Publications by authors named "Stacie Hudgens"

45 Publications

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

Lancet Gastroenterol Hepatol 2021 08 2;6(8):649-658. Epub 2021 Jun 2.

FSBSI N N Blokhin Russian Cancer Research Center, Moscow, Russia.

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.
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http://dx.doi.org/10.1016/S2468-1253(21)00110-2DOI Listing
August 2021

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.

J Affect Disord 2021 02 14;281:767-775. Epub 2020 Nov 14.

Janssen Research and Development LLC, San Diego, CA, US.

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 (SPRAVATO).

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.
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http://dx.doi.org/10.1016/j.jad.2020.11.066DOI Listing
February 2021

Clinical disease progression and biomarkers in Niemann-Pick disease type C: a prospective cohort study.

Orphanet J Rare Dis 2020 11 23;15(1):328. Epub 2020 Nov 23.

Orphazyme A/S, Copenhagen, Denmark.

Background: Niemann-Pick disease type C (NPC) is a rare, progressive, neurodegenerative disease associated with neurovisceral manifestations resulting from lysosomal dysfunction and aberrant lipid accumulation. A multicentre, prospective observational study (Clinical Trials.gov ID: NCT02435030) of individuals with genetically confirmed NPC1 or NPC2 receiving routine clinical care was conducted, to prospectively characterize and measure NPC disease progression and to investigate potential NPC-related biomarkers versus healthy individuals. Progression was measured using the abbreviated 5-domain NPC Clinical Severity Scale (NPCCSS), 17-domain NPCCSS and NPC clinical database (NPC-cdb) score. Cholesterol esterification and heat shock protein 70 (HSP70) levels were assessed from peripheral blood mononuclear cells (PBMCs), cholestane-3β,5α-,6β-triol (cholestane-triol) from serum, and unesterified cholesterol from both PBMCs and skin biopsy samples. The inter- and intra-rater reliability of the 5-domain NPCCSS was assessed by 13 expert clinicians' rating of four participants via video recordings, repeated after ≥ 3 weeks. Intraclass correlation coefficients (ICCs) were calculated.

Results: Of the 36 individuals with NPC (2-18 years) enrolled, 31 (86.1%) completed the 6-14-month observation period; 30/36 (83.3%) were receiving miglustat as part of routine clinical care. A mean (± SD) increase in 5-domain NPCCSS scores of 1.4 (± 2.9) was observed, corresponding to an annualized progression rate of 1.5. On the 17-domain NPCCSS, a mean (± SD) progression of 2.7 (± 4.0) was reported. Compared with healthy individuals, the NPC population had significantly lower levels of cholesterol esterification (p < 0.0001), HSP70 (p < 0.0001) and skin unesterified cholesterol (p = 0.0006). Cholestane-triol levels were significantly higher in individuals with NPC versus healthy individuals (p = 0.008) and correlated with the 5-domain NPCCSS (Spearman's correlation coefficient = 0.265, p = 0.0411). The 5-domain NPCCSS showed high ICC agreement in inter-rater reliability (ICC = 0.995) and intra-rater reliability (ICC = 0.937).

Conclusions: Progression rates observed were consistent with other reports on disease progression in NPC. The 5-domain NPCCSS reliability study supports its use as an abbreviated alternative to the 17-domain NPCCSS that focuses on the most relevant domains of the disease. The data support the use of cholestane-triol as a disease monitoring biomarker and the novel methods of measuring unesterified cholesterol could be applicable to support NPC diagnosis. Levels of HSP70 in individuals with NPC were significantly decreased compared with healthy individuals.

Trial Registration: CT-ORZY-NPC-001: ClincalTrials.gov NCT02435030, Registered 6 May 2015, https://clinicaltrials.gov/ct2/show/NCT02435030 ; EudraCT 2014-005,194-37, Registered 28 April 2015, https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-005194-37/DE . OR-REL-NPC-01: Unregistered.
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http://dx.doi.org/10.1186/s13023-020-01616-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684888PMC
November 2020

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

Clin Lymphoma Myeloma Leuk 2021 02 18;21(2):97-105. Epub 2020 Sep 18.

Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, TX.

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.
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http://dx.doi.org/10.1016/j.clml.2020.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878351PMC
February 2021

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

Patient 2021 03 1;14(2):249-268. Epub 2020 Nov 1.

Somni Bene Institut für Medizinische Forschung und Schlafmedizin Schwerin GmbH, Schwerin, Germany.

Background And Objective: Chronic insomnia has major consequences for daytime functioning, yet no fully validated patient-reported outcome instrument for once-daily assessments is available to measure these consequences. This study describes the development and psychometric evaluation of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ).

Methods: The Daytime Insomnia Symptom Scale (DISS), an existing 20-item instrument for assessing daytime functioning, was modified to give an 18-item version of the IDSIQ (IDSIQ-18) based on iterative qualitative interviews with 54 subjects with insomnia and expert input. The construct validity and other psychometric properties of the IDSIQ-18 were analyzed based on an interventional study (NCT03056053) in which subjects with insomnia received zolpidem (5 or 10 mg) daily for 2 weeks and an observational study among subjects with no diagnosis of insomnia (good sleepers). Participants in both studies completed the IDSIQ-18 daily for 2 weeks. Exit interviews were conducted with a sample of subjects who completed the interventional study to elicit concepts defining the experience of insomnia, to assess understanding of the response scales, and to determine meaningful change thresholds. Exploratory factor analysis and Rasch analysis were conducted to further assess the structure and latent model for the scoring of the final IDSIQ instrument. Further psychometric evaluation of the final IDSIQ was then conducted.

Results: Subjects in both the interventional study (N = 114) and observational study (N = 103) were predominantly female (65% for subjects with insomnia and 60% for good sleepers). Mean age was 51 years for subjects with insomnia and 45 years for good sleepers. Subjects in the exit interviews (N = 41) demonstrated a good understanding of the IDSIQ-18 response scales. Day 1 mean scores were higher (worse) in subjects with insomnia compared with good sleepers. Based on inter-item correlation, exploratory factor, and Rasch analyses and review of the qualitative data, four items were removed. This yielded the final IDSIQ, with 14 items comprising three domains: Alert/Cognition, Mood, and Sleepiness. The domain structure was determined in a confirmatory factor analysis. Evidence of internal consistency reliability was strong: day 1 Cronbach's alpha was 0.917 for IDSIQ total score and 0.806-0.918 for the domains. Test-retest reliability, assessed for subjects with insomnia with no change on the Patient Global Assessment of Disease Severity scale between day 1 and day 8, was also good (intra-class correlation coefficient 0.856-0.911). Meaningful change thresholds derived for this sample using anchor-based approaches were 20 for IDSIQ total score, 9 for the Alert/Cognition domain, 4 for the Mood domain, and 4 for the Sleepiness domain.

