[Special issue PRO] A demonstration of estimands and sensitivity analyses for time-to-deterioration of patient reported outcomes.

In oncology trials, health-related quality of life (HRQoL), specifically patient-reported symptom burden and functional status, can support the interpretation of survival endpoints, such as progression-free survival. However, applying time-to-event endpoints to patient-reported outcomes (PRO) data is challenging. For example, in time-to-deterioration analyses clinical events such as disease progression are common in many settings and are often handled through censoring the patient at the time of occurrence; however, disease progression and HRQoL are often related leading to informative censoring. Special consideration to the definition of events and intercurrent events (ICEs) is necessary. In this work, we demonstrate time-to-deterioration of PRO estimands and sensitivity analyses to answer research questions using composite, hypothetical, and treatment policy strategies applied to a single endpoint of disease-related symptoms. Multiple imputation methods under both the missing-at-random and missing-not-at-random assumptions are used as sensitivity analyses of primary estimands. Hazard ratios ranged from 0.52 to 0.66 over all the estimands and sensitivity analyses modeling a robust treatment effect favoring the treatment in time to disease symptom deterioration or death. Differences in the estimands include how people who experience disease progression or discontinue the randomized treatment due to AEs are accounted for in the analysis. We use the estimand framework to define interpretable and principled approaches for different time-to-deterioration research questions and provide practical recommendations. Reporting the proportions of patient events and patient censoring by reason helps understand the mechanisms that drive the results, allowing for optimal interpretation.

Meaningful Symptomatic Change in Patients With Myelofibrosis From the SIMPLIFY Studies.

OBJECTIVES: Patients with myelofibrosis develop symptoms due to bone marrow fibrosis, systemic inflammation, and/or organomegaly. Alleviating symptoms improves overall quality of life. Clinical trials have historically defined symptom response as a reduction of at least 50% in Total Symptom Score at week 24 compared with baseline. Whether 50% constitutes a meaningful benefit has not been established. This study determined the meaningful change threshold (MCT) for 2 momelotinib phase III trials, SIMPLIFY-1 and SIMPLIFY-2. METHODS: The absolute and percentage MCT was determined using anchor-based methods applied to the modified Myeloproliferative Neoplasm Symptom Assessment Form v2.0 and Patient Global Impression of Change. MCTs were applied retrospectively to determine responder rates. Generalized estimating equations estimated the treatment-related difference in likelihood of improvement. RESULTS: In SIMPLIFY-1, a Janus kinase inhibitor-naive population, the MCT was 8 points. In SIMPLIFY-2, a previously Janus kinase inhibitor-treated population, the MCT was 6 points. A 32% MCT was determined in both studies, showing that the historic 50% reduction threshold may be a conservative choice. In SIMPLIFY-1, a similar proportion of patients achieved responder status with 24 weeks of momelotinib or ruxolitinib therapy based on the absolute MCT (39% vs 41%, respectively). In SIMPLIFY-2, a significantly greater proportion of patients treated with momelotinib achieved responder states compared with best available therapy based on absolute and percent change MCTs. CONCLUSIONS: This study demonstrates that momelotinib provided clinically meaningful symptom benefit for patients with myelofibrosis and provides insight into the appropriateness of the symptom change threshold used in historical studies.

Meaningful Change Thresholds and Fatigue Severity Points on Patient-Reported Outcomes by the Fatigue Symptoms and Impacts Questionnaire in Patients With Relapsing Multiple Sclerosis.

