Two Methods, One Story? Comparing Results of a Choice Experiment and Multidimensional Thresholding From a Clinician Preference Study in Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVES: An increasing number of methods are used to elicit health preference information. It is unclear whether different elicitation methods produce similar results and policy advice. Here, we compared the results from a discrete choice experiment (DCE) and multidimensional thresholding (MDT) that were conducted in the same sample. METHODS: Clinicians (N = 350) completed a DCE and MDT to elicit their preferences for 4 attributes related to the medical management of subarachnoid hemorrhage after aneurysm repair. Preference weights were compared between the DCE and MDT using a complete combinatorial convolution test. Additionally, data from the DCE and MDT were used to compute preference-based net treatment values for 16 hypothetical treatment profiles versus 1000 simulated comparators. The implied treatment recommendations were compared between the DCE and MDT. RESULTS: Preference weight distributions and median weights did not differ significantly between the DCE and MDT for any attribute: likelihood of delayed cerebral ischemia (medians 0.48 vs 0.40; P = .41), risk of lung complications (medians 0.27 vs 0.30; P = .52), risk of hypotension (medians 0.10 vs 0.11; P = .55), and risk of anemia (medians 0.07 vs 0.07; P = .50). The DCE and MDT produced similar treatment net value distributions (P > .05) and implied the same treatment recommendations in 82.3% of cases. CONCLUSIONS: The DCE and MDT elicited similar preference distributions and produced the same treatment recommendations for most tested cases. However, the share of people supporting the average treatment recommendation differed. More research is needed to determine how these findings would compare with those in other populations (in particular, patients) and applications.

The relevance of fatigue to relapse rate in multiple sclerosis: Applying patient preference data to the OPTIMUM trial.

BACKGROUND: In the OPTIMUM trial in patients with relapsing MS, treatment differences in annualized relapse rate (ARR, 0.088) and change in fatigue at week 108 (3.57 points, measured using the Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis, symptom domain (FSIQ-RMS-S)) favored ponesimod over teriflunomide. However, the importance of the fatigue outcome to patients was unclear. OBJECTIVE: To assess the importance of the OPTIMUM FSIQ-RMS-S results using data from an MS discrete choice experiment (DCE). METHODS: The DCE included components to correlate levels of physical and cognitive fatigue with FSIQ-RMS-S scores. Changes in relapses/year and time to MS progression equivalent to the treatment difference in fatigue in OPTIMUM were determined for similar fatigue levels as mean baseline fatigue in OPTIMUM. RESULTS: DCE participants would accept 0.06 more relapses/year or a 0.15-0.17 year decrease in time to MS progression for a 3.57-point difference in physical fatigue on the FSIQ-RMS-S. To improve cognitive fatigue by 3.57-points on the FSIQ-RMS-S, DCE participants would accept 0.09-0.10 more relapses/year or a 0.24-0.28 year decrease in time to MS progression. CONCLUSION: MS patients would accept 0.06 more relapses/year to change their fatigue by a similar magnitude as the between-treatment difference observed in the OPTIMUM trial.

Patients' Preferences for Systemic Lupus Erythematosus Treatments-A Discrete Choice Experiment.

BACKGROUND: Symptoms of systemic lupus erythematosus (SLE) vary between patients, but those of increased disease activity typically include musculoskeletal and mucocutaneous manifestations such as joint pain, swelling, and rashes. Several treatment options are available to patients with SLE with variable efficacy. Many treatments, especially corticosteroids, cause unwanted side effects, although little is currently known about patients' preferences for treatments of SLE. OBJECTIVE: We aimed to identify which attributes of SLE treatment are valued by patients and to quantify their relative importance. METHODS: Adult participants with moderate-to-severe SLE were asked to make a series of choices between two hypothetical treatments in an online discrete choice experiment (DCE). A latent class model (LCL) was estimated to analyze choice data. Relative attribute importance (RAI) was calculated to determine the importance of each attribute to participants. RESULTS: A total of 342 participants from the USA completed the survey. A three-class LCL model was found to have the best fit. Class 1 (non-attenders) had non-significant preferences across all attributes. To achieve a better fit, a constrained LCL (cLCL) model was run with the two remaining classes. The most important attributes for participants in class 2 (benefit-seekers) were joint pain (RAI = 32.0%), non-joint pain (RAI = 21.8%), fatigue (RAI = 20.1%), and skin rashes and itching (RAI = 19.1%). The most important attributes for participants in class 3 (risk-avoiders) were risk of non-severe side effects from corticosteroids (RAI = 28.4%), risk of severe side effects from corticosteroids (RAI = 21.4%), and the risk of infections (RAI = 19.2%). Risk-avoiders were more likely to have been diagnosed with SLE for a longer period (>1 year) and were more likely to have experience with oral corticosteroids. CONCLUSIONS: SLE patients fall into two groups with distinct preferences: benefit-seekers, who prioritize reducing the impact of disease symptoms, and risk-avoiders, who prioritize avoiding treatment risks. The implication of this finding will depend on the reasons for these differences, which warrant further research. Our study suggests that these differences arise due to the impact of disease and treatment experience on preferences. If so, well-informed patients may not be willing to tolerate the risks associated with oral corticosteroids in exchange for their benefits.

