment satisfaction, linaclotide was associated with higher effectiveness (response: 39.3% vs 35.0%). For SBM frequency, linaclotide was slightly less effective compared to lubiprostone (response: 58.6% vs 59.6%), but also less costly. Base-case results were robust in sensitivity analysis.Linaclotide is less expensive with similar effectiveness when compared to lubiprostone for the treatment of CIC in adult patients.

Examine drug persistence by evaluating the hazard of discontinuation and of switching to different antihypertensive drugs in patients initiating treatment with a recently approved β-blocker, nebivolol, versus other β-blockers.This retrospective analysis included all patients diagnosed with hypertension in the MarketScan Database (January 2007 - December 2008) with at least two medical claims and no prior β-blocker prescriptions within 6 months of the initial prescription date. Multivariate Cox proportional hazard models (adjusted for baseline differences in demographics, previous use of other antihypertensive medications, initial doses and supply of medication, and number of distinct prescriptions at baseline) were used to assess the hazard of discontinuation, defined as the first prescription gap of ≥30 days, and to assess the hazard of switching to another antihypertensive drug, defined as a prescription fill for another antihypertensive drug within 15 days before and 30 days after discontinuation of the initial β-blocker.Of the 173,200 patients included in the study population, the adjusted hazard of discontinuation for nebivolol-initiated patients was 8-20% lower than that of patients who initiated treatment with atenolol (hazard ratio [HR] 0.82, p 0.001), metoprolol (HR 0.91, p 0.001), carvedilol (HR 0.92, p 0.001), or other β-blockers (HR 0.80, p 0.001). The adjusted hazard of nebivolol-treated patients switching to a different antihypertensive medication was 12-22% lower than that of the other four β-blocker cohorts (atenolol: HR 0.80, p 0.001; metoprolol: HR 0.86, p 0.001; carvedilol: HR 0.88, p 0.001; other β-blockers: HR 0.78, p 0.001). Sensitivity analyses defined discontinuation as prescription gaps of ≥45 days and ≥60 days and showed a lower hazard of discontinuation among patients initiating nebivolol than among patients initiating all other drug cohorts (p 0.001).Comparisons of non-randomized treatment groups may be confounded by unobserved differences in patients' baseline characteristics.Initiation with nebivolol was associated with greater persistence than initiation with atenolol, carvedilol, metoprolol, or other β-blockers.

SummaryObjectiveTo compare healthcare resource utilization and healthcare costs between COPD patients who used multiple long-acting inhalers versus those who used a single long-acting inhaler.MethodsCOPD patients meeting study inclusion criteria were identified in the Market Scan database (2004–2008) and were classified as being a multiple- or single-inhaler user. 11,747 multiple- and single-inhaler users were matched on baseline characteristics to balance disease severity. Patients were followed for 12 months. Incremental differences between the two groups were estimated for: number of exacerbations; time to first exacerbation; all-cause and COPD-related inpatient admissions, inpatient days, emergency room visits, urgent care visits, outpatient visits, and other medical services visits; all-cause and COPD-related healthcare costs. Multivariate regression analyses were also used to control for a number of potentially confounding factors.ResultsAfter controlling for a number of potentially confounding factors, multiple-inhaler users experienced significantly more exacerbations (0.52; p

Adolescents with newly diagnosed depression may not receive timely antidepressant therapy. Clinical and economic effects of early versus late treatment initiation are unclear.To compare effects of early versus late initiation of second-generation (SSRI/SNRI) antidepressants on emergency room (ER) visits, hospitalizations and healthcare costs in adolescents with depression.Patients aged 12-17 with a diagnosis of depression were identified in a claims database (1999-2007). Patients initiating antidepressants within 1 month of initial diagnosis were considered early initiators; patients initiating within 2-12 months were late initiators. Clinical resource use and healthcare costs were measured during the 6-month pre-index and 12-month post-index (study) periods and compared descriptively between groups. Logistic regression compared healthcare services utilization; a generalized linear model compared costs. All models were adjusted for baseline characteristics, including demographics, comorbidities, and healthcare services utilization.A total of 7344 adolescents met study criteria. 4415 (60%) initiated antidepressant treatment within 1 month of diagnosis. At baseline, early initiators had more all-cause inpatient visits (14 vs. 7%) and all-cause ER visits than late initiators (25 vs. 21%, both p0.01). They had higher medical ($1434 vs. $1160) and total costs ($1565 vs. $1290) (both p0.01). In the study period, late initiators had higher risk of ER visits (OR=1.13, p=0.03). They incurred higher medical costs ($5415 vs. $4061) and higher total healthcare costs ($6001 vs. $4907), but lower adjusted drug costs ($767 vs. $888) (all p0.01).Clinical data are scarce in the claims database, and the ability to observe disease severity and reasons for delayed treatment is limited. The definition of early and late initiation was based on empirical analysis, and no clear cutoff was identified beyond what was observed in the data.Adolescents who initiated SSRI/SNRI therapy earlier experienced lower risk of ER visits and had lower total costs compared to late initiators.

