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.

[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.

Reflections on estimands for patient-reported outcomes in cancer clinical trials.

It is common and important to include the patient's perspective of the impact of treatment on health-related quality of life (HRQoL) outcomes. In this commentary, we focus on applying the new addendum to ICH E9 guideline E9 (R1) relating to the estimand framework to Patient Reported Outcomes (PROs) collected in cancer clinical trials, from a statistician's viewpoint. Currently, common practice for statistical analysis of PRO endpoints of published cancer clinical trials demonstrates ambiguity, leaving critical questions unspecified, hindering conclusions about the effect of treatment on PRO endpoints as well as comparability between clinical trials. To avoid this scenario, we advocate the systematic use of the estimand framework which requires the prospective definition of clear PRO research questions. Among the five attributes of the estimands framework, the definition of the endpoint (what is the right PRO measure and timeframe to target and why?), the intercurrent event identification and management (what happens with PRO data post-disease progression, what is the impact of death?) and the population-level summary (what is an acceptable statistical summary for PRO data?) require the most attention for PRO estimands. We identify good practice and highlight discussion points including the challenges of statistical analysis in the presence of missing and/or unobservable data and in relation to death. Through this discussion we highlight that there is no "statistical magic", but that the estimand framework will help you find out what you really want to know when quantifying the benefit of treatments from the patients' perspective.

The estimand framework and its application in substance use disorder clinical trials: a case study.

Relapse rates among individuals with substance use disorder (SUD) remain high and new treatment approaches are needed, which require evaluation in randomized controlled trials (RCTs). Measurement and interpretation challenges for SUD RCT data are often ignored or presented only in statistical analysis plans. Since different analytic approaches may result in different estimates and thus interpretations of the treatment effect, it is important to present this clearly throughout the trial. Inconsistencies between study analyses and objectives present further challenges for interpretation and cross-study comparisons. The recent International Council for Harmonization (ICH) addendum provides standardized language and a common framework for aligning trial objectives, design, conduct, and analysis. The framework focuses on estimands, which describe the treatment effect and link the trial objective with the scientific question and the analytic approach. The use of estimands offers SUD researchers and clinicians the opportunity to explicitly address events that affect measurement and interpretation at the outset of the trial. Furthermore, the use of standard terminology can lead to clearer interpretations of SUD trials and the treatments evaluated in SUD trials. Resources for understanding and applying estimands are needed to optimize the use of this new, helpful framework. This Perspective provides this resource for SUD researchers. Specifically, it highlights the relevance of estimands for SUD trials. Furthermore, it demonstrates how estimands can be used to develop clinically relevant analyses to address challenges in SUD trials. It also shows how a standardized framework can be employed to improve the interpretation and presentation of SUD study findings.

Burden of illness of trigeminal neuralgia among patients managed in a specialist center in England.

BACKGROUND: Trigeminal neuralgia (TN) causes severe episodic, unilateral facial pain and is initially treated with antiepileptic medications. For patients not responding or intolerant to medications, surgery is an option. METHODS: In order to expand understanding of the pain-related burden of illness associated with TN, a cross-sectional survey was conducted of patients at a specialist center that utilizes a multidisciplinary care pathway. Participants provided information regarding their pain experience and treatment history, and completed several patient-reported outcome (PRO) measures. RESULTS: Of 129 respondents, 69/128 (54%; 1 missing) reported no pain in the past 4 weeks. However, 84 (65%) respondents were on medications, including 49 (38%) on monotherapy and 35 (27%) on polytherapy. A proportion of patients had discontinued at least one medication in the past, mostly due to lack of efficacy (n = 62, 48%) and side effects (n = 51, 40%). A total of 52 (40%) patients had undergone surgery, of whom 30 had microvascular decompression (MVD). Although surgery, especially MVD, provided satisfactory pain control in many patients, 29% of post-surgical patients reported complications, 19% had pain worsen or stay the same, 48% were still taking pain medications for TN, and 33% reported new and different facial pain. CONCLUSIONS: In most PRO measures, respondents with current pain interference had poorer scores than those without pain interference. In the Patient Global Impression of Change, 79% expressed improvement since beginning of treatment at this clinic. These results indicate that while the multidisciplinary approach can substantially alleviate the impact of TN, there remains an unmet medical need for additional treatment options.

