Cross-Sectional Quantitative Evaluation of a Novel Patient-Reported Outcome Measure in Familial Chylomicronemia Syndrome.

Background: Familial chylomicronemia syndrome (FCS) is a rare metabolic disorder that impacts physical, emotional, social, and cognitive functioning. The FCS-Symptom and Impact Scale (FCS-SIS) patient-reported outcome (PRO) measure assesses common symptoms and impacts of FCS. This study was conducted to evaluate cross-sectional psychometric properties of the FCS-SIS and its scoring method. Methods: This multisite, cross-sectional, observational study of individuals with FCS was conducted in the United States and Canada. Participants completed a survey composed of 7 PRO measures, including the FCS-SIS, and questions about clinical characteristics and demographics. The structure of the FCS-SIS was evaluated using inter-item and item-scale correlations and internal consistency reliability. Construct, known-groups, and criterion validity were evaluated by examining associations between FCS-SIS item and composite scores and other measures included within the survey. Results: Most of the 33 participants were female (63.6%) and White (78.1%). On average, participants reported first noticing FCS symptoms at ~16 years, with abdominal pain the most frequently reported initial symptom (n=20). Participants reported 2.5 acute pancreatitis attacks on average over the past year. Average FCS-SIS symptom item scores ranged from 1.8 to 3.9 (on a 0-to-10 scale [none-to-worst-possible]) within the 24-hour recall period, with an average Symptom composite score of 2.7. The average impact item scores on the FCS-SIS ranged from 1.6 to 3.0 (on a 0-to-4 scale), with an average Impact composite score of 2.1. Inter-item correlations between the FCS-SIS Symptom items ranged from 0.32 to 0.78. Corrected item-total correlations were highly satisfactory for Impact items, ranging from 0.62 to 0.85. All a priori validity hypotheses were supported by observed correlations and score differences between known groups. Conclusion: The results of this study support the structure, reliability, and validity of the FCS-SIS, laying the psychometric groundwork for longitudinal evaluation of its utility in assessing treatment benefit in FCS clinical studies.

Symptoms and impacts of familial chylomicronemia syndrome: a qualitative study of the patient experience.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare, hereditary, metabolic disorder. FCS causes high levels of triglycerides in the blood, which can lead to abdominal pain, xanthomas, and acute pancreatitis (AP). Volanesorsen, along with adherence to a very low-fat diet is used to reduce triglyceride levels in individuals with FCS. We aimed to understand the symptoms of FCS and their impact on health-related quality of life (HRQoL). METHODS: Interviews were conducted with individuals with genetically confirmed FCS in the UK and Spain, some of whom had been treated with volanesorsen. Interview guides were developed with input from a patient advocacy group to explore the symptoms, impacts and management of FCS. Interviews were conducted by telephone and were recorded and transcribed. Data were analyzed using thematic analysis and saturation was recorded. RESULTS: Seventeen interviews were conducted with individuals with FCS (aged 27-68 years), thirteen of whom were currently/previously treated with volanesorsen. Episodes of AP were the most impactful reported symptom, resulting in severe abdominal pain, nausea, vomiting, fever, bloating and appetite loss. Other symptoms and functional issues included abdominal pain, gastrointestinal symptoms, impaired cognitive function and fatigue. These had an impact on work, social activities, relationships and psychological wellbeing. These symptoms and impacts were illustrated in a conceptual model, including management strategies. The challenges of managing a low-fat diet and experience with volanesorsen were discussed. CONCLUSION: Individuals with FCS experience a range of interrelated symptoms and functional limitations which impact their broader HRQoL. Treatments which alleviate symptoms and reduce the incidence of AP episodes have the potential to improve the HRQoL of these individuals.

The impact of inotersen on Neuropathy Impairment Score in patients with hereditary transthyretin amyloidosis with polyneuropathy.