Meaningful Within-Patient Change in Subjective Total Sleep Time in Patients with Insomnia Disorder: An Analysis of the Sleep Diary Questionnaire Using Data from Open-Label and Phase III Clinical Trials.

BACKGROUND: The Sleep Diary Questionnaire (SDQ), a modified version of the Consensus Sleep Diary, is a 17-item sleep diary for assessing subjective total sleep time (sTST: total time spent asleep at night) and other sleep parameters in insomnia trials. sTST is a key parameter of efficacy in insomnia trials; however, the magnitude of improvement in this parameter that people with insomnia disorder consider clinically meaningful is unclear. OBJECTIVE: The aim of this study was to estimate meaningful within-patient change for sTST using clinical trial data. METHODS: Data were from an open-label trial of zolpidem and pooled data from a phase III placebo-controlled trial of daridorexant. In both trials, adults with moderate to severe insomnia completed the SDQ daily. Meaningful change in sTST was estimated in an anchor-based analysis using outcome measures that were correlated with change in weekly average sTST (Spearman correlation coefficient ≥ 0.30): the Insomnia Severity Index, patient global assessments and impressions of severity and change in daytime and night-time symptoms (PGA-S, PGI-S, PGI-C), and clinician global impressions of severity and change in patients' daytime symptoms (CGI-S, CGI-C). Meaningful within-patient change estimates were 'triangulated' to identify a value where they converged. RESULTS: In the open-label trial (N = 114), subjects with a 1-point or 1-step improvement on the anchors had mean increases in sTST of 60.1-83.2 min at day 8 and 55.5-68.2 min at day 15. For subjects with a 2-point or 2-step improvement on the anchors, mean increases in sTST were 79.6-81.4 min at day 8 and 80.1-93.5 min at day 15. In the phase III trial (N = 930), weekly average increases in sTST for subjects with a 1-point or 1-step improvement on the anchors were 39.3-46.7 min at month 1 and 47.3-58.3 min at month 3. For subjects with a 2-point or 2-step improvement on the anchors, mean increases in sTST were 60.7-76.2 min at month 1 and 70.1-87.7 min at month 3. Triangulation of these values supported a meaningful within-patient change threshold starting at 55 min. CONCLUSION: Increasing sTST is an important treatment outcome for people with insomnia. An increase in sleep time of approximately 55 min is meaningful to patients. CLINICAL TRIALS REGISTRATION: NCT03056053 (17 February 2017) and NCT03545191 (4 June 2018).

Clinicians' preferences for managing aneurysmal subarachnoid hemorrhage using endothelin receptor antagonists.