OBJECTIVES: The Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) is a new content-valid, concise, and reliable 20-item patient-reported outcome measure to evaluate the symptoms and impacts of fatigue in patients with relapsing forms of multiple sclerosis. Analyses were performed to derive meaningful change thresholds (MCTs) on patient-reported outcomes as measured by FSIQ-RMS and generate receiver operating characteristic (ROC) curves to determine fatigue severity cut points at baseline and change in severity at post-baseline and supplement the anchor-based MCT results. METHODS: Analyses were based on data from the OPTIMUM trial (NCT02425644). An anchor-based approach using uncollapsed changes on the Patient Global Impression of Severity at week 108 were used to determine the MCT for only the FSIQ-RMS Symptoms domain; distribution-based MCT estimations were conducted using baseline FSIQ-RMS Impacts scores. ROC curves with calculation of area under the curve were used to identify the best cut point. RESULTS: Based on the evidence provided by the anchor-based analyses using the Patient Global Impression of Severity as an anchor for the FSIQ-RMS Symptoms domain, meaningful score changes for improvement and deterioration were -6.3 and 6.3, respectively. Meaningful score changes for the FSIQ-RMS Physical, Cognitive/Emotional, and Coping Impacts domains using distribution-based methods were 10.8, 8.4, and 9.8, respectively. These results are supported by the ROC analyses. CONCLUSIONS: Thresholds to support interpretation of the FSIQ-RMS, such as MCTs, can be used to determine and categorize patients who have experienced a meaningful change in their MS-related fatigue (eg, responder analyses) in future clinical research studies.

Establishing Meaningful Change Thresholds in Patient-Reported Outcomes Among Patients With Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer in ALTA-1L Trial.

OBJECTIVES: An earlier study from the ALTA-1L trial of patients with anaplastic lymphoma kinase-positive non-small cell lung cancer demonstrated that brigatinib produces superior health-related quality of life (QoL) outcomes over crizotinib. This study aimed to derive meaningful change thresholds (MCTs) for European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and EORTC QLQ-LC13 to refine the earlier results. METHODS: Patients from the ALTA-1L trial were administered the EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires. Responses were analyzed using anchor-based analysis, graphical analysis, distribution-based analysis, longitudinal responder analysis, and time to deterioration. RESULTS: The patient-reported outcome population comprised 262 patients who completed the EORTC QLQ-C30 at baseline and at least 1 follow-up timepoint. Both anchors (QLQ-C30 items for overall health and QoL) had correlations >0.40 or < -0.40 with all functioning domains, fatigue, pain, appetite loss, and all dyspnea scores. Within-group analysis for most scales found the derived MCT was consistent with a cutoff of 10 points for classifying individual-patient change, except for 3-item dyspnea. The probability of improvement/remaining stable was significantly greater in the brigatinib group over crizotinib for the EORTC QLQ-C30 emotional functioning, appetite loss, and constipation domains. CONCLUSIONS: This study derived MCTs for EORTC QLQ-C30 and QLQ-LC13 domains that may be applied in future studies and again demonstrated the superiority of brigatinib over crizotinib in health-related QoL outcomes in patients with non-small cell lung cancer.

Quantitative and Qualitative Exploration of Meaningful Change on the Vineland Adaptive Behavior Scales (Vineland™-II) in Children and Adolescents with Autism Without Intellectual Disability Following Participation in a Clinical Trial.

Purpose: The VinelandTM Adaptive Behavior Scale is often used in autism spectrum disorder (ASD) trials. The Adaptive Behavior Composite Score (VABS-ABC) is the standardized overall score (the average of the Socialization, Communication and Daily Living skills domains), and the standardized 2-Domain Composite Score (VABS-2DC) is a novel outcome measure (average of the Socialization and Communication domains). A within-person meaningful change threshold (MCT) has not been established for the VABS-2DC. This paper presents a quantitative and qualitative interpretation of what constitutes a meaningful change in these scores to individuals with ASD without Intellectual Disability (ID; IQ≥70) and their families, as reported by their study partners (SPs). Participants and Methods: Data were obtained from the aV1ation clinical trial in children and adolescents with ASD and associated exit interviews. The intent-to-treat (ITT) clinical trial population included 308 individuals with autism (85.4% male; average age: 12.4 years [standard deviation (SD)=2.97]); 124 in the child cohort (aged 5 to 12 years; average age: 9.4 years [SD=1.86]), and 184 in the adolescent cohort (aged 13 to 17 years; average age: 14.5 years [SD=1.39]). Study partners of 86 trial participants were included in the Exit Interview Population (EIP): participants represented were 83.7% male, average age: 12.3 years [SD=2.98]). Anchor and distribution-based methods were used to estimate within-person change to support a responder definition, to aid interpretation of the clinical trial data; qualitative data were used to contextualize the meaning of changes observed. Results: A within-person MCT range of 4 to 8 points was proposed for both VABS-ABC and VABS-2DC, which was associated with at least a 1-point improvement on 4 different anchors. Evidence for this within-person MCT was further supported by qualitative data, which suggested any change was considered meaningful to the individual with ASD, as reported by their SP, no matter what the magnitude. Conclusion: A change in standardized score of 4 to 8 points constitutes a within-person MCT on both VABS-ABC and novel VABS-2DC in those with ASD and no ID. A change of this, or more, was reported by the SPs in this trial to be meaningful and highly impactful upon the individuals with ASD and their family.