Imputation strategies when a continuous outcome is to be dichotomized for responder analysis: a simulation study.

BACKGROUND: In many clinical trials continuous outcomes are dichotomized to compare proportions of patients who respond. A common and recommended approach to handling missing data in responder analysis is to impute as non-responders, despite known biases. Multiple imputation is another natural choice but when a continuous outcome is ultimately dichotomized, the specifications of the imputation model come into question. Practitioners can either impute the missing outcome before dichotomizing or dichotomize then impute. In this study we compared multiple imputation of the continuous and dichotomous forms of the outcome, and imputing responder status as non-response in responder analysis. METHODS: We simulated four response profiles representing a two-arm randomized controlled trial with a continuous outcome at four time points. We omitted data using six missing at random mechanisms, and imputed missing observations three ways: 1) replacing as non-responder; 2) multiply imputing before dichotomizing; and 3) multiply imputing the dichotomized response. Imputation models included the continuous response at all timepoints, and additional auxiliary variables for some scenarios. We assessed bias, power, coverage of the 95% confidence interval, and type 1 error. Finally, we applied these methods to a longitudinal trial for patients with major depressive disorder. RESULTS: Both forms of multiple imputation performed better than non-response imputation in terms of bias and type 1 error. When approximately 30% of responses were missing, bias was less than 7.3% for multiple imputation scenarios but when 50% of responses were missing, imputing before dichotomizing generally had lower bias compared to dichotomizing before imputing. Non-response imputation resulted in biased estimates, both underestimates and overestimates. In the example trial data, non-response imputation estimated a smaller difference in proportions than multiply imputed approaches. CONCLUSIONS: With moderate amounts of missing data, multiply imputing the continuous outcome variable prior to dichotomizing performed similar to multiply imputing the binary responder status. With higher rates of missingness, multiply imputing the continuous variable was less biased and had well-controlled coverage probabilities of the 95% confidence interval compared to imputing the dichotomous response. In general, multiple imputation using the longitudinally measured continuous outcome in the imputation model performed better than imputing missing observations as non-responders.

Implementation of tobacco cessation brief intervention in complementary and alternative medicine practice: qualitative evaluation.

BACKGROUND: This article presents findings from qualitative interviews conducted as part of a research study that trained Acupuncture, Massage, and Chiropractic practitioners' in Arizona, US, to implement evidence-based tobacco cessation brief interventions (BI) in their routine practice. The qualitative phase of the overall study aimed to assess: the impact of tailored training in evidence-based tobacco cessation BI on complementary and alternative medicine (CAM) practitioners' knowledge and willingness to implement BIs in their routine practice; and their patients' responses to cessation intervention in CAM context. METHODS: To evaluate the implementation of skills learned from a tailored training program, we conducted semi-structured qualitative interviews with 54 CAM practitioners in Southern Arizona and 38 of their patients. Interview questions focused on reactions to the implementation of tobacco cessation BIs in CAM practice. RESULTS: After participating in a tailored BI training, CAM practitioners reported increased confidence, knowledge, and motivation to address tobacco in their routine practice. Patients were open to being approached by CAM practitioners about tobacco use and viewed BIs as an expected part of wellness care. CONCLUSIONS: Tailored training motivated CAM practitioners in this study to implement evidence-based tobacco cessation BIs in their routine practice. Results suggest that CAM practitioners can be a valuable point of contact and should be included in tobacco cessation efforts.

Adolescent Smoking Cessation With Bupropion: The Role of Adherence.