BACKGROUND: Patients with hereditary transthyretin amyloidosis (ATTRv) frequently experience symptoms of polyneuropathy (PN) that worsen over time and impair daily functioning. Previous analyses supported efficacy of inotersen, an antisense oligonucleotide, to slow neuropathic progression in patients with ATTRv-PN, as indicated by larger mean changes, relative to placebo, in total score and several subscales of the Neuropathy Impairment Score (NIS), and for the subset of NIS items specific to lower limbs (NIS-LL) for the overall study sample. A key objective of the current study was to evaluate efficacy of inotersen for slowing neuropathic progression in NIS/NIS-LL within key clinical subgroups of patients with ATTRv-PN. Additionally, for this study, responder definition (RD) thresholds were estimated for NIS/NIS-LL total and subscale scores, for the purpose of evaluating clinically meaningful benefit of inotersen at the individual patient-level. METHODS: Post hoc analyses used data from the NEURO-TTR phase 3 trial of inotersen in patients with ATTRv-PN (NCT01737398). Treatment differences in mean changes on NIS/NIS-LL total and subscale scores from baseline to week 65 were examined within patient subgroups defined by clinical characteristics. Anchor- and distribution-based approaches estimated RDs for NIS/NIS-LL scores, with responders defined as patients who did not experience clinically meaningful neuropathic progression. Responder analyses compared the proportion of patients classified as responders for each NIS/NIS-LL score between treatment arms. RESULTS: Within each patient subgroup, mean increases in NIS/NIS-LL total and muscle weakness subscales were significantly smaller after 65 weeks of treatment with inotersen compared to placebo. Similar patterns were observed for some, but not all, subgroups on NIS/NIS-LL reflex subscale scores. Recommended RDs were 8.1 points for NIS total and 4.7 points for NIS-LL total. Patients receiving inotersen for 65 weeks were significantly less likely than those receiving placebo to exhibit clinically meaningful increases on NIS/NIS-LL total, muscle weakness, and sensation subscales. CONCLUSIONS: This study supports previous evidence for efficacy of inotersen in this patient population and provides interpretation guidelines for clinically meaningful changes in NIS/NIS-LL scores.

Qualitative development of the PROMIS Profile v1.0-Familial Chylomicronemia Syndrome (FCS) 28.

PURPOSE: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by high triglyceride levels, significant disease burden, and negative impacts on health-related quality of life. This project aimed to create a PROMIS-based patient-reported outcome measure that represents valid and important concerns for patients with FCS. METHODS: We reviewed the literature and data from a previous qualitative study of FCS to identify key FCS symptoms and impacts, which were mapped to PROMIS domains to create a pool of eligible items. Candidate items were reduced per expert feedback and patients with FCS completed cognitive interviews to confirm content validity and measure content. RESULTS: Literature and qualitative data review identified ten key symptoms and 12 key impacts of FCS, including abdominal pain, fatigue, difficulty thinking, and worry about pancreatitis attacks. We identified 96 items primarily from PROMIS, supplemented with items from the Quality of Life in Neurological Disorders™ (Neuro-QoL™) and the Functional Assessment of Chronic Illness Therapy (FACIT) measurement systems. This pool was reduced to 32 candidate items, which were assessed via cognitive interviews with eight participants with FCS. Cognitive interview results and additional expert feedback led to the removal of four items and finalization of the PROMIS Profile v1.0-familial chylomicronemia syndrome (FCS) 28. CONCLUSIONS: The PROMIS Profile v1.0-familial chylomicronemia syndrome (FCS) 28 provides strong content validity for assessing quality of life among patients with FCS. The benefits of PROMIS, including norm-referenced mean values for each measure, will facilitate comparison of patients with FCS to other clinical populations.

Clinical manifestations and healthcare utilization before diagnosis of transthyretin amyloidosis.

Introduction: Initial clinical manifestations of transthyretin amyloidosis (ATTR) are not well understood, making timely diagnosis challenging. Methods: Patients aged ≥68 years newly diagnosed with ATTR were identified using Medicare Research Identifiable Files. Symptom manifestation and healthcare utilization were measured during 3 years pre-diagnosis; demographics and comorbidity index during 1-year pre-diagnosis. Controls (ATTR-free) were matched 1:1 to patients with ATTR based on age, sex and region; same index date and enrollment as match. Results: We identified 552 matched ATTR-control pairs: mean age 78.3 (standard deviation 6.3) and 64.5% male. Among patients with ATTR (vs controls), cardiovascular conditions (92.9 vs 75.9%) and hospitalization (54.0 vs 35.5%) were frequent during 3 years pre-diagnosis. Conclusion: Patients with ATTR have multiple symptoms and hospitalizations pre-diagnosis, recognition of which may facilitate earlier diagnosis and treatment.

Long-term treatment effects of inotersen on health-related quality of life in patients with hATTR amyloidosis with polyneuropathy: Analysis of the open-label extension of the NEURO-TTR trial.

