Relationship between pruritus and sleep in participants with primary biliary cholangitis in the Phase 2b GLIMMER trial.

BACKGROUND: Cholestatic pruritus and fatigue are debilitating conditions associated with primary biliary cholangitis (PBC) and can significantly impact patients' quality of life. Pruritus in PBC often worsens at night and patients frequently report sleep disturbance, which contributes to cognitive symptoms and fatigue. Linerixibat is an ileal bile acid transporter inhibitor in clinical development for the treatment of pruritus associated with PBC and was recently assessed versus placebo in the Phase 2b GLIMMER trial. This post-hoc analysis assesses the relationship between pruritus severity and sleep disturbance in participants of GLIMMER regardless of treatment group. METHODS: GLIMMER (NCT02966834), a multicenter, double-blind, randomized, placebo-controlled trial, recruited 147 patients with PBC and moderate-to-severe pruritus. Following 4 weeks single-blind placebo, patients (randomized 3:1) received linerixibat or placebo for 12 weeks (to Week 16). Participants graded their itch (twice daily) and its interference with sleep (once daily) in an electronic diary using a 0-10 numerical rating scale (NRS). Weekly and monthly itch scores were calculated as the mean of the worst daily itch score over the respective time period. At study visits, participants completed the 5-D itch scale and the PBC-40 quality of life questionnaire, both of which contain an item specific to itch-related sleep disturbance. The impact of pruritus on sleep was assessed post hoc through correlations between the changes in NRS, 5-D itch, and PBC-40. RESULTS: Strong correlations were found between change from baseline in weekly itch and sleep NRS scores (r = 0.88 [95% confidence interval (CI): 0.83; 0.91]) at the end of treatment (Week 16), as well as in monthly itch and sleep NRS scores (r = 0.84 [95% CI: 0.80; 0.87]). Patients with improved weekly pruritus score severity category demonstrated reduced perceived sleep interference on average. Itch responders (≥2-point improvement in weekly itch score from baseline) displayed larger improvements in weekly sleep NRS score, 5-D itch, and PBC-40 sleep items, than itch non-responders (<2-point improvement). CONCLUSIONS: A strong correlation exists between changes in pruritus severity and sleep interference in patients with PBC; pruritus reduction could generate concomitant improvement in sleep.

Pruritus in primary biliary cholangitis is under-recorded in patient medical records.

OBJECTIVE: Cholestatic pruritus in primary biliary cholangitis (PBC) reduces patients' health-related quality of life (HRQoL). Despite this, existing research suggests that pruritus is under-recorded in patients' health records. This study assessed the extent to which pruritus was recorded in medical records of patients with PBC as compared with patient-reported pruritus, and whether patients reporting mild itch were less likely to have pruritus recorded. We also evaluated clinico-demographic characteristics and HRQoL of patients with medical record-documented and patient-reported pruritus. DESIGN: This cross-sectional study used clinical information abstracted from medical records, together with patient-reported (PBC-40) data from patients with PBC in the USA enrolled in the PicnicHealth cohort. Medical record-documented pruritus was classified as 'recent' (at, or within 12 months prior to, enrolment) or 'ever' (at, or any point prior to, enrolment). Patient-reported pruritus (4-week recall) was assessed using the first PBC-40 questionnaire completed on/after enrolment; pruritus severity was classified by itch domain score (any severity: ≥1; clinically significant itch: ≥7). Patient clinico-demographic characteristics and PBC-40 domain scores were described in patients with medical record-documented and patient-reported pruritus; overlap between groups was evaluated. Descriptive statistics were reported. RESULTS: Pruritus of any severity was self-reported by 200/225 (88.9%) patients enrolled; however, only 88/225 (39.1%) had recent medical record-documented pruritus. Clinically significant pruritus was self-reported by 120/225 (53.3%) patients; of these, 64/120 (53.3%) had recent medical record-documented pruritus. Patients reporting clinically significant pruritus appeared to have higher mean scores across PBC-40 domains (indicating reduced HRQoL), versus patients with no/mild patient-reported pruritus or medical-record documented pruritus. CONCLUSION: Compared with patient-reported measures, pruritus in PBC is under-recorded in medical records and is associated with lower HRQoL. Research based only on medical records underestimates the true burden of pruritus, meaning physicians may be unaware of the extent and impact of pruritus, leading to potential undertreatment.