INTRODUCTION: While many medications can be effective aids to quitting tobacco, real world adherence to smoking cessation medications may render a potentially effective medication ineffective. The present study investigated the role of adherence on treatment outcomes in a bupropion dose-response study among adolescent smokers trying to quit smoking. METHODS: Three hundred twelve adolescent boys (n = 143) and girls (n = 169) between the ages of 14-17 were enrolled in the study, and were randomly assigned to use either 300 mg, 150 mg or placebo bupropion to quit smoking. Among the eligibility criterion, participants had to smoke at least six cigarettes per day, be motivated to quit smoking (self report), have an exhaled carbon monoxide level greater than or equal to 10 ppm, and report at least two previous quit attempts. Adherence to medication was determined by both self-report and actual counts of unused medication and empty medication packaging. Smoking status was determined by a combination of self-report and biochemical verification (breath carbon monoxide and urine cotinine). RESULTS: Cotinine-confirmed quit rates were significantly higher as a function of high adherence (20.69%) relative to low adherence (0.00%) in the 300-mg Bupropion Sustained Release group. Overall adherence in all study conditions in this highly controlled study was high (74%), but was significantly lower in non-white participants. CONCLUSIONS: Effectiveness of bupropion for adolescent smoking cessation is contingent on achieving high rates of medication adherence, but considerable variations in adherence impacted outcomes. IMPLICATIONS: Few studies have assessed the safety and efficacy of medications to help adolescent smokers quit, and we conducted one such study assessing bupropion. In this analysis of that original study, we assess the role of adherence in use of medication and quit rates. We found that adherence was related to outcomes, particularly in the 300-mg dose of bupropion.

Printed Educational Materials' Impact on Tobacco Cessation Brief Interventions in CAM Practice: Patient and Practitioner Experiences.

Printed educational materials (PEMs) have long demonstrated their usefulness as economical and effective media for health communication. In this article, we evaluate the impact of targeted tobacco cessation PEMS for use along with a brief intervention training designed for three types of complementary and alternative medicine (CAM) practitioners: chiropractic, acupuncture, and massage. We describe how PEMs in CAM practitioners' offices were perceived and used by practitioners and by patients. Semistructured qualitative interviews were conducted with 53 practitioners and 38 of their patients. This analysis specifically focused on developing and distributing project-related posters and pamphlets in CAM practice. Our findings indicate that materials (1) legitimated tobacco-related expertise among CAM practitioners and tobacco-related conversations as part of routine CAM practice, (2) increased practitioners' willingness to approach the topic of tobacco with patients, (3) created an effective way to communicate tobacco-related information and broaden the reach of brief intervention initiatives, and (4) were given to patients who were not willing to engage in direct discussion of tobacco use with practitioners.

Considerations for practice-based research: a cross-sectional survey of chiropractic, acupuncture and massage practices.

BACKGROUND: Complementary and alternative medicine (CAM) use has steadily increased globally over the past two decades and is increasingly playing a role in the healthcare system in the United States. CAM practice-based effectiveness research requires an understanding of the settings in which CAM practitioners provide services. This paper describes and quantifies practice environment characteristics for a cross-sectional sample of doctors of chiropractic (DCs), licensed acupuncturists (LAcs), and licensed massage therapists (LMTs) in the United States. METHODS: Using a cross-sectional telephone survey of DCs (n = 32), LAcs (n = 70), and LMTs (n = 184) in the Tucson, AZ metropolitan area, we collected data about each location where practitioners work, as well as measures on practitioner and practice characteristics including: patient volume, number of locations where practitioners worked, CAM practitioner types working at each location, and business models of practice. RESULTS: The majority of practitioners reported having one practice location (93.8% of DCs, 80% of LAcs and 59.8% of LMTs) where they treat patients. Patient volume/week was related to practitioner type; DCs saw 83.13 (SD = 49.29) patients/week, LAcs saw 22.29 (SD = 16.88) patients/week, and LMTs saw 14.21 (SD =10.25) patients per week. Practitioners completed surveys for N = 388 practice locations. Many CAM practices were found to be multidisciplinary and/or have more than one practitioner: 9/35 (25.7%) chiropractic practices, 24/87 (27.6%) acupuncture practices, and 141/266 (53.0%) massage practices. Practice business models across CAM practitioner types were heterogeneous, e.g. sole proprietor, employee, partner, and independent contractor. CONCLUSIONS: CAM practices vary across and within disciplines in ways that can significantly impact design and implementation of practice-based research. CAM research and intervention programs need to be mindful of the heterogeneity of CAM practices in order to create appropriate interventions, study designs, and implementation plans.

Tobacco brief intervention training for chiropractic, acupuncture, and massage practitioners: protocol for the CAM reach study.