INTRODUCTION/AIMS: Hereditary transthyretin-mediated amyloidosis with polyneuropathy (hATTR-PN) progressively affects patients' functionality and compromises health-related quality of life (HRQL). The aim of this study was to quantify the projected long-term treatment effects of inotersen vs placebo on HRQL measures. METHODS: The inotersen phase 2/3 randomized, double-blind, placebo-controlled trial NEURO-TTR (NCT01737398, 65 weeks) and its subsequent open-label extension (OLE; NCT02175004, 104 weeks) included 172 (112 inotersen and 60 placebo) patients. Placebo double-blind period and overall inotersen-inotersen (double-blind/OLE) treatment period (170 weeks) data were used to extrapolate the long-term placebo-placebo effect using mixed-effects models with repeated measures. Changes from baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) and 36-Item Short Form Health Survey version 2 (SF-36v2) in hATTR-PN were estimated. Differences in changes were compared between the inotersen-inotersen and extrapolated placebo-placebo arms. RESULTS: Inotersen-inotersen patients maintained their HRQL with an observed change ranging from 10.3% improvement (Norfolk QoL-DN item "Pain kept you awake at night") to 11.6% deterioration (SF-36v2 Activities of Daily Living subdomain). The extrapolated placebo-placebo results suggest greater deterioration over time compared with inotersen-inotersen treatment on Norfolk QoL-DN total score (23.6; 95% confidence interval [CI], 8.9-38.3; P < .01), Activities of Daily Living (4.6; 95% CI, 2.0-7.3; P < .001), and "Pain kept you awake at night" (1.2; 95% CI, 0.4-1.9; P < .01). Similarly, greater deterioration was expected for the SF-36v2 Physical Component Summary (8.0; 95% CI, 3.2-12.8, P < .01), Bodily Pain (7.8; 95% CI, 2.0-13.5; P < .01), and Physical Functioning (10.6; 95% CI, 5.5-15.6; P < .0001). DISCUSSION: Long-term (>3 years) inotersen treatment was associated with slowing and, in some domains, halting of deterioration in key HRQL outcome measures, particularly physical functioning and pain.

Factors associated with increased health-related quality-of-life benefits in hereditary transthyretin amyloidosis polyneuropathy patients treated with inotersen.

INTRODUCTION/AIMS: Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a genetic condition associated with significant morbidity and mortality. In this study we aimed to identify patient subgroups exhibiting the greatest health-related quality of life (HRQL) benefit from inotersen treatment. METHODS: We examined data from the inotersen phase 2/3 randomized, controlled trial for ATTRv-PN, NEURO-TTR (NCT01737398, 66 weeks). LASSO regression models predicted changes in Norfolk QoL-DN total score (TQoL, range -4 to 136; higher scores indicate poorer HRQL) from baseline in the inotersen and placebo arm, respectively. Individualized efficacy scores (ES) were calculated as differences between predicted change scores had patients received inotersen vs placebo. Patients were ranked by ES to define the greatest-benefit subpopulation (top 50%). Characteristics of the top 50% and bottom 50% of patients were compared. RESULTS: The overall mean ± standard deviation TQoL change was -0.20 ± 19.13 for inotersen (indicating no change) and 10.77 ± 21.13 for placebo (indicating deterioration). Within the highest-benefit patients, mean TQoL change was -11.03 ± 17.06 (improvement) for inotersen and 11.24 ± 22.97 (deterioration) for placebo (P < .001). Compared with the overall population, patients in the greatest-benefit subpopulation were younger, more likely to have polyneuropathy disability (PND) scores 1 or 2, less likely to have received prior tafamidis or diflunisal treatment, and more likely to have Val30Met mutations and higher (worse) baseline TQoL. CONCLUSIONS: Patients who were younger and/or at earlier polyneuropathy stages experienced greater HRQL benefits from inotersen over 66 weeks. These findings underscore the need for early diagnosis and treatment initiation, especially among more severely affected patients in early stages of ATTRv-PN.

Responder analysis for neuropathic impairment and quality-of-life assessment in patients with hereditary transthyretin amyloidosis with polyneuropathy in the NEURO-TTR study.