Conclusions: These studies, which closely followed Food and Drug Administration Guidance for Industry on patient-reported outcome measures, support use of the IDSIQ as a fit-for-purpose measure for deriving valid and reliable endpoints in insomnia clinical research trials and real-world studies.
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http://dx.doi.org/10.1007/s40271-020-00474-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884372PMC
March 2021

Use of Patient-Reported Outcomes to Understand & Measure the Patient Experience of Novel Cell and Gene Therapies.

Ther Innov Regul Sci 2020 11 22;54(6):1566-1575. Epub 2020 Jun 22.

Friends of Cancer Research, 1800 M St. NW Suite 1050S, Washington, DC, 20036, USA.

Patient reported outcomes (PROs) are the gold standard for assessing patients' experience of treatment in oncology, defined in the 21st Century Cures Act as information about patients' experiences with a disease or condition, including the impact of a disease or condition, or a related therapy or clinical investigation on patients' lives; and patient preferences with respect to treatment of their disease or condition [1]. PROs provide a comprehensive assessment of the benefits and risks of new medical products, as well as essential data to inform real-world use. Although RCTs are the ultimate source for information for evaluating products in development, they are not always feasible for rare diseases with few or no effective treatment options available. Thus, it is important to consider other measures that can help to improve the strength of evidence for cell and gene therapies targeting rare indications. While collection of PROs and other patient experience endpoints does not resolve the difficulty of conducting trials in small populations, doing so contributes empirical evidence that informs both product development and patient access. Additionally, including routine collection of PROs in registries may provide supplemental data to further characterize the benefit:risk profile of cell and gene therapies at follow-up times that would be infeasible to operationalize in a clinical trial setting.
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http://dx.doi.org/10.1007/s43441-020-00184-6DOI Listing
November 2020

Improvements in Dysphagia and Pain With Swallowing in Patients With Eosinophilic Esophagitis Receiving Budesonide Oral Suspension.

Clin Gastroenterol Hepatol 2021 04 6;19(4):699-706.e4. Epub 2020 Apr 6.

Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Background & Aims: Quantification of eosinophilic esophagitis (EoE) symptoms is crucial for assessing treatment outcomes. We aimed to explore the effect of budesonide oral suspension (BOS) on dysphagia and pain with swallowing.

Methods: We performed a secondary analysis of data from a phase 2 multicenter, double-blind, trial (conducted from July 2012 through October 2014) of patients with EoE, 11-40 y old, who were randomly assigned to groups given placebo or BOS (2.0 mg twice daily) for 12 weeks. Symptoms were quantified using the Dysphagia Symptom Questionnaire (DSQ) from baseline to week 12 of therapy.

Results: Overall, 93 patients were randomly assigned to groups; the prespecified modified intention-to-treat analysis set comprised 87 patients (38 from the placebo group and 49 from the BOS group). Improvements from baseline in least-squares mean (standard error) DSQ (Q2+Q3) scores were observed. The difference between groups was statistically significant only at week 12 (placebo vs BOS: week 4, -4.9 [1.7] vs -7.4 [1.5]; P = .265; week 8, -7.4 [2.1] vs -10.3 [1.8]; P = .288; week 12, -7.5 [1.9] vs -14.3 [1.7]; P = .01). Similar findings were observed for pain (Q4) scores (placebo vs BOS: week 4, -2.5 [0.8] vs -3.3 [0.7]; P = .484; week 8, -3.0 [0.8] vs -4.9 [0.7]; P = .066; week 12, -3.1 [0.8] vs -4.9 [0.7]; P = .109). More severe DSQ and DSQ+pain scores were associated with presence of other symptoms (such as regurgitation) and physician-rated severity. Improvements in DSQ and DSQ+pain scores were greater in patients with either a histologic or endoscopic response than in patients without a response.

Conclusions: In a secondary analysis of data from a phase 2 trial of patients with EoE, we found evidence for improvements in dysphagia and pain scores in patients who received BOS (2.0 mg twice daily) vs placebo. Pain with swallowing should be considered in the clinical assessment of patients with EoE. ClinicalTrials.gov no: NCT01642212.
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http://dx.doi.org/10.1016/j.cgh.2020.03.060DOI Listing
April 2021

Evaluation of meaningful change in bowel movement frequency for patients with carcinoid syndrome.

J Patient Rep Outcomes 2019 Oct 26;3(1):64. Epub 2019 Oct 26.

Lexicon Pharmaceuticals Inc., 8800 Technology Forest Pl, The Woodlands, TX, USA.

Background: Carcinoid syndrome is associated with a reduced quality of life that can be attributed to symptoms such as diarrhea and fatigue as well as social and financial issues. This study was conducted to psychometrically assess meaningful change in bowel movement frequency among carcinoid syndrome patients using data from the TELESTAR clinical study.

Methods: An anchor-based approach for deriving meaningful change thresholds consisted of mapping change from baseline bowel movement frequency to other patient-reported assessments of change. These included the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core Questionnaire (QLQ-C30) Diarrhea Symptom responders, the EORTC Gastrointestinal NET questionnaire (GI.NET21) GI Symptom responders, and reported adequate relief at Week 12 (≥ 10-point score decrease from Day 1 to Week 12). Parameters included within-group mean change from baseline to Week 12, t-tests of the change (Wilcoxon rank sum for adequate relief), and effect size.

Results: There were 135 carcinoid syndrome patients with a mean baseline frequency of 5.7 bowel movements a day. A distribution-based method yielded meaningful change estimates of 0.62 bowel movements a day for overall frequency and 0.83 bowel movements a day at Week 12. Anchor-based analysis indicated a large effect size among patients who reported adequate relief at Week 12 (- 1.58; n = 18; P = 0.014), the QLQ-C30 Diarrhea domain responders (- 1.24; n = 40; P < 0.001), and the GI.NET21 GI Symptoms Domain responders (- 1.49; n = 25; P = 0.005). Exit interview data for meaningful change yielded effect size estimates of - 1.57 for overall change during the Double-blind Treatment Period and - 1.97 for change between Baseline and Week 12.

Conclusions: Meaningful change derivation is critical to interpret patient outcomes for evaluating treatment efficacy. In this study, carcinoid syndrome patients experienced clinically meaningful reductions in bowel movement frequency of ≥30% over 12 weeks with telotristat ethyl treatment.

Trial Registration: NCT01677910 .
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http://dx.doi.org/10.1186/s41687-019-0153-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815313PMC
October 2019

Psychometric evaluation of the PROMIS® Depression Item Bank: an illustration of classical test theory methods.

J Patient Rep Outcomes 2019 Jul 30;3(1):46. Epub 2019 Jul 30.

Department of Medical Psychology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.

Background: Psychometric theory offers a range of tests that can be used as supportive evidence of both validity and reliability of instruments aimed at measuring patient-reported outcomes (PRO). The aim of this paper is to illustrate psychometric tests within the Classical Test Theory (CTT) framework, comprising indices that are frequently applied to assess item- and scale-level psychometric properties of PRO instruments.