Background: The endothelin receptor antagonist (ERA) clazosentan is being investigated for the medical prevention of cerebral vasospasm and associated complications, such as delayed cerebral ischemia (DCI), after aneurysmal subarachnoid hemorrhage (aSAH). This study quantified how clinicians weigh the benefits and risks of ERAs for DCI prevention to better understand their treatment needs and expectations. Methods: An online choice experiment was conducted to elicit preferences of neurologists, intensivists, and neurosurgeons treating aSAH in the US and UK for the use of ERAs. The design of the choice experiment was informed by a feasibility assessment (N = 100), one-on-one interviews with clinicians (N = 10), a qualitative pilot (N = 13), and a quantitative pilot (N = 50). Selected treatment attributes included in the choice experiment were: one benefit (likelihood of DCI); and three risks (lung complications, hypotension, and anemia). In the choice experiment, clinicians repeatedly chose best and worst treatment options based on a scenario of a patient being treated in the ICU after aneurism repair. A correlated mixed logit model determined the relative attribute importance (RAI) and associated highest density interval (HDI) as well as acceptable benefit-risk trade-offs. Results: The final choice experiment was completed by 350 clinicians (116 neurologists, 129 intensivists/intensive care clinicians, and 105 neurosurgeons; mean age, 47.4 years). Reducing the likelihood of DCI (RAI = 56.5% [HDI, 53.6-59.5%]) had the largest impact on clinicians' treatment choices, followed by avoiding the risks of lung complications (RAI = 29.6% [HDI, 27.1-32.3%]), hypotension (RAI = 9.2% [HDI, 7.5-10.8%]), and anemia (RAI = 4.7% [HDI, 3.7-5.8%]). Clinicians expected the likelihood of DCI to decrease by ≥8.1% for a 20% increase in the risk of lung complications, ≥2.4% for a 20% increase in the risk of hypotension, and ≥1.2% for a 20% increase in the risk of anemia. Conclusions: Clinicians were willing to accept certain increased risks of adverse events for a reduced risk of DCI after aSAH. The likelihood of DCI occurring after aSAH can therefore be considered a clinically relevant endpoint in aSAH treatment development. Thus, evaluations of ERAs might focus on whether improvements (i.e., reductions) in the likelihood of DCI justify the risks of adverse events.

Meaningful Within-Patient Change on the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ): Analysis of Phase III Clinical Trial Data of Daridorexant.

BACKGROUND: The Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) is a new validated 14-item patient-reported outcome (PRO) instrument for evaluating daytime functioning in people with insomnia. It comprises three domains: Alert/Cognition, Mood, and Sleepiness. OBJECTIVE: The aim of this analysis was to estimate the minimum within-patient change for IDSIQ scores that an adult patient with insomnia would consider meaningful. METHODS: Data were from a randomized, double-blind, placebo-controlled, phase III clinical trial of daridorexant in adults with insomnia. Subjects completed the IDSIQ daily in the evening, with a recall period of 'today', throughout the 3-month double-blind treatment period. Scores were calculated as a weekly average. Each IDSIQ item was scored on an 11-point numeric rating scale ranging from 0 (not at all/none at all) to 10 (very/a lot), with a higher score indicating a greater severity or impact. PRO measures with correlation coefficients ≥0.30 were included in a subsequent anchor-based analysis. For the IDSIQ total score and each IDSIQ domain, meaningful within-patient change was estimated as the minimum score change patients would consider meaningful in an anchor-based analysis using data from PRO instruments capturing daytime and night-time insomnia symptoms (the Insomnia Severity Index [four items, each scored 0-4, with a higher score indicating greater symptom severity; assessed at screening, baseline, month 1 and month 3], Patient Global Assessment of Disease Severity [6-point scale from 'none' to 'very severe'; assessed weekly], Patient Global Impression of Severity [4-point scale from 'none' to 'severe'; assessed weekly], and Patient Global Impression of Change [7-point scale from 'very much better' to 'very much worse'; assessed weekly for night-time and daytime symptoms separately]). A supplemental distribution-based analysis was also conducted to support the anchor-based analysis. RESULTS: The analysis included 930 subjects aged 18-88 years. Spearman correlation coefficients for the relationships between score changes/ratings for anchors and the IDSIQ (0.36-0.44 at month 1, 0.45-0.57 at month 3) were all above the prespecified threshold of 0.30. Mean IDSIQ score changes at months 1 and 3 based on the different anchors supported meaningful within-patient change estimates starting at 17 points for the IDSIQ total score, 9 points for the Alert/Cognition domain, and 4 points for the Mood and Sleepiness domains. CONCLUSION: This analysis demonstrates the meaningful within-patient change for the IDSIQ total score and domain scores, that the instrument is sensitive to changes in the patient experience of insomnia, and that it can be used in clinical trials to evaluate changes in daytime functioning. CLINICAL TRIALS REGISTRATION: NCT03545191 (4 June 2018).

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

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

Treatment preferences in relation to fatigue of patients with relapsing multiple sclerosis: A discrete choice experiment.