To estimate, from a third-party payer's perspective, the effects of switching from escitalopram to citalopram, after the generic entry of citalopram, on hospitalization and healthcare costs among adult MDD patients who were on escitalopram therapy.Adult MDD patients treated with escitalopram were identified from Ingenix Impact claims database. MDD- and mental health (MH)-related hospitalization rates and healthcare costs were compared between 'switchers' (patients who switched to citalopram after its generic entry) and 'non-switchers'. MDD- and MH-related outcomes were defined as having a primary or a secondary diagnosis of ICD-9-CM = 296.2x, 296.3x and ICD-9-CM = 290-319, respectively. A propensity score matching method that estimated the likelihood of switching using baseline characteristics was used. Outcomes were examined for both 3-month and 6-month post-index periods.The sample included 3,427 matched pairs with balanced baseline characteristics. Switchers were more likely to incur an MDD-related (odds ratio [OR] = 1.52) and MH-related hospitalization (OR = 1.34) during the 6-month post-index period (both p0.05). Compared to switchers, non-switchers had significantly lower MDD- and MH-related hospitalization costs ($248.3 and $219.8 lower, respectively) and medical costs ($277.4 and $246.4 lower, respectively) (all p0.05). Although non-switchers had significantly higher MDD- and MH-related prescription drug costs, overall they had significantly lower total MDD- and MH-related healthcare costs ($109.9 and $93.6 lower, respectively; both p0.001). The 3-month results were consistent with these 6-month findings.The study limitations included limited generalizability of study findings, inability to differentiate switching from escitalopram to citalopram due to medical reasons versus non-medical reasons, and exclusion of indirect costs from cost calculations.Compared to patients maintaining on escitalopram, switchers from escitalopram to citalopram experienced higher risk of MDD- and MH-related hospitalization and incurred higher total MDD- and MH-related healthcare costs. The economic consequences of therapeutic substitution should take into account total healthcare costs, not just drug acquisition costs.

Diabetic peripheral neuropathy (DPN) occurs in 26–47 % of diabetes patients and may have negative impacts on physical functioning, sleep, well-being, and quality of life. The Diabetic Peripheral Neuropathic Pain Impact measure (DPNPI) was developed to measure disease impacts and treatment effects. Presented are the DPNPI conceptual development and validation findings. The DPNPI was developed following the FDA Guidance for Industry on patient-reported outcome (PRO) measures. Concept elicitation (CE) included literature review, clinical expert interviews, and patient interviews/focus groups. Qualitative data were analyzed following grounded theory principles, and draft items were cognitively debriefed. The measure underwent psychometric validation, and an a priori statistical analysis plan assessed the measurement model, reliability, and validity. Simultaneous analyses of item functioning were conducted using Rasch measurement theory (RMT). All tests were performed for the total score and each domain. Twenty-five patients and three clinical experts participated in CE which resulted in a 27-item validation ready measure. In the validation study (N = 124), nine draft items were dropped due to high missing data and/or high correlations between items. Factor analysis revealed three domains: physical functioning/mobility, sleep, and daily activities. RMT confirmed adequate item fit and placement within domains. Internal consistency ranged from 0.91 to 0.96 and test–retest from 0.84 to 0.91. All prespecified hypotheses for convergent and discriminant validity were met. CE and psychometric results provide evidence that the final, 18-item DPNPI is a reliable and valid PRO measure of disease impacts and treatment for DPNP. Further validation work should include responsiveness assessment.