Methods: Using data on the PROMIS Depression Item Bank, typical CTT indices for the assessment of psychometric properties are illustrated, including content validity, item-level data exploration, reliability, and construct validity, particularly confirmatory factor analysis, to test the unidimensionality assumption underlying the item bank. Analyses are carried out on an original item set of 51 depression items, the final (official) PROMIS Depression Item Bank consisting of 28 items, and an 8-item short form.

Results: The analyses reported provide an informative illustration on how item- and scale-level reliability and validity statistics can be used to assess the psychometric quality of a PRO instrument. The results illustrate how the reported statistics can be used for item selection from an item pool (here: 51 items). Both the (final) 28-item bank and the 8-item short form show good psychometric properties supporting the high quality of individual items and the unidimensionality assumption of the item bank.

Conclusions: It is our hope that our illustration of CTT methods, in conjunction with two companion papers illustrating modern test theory methods, will help researchers to confidently apply a range of statistical tests to evaluate item- and scale-level psychometric performance of PRO instruments.
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http://dx.doi.org/10.1186/s41687-019-0127-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663945PMC
July 2019

Exploring content and psychometric validity of newly developed assessment tools for itch and skin pain in atopic dermatitis.

J Patient Rep Outcomes 2019 Jul 16;3(1):42. Epub 2019 Jul 16.

Dermatology Medical Social Sciences, Preventive Medicine, Northwestern University, NMH/Arkes Family Pavilion, Ste 1600, 676 N Saint Clair, Chicago, IL, 60611, USA.

Background: Atopic dermatitis (AD) is a common skin disorder characterized by chronic inflammation, altered skin barrier function, and inflammatory cell skin infiltration that decreases health-related quality of life (HRQoL). The study objective was to understand the patient perspective of AD burden and determine suitable patient-reported outcome (PRO) measures.

Methods: This mixed methods study involved the collection of qualitative and quantitative information from adults (≥ 18 years old) and adolescents (12 - 17 years old) with clinician-confirmed AD regarding their experiences of AD symptoms and its impact on HRQoL. The first part of the study included three stages: in-person concept elicitation (CE) interviews, a 2-week daily electronic diary (eDiary) study, and in-person cognitive debriefing (CD) interviews. An Itch numeric rating scale (NRS) (v1.0) and a Skin Pain NRS (v1.0) evaluation during CD interviews required participants to think about their 'worst' itch and 'worst' skin pain in the past 24 h. Other PRO measures allowed for psychometric testing. The second part of the study involved telephone-depth interviews (TDIs) and qualitative feedback from participants who had not participated in the CD interviews. Qualitative data were thematically analyzed. Psychometric evaluation of NRS measures was performed using eDiary data.

Results: In the CE interviews, itch and/or itching and skin pain were the most prevalent symptoms consistently discussed by participants. Both NRS measures demonstrated strong psychometric reliability and were applicable across ages with suitable concurrent validity. During the CD interviews, some participants focused their answers on their 'average' itch/itching in the past 24 h, rather than their 'worst' itch. Some participants answered the Skin Pain NRS thinking about general pain or other types of pain, rather than skin pain specifically. Consequently, modifications to both measures addressed these issues and re-tested as paper-and-pen versions in subsequent TDIs. Itch NRS (v2.0) modifications helped participants focus on their worst itching. Most participants preferred Skin Pain NRS v2.0b, which included skin pain descriptors.

Conclusions: Itching and skin pain are the most important and relevant AD symptoms. The Itch NRS (v2.0) and Skin Pain NRS (v2.0b) appear to be appropriate endpoints for the assessment of itching and skin pain severity for clinical trials with adults and adolescents with AD.
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http://dx.doi.org/10.1186/s41687-019-0128-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635522PMC
July 2019

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

Patient Relat Outcome Meas 2019 16;10:129-140. Epub 2019 Apr 16.

Concord Cancer Centre and Sydney Medical School, University of Sydney, Sydney, NSW, Australia.

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.
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http://dx.doi.org/10.2147/PROM.S178963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489631PMC
April 2019

Investigation of the psychometric properties of the inclusion body myositis functional rating scale with rasch analysis.

Muscle Nerve 2019 08 7;60(2):161-168. Epub 2019 Jun 7.

Queen Square MRC Centre for Neuromuscular Diseases, Institute of Neurology, University College London, 8-11 Queen Square, London WC1N 3BG, United Kingdom.

Introduction: The Inclusion Body Myositis Functional Rating Scale (IBMRFS) is a 10-item clinician-rated ordinal scale developed for people with inclusion body myositis.

Methods: Single observations of the IBMFRS were collected from 132 patients. After Rasch analysis, modifications were made to the scale to optimize fit to the Rasch model while maintaining clinical validity and utility.

Results: The original IBMFRS did not fit the assumptions of the Rasch model because of multidimensionality of the scale. Items assessed local dependence, disordered step thresholds, and differential item functioning. Deconstructing the scale into upper limb (IBMFRS-UL) and lower limb (IBMFRS-LL) scales improved fit to the Rasch model. A 9-item scale with the swallowing item removed (IBMFRS-9) remained multidimensional but demonstrated the ability to discriminate patients along the severity continuum. IBMFRS-UL, IBMFRS-LL, and IBMFRS-9 scores were transformed to a 0-100 scale for comparability.

Discussion: This analysis has led to the development of 3 optimized versions of the IBMFRS. Muscle Nerve 60: 161-168, 2019.
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http://dx.doi.org/10.1002/mus.26521DOI Listing
August 2019

Development and Validation of the FSIQ-RMS: A New Patient-Reported Questionnaire to Assess Symptoms and Impacts of Fatigue in Relapsing Multiple Sclerosis.

Value Health 2019 04 21;22(4):453-466. Epub 2019 Feb 21.

Comprehensive Multiple Sclerosis Center, Thomas Jefferson University, Philadelphia, PA, USA.

Objectives: A new patient-reported outcome (PRO) instrument to measure fatigue symptoms and impacts in relapsing multiple sclerosis (RMS) was developed in a qualitative stage, followed by psychometric validation and migration from paper to an electronic format.

Methods: Adult patients with relapsing-remitting multiple sclerosis (RRMS) were interviewed to elicit fatigue-related symptoms and impacts. A draft questionnaire was debriefed in cognitive interviews with further RRMS patients, and revised. Content confirmation interviews were conducted with patients with progressive-relapsing multiple sclerosis (PRMS) and relapsing secondary-progressive multiple sclerosis (RSPMS). Psychometric analyses used data from adult patients with different RMS subtypes and matched non-RMS controls in a multicenter, observational study. After item reduction, the final instrument was migrated to a smartphone (eDiary) and usability was confirmed in interviews with additional adult RMS patients.