OBJECTIVE: Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a rare disease characterized by rapid neuropathic progression. In pivotal studies of gene-silencing treatments, the modified Neuropathy Impairment Score + 7 tests (mNIS + 7) and Norfolk-Quality of Life (QOL)-Diabetic Neuropathy (DN) questionnaire assessed treatment impact on neuropathic progression. Establishing responder definition (RD) thresholds for these measures would enable evaluation of clinically meaningful treatment benefit. METHODS: mNIS + 7 and Norfolk-QOL-DN were administered at baseline and week 65 to 165 adults with ATTRv-PN receiving inotersen (n = 106) or placebo (n = 59) in the NEURO-TTR study. Anchor-based approaches for estimating RD thresholds were used for Norfolk QOL-DN, while distribution-based approaches were used for both measures. Responders were patients with a score change < RD, indicating improvement or stabilization (i.e., no clinically meaningful progression). Odds ratios (ORs) and Fisher's exact tests compared proportions of responders by treatment. RESULTS: The mean RD estimates were 12.2 points and 8.8 points for mNIS + 7 and Norfolk QOL-DN, respectively. The proportions of patients whose change in score indicated improvement or stabilization were statistically significantly larger for inotersen than placebo for all estimated RD thresholds for mNIS + 7 (64-86% responders for inotersen vs. 27-46% for placebo, ORs = 3.8-7.2, ps < 0.001) and Norfolk QOL-DN (66-81% vs. 35-56%, ORs = 2.4-3.6, ps < 0.05). DISCUSSION: Establishing RD thresholds for these instruments enables evaluation of clinically relevant and individual-level treatment benefit on neuropathic progression. Across RDs estimated using multiple methods, a higher proportion of patients receiving inotersen than placebo showed improved or stabilized neuropathic progression at week 65. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01737398; Date of registration: November 29, 2012.

Disease Burden and Treatment Patterns Associated With Eosinophilic Esophagitis in the United States: A Retrospective Claims Study.

GOALS: This US-based, retrospective claims study aimed to investigate disease burden and treatment patterns in patients with eosinophilic esophagitis (EoE), and to compare health care resource use (HCRU) in patients with EoE and matched controls without EoE. MATERIALS AND METHODS: Patients with a diagnosis of EoE and ≥12 months of prediagnosis data were identified from the Truven Health MarketScan Research databases (January 2008 to September 2016) and followed up from the diagnosis date until termination of eligibility for a health plan. Patient clinical characteristics and HCRU were recorded in the 12 months before diagnosis; HCRU and treatment patterns were recorded during follow-up. HCRU in patients with EoE and matched controls was compared during the 12-month postdiagnosis period. RESULTS: Among the 23,003 patients with EoE (mean age: 34.3 y; 64.8% male), gastroesophageal reflux disease was the most common prediagnosis condition (34.6%). After diagnosis, the most common off-label, first-line treatments were proton pump inhibitor monotherapy (52.8%) and topical corticosteroid monotherapy (21.5%). Overall, 3336 patients (14.5%) received at least 3 lines of off-label pharmacotherapy. Outpatient visits (recorded in 99.9% of patients on and postdiagnosis) were most frequently to gastroenterologists/pediatric gastroenterologists (49.5% prediagnosis, 72.6% on and postdiagnosis). Inpatient admissions and outpatient and emergency room visits were more likely in patients with EoE than in matched controls (P<0.0001). CONCLUSIONS: Patients with EoE in the USA experience a high disease burden both before and after diagnosis, which requires significant HCRU. Our findings highlight the unmet need for adequate control of EoE-related symptoms.

Early Data on Long-term Impact of Inotersen on Quality-of-Life in Patients with Hereditary Transthyretin Amyloidosis Polyneuropathy: Open-Label Extension of NEURO-TTR.

INTRODUCTION: Patients with hereditary transthyretin amyloidosis associated with polyneuropathy (ATTRv-PN) experience deterioration in health-related quality of life (HRQOL) as the disease progresses. Findings from the randomized placebo-controlled phase III NEURO-TTR study showed treatment benefit of inotersen, an antisense oligonucleotide, for preserving or improving HRQOL after 65 weeks of treatment. The current analysis examines longitudinal trends in specific aspects of HRQOL, including polyneuropathy symptoms, daily activities, and physical, role, and social functioning in patients with ATTRv-PN receiving long-term treatment in a follow-up open-label extension (OLE) study. METHODS: One-hundred thirty-five patients with ATTRv-PN were enrolled in an ongoing 5-year OLE study following completion of NEURO-TTR. Eighty-five patients received continuous weekly treatment with inotersen in both studies (inotersen-inotersen group), while 50 patients switched from placebo to inotersen at OLE study baseline (placebo-inotersen group). Descriptive analyses of changes in domain scores and item responses through week 104 of the OLE study were conducted for measures of neuropathy-related and generic HRQOL: Norfolk QOL-Diabetic Neuropathy (DN) questionnaire and SF-36v2® Health Survey (SF-36v2), respectively. RESULTS: For both inotersen-inotersen and placebo-inotersen groups, all Norfolk QOL-DN and most SF-36v2 domain scores remained stable from OLE baseline through week 104. Differences in HRQOL between the two groups at OLE baseline were sustained through week 104. Analysis of item responses from NEURO-TTR baseline to OLE study week 104 (170 weeks) for the inotersen-inotersen group found no notable increases in the proportion of patients reporting substantial impairments across a wide variety of symptoms, daily activities, and functioning. CONCLUSION: Long-term treatment with inotersen preserved HRQOL for patients with ATTRv-PN for periods of up to 3 years. The gap in HRQOL between those who had previously received inotersen or placebo in NEURO-TTR did not close by week 104 of the OLE phase, indicating the importance of early treatment for maintaining HRQOL in these patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers NCT01737398 for NEURO-TTR study; NCT02175004 for OLE study INFOGRAPHIC.

