Eosinophil Depletion with Benralizumab for Eosinophilic Esophagitis.

BACKGROUND: Benralizumab is an eosinophil-depleting anti-interleukin-5 receptor α monoclonal antibody. The efficacy and safety of benralizumab in patients with eosinophilic esophagitis are unclear. METHODS: In a phase 3, multicenter, double-blind, randomized, placebo-controlled trial, we assigned patients 12 to 65 years of age with symptomatic and histologically active eosinophilic esophagitis in a 1:1 ratio to receive subcutaneous benralizumab (30 mg) or placebo every 4 weeks. The two primary efficacy end points were histologic response (≤6 eosinophils per high-power field) and the change from baseline in the score on the Dysphagia Symptom Questionnaire (DSQ; range, 0 to 84, with higher scores indicating more frequent or severe dysphagia) at week 24. RESULTS: A total of 211 patients underwent randomization: 104 were assigned to receive benralizumab, and 107 were assigned to receive placebo. At week 24, more patients had a histologic response with benralizumab than with placebo (87.4% vs. 6.5%; difference, 80.8 percentage points; 95% confidence interval [CI], 72.9 to 88.8; P<0.001). However, the change from baseline in the DSQ score did not differ significantly between the two groups (difference in least-squares means, 3.0 points; 95% CI, -1.4 to 7.4; P = 0.18). There was no substantial between-group difference in the change from baseline in the Eosinophilic Esophagitis Endoscopic Reference Score, which reflects endoscopic abnormalities. Adverse events were reported in 64.1% of the patients in the benralizumab group and in 61.7% of those in the placebo group. No patients discontinued the trial because of adverse events. CONCLUSIONS: In this trial involving patients 12 to 65 years of age with eosinophilic esophagitis, a histologic response (≤6 eosinophils per high-power field) occurred in significantly more patients in the benralizumab group than in the placebo group. However, treatment with benralizumab did not result in fewer or less severe dysphagia symptoms than placebo. (Funded by AstraZeneca; MESSINA ClinicalTrials.gov number, NCT04543409.).

Benralizumab does not elicit therapeutic effect in patients with chronic spontaneous urticaria: results from the phase IIb multinational randomized double-blind placebo-controlled ARROYO trial.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a relatively common skin disease associated with hives and angio-oedema. Eosinophils play a role in CSU pathogenesis. Benralizumab, an anti-interleukin-5 receptor-α monoclonal antibody, has been shown to induce nearly complete depletion of eosinophils. OBJECTIVES: To determine the clinical efficacy and safety of benralizumab in patients with CSU who were symptomatic despite H1 antihistamine treatment. METHODS: The 24-week, randomized, double-blind, placebo-controlled, phase IIb portion of the ARROYO trial enrolled adult patients with CSU who were currently on H1 antihistamine treatment. Patients were randomized to one of five treatment groups according to benralizumab dose and regimen for a 24-week treatment period. The primary endpoint was change from baseline in Itch Severity Score (ISS)7 at week 12. The key secondary endpoint was change from baseline in Urticaria Activity Score (UAS)7 at week 12. Additional secondary endpoints included other metrics to assess CSU at week 24, blood eosinophil levels, and pharmacokinetics and immunogenicity assessments. Exploratory subgroup analyses were conducted to explore responses according to demographics, clinical features and biomarkers. Safety was assessed in all treatment groups. RESULTS: Of 155 patients, 59 were randomized to benralizumab 30 mg, 56 to benralizumab 60 mg and 40 to placebo. Baseline and disease characteristics were consistent with what was expected for patients with CSU. There were no significant differences in change from baseline in ISS7 score at week 12 between benralizumab and placebo [benralizumab 30 mg vs. placebo, least-squares mean difference -1.01, 95% confidence interval (CI) -3.28 to 1.26; benralizumab 60 mg vs. placebo, least-squares mean difference -1.79, 95% CI -4.09 to 0.50] nor in change from baseline in UAS7 score at week 12 between benralizumab and placebo (benralizumab 30 mg vs. placebo, P = 0.407; benralizumab 60 mg vs. placebo, P = 0.082). Depletion of blood eosinophil levels was observed at week 24 in patients treated with benralizumab. All other secondary endpoints and exploratory/subgroup analyses indicated no significant differences between benralizumab and placebo. Safety results were consistent with the known profile of benralizumab. CONCLUSIONS: Although benralizumab resulted in near-complete depletion of blood eosinophils, there was no clinical benefit over placebo.