Results: The qualitative stage included 37 RRMS, 5 PRMS, and 5 RSPMS patients. Saturation of concepts was reached during concept elicitation. Cognitive interviews confirmed that participants understood the instructions, items, and response options of the instrument-named FSIQ-RMS-as intended. Psychometric validation included 164 RMS and 74 control patients. Internal consistency and test-retest reliability were demonstrated. The symptoms domain discriminated along the RMS symptom-severity continuum and between patients and controls. Patients were able to attribute fatigue-related symptoms to RMS. Usability and conceptual equivalence of the eDiary were confirmed (n = 10 participants).

Conclusions: With 7 symptom items and 13 impact items (in 3 impacts subdomains: physical, cognitive and emotional, and coping) after item reduction, the FSIQ-RMS is a comprehensive, valid, and reliable measure of fatigue-related symptoms and impacts in RMS patients.
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http://dx.doi.org/10.1016/j.jval.2018.11.007DOI Listing
April 2019

Relationship Between Symptoms and Health-related Quality-of-life Benefits in Patients With Carcinoid Syndrome: Post Hoc Analyses From TELESTAR.

Clin Ther 2018 12 24;40(12):2006-2020.e2. Epub 2018 Nov 24.

Dana-Farber Cancer Institute, Boston, MA, USA.

Purpose: Patients with metastatic neuroendocrine tumors and carcinoid syndrome (CS) may experience chronic, recurring symptoms despite somatostatin analogue therapy. Little is known about the relationship between bowel movement (BM) frequency, patient-reported symptoms and health-related quality of life (QoL). Data from the TELESTAR study were used in exploratory, post hoc analyses to understand the relationship between durable reductions in BM frequency, symptom relief, and health-related QoL.

Methods: Patients with metastatic neuroendocrine tumors and CS in the Phase III TELESTAR study were randomized (1:1:1) to receive telotristat ethyl (TE) 250 mg, TE 500 mg, or placebo three times daily (TID) during a 12-week double-blind treatment period (DBTP). All patients received TE 500 mg TID in an open-label extension (OLE) to Week 48. Durable response was predefined. Analyses compared durable responders (DRs) and non-durable responders (NDRs), irrespective of treatment group, at Weeks 12, 24, and 48.

Findings: At the start of the DBTP, 135 patients were randomized, 45 patients each to TE 250 mg, TE 500 mg, and placebo. After the 12-week DBTP, 48 of 135 patients were DRs (TE 250 mg, n = 20; TE 500 mg, n = 19; placebo, n = 9). Of the 115 patients who entered the OLE, 35 were DRs initially randomized to TE 250 mg (n = 18) or 500 mg (n = 17), 29 of whom maintained a durable response throughout the OLE. Of the 71 DBTP-NDRs (inclusive of patients initially randomized to placebo), 28 became OLE-DRs. There were 29 NDRs initially randomized to placebo who entered the OLE, 16 of whom became DRs when switched to TE 500 mg. DRs during the DBTP had greater symptom improvements in the DBTP; these improvements continued over the OLE. DBTP-DRs also maintained more meaningful QoL improvements in EORTC QLQ-C30 global health status, nausea and vomiting, pain, diarrhea, and EORTC QLQ-GINET21 gastrointestinal symptoms over the DBTP and OLE periods than DBTP-NDRs.

Implications: These results suggest that sustained improvements in BM frequency in patients with CS may have multifaceted, long-term effects on a patient's well-being. ClinicalTrials.gov identifiers: NCT01677910.
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http://dx.doi.org/10.1016/j.clinthera.2018.10.008DOI Listing
December 2018

Effect of apalutamide on health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: an analysis of the SPARTAN randomised, placebo-controlled, phase 3 trial.

Lancet Oncol 2018 10 10;19(10):1404-1416. Epub 2018 Sep 10.

Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.

Background: In the SPARTAN trial, addition of apalutamide to androgen deprivation therapy, as compared with placebo plus androgen deprivation therapy, significantly improved metastasis-free survival in men with non-metastatic castration-resistant prostate cancer who were at high risk for development of metastases. We aimed to investigate the effects of apalutamide versus placebo added to androgen deprivation therapy on health-related quality of life (HRQOL).

Methods: SPARTAN is a multicentre, international, randomised, phase 3 trial. Participants were aged 18 years or older, with non-metastatic castration-resistant prostate cancer, a prostate-specific antigen doubling time of 10 months or less, and a prostate-specific antigen concentration of 2 ng/mL or more in serum. Patients were randomly assigned (2:1) to 240 mg oral apalutamide per day plus androgen deprivation therapy, or matched oral placebo plus androgen deprivation therapy, using an interactive voice randomisation system. Permuted block randomisation was used according to the three baseline stratification factors: prostate-specific antigen doubling time (>6 months vs ≤6 months), use of bone-sparing drugs (yes vs no), and presence of local-regional nodal disease (N0 vs N1). Each treatment cycle was 28 days. The primary endpoint was metastasis-free survival. The trial was unblinded in July, 2017. In this prespecified exploratory analysis we assessed HRQOL using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-3L questionnaires, which we collected at baseline, day 1 of cycle 1 (before dose), day 1 of treatment cycles 1-6, day 1 of every two cycles from cycles 7 to 13, and day 1 of every four cycles thereafter. This study is registered with ClinicalTrials.gov, number NCT01946204.

Findings: Between Oct 14, 2013, and Dec 15, 2016, we randomly assigned 1207 patients to receive apalutamide (n=806) or placebo (n=401). The clinical cutoff date, as for the primary analysis, was May 19, 2017. Median follow-up for overall survival was 20·3 months (IQR 14·8-26·6). FACT-P total and subscale scores were associated with a preservation of HRQOL from baseline to cycle 29 in the apalutamide group; there were similar results for EQ-5D-3L. At baseline, the mean for FACT-P total score in both the apalutamide and placebo groups were consistent with the FACT-P general population norm for US adult men. Group mean patient-reported outcome scores over time show that HRQOL was maintained from baseline after initiation of apalutamide treatment and was similar over time among patients receiving apalutamide versus placebo. Least-squares mean change from baseline shows that HRQOL deterioration was more apparent in the placebo group.

Interpretation: In asymptomatic men with high-risk non-metastatic castration-resistant prostate cancer, HRQOL was maintained after initiation of apalutamide treatment. Considered with findings from SPARTAN, patients who received apalutamide had longer metastasis-free survival and longer time to symptomatic progression than did those who received placebo, while preserving HRQOL.

Funding: Janssen Research & Development.
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http://dx.doi.org/10.1016/S1470-2045(18)30456-XDOI Listing
October 2018

Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial.

Lancet Oncol 2018 09 9;19(9):1192-1204. Epub 2018 Aug 9.

Columbia University Medical Center, New York, NY, USA.

Background: Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab, a novel monoclonal antibody directed against C-C chemokine receptor 4, with vorinostat in patients with previously treated cutaneous T-cell lymphoma.