Cholestatic Pruritus Treatments in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis: A Systematic Literature Review.

BACKGROUND AND AIMS: We conducted a systematic literature review to understand the evidence supporting treatment decisions for cholestatic pruritus associated with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). METHODS: Studies that enrolled ≥ 75% participants with PBC or PSC and reported ≥ 1 endpoint(s) related to efficacy, safety, health-related quality of life (HRQoL) or other patient-reported outcomes were included. Bias was assessed using the Cochrane risk of bias tool for randomised controlled trials (RCTs) and the Quality of Cohort studies tool for non-RCTs. RESULTS: Thirty-nine publications were identified, covering 42 studies and six treatment classes (including investigational and approved products): anion-exchange resins, antibiotics (rifampicin/derivatives), opiates, selective serotonin reuptake inhibitors, fibrates, ileal bile acid transporter inhibitors and other agents not categorised in these six classes. Across studies, median sample size was small (n = 18), 20 studies were over 20 years old, 25 followed patients for ≤ 6 weeks, only 25 were RCTs. Pruritus was assessed using several different tools, with inconsistencies in their application. Cholestyramine, considered first-line therapy for moderate-severe cholestatic pruritus, was assessed in six studies (two RCTs) including 56 patients with PBC and 2 with PSC, with evidence of efficacy demonstrated in only three studies, among which, two RCTs were assessed as having a high risk of bias. Findings were similar for other drug classes. CONCLUSIONS: There is a lack of consistent and reproducible evidence available on efficacy, impact on HRQoL, and safety of cholestatic pruritus treatments, leaving physicians to rely on clinical experience rather than evidence-based medicine for treatment selection.

Impact of Pruritus on Quality of Life and Current Treatment Patterns in Patients with Primary Biliary Cholangitis.

BACKGROUND AND AIMS: Patients with primary biliary cholangitis (PBC) often suffer with pruritus. We describe the impact of pruritus on quality of life and how it is managed in a real-world cohort. METHODS: TARGET-PBC is a longitudinal observational cohort of patients with PBC across the USA. Data include information from medical records for three years prior to the date of consent up to 5 years of follow-up. Enrolled patients were asked to complete patient-reported outcome surveys: PBC-40, 5-D itch, and the PROMIS fatigue survey. Kruskal-Wallis tests were used to compare differences in symptoms between groups. RESULTS: A total of 211 patients with completed PRO surveys were included in the current study. PRO respondents were compared with non-respondents in the TARGET-PBC population and were broadly similar. Pruritus was reported in 170 patients (81%), with those reporting clinically significant pruritus (30%) scoring worse across each domain of the PBC-40 and 5-D itch, more frequently having cirrhosis, and having significantly greater levels of fatigue. Patients reporting clinically significant pruritus were more likely to receive treatment, but 33% had never received treatment (no itch = 43.9%, mild itch = 38.3%). CONCLUSIONS: The prevalence of pruritus was high in this population, and those reporting clinically significant pruritus had a higher likelihood of having advanced disease and worse quality of life. However, this study found that pruritus in PBC is under-treated. This may be due in part to ineffectiveness of current treatments, poor tolerance, or the lack of FDA-approved medications for pruritus.

Clinical and Economic Outcomes of Erythropoiesis-Stimulating Agent Hyporesponsiveness in the Post-Bundling Era.