Chronic spontaneous urticaria (CSU) is a common disease characterized by hives, itching and inflammation (swelling) of the skin. CSU is mainly driven by what we call 'mast cells'. 'Eosinophils' are a type of white blood cell that protect the body from infections and allergens. These cells are abundant in skin biopsy samples of people with CSU, especially in the hives that contribute to swelling. Therefore, we thought that reducing eosinophils would be beneficial for treating CSU. Benralizumab is a drug that has been shown to reduce eosinophils in other diseases. This study, called 'ARROYO', was a 24-week clinical trial that compared benralizumab treatment with a placebo (inactive medicine) in adults with CSU who were taking antihistamines. We aimed to determine whether benralizumab would improve symptoms of CSU over time. Several assessments were used to measure changes in CSU symptoms, including hives, severity of itchiness, swelling of the skin, and other aspects related to overall psychological and physical wellbeing. The characteristics of the 155 people who took part in this study were consistent with what was expected for patients with CSU. We found that while benralizumab reduced eosinophil levels in people with CSU, there were no differences in symptoms in people receiving benralizumab compared with those receiving placebo. There were no new safety concerns related to benralizumab and no deaths. Overall, although benralizumab is effective at reducing the number of eosinophils, it is not effective at treating the symptoms of CSU. More studies are needed to uncover potential treatment targets in CSU.

A Randomized, Multicenter, Prospective, Crossover, Open-Label Study of Factors Associated With Patient Preferences for Naloxegol or PEG 3350 for Opioid-Induced Constipation.

OBJECTIVES: To determine patient preference for treating opioid-induced constipation (OIC) using naloxegol or polyethylene glycol (PEG) 3350 in patients receiving opioids for noncancer pain. METHODS: This crossover study included two 2-week active treatment periods, each preceded by a 1-week washout period (NCT03060512). Individuals with baseline Bowel Function Index scores ≥30 were randomized to 1 of 2 treatment sequences (naloxegol/PEG 3350 or PEG 3350/naloxegol). Patient preference (primary end point) was measured at the end of the second treatment period. RESULTS: Of 276 patients randomized, 246 completed both treatment periods and reported preference (per protocol). Similar proportions of patients reported overall preference for naloxegol (50.4%) or PEG 3350 (48.0%; P = 0.92); 1.6% reported no preference. Medication characteristics influencing preference were similar for both treatments, except convenience and working quickly, which were strong influences of preference for higher proportions of patients preferring naloxegol (69.9% and 39.0%, respectively) vs those preferring PEG 3350 (29.9% and 27.4%, respectively). Patients aged <50 years or receiving laxatives within the previous 2 weeks generally preferred naloxegol. Changes from baseline in overall Bowel Function Index and Patient Global Impression of Change scores were similar between treatments, but analyses according to treatment preference revealed clinical improvement aligned with reported preference. Safety profiles were generally consistent with known medication profiles. CONCLUSIONS: Almost equal proportions of patients with OIC reported similar preference for daily naloxegol or PEG 3350 treatment, and their preference was generally supported by clinically relevant and measurable improvements in OIC symptoms.

Impact of opioid-induced constipation on healthcare resource utilization and costs for cancer pain patients receiving continuous opioid therapy.