Methods: In this open-label, international, phase 3, randomised controlled trial, we recruited patients with relapsed or refractory mycosis fungoides or Sézary syndrome at 61 medical centres in the USA, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia. Eligible patients were aged at least 18 years (in Japan, ≥20 years), had failed (for progression or toxicity as assessed by the principal investigator) at least one previous systemic therapy, and had an Eastern Cooperative Oncology Group performance score of 1 or less and adequate haematological, hepatic, and renal function. Patients were randomly assigned (1:1) using an interactive voice web response system to mogamulizumab (1·0 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily). Stratification was by cutaneous T-cell lymphoma subtype (mycosis fungoides vs Sézary syndrome) and disease stage (IB-II vs III-IV). Since this study was open label, patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival by investigator assessment in the intention-to-treat population. Patients who received one or more doses of study drug were included in the safety analyses. This study is ongoing, and enrolment is complete. This trial was registered with ClinicalTrials.gov, number NCT01728805.

Findings: Between Dec 12, 2012, and Jan 29, 2016, 372 eligible patients were randomly assigned to receive mogamulizumab (n=186) or vorinostat (n=186), comprising the intention-to-treat population. Two patients randomly assigned to mogamulizumab withdrew consent before receiving study treatment; thus, 370 patients were included in the safety population. Mogamulizumab therapy resulted in superior investigator-assessed progression-free survival compared with vorinostat therapy (median 7·7 months [95% CI 5·7-10·3] in the mogamulizumab group vs 3·1 months [2·9-4·1] in the vorinostat group; hazard ratio 0·53, 95% CI 0·41-0·69; stratified log-rank p<0·0001). Grade 3-4 adverse events of any cause were reported in 75 (41%) of 184 patients in the mogamulizumab group and 76 (41%) of 186 patients in the vorinostat group. The most common serious adverse events of any cause were pyrexia in eight (4%) patients and cellulitis in five (3%) patients in the mogamulizumab group; and cellulitis in six (3%) patients, pulmonary embolism in six (3%) patients, and sepsis in five (3%) patients in the vorinostat group. Two (67%) of three on-treatment deaths with mogamulizumab (due to sepsis and polymyositis) and three (33%) of nine on-treatment deaths with vorinostat (two due to pulmonary embolism and one due to bronchopneumonia) were considered treatment-related.

Interpretation: Mogamulizumab significantly prolonged progression-free survival compared with vorinostat, and could provide a new, effective treatment for patients with mycosis fungoides and, importantly, for Sézary syndrome, a subtype that represents a major therapeutic challenge in cutaneous T-cell lymphoma.

Funding: Kyowa Kirin.
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http://dx.doi.org/10.1016/S1470-2045(18)30379-6DOI Listing
September 2018

Quality of life in patients with recurrent ovarian cancer treated with niraparib versus placebo (ENGOT-OV16/NOVA): results from a double-blind, phase 3, randomised controlled trial.

Lancet Oncol 2018 08 17;19(8):1117-1125. Epub 2018 Jul 17.

Department of Oncology, Rigshospitalet, Copenhagen, Denmark.

Background: Quality of life (QOL) has become an important complementary endpoint in cancer clinical studies alongside more traditional assessments (eg, tumour response, progression-free survival, overall survival). Niraparib maintenance treatment has been shown to significantly improve progression-free survival in patients with recurrent ovarian cancer. We aimed to assess whether the benefits of extending progression-free survival are offset by treatment-associated toxic effects that affect QOL.

Methods: The ENGOT-OV16/NOVA trial was a multicentre, double-blind, phase 3, randomised controlled trial done in 107 study sites in the USA, Canada, Europe, and Israel. Patients with recurrent ovarian cancer who were in response to their last platinum-based chemotherapy were randomly assigned (2:1) to receive either niraparib (300 mg once daily) as a maintenance treatment or placebo. Randomisation was stratified based on time to progression after the penultimate platinum-based regimen, previous use of bevacizumab, and best response (complete or partial) to the last platinum-based regimen with permuted-block randomisation (six in each block) using an interactive web response system. The trial enrolled two independent cohorts on the basis of germline BRCA (gBRCA) mutation status (determined by BRACAnalysis Testing, Myriad Genetics, Salt Lake City, UT, USA). The primary endpoint of the trial was progression-free survival, and has already been reported. In this study, we assessed patient-reported outcomes (PROs) in the intention-to-treat population using the Functional Assessment of Cancer Therapy-Ovarian Symptoms Index (FOSI) and European QOL five-dimension five-level questionnaire (EQ-5D-5L). We collected PROs from trial entry every 8 weeks for the first 14 cycles and every 12 weeks thereafter. If a patient discontinued, we collected PROs at discontinuation and during a postprogression visit 8 weeks (plus or minus 2 weeks) later. We assessed the effect of haematological toxic effects on QOL with disutility analyses of the most common grade 3-4 adverse events (thrombocytopenia, anaemia, and neutropenia) using a mixed model with histology, region, previous treatment, age, planned treatment, and baseline score as covariates. This study is registered with ClinicalTrials.gov, number NCT01847274.

Findings: Between Aug 28, 2013, and June 1, 2015, 553 patients were enrolled and randomly assigned to receive niraparib (n=138 in the gBRCAmut cohort, n=234 in the non-gBRCAmut cohort) or placebo (n=65 in the gBRCAmut cohort, n=116 in the non-gBRCAmut cohort). The mean FOSI score at baseline was similar between the two groups (range between 25·0-25·6 in the two groups). Overall QOL scores remained stable during the treatment and preprogression period in the niraparib group; no significant differences were observed between the niraparib and placebo group, and preprogression EQ-5D-5L scores were similar between the two groups in both cohorts (0·838 [0·0097] in the niraparib group vs 0·834 [0·0173] in the placebo group in the gBRCAmut cohort; and 0·833 [0·0077] in the niraparib group vs 0·815 [0·0122] in the placebo group in the non-gBRCAmut cohort). The most common adverse events reported at screening (baseline) were lack of energy (425 [79%]; 97 [18%] reporting severe lack of energy), pain (236 [44%]), and nausea (118 [22%]). All symptoms, except nausea, either remained stable or improved over time in the niraparib group. The most common grade 3 or 4 toxicities observed in the niraparib group were haematological in nature: thrombocytopenia (124 [34%] of 367 patients), anaemia (93 [25%]), and neutropenia (72 [20%]); disutility analyses showed no significant QOL impairment associated with these toxic effects.

Interpretation: These PRO data suggest that women who receive niraparib as maintenance treatment for recurrent ovarian cancer after responding to platinum treatment are able to maintain QOL during their treatment when compared with placebo.

Funding: TESARO.
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http://dx.doi.org/10.1016/S1470-2045(18)30333-4DOI Listing
August 2018

Effect of ombitasvir/paritaprevir/ritonavir + dasabuvir regimen on health-related quality of life for patients with hepatitis C.

Liver Int 2018 08 12;38(8):1377-1394. Epub 2018 Feb 12.

Health Economics and Outcomes Research, AbbVie Inc., North Chicago, IL, USA.