Background: Treatment decisions for multiple sclerosis (MS) are influenced by many factors such as disease symptoms, comorbidities, and tolerability. Objective: To determine how much relapsing MS patients were willing to accept the worsening of certain aspects of their MS in return for improvements in symptoms or treatment convenience. Methods: A web-based discrete choice experiment (DCE) was conducted in patients with relapsing MS. Multinomial logit models were used to estimate relative attribute importance (RAI) and to quantify attribute trade-offs. Results: The DCE was completed by 817 participants from the US, the UK, Poland, and Russia. The most valued attributes of MS therapy to participants were effects on physical fatigue (RAI = 22.3%), cognitive fatigue (RAI = 22.0%), relapses over 2 years (RAI = 20.7%), and MS progression (RAI = 18.4%). Participants would accept six additional relapses in 2 years and a decrease of 7 years in time to disease progression to improve either cognitive or physical fatigue from "quite a bit of difficulty" to "no difficulty." Conclusion: Patients strongly valued improving cognitive and physical fatigue and were willing to accept additional relapses or a shorter time to disease progression to have less fatigue. The impact of fatigue on MS patients' quality of life should be considered in treatment decisions.

Preferences of patients for benefits and risks of insomnia medications using data elicited during two phase III clinical trials.

STUDY OBJECTIVES: To elicit the trade-offs patients are willing to make between benefits and risks of medications for chronic insomnia, with the purpose of allowing a patient-centric interpretation of clinical trial data. METHODS: A discrete choice experiment (DCE) was included in the two placebo-controlled phase III trials that evaluated the efficacy and safety of daridorexant. The DCE design was informed by a two-phase qualitative study, followed by qualitative and quantitative pilot testing before fielding. Relative attribute importance (RAI) and acceptable trade-offs between benefits and risks were obtained using a mixed logit model. RESULTS: Preferences were elicited from 602 trial participants (68.1% female, aged 58.6 ± 14.5 years). Preferences were most affected by daytime functioning (RAI = 33.7%) as a treatment benefit and withdrawal symptoms (RAI = 27.5%) as a risk. Patients also valued shorter sleep onset (RAI = 6.4%), longer sleep maintenance (RAI = 5.4%), reduced likelihood of abnormal thoughts and behavioral changes (RAI = 11.3%), reduced likelihood of dizziness/grogginess (RAI = 9.2%), and reduced likelihood of falls at night (RAI = 6.5%). Patients were willing to make trade-offs between these attributes. For example, they would accept an additional 18.8% risk of abnormal thoughts and behavioral changes to improve their daytime functioning from difficult to restricted and an additional 8.1% risk of abnormal thoughts and behavioral changes to avoid moderate withdrawal effects. CONCLUSIONS: Patients with insomnia were willing to make trade-offs between multiple benefits and risks of pharmacological treatments. Because patients valued daytime functioning more than sleep latency and duration, we recommend that functional outcomes and sleep quality be considered in treatment development and evaluation.

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

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.

Benefit-Risk or Risk-Benefit Trade-Offs? Another Look at Attribute Ordering Effects in a Pilot Choice Experiment.

BACKGROUND: Studies recommend randomising the order of attributes in discrete choice experiments (DCEs) to avoid bias; however, in a benefit-risk setting, this may increase the cognitive burden of respondents who compare the benefits and risks of treatments, or may affect their decision-making process. Based on these concerns, this paper explored attribute ordering effects in a benefit-risk DCE. METHOD: Attribute ordering effects were explored in a large pilot DCE relating to the medical treatment of insomnia. Participants were randomised to one of three presentation orders: (1) benefits were presented before risks (BR); (2) risks were presented before benefits (RB); (3) all attributes were randomised (RN). For the RB and BR presentation orders, attributes were randomised within benefits and risks. Responses were assessed in three ways. First, variations in respondents' self-reported choice certainty were obtained. Second, variations in failure rates of stability and dominance tests were calculated. Third, a heteroscedastic error component model tested for differences in choice consistency across the three attribute orderings. RESULTS: The final analysis included 156 respondents (RN: 54; BR: 49; RB: 53). No differences were found between the presentation orders with respect to stated choice certainty, or the proportion of respondents failing either the dominance or stability test. However, deterministic attribute grouping was associated with higher choice consistency. CONCLUSION: To increase choice consistency, DCE attributes should be randomised within logical groups that may be further randomised to reduce the risk of ordering effects.