BACKGROUND: Tobacco use remains the leading cause of morbidity and mortality in the US. Effective tobacco cessation aids are widely available, yet underutilized. Tobacco cessation brief interventions (BIs) increase quit rates. However, BI training has focused on conventional medical providers, overlooking other health practitioners with regular contact with tobacco users. The 2007 National Health Interview Survey found that approximately 20% of those who use provider-based complementary and alternative medicine (CAM) are tobacco users. Thus, CAM practitioners potentially represent a large, untapped community resource for promoting tobacco cessation and use of effective cessation aids. Existing BI training is not well suited for CAM practitioners' background and practice patterns, because it assumes a conventional biomedical foundation of knowledge and philosophical approaches to health, healing and the patient-practitioner relationship. There is a pressing need to develop and test the effectiveness of BI training that is both grounded in Public Health Service (PHS) Guidelines for tobacco dependence treatment and that is relevant and appropriate for CAM practitioners. METHODS/DESIGN: The CAM Reach (CAMR) intervention is a tobacco cessation BI training and office system intervention tailored specifically for chiropractors, acupuncturists and massage therapists. The CAMR study utilizes a single group one-way crossover design to examine the CAMR intervention's impact on CAM practitioners' tobacco-related practice behaviors. Primary outcomes included CAM practitioners' self-reported conduct of tobacco use screening and BIs. Secondary outcomes include tobacco using patients' readiness to quit, quit attempts, use of guideline-based treatments, and quit rates and also non-tobacco-using patients' actions to help someone else quit. DISCUSSION: CAM practitioners provide care to significant numbers of tobacco users. Their practice patterns and philosophical approaches to health and healing are well suited for providing BIs. The CAMR study is examining the impact of the CAMR intervention on practitioners' tobacco-related practice behaviors, CAM patient behaviors, and documenting factors important to the conduct of practice-based research in real-world CAM practices.

Association of Tafamidis With Health Status in Patients With ATTR Cardiac Amyloidosis: A Post Hoc Analysis of the ATTR-ACT Randomized Clinical Trial.

Importance: Tafamidis reduced all-cause mortality and cardiovascular-related hospitalizations and minimized patient-reported health status deterioration at 30 months in patients with transthyretin (ATTR) amyloidosis. However, the clinical significance of health status changes remains unclear, particularly in patients with New York Heart Association (NYHA) class III symptoms who experienced more cardiovascular-related hospitalizations than those with NYHA class I-II symptoms. Objective: To evaluate the health status of patients taking tafamidis with baseline NYHA class III symptoms. Design, Setting, and Participants: This randomized clinical trial post hoc analysis evaluated data for patients with transthyretin (ATTR) cardiac amyloidosis and NYHA class I-III symptoms at baseline who were enrolled in ATTR-ACT, a placebo-controlled study of tafamidis held at 48 sites in 13 countries. Interventions: Tafamidis meglumine, 80 mg or 20 mg (pooled cohort), vs placebo. Main Outcomes and Measures: Established thresholds for clinical benefit on the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) were used to define response groups (very large decline to very large improvement); the proportion of patients in each group was calculated within each baseline NYHA class. Results: Among 441 patients (264 tafamidis, 177 placebo), the mean (SD) age was 74.3 (7.0) years; 398 (90%) were male and 43 (10%) were female. Mean (SD) baseline KCCQ-OS scores were 67.3 (21.4) in the tafamidis group and 65.9 (21.7) in the placebo group (range: 0-100, with 100 indicating the best health). There was a significant shift toward better KCCQ-OS scores in patients receiving tafamidis (odds ratio for 10-point improvement 2.4; 95% CI, 1.6-3.4; P < .001). More patients taking tafamidis were alive and not worse at all time points (37% vs 15% at month 30). These findings were similar in patients with NYHA class III symptoms. In patients with NYHA class III symptoms alive at 30 months, improvements in health status were more common (35% vs 10%) and declines were less common (38% vs 57%) with tafamidis vs placebo. Conclusions and Relevance: In ATTR-ACT, although patients with baseline NYHA class III symptoms had worse overall outcomes, treatment with tafamidis yielded better health status compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT01994889.

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.

Missing data in palliative care research: estimands and estimators.