Hereditary transthyretin amyloidosis with polyneuropathy is a rare disease that causes damage to nerves in the limbs, leading to pain, numbness, loss of sensitivity, and muscle weakness, with eventual loss of the ability to walk (i.e., patients require a wheelchair or are bedridden). As the disease progresses, patients' quality of life, including their ability to engage in everyday activities, socialize with others, work, and live independently, continually worsens. In a recent clinical trial (the NEURO-TTR study), patients with this disease randomized to receive the drug inotersen for 66 weeks maintained their quality of life, while patients randomized to receive a placebo showed continued worsening. All patients completing the NEURO-TTR study could participate in an extension study during which all patients knowingly received inotersen for up to 5 years. We examined quality of life in patients through the first 2 years of this extension study. For all patients, regardless of previous treatment (inotersen or placebo), most aspects of quality of life did not change throughout the 2-year extension study, showing that inotersen can preserve quality of life of these patients for up to 2­3 years. However, while quality of life in patients who had received placebo in the NEURO-TTR study did not get worse during the extension study, it also did not improve to match that of patients who received inotersen during the NEURO-TTR study. This finding shows the importance of treating these patients with inotersen as early as possible to preserve their quality of life before it substantially deteriorates.

Development of a novel PRO instrument for use in familial chylomicronemia syndrome.

BACKGROUND: Familial chylomicronemia syndrome (FCS), a rare genetic disorder characterized by high levels of circulating triglycerides, negatively impacts multiple organs, including the liver and pancreas. OBJECTIVE: The objective of this study was to develop and support the content validity of a novel patient-reported outcome (PRO) measure addressing FCS symptoms and impacts. To facilitate use in clinical trials of new treatments, evidence supporting the new measure needed to be consistent with regulatory guidance and requirements. METHODS: A pool of items addressing symptoms and impacts of FCS was initially developed based on data from a large burden-of-illness study with patients with FCS as well as a review of available literature and existing PRO measures. Two rounds of qualitative interviews were conducted with patients with FCS (N = 10) to refine the draft items and support the measure's content validity. Each interview began with concept elicitation followed by cognitive debriefing of the draft FCS measure. RESULTS: Patient-reported symptoms and impacts of FCS were generally consistent with those identified by the burden-of-illness study; abdominal pain was particularly prevalent and salient for patients. Suggested changes to the draft item pool were generally minor. Comprehensibility and ease of completion for the final instrument were confirmed during the second set of interviews. CONCLUSION: The content validity of the final 17-item FCS Symptoms and Impacts Scale is strongly supported by patient input gathered through both a large burden-of-illness study and qualitative research. To further support use in clinical trials, psychometric evaluation of the measure is underway.

Rate of neuropathic progression in hereditary transthyretin amyloidosis with polyneuropathy and other peripheral neuropathies: a systematic review and meta-analysis.

BACKGROUND: We aimed to compare neuropathic progression rate between hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and other peripheral neuropathies, including diabetic peripheral neuropathy (DPN) and Charcot-Marie-Tooth disease (CMT). METHODS: Literature searches identified studies reporting neuropathic progression, measured by Neuropathy Impairment Score (NIS) or NIS-Lower Limbs (NIS-LL). Our study also included unpublished data from a clinical registry of patients who were diagnosed with different peripheral neuropathies and seen at the Oregon Health & Science University (OHSU) during 2016-2020. Meta-analysis and meta-regression models examined and compared annual progression rates, calculated from extracted data, between studies of ATTRv-PN and other peripheral neuropathies. RESULTS: Data were synthesized from 15 studies in which NIS and/or NIS-LL total scores were assessed at least twice, with ≥12 weeks between assessments, among untreated patients with ATTRv-PN or other peripheral neuropathies. Meta-analysis models yielded that the annual progression rate in NIS total scores was significantly different from zero for studies in ATTRv-PN and CMT (11.77 and 1.41; both P < 0.001), but not DPN (- 1.96; P = 0.147). Meta-regression models showed significantly faster annual progression in studies in ATTRv-PN, which statistically exceeded that in other peripheral neuropathies by 12.45 points/year for NIS, and 6.96 for NIS-LL (both P < 0.001). CONCLUSIONS: Peripheral nervous function deteriorates more rapidly in patients with ATTRv-PN than for other peripheral neuropathies. These findings may improve understanding of the natural history of neuropathy in ATTRv-PN, facilitate early diagnosis, and guide the development of assessment tools and therapies specifically targeting neuropathic progression in this debilitating disease.