PURPOSE: Opioid therapy is often associated with adverse effects, including opioid-induced constipation (OIC), in patients receiving opioids for cancer pain. This retrospective observational cohort study evaluated healthcare utilization and costs during the first year after initiating opioid therapy among cancer patients with (cohort 1) and without (cohort 2) constipation. METHODS: This study used administrative claims data from the HealthCore Integrated Research Environment between January 1, 2006, and April 30, 2014. Eligible patients included adults ≥ 18 years with a diagnosis of cancer who initiated continuous opioid therapy (≥ 30 days). Propensity scores were used to match patients with constipation in a 1:1 ratio to those without constipation. Generalized linear models were used to evaluate healthcare utilization and costs during the 12 months after initiating opioid therapy. RESULTS: After matching, 1369 patients were included in each cohort. Patients with constipation were more than twice as likely as those without constipation to have an all-cause inpatient hospitalization (odds ratio [95% confidence interval (CI)], 2.47 [2.11-2.90]), or pain-related hospitalization (2.15 [1.82-2.54]) during the 12 months after initiating therapy. Mean unadjusted overall healthcare costs during the first 12 months post-index were $21,629 (95% CI, $14,850-$29,018) higher for patients with constipation than for those without constipation. For patients with constipation, total mean (SD) constipation-related costs were $9196 ($26,896). CONCLUSIONS: These results suggest that OIC is associated with significantly increased healthcare and economic burden in cancer pain patients and that early and ongoing recognition and management of OIC are unmet needs in this population.

Analysis of Patient-Provider Interactions Regarding the Burden and Treatment of Opioid-Induced Constipation in Adults with Chronic Noncancer Pain.

OBJECTIVE: This analysis of patient-health care provider discussions of opioid-induced constipation (OIC) evaluated the dynamics of interactions, identified communication gaps, and assessed the functional burden of opioid-induced constipation on patients' lives. DESIGN: Retrospective analysis of a Health Insurance Portability and Accountability Act-compliant database of >120,000 patient-provider conversations. SETTING: Outpatient offices in the United States. METHODS: Conversations between providers and patients prescribed opioids that occurred in the United States (January 2014-May 2016) and included a discussion of opioid-induced constipation were identified. Demographics and prespecified opioid-induced constipation conversation characteristics were evaluated for these conversations. RESULTS: This analysis included 216 patient-provider discussions. Most patients (76.4% [165/216]) were ≥50 years old. Most conversations were with pain management specialists (39.8% [86/216]) or primary care physicians (36.6% [79/216]). Overall, 64.4% (139/216) of patients reported experiencing symptoms of constipation. Health care providers indicated that symptoms of constipation could be caused by opioid use for 75.5% (105/139) of patients with constipation. In most cases (82.4% [178/216]), providers did not probe about specific constipation symptoms. Few patients (11.5% [16/139]) with OIC discussed the burden of OIC with their providers; burdens reported by patients with OIC included emergency room visits and reduced food or fluid intake. No specific action was recommended for 33.8% (47/139) of patients with constipation. CONCLUSIONS: In this analysis, when opioid-induced constipation was discussed, health care providers did not inquire about specific symptoms for most patients, opioids were not cited as a cause of constipation in approximately one-quarter of patients with opioid-induced constipation, and no clear treatment plan or guidance was recommended for one-third of patients. Results of this analysis suggest that more education may be needed to improve patient-provider communication about opioid-induced constipation.

The Burden of Opioid-Induced Constipation in Younger Patients with Chronic Noncancer Pain.

Objective: The purpose of this analysis was to evaluate the experience of opioid-induced constipation in younger patients and identify differences in the experience of opioid-induced constipation and its symptoms between younger patients (<50 years) and older patients (50-64 years). Design: Post hoc analysis of data from a 24-week prospective, multinational, longitudinal observational cohort study (NCT01928953). Setting: Outpatient clinics in the United States, Canada, Germany, and United Kingdom. Subjects: Two age-based subgroups of adult patients with chronic noncancer pain receiving four or more weeks of daily opioid therapy and experiencing opioid-induced constipation within the previous two weeks. Methods: The number of spontaneous bowel movements, frequency of constipation symptoms, amount of bother associated with symptoms, Patient Assessment of Constipation-Symptoms questionnaire, and health-related quality of life and function outcomes. Results: Overall, 419 patients were included in this analysis (younger patients, N = 184; older patients, N = 235). Among younger and older patients, respectively, constipation occurred within the first week after initiating opioid therapy for 32.8% and 35.9%. At baseline, the mean numbers of spontaneous bowel movements/week were 1.3 and 1.5, and moderate opioid-induced constipation-related interference with pain management was reported by 46.6% and 44.5%. Younger patients generally reported that opioid-induced constipation symptoms were more bothersome than did older patients. The impact of opioid-induced constipation on health-related quality of life, work productivity, and day-to-day activities was comparable. Conclusions: In these patients receiving opioid therapy for chronic noncancer pain, the burden of opioid-induced constipation was comparable or greater for patients aged <50 years compared with that for patients aged 50-64 years.