Development and validation of a psoriasis treatment acceptability measure through group concept mapping.

BACKGROUND: Psoriasis is a common autoimmune dermatologic condition which has a pronounced negative impact on patient quality of life and disease burden. Currently, there are a number of treatments available for psoriasis, with differences in efficacy, mechanism of action, mode of administration, adverse effects, and tolerability. However, a reliable, validated patient-reported instrument to address patient expectations and of psoriasis treatment has not been developed. This project was undertaken with the aim of developing a fit-for-purpose self-reported instrument to inform patient expectations and preferences of psoriasis treatments. METHODS: Two studies, both utilizing qualitative and quantitative methods, were conducted in patients within the entire spectrum of psoriasis severity. In Study 1, a group concept mapping (GCM) exercise was conducted with dermatologists and moderate-to-severe psoriasis patients to identify concepts important in the treatment of psoriasis. In Study 2, a preliminary Treatment Acceptability Questionnaire (TAQ) was developed using GCM-derived concepts from Studies 1 and 2, followed by cognitive debriefing (CD) telephone interviews of the preliminary TAQ. In Study 2, another GCM exercise was conducted with mild and newly diagnosed psoriasis patients. Psychometric analyses were performed on the TAQ to evaluate validity and reliability. RESULTS: The Study 1 GCM exercise generated 43 concepts from moderate-to-severe psoriasis patients (n = 20) and dermatologists (n = 10). In Study 2, 37 GCM concepts were generated from mild and newly diagnosed psoriasis patients (n = 20). From the 2 GCM exercises, 28 concepts were selected to form the preliminary TAQ; CD interviews indicated strong understanding and relevance of TAQ items among patients with disease ranging from mild to severe. The final TAQ consisted of 20 items; psychometric analysis demonstrated strong validity and reliability of the TAQ. CONCLUSIONS: The TAQ is a novel psychometrically validated patient-reported instrument to inform healthcare providers of patients' expectations of and preferences for treatment of their psoriasis and can help in shared decision making between patients and physicians.

Study to Assess Content Validity and Interrater and Intrarater Reliability of the Inclusion Body Myositis Functional Rating Scale.

Background and Objectives: Sporadic inclusion body myositis (IBM) is a rare, muscle-wasting disease that negatively affects health-related quality of life. Although a measure that has been developed to assess the impact of IBM, the IBM Functional Rating Scale (IBMFRS) has limited evidence of content validity or reliability, and what constitutes a meaningful change threshold; this study was conducted to address these gaps. Methods: Adult patients with a clinical diagnosis of IBM from the United Kingdom and disease area expert health care professionals from the United States and United Kingdom took part in this study. This study consisted of 5 stages including phone interviews (physicians), face-to-face interviews (patients), face-to-face ratings, phone ratings, and ratings of videos using the IBMFRS. Results: The IBMFRS adequately captures all core functional impacts of IBM, which was corroborated by both patient participants and physicians when debriefing the measure. Physicians and patient participants all thought any change on the measure would be meaningful change for a patient, either improvement or worsening. The quantitative analysis demonstrated good interrater reliability for face-to-face ratings (intraclass correlation coefficient [ICC] >0.7) and for video ratings (ICC >0.9). Intrarater reliability was excellent for face-to-face and video ratings (ICC >0.9). Equivalence between the modes of administration, face-to-face vs phone, was also excellent (ICC >0.9). Discussion: The IBMFRS is content valid in assessing the key functional impacts of IBM, and any change would be meaningful. It is reliable both within and across raters, and there is equivalence between different modes of administration (face-to-face vs phone).