The patient journey toward a diagnosis of hereditary transthyretin (ATTRv) amyloidosis.

BACKGROUND: Despite emerging treatments for hereditary transthyretin (ATTRv) amyloidosis, the disease is often misdiagnosed, with reported diagnostic delays of up to several years. Knowledge of the patient journey leading up to diagnosis may help to promote earlier intervention. The study's objective was to examine patient clinical characteristics and healthcare utilization prior to ATTRv amyloidosis diagnosis. METHODS: Patients ≥ 18 years and newly diagnosed with ATTRv amyloidosis identified in IBM® MarketScan® Commercial and Medicare Supplemental data using a claims-based algorithm as follows: diagnosis required ≥ 1 medical claim with relevant amyloidosis diagnosis code (ICD-10-CM: E85.0-.4, E85.89, E85.9; excludes light chain and wild type) during identification (ID) period (1/1/2016-12/31/2017), and ≥ 1 occurrence of qualifying criteria during 2011-2017: ≥ 15 days diflunisal use without > 30-day gap, liver transplant, or claim with specific codes E85.1 or E85.2. The index date was defined as the date of first claim with amyloidosis diagnosis code in ID period. Patients had continuous enrollment ≥ 5 years pre-index date (look-back period). Occurrence of selected comorbid conditions and symptoms and healthcare utilization (testing, emergency department visits and hospitalization) measured during the look-back period; demographics, physician specialty, and Charlson comorbidity index (CCI) measured 1 year pre-index. Patients with an ICD-9/10 amyloidosis code during the look-back period were excluded. An ATTRv-free reference cohort was created from a random sample of enrollees who lacked any diagnosis of amyloidosis and matched 3:1 to ATTRv patients on age, gender, and region to provide reference values; same index and enrollment requirement as match. RESULTS: For the 141 qualifying patients with ATTRv and 423 matched controls, mean (standard deviation) age was 62.5 (14.2) years and 53.9% were female. Mean CCI for ATTRv cohort was 2.7 (3.0) versus 1.1 (1.9) among controls. Selected comorbidities, testing, visits, and hospitalization were common among patients with ATTRv during the look-back period with higher rates versus controls. CONCLUSIONS: Patients with ATTRv amyloidosis experience multiple neurological, cardiovascular, and other clinical manifestations, testing, and hospitalization prior to diagnosis. Occurrence of potential markers of illness is most common in the year before diagnosis.

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

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.

The Clinical and Economic Burden of Newly Diagnosed Hereditary Transthyretin (ATTRv) Amyloidosis: A Retrospective Analysis of Claims Data.

INTRODUCTION: Little is known about the burden of hereditary transthyretin (ATTRv) amyloidosis, a genetic, progressive, and fatal disease caused by extracellular deposition of transthyretin amyloid fibrils. The study's aim was to estimate costs and disease burden associated with ATTRv amyloidosis in a real-world setting. METHODS: Using IBM® MarketScan® Commercial and Medicare Supplemental data, we identified patients at least 18 years of age with newly diagnosed ATTRv amyloidosis. Diagnosis required at least one medical claim with relevant diagnosis code (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] 277.30-.31, 277.39; ICD-10-CM E85.0-.4, E85.89, E85.9) between January 1, 2014 and December 31, 2016, and at least one additional criterion occurring during study period (2013-2017): at least 15 days diflunisal use without more than a 30-day gap; liver transplant; or claim with codes E85.1 or E85.2. First diagnosis date was study index. Continuous enrollment 1-year pre-index (baseline) and post-index (follow-up) was required. Patients with baseline amyloidosis diagnosis were excluded. Outcomes of interest were comorbidities and 1-year follow-up healthcare utilization and costs (also reported quarterly). RESULTS: Among 185 qualifying patients, mean age was 59.2 years (standard deviation 15.2), 54.1% were female, and baseline Charlson comorbidity index was 2.2 (2.5). Neuropathy (30.3%), diabetes (27.0%), and cardiovascular-related comorbidities, including dyspnea (25.9%) and congestive heart failure (21.6%), were common during follow-up. Nearly a quarter of patients (24.9%) were hospitalized during follow-up. Most hospitalizations and emergency department visits occurred in the first quarter post-diagnosis (18.9%, 17.8%, respectively) and dropped in subsequent quarters. The annual mean total cost was $64,066, with inpatient services contributing the majority of the expenses ($34,461), followed by outpatient ($23,853), and then pharmacy ($5752). As with utilization, costs were highest in the first quarter post-diagnosis and dropped in subsequent quarters. CONCLUSION: Patients newly diagnosed with ATTRv amyloidosis have substantial healthcare utilization and costs in the first year, primarily the initial months, post-diagnosis. Further research should examine later costs associated with disease progression and end-of-life care.