Background & Aims: This study analyses health-related quality of life data from 8 randomized clinical trials using ombitasvir/paritaprevir/ritonavir and dasabuvir ± ribavirin to investigate: (i) the impact of the treatment vs placebo during treatment on health-related quality of life; (ii) the sustainability of such treatment effect after 12-week treatment period; and (iii) if results from (i) and (ii) differ in subgenotypes 1a vs 1b.

Methods: Six registration trials and 2 post-approval trials were pooled and analysed using longitudinal mixed models to estimate the effect of ombitasvir/paritaprevir/ritonavir and dasabuvir ± ribavirin on health-related quality of life outcomes adjusting for baseline scores, as well as patient demographics and clinical characteristics.

Results: Patients treated with ribavirin-free ombitasvir/paritaprevir/ritonavir and dasabuvir regimen reported statistically significant increase in health-related quality of life outcomes as compared to placebo patients. While ombitasvir/paritaprevir/ritonavir and dasabuvir + ribavirin treatment saw statistically significant decline in health-related quality of life outcomes during treatment vs baseline and placebo, effect on health-related quality of life outcomes associated with ribavirin did not persist in the post-treatment period for ombitasvir/paritaprevir/ritonavir and dasabuvir patients followed for up to 52 weeks. The analysis also found Genotype 1b patients reported greater improvements in health-related quality of life as compared to genotype 1a patients.

Conclusions: During the active treatment period, small but statistically significant decrements in health-related quality of life outcomes were observed potentially driven by ribavirin, which were not sustained during the post-treatment follow-up period. Differences were observed by patient subgenotype, where health-related quality of life improvements were consistently higher for genotype 1b patients as compared to genotype 1a patients.
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http://dx.doi.org/10.1111/liv.13690DOI Listing
August 2018

Evaluation of Quality of Life at Progression in Patients with Soft Tissue Sarcoma.

Sarcoma 2017 23;2017:2372135. Epub 2017 Apr 23.

Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands.

. Soft Tissue Sarcoma (STS) is a rare malignancy of mesodermal tissue, with international incidence estimates between 1.8 and 5 per 100,000 per year. Understanding quality of life (QoL) and the detrimental impact of disease progression is critical for long-term care and survival. . The primary objective was to explore the relationship between disease progression and health-related quality of life (HRQoL) using data from Eisai's study (E7389-G000-309). . This was a 1 : 1 randomized, open-label, multicenter, Phase 3 study comparing the efficacy and safety of eribulin versus dacarbazine in patients with advanced STS. The QoL analysis was conducted for the baseline and progression populations using the European Organization for Research and Treatment of Cancer 30-item core QoL questionnaire (EORTC QLQ-C30). . There were no statistical differences between the two treatment arms at baseline for any domain ( > 0.05; = 452). Of the 399 patients who experienced disease progression (unadjusted and adjusting for histology), dacarbazine patients had significantly lower Global Health Status, Physical Functioning scores, and significantly worse Nausea and Vomiting, Insomnia, and Appetite Loss ( < 0.05). . These results indicate differences in HRQoL overall and at progression between dacarbazine and eribulin patients, with increases in symptom severity observed among dacarbazine patients.
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http://dx.doi.org/10.1155/2017/2372135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420413PMC
April 2017

Effect of Adalimumab on Visual Functioning in Patients With Noninfectious Intermediate Uveitis, Posterior Uveitis, and Panuveitis in the VISUAL-1 and VISUAL-2 Trials.

JAMA Ophthalmol 2017 06;135(6):511-518

Bristol Eye Hospital, University of Bristol, Bristol, England7National Institute for Health Research Biomedical Research Centre, Moorfields Eye Hospital, London, England8Institute of Ophthalmology, University College London, London, England.

Importance: Adalimumab was recently approved for the treatment of noninfectious intermediate uveitis, posterior uveitis, and panuveitis.

Objective: To assess the effect of adalimumab on the visual functioning and quality of life in patients with corticosteroid-dependent noninfectious intermediate uveitis, posterior uveitis, and panuveitis.

Design: A post hoc analysis of clinical trials of adults with active (VISUAL-1) and inactive (VISUAL-2) noninfectious intermediate uveitis, posterior uveitis, and panuveitis was conducted in the United States, Canada, Europe, Israel, Australia, Latin America, and Japan. A total of 217 patients (110 adalimumab, 107 placebo) in VISUAL-1 and 226 patients (115 adalimumab, 111 placebo) in VISUAL-2 were studied using intent-to-treat analyses. The clinical trials were conducted between August 10, 2010, and May 14, 2015.

Interventions: In VISUAL-1 and VISUAL-2, patients were randomized to receive adalimumab, 80-mg, subcutaneous loading dose followed by 40 mg every other week or placebo for 80 weeks. All patients underwent prednisone tapering, with patients in VISUAL-1 receiving an initial prednisone burst.

Main Outcomes And Measures: The 25-item National Eye Institute Vision Function Questionnaire (NEI VFQ-25) composite score questionnaire assessed the impact of visual impairment from the patient's perspective; scores on the questionnaire range from 0 to 100, with higher scores indicating better vision-related quality of life. The change in NEI VFQ-25 from best state achieved prior to week 6 (VISUAL-1) and from baseline state (VISUAL-2) to the final or early termination visit was determined in each group and statistically compared using analysis of variance. The temporal effects of adalimumab and placebo on NEI VFQ-25 were investigated using a longitudinal model.

Results: Of the 217 patients in VISUAL-1, 124 (57.1%) were women; the mean (SD) age was 42.7 (14.9) years. Of the 226 patients in VISUAL-2, 138 (61.1%) were women; the mean (SD) age was 42.5 (13.4). In VISUAL-1, the change from final score to best score in NEI VFQ-25 was -1.30 for adalimumab and -5.50 for placebo-a difference of 4.20 (95% CI, 1.04 to 7.36; P = .01) associated with adalimumab compared with placebo. In VISUAL-2, the change from baseline NEI VFQ-25 was 3.36 for adalimumab and 1.24 for placebo-a difference of 2.12 (95% CI, -0.81 to 5.04; P = .16). In both trials, the longitudinal models showed a significant difference in NEI VFQ-25 between adalimumab and placebo of 3.07 (95% CI, 2.09 to 4.06; P < .001) and 4.66 (95% CI, 0.05 to 9.26; P = .048) in the VISUAL-1 (74.15 vs 71.08) and VISUAL-2 (82.39 vs 77.73) trials, respectively.

Conclusions And Relevance: This post hoc analysis suggests that adalimumab is associated with statistically significant and clinically meaningful improvements in patient-reported visual functioning for patients with noninfectious intermediate uveitis, posterior uveitis, and panuveitis.

Trial Registration: clinicaltrials.gov Identifiers: NCT01138657 (VISUAL-1) and NCT01124838 (VISUAL-2).
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http://dx.doi.org/10.1001/jamaophthalmol.2017.0603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847080PMC
June 2017

Psychometric validation of the Dysphagia Symptom Questionnaire in patients with eosinophilic esophagitis treated with budesonide oral suspension.