Symptomatic benefit of momelotinib in patients with myelofibrosis: Results from the SIMPLIFY phase III studies.

BACKGROUND: Myelofibrosis (MF)-associated constitutional symptoms can severely impact health-related quality of life. Clinical trials in MF traditionally measure symptom response to treatment as a landmark endpoint of total symptom score (TSS) reduction ≥50% from baseline. However, this dichotomous assessment provides a limited view of clinically relevant symptomatic changes. Herein we evaluated longitudinal change from baseline in TSS over the continuous 24-week period and individual symptom scores to obtain a more comprehensive understanding of symptom benefits experienced by patients with MF receiving therapy. METHODS: Longitudinal symptom change was evaluated using mixed-effect model repeated measure (MMRM) methodology with individual item-level analyses to complement the interpretation of the landmark symptom results in the completed phase III SIMPLIFY studies of momelotinib in MF. MMRM compared mean change in TSS from baseline with Week 24 using data from all patient visits. Generalized estimating equations were used to estimate item-level odds ratios using multiple predictive imputations for missing data. RESULTS: Momelotinib and ruxolitinib groups reported similar overall symptom improvements, with a TSS difference of <1.5 points between groups for each post-baseline visit in SIMPLIFY-1. In SIMPLIFY-2, the improvement in TSS observed in momelotinib-treated patients was consistent with that observed in SIMPLIFY-1, whereas progressive TSS deterioration was observed with control. Item-level scores were heterogeneous in both studies. A similar and greater proportion of momelotinib-treated patients were categorized as "improved" or "stable" compared with control in SIMPLIFY-1 and SIMPLIFY-2, respectively. Odds ratios for between-group comparison ranged from 0.75 to 1.21 in SIMPLIFY-1, demonstrating similarity in likelihood of symptom improvement. In SIMPLIFY-2, the likelihood of symptom improvement in each item was higher in the momelotinib arm. CONCLUSIONS: These findings suggest that momelotinib provides clinically relevant symptom benefits in the JAK inhibitor-naïve and JAK inhibitor-exposed settings.

Summary of Research: Development and Validation of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ).

This is a summary of the original article 'Development and Validation of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ)'. Individuals with insomnia are best positioned to assess the impact of insomnia on their quality of life. Patient reported outcomes (PROs) are self-reported health measures created to allow people to record their experience of their disease. Chronic insomnia has a major impact on daytime functioning for patients, and on their quality of life. This summary of research provides an overview of a previously published article detailing the development and evaluation of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ), as a tool to allow people with insomnia to report their experience of the impact on their daytime functioning.

Best Practice Recommendations for Electronic Patient-Reported Outcome Dataset Structure and Standardization to Support Drug Development.

The electronic patient-reported outcome (ePRO) Dataset Structure and Standardization Project is a multistakeholder initiative formed by Critical Path Institute's PRO Consortium and Electronic Clinical Outcome Assessment (eCOA) Consortium to address issues related to ePRO dataset structure and standardization and to provide best practice recommendations for clinical trial sponsors and eCOA providers. Given the many benefits of utilizing electronic modes to capture PRO data, clinical trials are increasingly using these methods, yet there are challenges to using data generated by eCOA systems. Clinical Data Interchange Standards Consortium (CDISC) standards are used in clinical trials to ensure consistency in data collection, tabulation, and analysis and to facilitate regulatory submission. Currently, ePRO data are not required to follow a standard model, and the data models used often vary by eCOA provider and sponsor. This lack of consistency creates risks for programming and analysis and difficulties for analytics functions generating the required analysis and submission datasets. There is a disconnect between data standards used for study data submission and those used for data collection via case report forms and ePRO forms, which would be mitigated through the application of CDISC standards for ePRO data capture and transfer. The project was formed to collate and examine the issues arising from the lack of adoption of standardized approaches and this paper details recommendations to address those issues. Recommendations to address issues with ePRO dataset structure and standardization include adopting CDISC standards in the ePRO data platform, timely involvement of key stakeholders, ensuring ePRO controls are implemented, addressing issues of missing data early in development, ensuring quality control and validation of ePRO datasets, and use of read-only datasets.