RATIONALE & OBJECTIVE: Since the change in erythropoiesis-stimulating agent (ESA) labeling and bundling of dialysis services in the United States, few studies have addressed the clinical importance of ESA hyporesponsiveness and none have considered health care resource use in this population. We aimed to further explore ESA hyporesponsiveness and its consequences. STUDY DESIGN: Retrospective observational cohort study. SETTING & PARTICIPANTS: US Renal Data System Medicare participants receiving dialysis with a minimum 6 months of continuous ESA use from 2012 to 2014. PREDICTORS: Erythropoietin resistance index (≥2.0 U/kg/wk/g/L) and ESA dose were used to identify ESA hyporesponders and hyporesponsive subgroups: isolated, intermittent, and chronic. OUTCOMES: Associations between ESA responsiveness and mortality, cardiovascular hospitalization rates, and health care resource use were evaluated and compared across subgroups. ANALYTICAL APPROACH: Baseline characteristics were compared using Wilcoxon rank sum tests for continuous variables and χ2 tests for categorical variables. Incidence rates of health care resource use were modeled using an unadjusted and adjusted generalized linear model. RESULTS: Of 834,115 dialysis patients in the CROWNWeb database, 38,891 ESA hyporesponders and 59,412 normoresponders met all inclusion criteria. Compared with normoresponders, hyporesponders were younger women, weighed less, and had longer durations of dialysis (all P < 0.001). Hyporesponders received 3.8-fold higher ESA doses (mean, 94,831 U/mo) and erythropoietin resistance index was almost 5 times higher than in normoresponders. Hyporesponders had lower hemoglobin levels and parathyroid hormone levels > 800 pg/mL, and iron deficiency was present in 26.5% versus 10.9% in normoresponders. One-year mortality was higher among hypo- compared with normoresponders (25.3% vs 22.6%). Hyporesponders also had significantly higher rates of hospitalization for cardiovascular events, emergency department visits, inpatient stays, home health agency visits, skilled nursing facility, and hospice days. LIMITATIONS: Only US Medicare patients were included and different hyporesponder definitions may have influenced the results. CONCLUSIONS: This study explored ESA hyporesponsiveness using new definitions and incorporated clinical and economic outcomes. It established that ESA-hyporesponsive dialysis patients had higher mortality, cardiovascular hospitalization rates, and health care costs as compared with ESA-normoresponsive patients.

Health-related quality of life in Parkinson's: impact of 'off' time and stated treatment preferences.

PURPOSE: Long-term levodopa therapy and related fluctuating plasma concentrations are associated with between-dose periods of 'off time' resulting in substantial variation in symptoms and functioning throughout the day in people with Parkinson's (PwP). METHODS: PwP across UK, France, Spain and Italy completed an online survey to explore: the impact of 'off time' on (1) health-related quality of life (HRQL) and (2) on functioning and ability to undertake usual activities; (3) the value of 'off time' relative to other factors associated with Parkinson's through a stated preference discrete choice experiment (SPDCE). RESULTS: In total, 305 PwP completed the online survey. Overall mean HRQL (utility) score was significantly lower for 'off time' (0.37) than for 'on time' (0.60). All attributes within the SPDCE were significant predictors of treatment choice, although increased duration of 'on time' (per hour per day: odds ratio (OR) = 1.40) and predictability of 'off time' to within 30 min (OR = 1.42) were valued most highly. CONCLUSIONS: 'On time' and predictability of 'off time' are highly valued by PwP. Due to substantial diurnal variation of Parkinson's symptoms, standard patient-reported outcome (PRO) assessments may not adequately capture the impact of 'off time' on HRQL and participation in daily activities.

Clinical Outcomes After Insulin Initiation in Patients with Type 2 Diabetes: 24-Month Results from INSTIGATE.