PROMIS® and Neuro-QoLTM measures are valid measures of health-related quality of life among patients with familial chylomicronemia syndrome.

Background: FCS significantly affects health-related quality of life (HRQOL). Legacy patient-reported outcome measures are often not sensitive to FCS's impact. NIH PROMIS and Neuro-QoL measures may accurately capture HRQOL in FCS patients. This study assessed a broad range of PROMIS and Neuro-QoL measures covering physical, mental, and social HRQOL to determine their suitability for the FCS population.Methods: Adult FCS patients in the United States (N = 25) were recruited to an online survey study and completed several PROMIS short forms and Neuro-QoL computer adaptive tests.Results: Scores were more than 0.5 standard deviations (SD) worse than the normative mean on 10 of 16 normed measures, and more than 0.75 SDs worse than the normative mean on two measures. Responses at the floor and ceiling were occasionally observed, marginal reliabilities were strong, and significant differences across performance status (ps < 0.05) provided preliminary support for construct validity. The measures correlated with each other strongly and as expected.Conclusion: Results support the ability of PROMIS and Neuro-QoL measures to detect HRQOL impairment among patients with FCS. PROMIS and Neuro-QoL measures captured the functional impact and symptom burden associated with FCS, and the broad range of symptom severity experienced by patients with FCS.

Prevalence and Characteristics of Dysphagia Based on a Population-Based Survey.

BACKGROUND & AIMS: Although dysphagia is common, there is limited information about the prevalence and burden of illness of dysphagia in the United States. We performed a population-based survey of more than 31,000 adults to evaluate the epidemiology, clinical characteristics, and health care-seeking behavior of individuals with dysphagia. METHODS: We performed a cross-sectional analysis of adults in the United States who completed an online, self-administered health survey from April 4 through April 19, 2018. All respondents were asked which of the following symptoms they had ever experienced (presented in random order): dysphagia, abdominal pain, bloating, bowel incontinence, constipation, diarrhea, heartburn/reflux, nausea/vomiting, or none of the above. Only respondents who selected dysphagia continued the remaining survey, which included questions about dysphagia severity, use of compensatory maneuvers, health care seeking, and esophageal comorbidities. We used multivariable regression methods to adjust for confounding. RESULTS: Of 31,129 individuals who participated in the survey, 4998 respondents (16.1%) reported experiencing dysphagia; 92.3% of these had symptoms in the previous week. We found that 16.3% of respondents described their dysphagia over the previous 7 days as either quite a bit or very severe. Drinking liquids to help with dysphagia (86.0%) and taking longer to finish eating (76.5%) were the most common compensatory maneuvers. Overall, 51.1% of individuals sought care for their difficulty swallowing; older age, male sex, having a usual source of care and insurance, having comorbidities, and more severe dysphagia symptoms increased the odds for seeking care (P < .05). The most commonly reported esophageal comorbidities were gastroesophageal reflux disease (30.9%), eosinophilic esophagitis (8.0%), and esophageal stricture (4.5%). CONCLUSIONS: In a large population-based survey, we found that dysphagia is common; 1 of 6 adults reported experiencing difficulty swallowing. However, half of individuals have not discussed their symptoms with a clinician and many could have treatable disorders.

Development of a Patient-Reported Outcome Measure for Chronic Hypoparathyroidism.