A Study Design to Harmonize Patient-Reported Outcomes Across Data Sets.

PURPOSE: Using patient-reported outcomes (PROs) provides important insights from the patient's perspective and can be valuable to monitor and manage treatment-related adverse events during cancer treatment. Additionally, the digital administration of PROs (electronic PROs [ePROs]) provides real-time updates to clinical care teams on treatment-related symptoms in-between clinic visits. However, given the variability in the methodology and timing of the data collection, using and harmonizing these data across different systems remains challenging. Identifying data elements to capture and operating procedures for harmonization across ePRO tools will expedite efforts to generate relevant and robust data on use of ePRO data in clinical care. METHODS: Friends of Cancer Research assembled a consortium of project partners from key health care sectors to align on a framework for ePRO data capture across ePRO tools and assessment of the impact of ePRO data capture on patient outcomes. RESULTS: We identified challenges and opportunities to align ePRO data capture across ePRO tools and aligned on key data elements for assessing the impact of ePRO data capture on patient care and outcomes. Ultimately, we proposed a study protocol to leverage ePRO data for symptom and adverse event management to measure real-world effectiveness of ePRO tool implementation on patient care and outcomes. CONCLUSION: This work provides considerations for harmonizing ePRO data sets and a common framework to align across multiple ePRO tools to assess the value of ePROs for improving patient outcomes. Future efforts to interpret evidence and evaluate the impact of ePRO tools on patient outcomes will be aided by improved alignment across studies.

Comparability of a provisioned device versus bring your own device for completion of patient-reported outcome measures by participants with chronic obstructive pulmonary disease: quantitative study findings.

OBJECTIVE: To quantitatively compare equivalence and compliance of patient-reported outcome (PRO) data collected via provisioned device (PD) versus bring your own device (BYOD). METHODS: Participants with stable chronic obstructive pulmonary disease (COPD) completed the EXAcerbations of Chronic Pulmonary Disease Tool (EXACT®) daily and COPD Assessment Test™ (CAT) and Patient Global Impression of Severity (PGIS) of COPD weekly on either PD or BYOD for 15 days, then switched device types for 15 days. EXACT was scored using the Evaluating Respiratory Symptoms in COPD (E-RS®: COPD) algorithm and equivalence assessed using intraclass correlation coefficients (ICCs) adjusting for cross-over sequence, period, and time. Two one-sided tests (TOSTs) used ICC adjusted means with 10%, 20%, and 40% of total score tested as equivalence margins. Compliance and comfort with technology were assessed. Equivalence across 3 device screen sizes was assessed following the second completion period. RESULTS: Participants (N = 64) reported high comfort with technology, with 79.7% reporting being "quite a bit" or "very" comfortable. Weekly compliance was high (BYOD = 89.7-100%; PD = 76.9-100%). CAT and E-RS: COPD scores correlated well with PGIS (r > 0.50) and demonstrated equivalence between PD and BYOD completion (ICC = 0.863-0.908). TOST equivalence was achieved within 10% of the total score (p > 0.05). PRO measure scores were equivalent across 3 different screen sizes (ICC = 0.972-0.989). CONCLUSIONS: Measure completion was high and scores equivalent between PD and BYOD, supporting use of BYOD in addition to PD for collecting PRO data in COPD studies and in demographically diverse patient populations.

Comparability of a provisioned device versus bring your own device for completion of patient-reported outcome measures by participants with chronic obstructive pulmonary disease: qualitative interview findings.