To use techniques of decision-analytic modeling to evaluate the effectiveness and costs of linaclotide vs lubiprostone in the treatment of adult patients with irritable bowel syndrome with constipation (IBS-C).Using model inputs derived from published literature, linaclotide Phase III trial data and a physician survey, a decision-tree model was constructed. Response to therapy was defined as (1) a ≥ 14-point increase from baseline in IBS-Quality-of-Life (IBS-QoL) questionnaire overall score at week 12 or (2) one of the top two responses (moderately/significantly relieved) on a 7-point IBS symptom relief question in ≥ 2 of 3 months. Patients who do not respond to therapy are assumed to fail therapy and accrue costs associated with a treatment failure. Model time horizon is aligned with clinical trial duration of 12 weeks. Model outputs include number of responders, quality-adjusted life-years (QALYs), and total costs (including direct and indirect). Both one-way and probabilistic sensitivity analyses were conducted.Treatment for IBS-C with linaclotide produced more responders than lubiprostone for both response definitions (19.3% vs 13.0% and 61.8% vs 57.2% for IBS-QoL and symptom relief, respectively), lower per-patient costs ($803 vs $911 and $977 vs $1056), and higher QALYs (0.1921 vs 0.1917 and 0.1909 vs 0.1894) over the 12-week time horizon. Results were similar for most one-way sensitivity analyses. In probabilistic sensitivity analyses, the majority of simulations resulted in linaclotide having higher treatment response rates and lower per-patient costs.There are no available head-to-head trials that compare linaclotide with lubiprostone; therefore, placebo-adjusted estimates of relative efficacy were derived for model inputs. The time horizon for this model is relatively short, as it was limited to the duration of available clinical trial data.Linaclotide was found to be a less costly option vs lubiprostone for the treatment of adult patients with IBS-C.

Exacerbations are a major contributor to the large burden of treating chronic obstructive pulmonary disease (COPD). Estimates of exacerbation costs in the United States are limited.To estimate incremental costs associated with COPD exacerbation, particularly severe exacerbation, in the United States.COPD patients with at least one exacerbation were identified in the Thomson Reuters MarketScan administrative claims database. A COPD exacerbation was defined as patient use of oral or parenteral corticosteroids on the same day or within 7 days following a claim with a COPD diagnosis. Severe exacerbation was further defined if the exacerbation was associated with hospitalization or death. Healthcare costs and exacerbations were evaluated at quarterly intervals starting from patients' first observed claim with COPD diagnostic code in the database. Incremental costs associated with exacerbation were estimated as cost differences between quarters with exacerbation and quarters without exacerbation.A total of 2644,174 patient-quarters, derived from 228,978 COPD patients, were included in the analysis. The average patient was followed an average of 2.9 years. The mean total cost was $17,016 per patient-quarter with severe exacerbation, $6628 per patient-quarter with non-severe exacerbation, an average of $8726 per patient-quarters with any exacerbation compared to $4762 per patient-quarter with no exacerbation. After adjusting for patient demographics, the mean incremental total cost was $11,261 per patient-quarter with severe exacerbation, $1509 per patient-quarter for non-severe exacerbation, and $3439 per patient-quarter with any exacerbation compared with patient-quarters with no exacerbation.The method used for defining exacerbations does not capture mild exacerbations. Additional limitations exist due to the nature of claims data.Exacerbations, especially severe ones, result in a significant economic burden for third-party payers. Effective management of COPD and prevention of exacerbations may lead to improved patient outcomes and reduction in total healthcare costs for long-term management of COPD.

Background To reduce pharmacy costs, managed care organizations encourage therapeutic substitution from brand to a generic product. However, little is known about whether these cost-containment strategies can also potentially lower total expenditures for payers in treatment of major depressive disorder (MDD). Objective: To compare economic outcomes of patients with MDD who were switched from a brand selective serotonin reuptake inhibitor (SSRI) to an alternative generic SSRI for nonmedical reasons versus patients who continued on the brand SSRI. Methods: Adult MDD patients in the Ingenix Impact Database (2003–2007) were considered “switchers” if they received treatment with a brand SSRI and were later switched to an alternative generic SSRI for nonmedical reasons. Patients who remained on the brand SSRI (nonswitchers) were matched 1:1 with switchers. All-cause, mental health-related, and MDD-related rates of hospitalizations/emergency department (ED) visits and costs over 6 months were compared both descriptively and by using adjusted regression models. A subgroup analysis on patients who were switched from escitalopram (Lexapro) to an alternative generic SSRI was also performed. Results: The study included 4449 matched pairs. Compared with nonswitchers, switchers had higher risk of all-cause, mental health–related, and MDD-related use of hospitalizations/ED visits (OR 1.15, 1.34, and 1.54, respectively; all p < 0.01) and higher risk-adjusted mental health–related and MDD-related medical costs ($219 and $222, respectively; both p < 0.05). Subgroup analysis on escitalopram showed similar results; switchers experienced higher risk of any-cause, mental health–related, and MDD-related use of hospitalizations/ED visits (OR 1.21, 1.41, and 1.53, respectively; all pConclusions: Compared with patients who continued on their patented SSRIs, patients who switched to a generic SSRI incurred more resource use of hospitalizations/ED visits and higher MDD-related health-care costs. The effects of therapeutic substitution should be carefully examined, because use of generic alternatives may not be a cost-saving strategy when total health-care costs are considered.