J Patient Rep Outcomes 2017 12;1(1). Epub 2017 Sep 12.

Formerly at Meritage Pharma, Inc., 12555 High Bluff Drive #385, San Diego, CA 92130 USA.

Background: Eosinophilic esophagitis (EoE) is characterized by high levels of eosinophils in the esophageal mucosa. Patients with the disease present with a range of symptoms, including dysphagia (difficulty swallowing). The aim of this analysis was to assess the psychometric properties of the Dysphagia Symptom Questionnaire (DSQ), a patient-reported outcome (PRO) measure of dysphagia associated with EoE. Psychometric properties of the DSQ were assessed using data collected from a 12-week, phase 2, multicenter, randomized, double-blind, placebo-controlled trial of budesonide oral suspension in adolescents and adults (11-40 years old) with EoE.

Results: The study population comprised 93 patients with EoE; 94.6% of whom were white, 68.8% were male and the mean age (standard deviation) was 21.6 (7.7) years. Patients had been diagnosed with EoE for a mean of 37.6 months before study initiation. The DSQ was feasible to implement with few item-level data missing at baseline. Item discrimination was high, with floor and ceiling effects below the predefined threshold (≤9%). Higher DSQ scores corresponded with presence and increased severity of dysphagia, indicative of strong item discrimination among patients at baseline (threshold >50%). The DSQ was able to detect changes in symptoms over time and produced similar outcomes to those from physician- and other patient-rated measures, supportive of construct validity. The DSQ had strong test-retest reliability (intraclass correlation coefficient,  = 0.82); and was also responsive to disease-level changes, with higher DSQ scores corresponding to increased esophageal eosinophilic burden. Lastly, the percentage changes in the minimal clinically important difference and clinically important difference in DSQ score were estimated at -27.4% and -55.4%, respectively.

Conclusions: These analyses support the DSQ as a valid and reliable measure of dysphagia in patients with EoE. Changes in DSQ scores suggest a level of agreement between clinician, patient and histologic response. The DSQ should therefore be considered a viable PRO measure of dysphagia for use in future therapeutic studies of EoE.
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http://dx.doi.org/10.1186/s41687-017-0006-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934937PMC
September 2017

Validation of a treatment satisfaction questionnaire in non-Hodgkin lymphoma: assessing the change from intravenous to subcutaneous administration of rituximab.

Patient Prefer Adherence 2016 13;10:1767-1776. Epub 2016 Sep 13.

Genentech, South San Francisco, CA, USA.

Background: A subcutaneous (SC) formulation of rituximab (MabThera/Rituxan) has been developed that could reduce administration time and improve patient satisfaction with treatment. The Rituximab Administration Satisfaction Questionnaire (RASQ) was created to assess patients' perceptions and satisfaction with rituximab SC (RASQ-SC) or rituximab intravenous (RASQ-IV). We assessed the content validity and psychometric properties of RASQ in patients with non-Hodgkin lymphoma.

Methods: Face and content validity of RASQ-SC and RASQ-IV were qualitatively assessed using 60-minute combined concept elicitation and cognitive debriefing interviews. Psychometric validation of RASQ (item performance and reliability) was assessed quantitatively against the established Cancer Therapy Satisfaction Questionnaire (CTSQ), using questionnaire data from the PrefMab (NCT01724021) and MabCute (NCT01461928) clinical studies.

Results: RASQ-IV demonstrated excellent coverage of concepts relevant to patients' (n=10) own treatment experiences and no new concepts were identified. Patients' expectations of rituximab SC were conceptually consistent with items included in the RASQ-SC, suggesting that the tool is also conceptually adequate. In 1,051 patients from PrefMab and MabCute, correlations with domains such as "RASQ: Physical Impacts" and "CTSQ: Feelings About Side Effects", "RASQ: Physical Impacts" and "CTSQ: Satisfaction With Therapy", and "RASQ: Satisfaction" and "CTSQ: Satisfaction With Therapy", achieved moderate-to-high correlations (>0.4) for convergent domains and <0.3 for divergent domains.

Conclusion: This study supports the qualitative face and content validity and psychometric validity of RASQ-IV and RASQ-SC. Minor revisions were made to the questionnaires to enhance clarity and aid consistent reporting.
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http://dx.doi.org/10.2147/PPA.S108489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5028167PMC
September 2016

Psychometric assessment of the IBS-D Daily Symptom Diary and Symptom Event Log.

Qual Life Res 2016 12 24;25(12):3197-3208. Epub 2016 Jun 24.

Clinical Outcomes Solutions, Tucson, AZ, USA.

Purpose: Diarrhea-predominant irritable bowel syndrome (IBS-D) can considerably impact patients' lives. Patient-reported symptoms are crucial in understanding the diagnosis and progression of IBS-D. This study psychometrically evaluates the newly developed IBS-D Daily Symptom Diary and Symptom Event Log (hereafter, "Event Log") according to US regulatory recommendations.

Methods: A US-based observational field study was conducted to understand cross-sectional psychometric properties of the IBS-D Daily Symptom Diary and Event Log. Analyses included item descriptive statistics, item-to-item correlations, reliability, and construct validity.

Results: The IBS-D Daily Symptom Diary and Event Log had no items with excessive missing data. With the exception of two items ("frequency of gas" and "accidents"), moderate to high inter-item correlations were observed among all items of the IBS-D Daily Symptom Diary and Event Log (day 1 range 0.67-0.90). Item scores demonstrated reliability, with the exception of the "frequency of gas" and "accidents" items of the Diary and "incomplete evacuation" item of the Event Log. The pattern of correlations of the IBS-D Daily Symptom Diary and Event Log item scores with generic and disease-specific measures was as expected, moderate for similar constructs and low for dissimilar constructs, supporting construct validity. Known-groups methods showed statistically significant differences and monotonic trends in each of the IBS-D Daily Symptom Diary item scores among groups defined by patients' IBS-D severity ratings ("none"/"mild," "moderate," or "severe"/"very severe"), supporting construct validity.

Conclusions: Initial psychometric results support the reliability and validity of the items of the IBS-D Daily Symptom Diary and Event Log.
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http://dx.doi.org/10.1007/s11136-016-1335-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102981PMC
December 2016

Interpretation of verbal descriptors for response options commonly used in verbal rating scales in patient-reported outcome instruments.

Qual Life Res 2016 12 13;25(12):3181-3189. Epub 2016 Jun 13.

Patient-Reported Outcome Consortium, Critical Path Institute, Tucson, AZ, USA.

Purpose: To assess the variation in the interpretation of common verbal descriptors (VDs) used in response scales and examine factors associated with those interpretations.