INTRODUCTION: To examine changes in insulin regimens and glycemic control during the 24 months after initiation of insulin in patients with type 2 diabetes mellitus. METHODS: Data were collected over a 24-month period from patients requiring insulin initiation as part of usual care, in a prospective, observational study. Changes in insulin regimens and hemoglobin A(1c) (HbA(1c)) were examined within countries (Germany, Greece, Spain) and overall. RESULTS: Prandial insulin only was most commonly initiated in Germany, while basal or premixed formulations were initiated in Greece and Spain. In Germany, compared with Greece or Spain, the patients were slightly younger and had a shorter diabetes duration when initiating insulin. For patients overall, 76.1% did not change their insulin regimen between initiation and 24 months. The most obvious change was a shift from prandial to basal/bolus in Germany, with almost doubling of mean daily insulin dose; in Greece and Spain, more patients stopped using insulin and the trend to more complex regimens was not seen. Overall, mean (SD) HbA(1c) decreased from baseline (9.4 [1.7]%) to 6 months (7.2 [1.0]%), but with little further change through 24 months (7.2 [1.1]%). HbA(1c) change with basal/bolus insulin (-2.6 [2.0]%, baseline 10.1%) was greater than with basal only (-2.0 [1.8]%, baseline 9.3%). Mean HbA(1c) less than 7% was achieved and maintained over 24 months in Germany, but was not achieved at any time in Greece or Spain. CONCLUSIONS: Within 24 months of insulin initiation, the majority of patients with type 2 diabetes remained on the same insulin regimen initially instigated, despite the well-established progressive loss of prandial and basal endogenous insulin secretion. Adequate glycemic control was best achieved where insulin dosage adjustments and insulin intensification took place.

Increase in direct diabetes-related costs and resource use in the 6 months following initiation of insulin in patients with type 2 diabetes in five European countries: data from the INSTIGATE study.

BACKGROUND: The purpose of this study was to describe the resource use and associated direct costs of diabetes care for patients with type 2 diabetes mellitus in the 6 months before and after initiation of insulin therapy. METHODS: INSTIGATE is a prospective, noninterventional, multicenter study of patients with type 2 diabetes who were initiating insulin for the first time as part of their usual care in 2006. The study was conducted in France, Germany, Greece, Spain, and the UK, and observed the course of diabetes therapy for up to 6 months. Direct medical costs were evaluated from the national health care system (third-party payer) perspective at 2006 prices. RESULTS: Of the 1153 patients with type 2 diabetes, 1051 (91.2%) had follow-up visits in the 6 months after insulin initiation and were included in the cost analysis. In all countries in our study, mean total direct costs per patient increased in the 6-month follow-up period, compared with the 6-month period prior to insulin initiation, and ranged from €577 in Greece to €1402 in France. The incremental cost of adding insulin treatment ranged from €81 in France to €471 in Spain. CONCLUSION: In all countries, the mean total direct cost of care for diabetes increased after starting insulin. The breakdown of total direct costs by expenditure category varied considerably across countries, reflecting differences in resource use patterns, prices of medical resources, and different health care systems.

Clinical outcomes after insulin initiation in patients with type 2 diabetes: 6-month data from the INSTIGATE observational study in five European countries.

OBJECTIVES: To examine insulin regimens and factors that affect glycaemic control at 6 months after initiation of insulin therapy in patients with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: Information on patients requiring insulin initiation as part of usual care was collected in a prospective, observational, open-label study in five European countries. Univariate and multiple regression analyses were used to investigate factors associated with HbA1c achieved at 6 months. RESULTS: Mean HbA1c for all patients at baseline was 9.6 ± 1.8%. Long/intermediate-acting insulin only was most commonly initiated in France and Spain, while long/intermediate or pre-mixed formulations were initiated in Greece and UK. This was consistent with guidelines used in those countries and there was little change in insulin regimen at 6 months in these countries. In Germany, short-acting insulin only was favoured at baseline and there was a shift towards basal/bolus regimens at 6 months, which reflected the local guidelines for insulin initiation in Germany. Mean HbA1c reduction was greatest in Germany (-2.3%), which was the only country to achieve a mean of <7% at 6 months. In all countries, HbA1c achieved at 6 months was associated with baseline HbA1c. Differences between countries were seen for influence of factors such as BMI, duration of diabetes, insulin regimen, insulin dose and number of oral anti-diabetes drugs on HbA1c achieved. Explained variability for the factors ranged from 5.6% to 22.9%. CONCLUSIONS: Differences in insulin regimen were observed between countries, and appeared to reflect the guidelines and treatment regimens used.