BACKGROUND: There is interest in participants using their own smartphones or tablets ("bring your own device"; BYOD) to complete patient-reported outcome (PRO) measures in clinical studies. Our study aimed to qualitatively evaluate participants' experience using a provisioned device (PD) versus their own smartphone (BYOD) for this purpose. METHODS: Participants with chronic obstructive pulmonary disease (COPD) were recruited for this observational, cross-over study and completed PRO measures daily on one device type for 15 days, then switched to the other device type to complete the same measures for another 15 days. After each 15-day period, semi-structured interviews were conducted about their experience with the device. RESULTS: Of 64 participants enrolled, the final qualitative analysis populations comprised those who participated in an interview without protocol violations. Thus, the qualitative longitudinal population (LP) included n = 57 (89%), while the qualitative cross-sectional population (CSP) included n = 60 (94%). CSP participants found both device types easy to use. Twenty CSP participants (33%) reported missing data entry on at least one day when using PD, and 24 (40%) reported missing at least one day when using BYOD. In the LP, preference for one of the device types was somewhat evenly split; 45.6% (n = 26) preferred PD and 50.9% (n = 29) preferred BYOD. The most common reason for preferring PD was that it was "dedicated" to the study; the "convenience" of carrying a single device was the main reason for preferring BYOD. CONCLUSION: The findings from the interviews demonstrated few differences in participants' experience completing PRO measures on a PD versus BYOD. Our study supports the use of BYOD as a potential addition to PD for collecting PRO data and contributes evidence that BYOD may be employed to collect PRO data in demographically diverse patient populations.

Development of the Bleeding and Pelvic Discomfort Scale for Use in Women With Heavy Menstrual Bleeding Associated With Uterine Fibroids.

OBJECTIVES: This study aimed to define a cardinal symptom burden measure based on items from the Uterine Fibroid Symptom and Quality of Life questionnaire for use as a clinical trial endpoint. METHODS: Exploratory factor analysis was computed to assess the Uterine Fibroid Symptom and Quality of Life symptom severity scale factor structure, using phase 2 data. Pooled blinded data from phase 3 studies were used for the confirmatory factor analysis and the psychometric evaluation of the new measure. Exit interviews in 30 patients from phase 3 studies provided additional qualitative evidence. A meaningful change threshold was determined using anchor-based analyses supported by patient feedback in the exit interviews. RESULTS: Three factors emerged from the exploratory factor analysis. Factor 1, called the bleeding and pelvic discomfort (BPD) scale, consists of cardinal symptoms, measuring menstrual distress owing to heavy bleeding, passing blood clots, and feeling tightness or pressure in pelvic area. Patients generally understood the items in the scale and the recall period as intended. The BPD scale had good item performance and internal consistency reliability, strong item-to-total correlations, good item discrimination, known-groups validity, and ability to detect change. A 20-point change on the BPD scale was determined as the clinically meaningful change threshold. CONCLUSIONS: The BPD scale assesses symptom burden owing to bleeding, passing blood clots, and pelvic pressure. The subscale is based on a subset of items selected to measure the cardinal symptoms of uterine fibroids in a clinical trial setting. The responder threshold evaluates whether patients experience a meaningful treatment benefit over the on-treatment period.

Validation of the Physician's Global Assessment of Fingernail Psoriasis by Rheumatologists Treating Psoriatic Arthritis.

OBJECTIVES: This study aimed to assess the content validity and reliability of the Physician's Global Assessment of Fingernail Psoriasis (PGA-F) by rheumatologists treating patients with psoriatic arthritis. METHODS: There were 3 stages of analyses with 3 clinician cohort groups. Stage 1 (concept confirmation) included rheumatologist qualitative data (cohort 1) to establish content validity, acceptability, utility, and feasibility of the PGA-F in assessing nail severity. Quantitative information regarding the response category utilization in nail abnormalities was assessed by photographs. Stage 2 (inter-rater reliability) involved quantitative analysis of PGA-F data from study investigators, including rheumatologists, involved in a phase III clinical study (cohort 2) and a cohort of newly recruited rheumatologists (cohort 3). Stage 3 included known-groups validity. RESULTS: Qualitative analyses identified consensus that the PGA-F severity levels are comprehensive of real-world patient symptoms and the instrument is simple to use and understand. Psychometric analyses support the PGA-F as a clinical outcome assessment tool. Inter-rater reliability showed rheumatologist agreement across the fingernail psoriasis severity spectrum. They were monotonically ordered by the hypothesized severity structure with excellent fit to the clinicians who evaluated them. Agreement on the rank order of the severity of the photographs in this target rheumatologist population was consistent with previous reports by dermatologists. CONCLUSIONS: The PGA-F was shown to be usable by rheumatologists to measure patients along the full range of the fingernail psoriasis severity spectrum, have a strong relationship with a conceptually similar reference measure, differentiate among patients based on fingernail psoriasis severity, and detect category severity change over a 24-week period.