Methods: Subjects were recruited through MediGuard and they assigned interpretation scores (11-point scale; 0 = lowest possible, 10 = highest possible) to five common sets of VDs: set one (none, mild, moderate, severe, very severe); set two (never, rarely, sometimes, often, always); set three (poor, fair, good, very good, excellent); set four (not at all, a little bit, moderately, quite a bit, extremely); and set five (not at all, a little bit, somewhat, quite a bit, very much). One-sample test for proportions and T-tests examined equality of proportions (anchors) and means scores (non-anchors) with the fixed intervals (0.0, 2.5, 5.0, 7.5, and 10.0). Ordinal regression examined adjusted associations between demographic/clinical factors and VD scores.

Results: Of the 350 subjects, 68 % were females and mean (SD) age was 56.9 (12.1). Two sets had two VDs with mean (95 % CI) scores not different than the fixed intervals. Set one had mild = 2.50 (2.33; 2.66) and moderate = 5.01 (4.89; 5.13) with 98.8 % (97.3 %; 100 %) assigning none = 0. Set five had a little bit = 2.35 (2.17; 2.53) and quite a bit = 7.65 (7.43; 7.87) with 95.0 % (95 % CI 91.7; 98.2) assigning not at all = 0. Significant associations (p ≤ 0.05) included age and education with somewhat and income and comorbidities with very severe. Age, sex, and education showed associations with other VDs albeit in nonsignificant models.

Conclusions: Sets one and five yielded data closest to the fixed intervals. Demographic and clinical factors are associated with the interpretation of some VDs and should be adjusted for in analyses of non-randomized data.
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http://dx.doi.org/10.1007/s11136-016-1333-3DOI Listing
December 2016

Validation of a Patient-reported Outcome (PRO) Measure and a Clinician-reported Outcome (CRO) Measure to Assess Satisfaction with Pharmacologic Stress Agents for Single-photon Emission Computed Tomography (SPECT) Myocardial Perfusion Imaging (MPI).

Clin Ther 2016 05 15;38(5):1141-50. Epub 2016 Mar 15.

Health Economics and Clinical Outcomes Research, Astellas Pharma Global Development, Northbrook, Illinois.

Purpose: The objective of this study was to develop and validate clinician and patient measures of satisfaction for pharmacologic stress agents (PSAs) used in single-photon emission computed tomography myocardial perfusion imaging procedures.

Methods: Two questionnaires were developed: the Clinician Satisfaction and Preference Questionnaire (CSPQ) and the Patient Satisfaction and Preference Questionnaire (PSPQ). Items were developed, and the content validity of the questionnaires was ensured by participants' involvement in the item generation (5 clinician and 18 patient face-to-face concept elicitation interviews) and item modification phases (5 clinician and 10 patient face-to-face cognitive debriefing interviews). Psychometric validation of the satisfaction component of the questionnaires was conducted in a sample of 9 clinicians and 90 patients.

Findings: After initial patient interviews and cognitive interviews, two 8-item instruments were developed with each containing an optional PSA preference question. The PSPQ assessed patients' receptiveness and satisfaction with the PSA that they received. The CSPQ assessed clinicians' satisfaction with the time and ease of PSA preparation, administration, and monitoring of the PSA. The optional preference question in both instruments assesses preference among PSAs. In a multicenter observational study of 88 patients and 9 clinicians, the PSPQ Preparation and Reaction to Agent scales elicited reliability coefficients of 0.90 and 0.87, respectively. In addition, the test-retest reliability was acceptable for all PSPQ scales (intraclass correlation coefficient range, 0.73-0.86). Concurrent validity with the Treatment Satisfaction Questionnaire for Medication (TSQM) indicates low-to-moderate correlations between the Effectiveness, Convenience, and Global Satisfaction scales of the TSQM with the PSPQ Satisfaction with Administration, Satisfaction with Effects, and Overall Satisfaction items (range, 0.46-0.78). Analysis of the CSPQ found that both the Preparation and Reaction to Agent subscales indicated strong internal consistency (α = 0.98 and 0.99, respectively).

Implications: The PSPQ and CSPQ were developed and validated with rigorous methods. The instruments and their domains found strong internal consistency and good test-retest reliability. These questionnaires, when used as measures of treatment satisfaction in clinical trials, real-world observational studies, or by clinicians in their own laboratories, may help patients and clinicians better understand the impact of single-photon emission computed tomography myocardial perfusion imaging pharmacologic stress testing.
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http://dx.doi.org/10.1016/j.clinthera.2016.02.024DOI Listing
May 2016

Health-related quality of life in patients with locally advanced or metastatic breast cancer treated with eribulin mesylate or capecitabine in an open-label randomized phase 3 trial.

Breast Cancer Res Treat 2015 Dec 14;154(3):509-20. Epub 2015 Nov 14.

Department of Oncology, Leeds Institute of Cancer and Pathology, and St James's Institute of Oncology, University of Leeds, Leeds, LS9 7TF, England, UK.

The clinical benefit of eribulin versus capecitabine was evaluated using health-related quality of life (HRQoL) data from a phase 3 randomized trial in patients with pretreated advanced/metastatic breast cancer (ClinicalTrials.gov identifier: NCT00337103). The study population has been described previously (Kaufman et al. in J Clin Oncol 33:594-601, 2015). Eligible patients received eribulin (1.4 mg/m(2) intravenously on days 1 and 8) or capecitabine (1.25 g/m(2) orally twice daily on days 1-14) per 21-day cycles. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-life Questionnaire-Core 30 questions (QLQ-C30) and breast module-23 questions (QLQ-BR23), administered at baseline through 24 months, until disease progression or other antitumor treatment initiation. Minimally important difference (MID) and time to symptom worsening (TSW) were investigated. 1062 (96.4 %) Patients completed the EORTC questionnaire at baseline; overall, compliance was ≥80 %. Patients receiving capecitabine versus eribulin had significantly worse symptoms (higher scores) for nausea/vomiting (MID 8; P < 0.05) and diarrhea (MID 7; P < 0.05). Treatment with eribulin versus capecitabine, led to worse systemic therapy side-effects (dry mouth, different tastes, irritated eyes, feeling ill, hot flushes, headaches, and hair loss; MID 10; P < 0.01). Clinically meaningful worsening was observed for future perspective (MID 10; P < 0.05) with capecitabine and for systemic therapy side-effects scale (MID 10; P < 0.01) with eribulin. Patients receiving capecitabine experienced more-rapid deterioration in body image (by 2.9 months) and future perspective (by 1.4 months; P < 0.05) compared with those on eribulin; the opposite was observed for systemic side-effects where patients receiving eribulin experienced more-rapid deterioration than those receiving capecitabine (by 2 months; P < 0.05). Eribulin and capecitabine were found to have similar impact on patient functioning with no overall difference in HRQoL. Patients receiving eribulin reported worse systemic side-effects of chemotherapy but reduced gastrointestinal toxicity compared with capecitabine.
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http://dx.doi.org/10.1007/s10549-015-3633-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661183PMC
December 2015
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