There are several methodological challenges when conducting randomised controlled trials in palliative care. These include worsening function and high mortality, leading to treatment discontinuation, some of which will be unrelated to the intervention being evaluated.Recently, a new framework for handling postrandomisation events, such as attrition, has been released. This framework aims to align trial objectives, design, conduct and analysis by clarifying what and how to estimate treatment effects in the presence of data affected by postrandomisation events.The purpose of this paper is to introduce palliative care researchers to this framework and how it can guide trial design, and efficacy and safety analysis in a palliative care context where individual withdrawal from the trial is common.In this paper, we describe the estimand framework and the background for it. We also consider postrandomisation events that are frequently encountered in palliative care trials and how these might affect objectives of interest. We then construct efficacy and safety estimands for a trial in palliative care. Better trial design and alignment of objectives with analysis can improve our understanding of what treatments do and do not work in palliative care.

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.

Meaningful Change in Depression Symptoms Assessed with the Patient Health Questionnaire (PHQ-9) and Montgomery-Åsberg Depression Rating Scale (MADRS) Among Patients with Treatment Resistant Depression in Two, Randomized, Double-blind, Active-controlled Trials of Esketamine Nasal Spray Combined With a New Oral Antidepressant.

BACKGROUND: Patients with major depressive disorder who do not respond to ≥2 different pharmacological treatments within the current depressive episode are considered to have treatment resistant depression (TRD). This analysis determined meaningful change thresholds (MCT) of the Patient Health Questionnaire (PHQ-9) and Montgomery-Åsberg Depression Rating Scale (MADRS) using anchor-based methods and compared proportions of meaningful changes in patients with TRD across treatment groups from two Phase 3 trials for esketamine nasal spray (SPRAVATOTM). METHODS: Data from two Phase 3 trials in patients with TRD, TRANSFORM-1 and -2, were used in this analysis. The MCTs for the PHQ-9 and MADRS were derived using a clinician global impression of severity anchor. Blinded probability density functions displayed score distributions between anchor categories. Proportions of meaningful response were compared between treatment groups using chi-square tests supported by unblinded cumulative distribution functions of change scores. RESULTS: Baseline scores were similar for the PHQ-9 and MADRS between the esketamine/antidepressant (AD) and AD/placebo groups. The most appropriate MCT on the PHQ-9 was -6 points. By Day 28, 86.5% of patients reached or exceeded the PHQ-9 MCT in the esketamine/AD group compared to 70% in the placebo/AD group. The most appropriate MCT for the MADRS was -10 points. By Day 28, 78.2% of patients reached or exceeded the MADRS MCT in the esketamine/AD group compared to 65.0% in the placebo/AD group. CONCLUSIONS: Individual-level meaningful change for the PHQ-9 and MADRS was effectively quantified using a clinical anchor to interpret efficacy from patients with TRD and their treating clinicians.

Quality of Life Effect of the Anti-CCR4 Monoclonal Antibody Mogamulizumab Versus Vorinostat in Patients With Cutaneous T-cell Lymphoma.

BACKGROUND: Sézary syndrome (SS) and mycosis fungoides (MF), 2 types of cutaneous T-cell lymphoma, cause significant morbidity and adversely affect patients' quality of life (QoL). The present study assessed the QoL measurement changes in patients receiving mogamulizumab versus vorinostat. PATIENTS AND METHODS: A multicenter phase III trial was conducted of patients with stage IB-IV MF/SS with ≥ 1 failed systemic therapy. The QoL measures included Skindex-29 and the Functional Assessment of Cancer Therapy-General. The symptoms, function, and QoL subdomains were longitudinally modeled using mixed models with prespecified covariates. Meaningful change thresholds (MCTs) were defined using distribution-based methods. The categorical changes by group over time and the time to clinically meaningful worsening were analyzed. RESULTS: Of the 372 randomized patients, mogamulizumab demonstrated improvement in Skindex-29 symptoms (cycles 3, 5, and 7; P < .05) and functional (cycles 3 and 5; P < .05) scales. A significantly greater proportion of mogamulizumab-treated patients improved by MCTs or more from baseline in the Skindex-29 symptoms domain (cycles 3, 5, 7, and 11) and functioning domain (cycle 5). Significant differences in the Functional Assessment of Cancer Therapy-General physical well-being (cycles 1, 3, and 5; P < .05) were observed in favor of mogamulizumab and a greater proportion of patients had declined by MCTs or more at cycles 1, 3, 5, and 7 with vorinostat treatment. The median time to symptom worsening using Skindex-29 was 27.4 months for mogamulizumab versus 6.6 months for vorinostat. In the patients with SS, the time to worsening favored mogamulizumab (P < .005) for all Skindex-29 domains. The time to worsening was similar for the 2 MF treatment arms. CONCLUSION: The symptoms, function, and overall QoL of patients with MF/SS favored mogamulizumab over vorinostat across all time points. Patients with the greatest symptom burden and functional impairment derived the most QoL benefit from mogamulizumab.