INTRODUCTION: A patient-reported outcome (PRO) measure specific to chronic hypoparathyroidism is lacking to facilitate the evaluation of treatment. A PRO measure that followed the recommendations of the US Food and Drug Administration (FDA) PRO guidance was created to address key hypoparathyroidism symptoms. METHODS: A literature review was conducted to identify symptoms of hypoparathyroidism and any existing PRO measures appropriate for evaluating these symptoms, followed by concept elicitation interviews involving six individuals with hypoparathyroidism. On the basis of the results of the literature review and interviews, a draft item pool was developed and refined through two sets of cognitive debriefing interviews with six additional patients. A translatability assessment was also conducted to evaluate concepts, phrases, or components of the items that could be problematic in future translations and to identify culturally specific phrasing. RESULTS: No PRO measures appropriate to address hypoparathyroidism symptoms documented in the literature were identified. Qualitative research participants included 11 women and one man, with an average age of 49 years; the majority (10) of these participants were white. Concept elicitation interview results were generally consistent with the results of the literature review; the most commonly reported symptoms included issues with cognition, often described as "brain fog" (n = 6), muscle cramping (n = 5), tingling (n = 5), and muscle spasms or twitching (n = 4). The initial draft item pool included 20 items; based upon participant feedback, the final Hypoparathyroidism Symptom Diary comprised 13 items and was found to be easily understood and relevant to the participants. No significant issues were identified by the translatability assessment. CONCLUSION: The Hypoparathyroidism Symptom Diary was developed following the recommendations of the FDA's PRO guidance. The measure addresses a comprehensive set of symptoms, as well as key impacts of hypoparathyroidism deemed important by patients. FUNDING: Shire Human Genetic Therapies, Inc., Lexington, MA, USA, a member of the Takeda group of companies.

Psychometric evaluation of the hypoparathyroidism symptom diary.

PURPOSE: To conduct an initial psychometric evaluation of the reliability and validity of the Hypoparathyroidism Symptom Diary (HPT-SD). PATIENTS AND METHODS: Data were collected during a cross-sectional, observational study. Participants with self-reported hypoparathyroidism (HPT) completed the HPT-SD, the Functional Assessment in Cancer Therapy-Cognitive Function (FACT-Cog), the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), and the Hospital Anxiety and Depression Scale (HADS) measures. Item- and scale-level internal consistency reliability, known-groups validity, and construct validity were evaluated. Subscales were identified and preliminary scoring algorithms were developed. RESULTS: The study included 52 participants (mean age, 51 years). Overall, the measurement properties of the HPT-SD were very good. Item-level response frequency distributions showed evidence of possible floor effects for four muscle-related symptom items. Inter-item correlations revealed a pattern of relationships among symptom items (r=0.3-0.8) and among impact items (r=0.5-0.7) and provided evidence for two HPT-SD subscales: Symptoms and Impacts. Construct validity correlations supported a priori convergent validity hypotheses (|r|≥0.4) between HPT-SD subscales and the FACT-Cog, FACIT-Fatigue, and HADS. Mean HPT-SD Symptom and Impact scores were in the expected direction and significantly different between subgroups of patients with high and low HPT disease severity. CONCLUSION: Results indicate that the HPT-SD is an appropriate measure of HPT-related symptoms and impacts. Floor effects may be attributed to the observational study design: participants manage symptoms with calcium and active vitamin D supplements prior to an escalation in severity. Future studies should assess the HPT-SD measurement properties using longitudinal study designs.

Lumacaftor/Ivacaftor reduces pulmonary exacerbations in patients irrespective of initial changes in FEV1.

BACKGROUND: Improved lung function and fewer pulmonary exacerbations (PEx) were observed with lumacaftor/ivacaftor (LUM/IVA) in patients with cystic fibrosis homozygous for F508del. It is unknown whether PEx reduction extends to patients without early lung function improvement. METHODS: Post hoc analyses of pooled phase 3 data (NCT01807923, NCT01807949) categorized LUM/IVA-treated patients by percent predicted forced expiratory volume in 1 s (ppFEV1) change from baseline to day 15 into threshold categories (absolute change ≤0 vs >0; relative change <5% vs ≥5%) and compared PEx rates vs placebo. RESULTS: LUM (400 mg q12h)/IVA (250 mg q12h)-treated patients (n = 369) experienced significantly fewer PEx vs placebo, regardless of threshold category. With LUM/IVA, PEx rate per patient per year was 0.60 for those with absolute change in ppFEV1 > 0 and 0.85 for those with absolute change ≤0 (respective rate ratios vs placebo [95% CI]: 0.53 [0.40-0.69; P < .0001], 0.74 [0.55-0.99; P = .04]). CONCLUSIONS: LUM/IVA significantly reduced PEx, even in patients without early lung function improvement.