Evaluation of Individual Items of the Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) in Adults with Treatment-Resistant Depression Treated with Esketamine Nasal Spray Combined with a New Oral Antidepressant.

OBJECTIVE: The objective of this study was to determine which symptoms measured by the Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) improve in those treated with esketamine nasal spray in combination with oral antidepressant (AD) compared with those treated with placebo plus AD for adult patients with treatment-resistant depression (TRD). These results complement the interpretation of PHQ-9 and MADRS total scores. METHODS: The TRANSFORM 2 study evaluated the efficacy and safety of esketamine nasal spray in combination with AD. This post-hoc analysis used PHQ-9 and MADRS data to evaluate symptom changes. The total scores change and proportions of individual item change scores on the PHQ-9 and MADRS were evaluated at days 15 and 28; analysis of variance was used to test differences on total scores. Generalized estimation equations of logistic regression models were used to estimate the likelihood of improvement on instrument items. RESULTS: The mean total score reduction of the PHQ-9, indicating improvement, was greater in the esketamine plus AD arm compared with placebo plus AD at day 15 (- 1.8; p = 0.045) and day 28 (- 2.8; p = 0.006). Proportions of those who improved (≥ 1 point on a 4-point scale and ≥ 2 points on a 7-point scale for the PHQ-9 and MADRS, respectively) was greater in the esketamine plus AD group compared with the placebo plus AD group across all items. The odds of improving for those in the esketamine plus AD group compared with the placebo plus AD group were over two times greater on the PHQ-9 items: "Little interest/pleasure in things" (OR 2.252, 95% CI 1.165-4.355); "Feeling down, depressed, or hopeless" (OR 2.767, 95% CI 1.400-5.470); and "Feeling tired or having little energy" (OR 2.171, 95% CI 1.153-4.087). The mean reduction in total scores on the MADRS, indicating improvement, was numerically greater at day 15 (- 2.0; p = 0.189) and statistically significantly greater at day 28 (- 4.4; p = 0.017) in the esketamine plus AD arm compared with placebo plus AD. The odds of improving for those in the esketamine plus AD group compared with the placebo plus AD group were over two times greater on the MADRS items measuring "Apparent sadness" (OR 2.007, 95% CI 1.096-3.674); and "Inability to feel" (OR 2.099, 95% CI 1.180-3.735). CONCLUSION: Improvement in mean total scores in those treated with esketamine plus AD compared with placebo plus AD are important results to confirm efficacy. The odds of improving in those treated with esketamine plus AD was at least two times greater than with placebo plus AD on three patient- and two clinician-reported individual symptoms of TRD. These findings provide patient-relevant quantification of the esketamine plus AD treatment benefit, adding understanding as to which symptoms are most improved with treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02418585; first posted 16 April 2015.

Psychometric validation and interpretation of the Nocturia Impact Diary in a clinical trial setting.

PURPOSE: Psychometric evaluation of the Nocturia Impact (NI) Diary was conducted to support its use as a trial endpoint. METHODS: As part of a randomized, controlled Phase 2 clinical trial investigating a novel drug candidate for nocturnal polyuria, adult nocturia patients completed the NI Diary and a voiding diary for three nights preceding their clinic visit at Baseline and Weeks 1, 4, 8, and 12 (end of treatment). Exit interviews were conducted to obtain patient impressions of the NI Diary. RESULTS: A total of N = 302 participants were included. Confirmatory factor analysis (CFA) indicated that the 11-item measure is unidimensional with values of CFI, TLI, and RMSEA meeting relevant thresholds. Good internal consistency (Cronbach's α 0.941) and test-retest reliability (intra-class correlation coefficients 0.730-0.880). Convergent validity with two reference measures was demonstrated with strong correlations of 0.573-0.730 were shown. Significant differences (P = 0.0018, standardized effect size = 0.372) between groups defined by number of night-time voids supported known-groups validity. Exit interviews in 66 patients indicated all participants experienced improvement in at least 1 NI Diary item and that a 1-point improvement on the item response scale and 1-void reduction per night (associated with an average best cut point on ROC analysis of - 11.6) constituted meaningful improvement. Anchor and distribution-based analyses identified a meaningful change threshold of - 15 to - 18 points on the NI Diary. CONCLUSION: The NI Diary is a reliable and valid patient-reported psychometric instrument which is fit-for-purpose to evaluate the impact of nocturia on patient quality of life in the clinical trial setting. Trial registration number and registration date NCT03201419; June 28, 2017.