Analytical approaches and estimands to take account of missing patient-reported data in longitudinal studies.

Patient-reported outcomes, such as quality of life, functioning, and symptoms, are used widely in therapeutic and behavioral trials and are increasingly used in drug development to represent the patient voice. Missing patient reported data is common and can undermine the validity of results reporting by reducing power, biasing estimates, and ultimately reducing confidence in the results. In this paper, we review statistically principled approaches for handling missing patient-reported outcome data and introduce the idea of estimands in the context of behavioral trials. Specifically, we outline a plan that considers missing data at each stage of research: design, data collection, analysis, and reporting. The design stage includes processes to prevent missing data, define the estimand, and specify primary and sensitivity analyses. The analytic strategy considering missing data depends on the estimand. Reviewed approaches include maximum likelihood-based models, multiple imputation, generalized estimating equations, and responder analysis. We outline sensitivity analyses to assess the robustness of the primary analysis results when data are missing. We also describe ad-hoc methods, including approaches to avoid. Last, we demonstrate methods using data from a behavioral intervention, where the primary outcome was self-reported cognition.

Integrative tobacco cessation: A survey assessing past quit strategies and future interest.

PURPOSE: Tobacco cessation remains a public health priority. Unassisted quits are most common despite evidence for a combination of guideline-recommended strategies. This paper reports findings from a pilot study designed to assess past quit strategies and tobacco users' receptiveness to using an integrative clinic that offers both conventional and alternative treatments for future cessation attempts. METHODS: Participants were recruited from a pool of individuals reporting for jury duty. Paper-pencil surveys assessed smoking, past cessation behaviors, and interest in use of the integrative clinic which offers both conventional and alternative treatments. Current and former smokers (n=304) returned surveys. RESULTS: Using multivariate logistic regression, past physiological quit strategies, past behavioral quit strategies, and use of multiple quit strategies increased agreement with interest in future use of an integrative clinic option. Additionally, there is support for the notion that if such a clinic were offered, smokers may be inclined to use this resource for a future quit attempt. CONCLUSIONS: An integrative clinic option for tobacco cessation may encourage smokers to try to quit, especially for those who have used varied cessation strategies in the past. Motivating smokers to use a combined approach for tobacco cessation is a potential future direction for tobacco cessation treatment. Developing and testing an integrative approach may support this effort.

BMI changes in adolescents treated with bupropion SR for smoking cessation.

OBJECTIVE: Adolescent overweight and obesity and smoking continue to be very important health challenges because of their lasting effects on overall health. Weight gain after smoking cessation is a barrier to quitting as well as a negative consequence to health. This study reports changes in the body mass index (BMI) z-scores of adolescent smokers participating in a dose-ranging clinical trial of bupropion SR (150 mg/day and 300 mg/day) for smoking cessation. METHODS: A total of N = 296 adolescent smokers (placebo n = 100, 150 mg/day n = 101, 300 mg/day n = 95) with a BMI z-score of 0.5 (sd: 1.4), 0.5 (sd: 1.3), and 0.5 (sd: 1.2) in the placebo, 150 mg/day, and 300 mg/day groups, respectively, were followed for 6 months. RESULTS: Adolescents in the 300 mg/day group had a significant reduction in BMI z-score 6 weeks after quitting (ß = -0.16, CI = (-0.29, -0.04), P-value = 0.01). This result was not sustained at the 6-month follow-up. CONCLUSIONS: A reduction in BMI z-score during smoking cessation with bupropion has important implications for the future of adolescent smoking cessation. These results are particularly relevant for adolescents who have either overweight or obesity or who have reservations about quitting for fear of gaining weight or BMI.