Lenvatinib versus sorafenib for first-line treatment of unresectable hepatocellular carcinoma: patient-reported outcomes from a randomised, open-label, non-inferiority, phase 3 trial.

BACKGROUND: Hepatocellular carcinoma is the third-leading cause of cancer-related death worldwide. Preservation of health-related quality of life (HRQOL) during treatment is an important therapeutic goal. The aim of this study was to evaluate the effect of treatment with lenvatinib versus sorafenib on HRQOL. METHODS: REFLECT was a previously published multicentre, randomised, open-label, non-inferiority phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib as a first-line systemic treatment for unresectable hepatocellular carcinoma. Eligible patients were aged 18 years or older with unresectable hepatocellular carcinoma and one or more measurable target lesion per modified Response Evaluation Criteria in Solid Tumors criteria, Barcelona Clinic Liver Cancer stage B or C categorisation, Child-Pugh class A, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or lower, and adequate organ function. Patients were randomly assigned (1:1) via an interactive voice-web response system; stratification factors for treatment allocation included region; macroscopic portal vein invasion, extrahepatic spread, or both; ECOG performance status; and bodyweight. Patient-reported outcomes (PROs), collected at baseline, on day 1 of each subsequent cycle, and at the end of treatment, were evaluated in post-hoc analyses of secondary and exploratory endpoints in the analysis population, which was the subpopulation of patients with a PRO assessment at baseline. A linear mixed-effects model evaluated change from baseline in PROs, including European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and hepatocellular carcinoma-specific QLQ-HCC18 scales (both secondary endpoints of the REFLECT trial). Time-to-definitive-deterioration analyses were done based on established thresholds for minimum differences for worsening in PROs. Responder analyses explored associations between HRQOL and clinical response. This study is registered with ClinicalTrials.gov, NCT01761266. FINDINGS: Of 954 eligible patients randomly assigned to lenvatinib (n=478) or sorafenib (n=476) between March 14, 2013, and July 30, 2015, 931 patients (n=468 for lenvatinib; n=463 for sorafenib) were included in this analysis. Baseline PRO scores reflected impaired HRQOL and functioning and considerable symptom burden relative to full HRQOL. Differences in overall mean change from baseline estimates in most PRO scales generally favoured the lenvatinib over the sorafenib group, although the differences were not nominally statistically or clinically significant. Patients treated with lenvatinib experienced nominally statistically significant delays in definitive, meaningful deterioration on the QLQ-C30 fatigue (hazard ratio [HR] 0·83, 95% CI 0·69-0·99), pain (0·80, 0·66-0·96), and diarrhoea (0·52, 0·42-0·65) domains versus patients treated with sorafenib. Significant differences in time to definitive deterioration were not observed for other QLQ-C30 domains, and there was no difference in time to definitive deterioration on the global health status/QOL score (0·89, 0·73-1·09). For most PRO scales, differences in overall mean change from baseline estimates favoured responders versus non-responders. Across all scales, HRs for time to definitive deterioration were in favour of responders; median time to definitive deterioration for responders exceeded those for non-responders by a range of 4·8 to 14·6 months. INTERPRETATION: HRQOL for patients undergoing treatment for unresectable hepatocellular carcinoma is an important therapeutic consideration. The evidence of HRQOL benefits in clinically relevant domains support the use of lenvatinib compared with sorafenib to delay functional deterioration in advanced hepatocellular carcinoma. FUNDING: Eisai and Merck Sharp & Dohme.