Clinical and Functional Characteristics of Nursing Facility Residents with Opioid-Induced Constipation.

OBJECTIVE: Our goal was to determine the prevalence, clinical characteristics, and treatment differences of opioid-induced constipation (OIC) in older adults with noncancer pain compared with opioid-treated patients without OIC. DESIGN: Retrospective database analysis. SETTING: United States nursing facilities: Patients, Participants, facility residents. INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): Minimum data set and prescription claims, pain, impaired cognition, falls, delirium, and drug treatment. RESULTS: We found an OIC prevalence of 8.9%. Nursing facility residents with OIC are more likely to have severe pain (31.3% vs. 29%; P < 0.001), pain in the last 5 days (71.2% vs. 69.2%; P < 0.001), almost constant pain (18.1% vs.13.3%; P < 0.001), and pain interfering with daily activities (36.1% vs. 30%; P < 0.001). Strong opioids were more likely prescribed and the duration of use was longer than in non-OIC nursing facility residents. Cognitive impairment (56.3% vs. 49.8%; P < 0.001), fall rate (4.8% vs. 2.5%; P = 0.023), delirium indicators (confusion assessment method; P < 0.001), urinary incontinence (59.1% vs. 54.9%; P < 0.001), depression (66.5% vs. 61.6%; P < 0.001), and depression severity score (4.7% vs. 4.3%; P < 0.001) were higher in nursing facility residents with OIC. Nursing facility residents with OIC had a higher percentage of concomitantly prescribed anticholinergic medications (76.7% vs. 70.0%; P < 0.001) and a higher mean anticholinergic burden score (1.4% vs. 1.1%; P < 0.001). Over-the-counter laxatives were used more often than prescription laxatives: polyethylene glycol (43%), docusate (31.1%), and senna/sennosides (23%) vs. lactulose (18.1%) and lubiprostone (2.2%). CONCLUSION: Nursing facility residents with OIC experience suboptimal pain relief, additional anticholinergic adverse drug-related effects, and a decreased quality of life.

Bipolar II compared with bipolar I disorder: baseline characteristics and treatment response to quetiapine in a pooled analysis of five placebo-controlled clinical trials of acute bipolar depression.

BACKGROUND: Bipolar I and II represent the most common and severe subtypes of bipolar disorder. Although bipolar I disorder is relatively well studied, the clinical characteristics and response to treatment of patients with bipolar II disorder are less well understood. METHODS: To compare the severity and burden of illness of patients with bipolar II versus bipolar I disorder, baseline demographic, clinical, and quality of life data were examined in 1900 patients with bipolar I and 973 patients with bipolar II depression, who were enrolled in five similarly designed clinical placebo-controlled trials of quetiapine immediate-release and quetiapine extended-release. Acute (8 weeks) response to treatment was also compared by assessing rating scale scores, including Montgomery-Åsberg depression rating scale, Hamilton rating scale for anxiety, Young mania rating scale, and clinical global impression-severity scores, in the bipolar I and II populations in the same pooled database. RESULTS: Patients with bipolar I and bipolar II depression were similar in demographics, baseline rating scale scores (depression, anxiety, mania, and quality of life), and mood episode histories. Symptom improvements in response to quetiapine were greater versus comparators (lithium, paroxetine, and placebo) at 4 and 8 weeks in both bipolar I and II patients. Patients with the bipolar II subtype initially showed slower responses to all treatments, but, by 8 weeks, attained similar symptom improvement as patients with bipolar I depression. CONCLUSIONS: Pooled analysis of five clinical trials of quetiapine demonstrated that patients with bipolar II depression have a similar burden of illness and quality of life to patients with bipolar I. Bipolar II patients consistently showed a slower response to treatments than bipolar I patients, but, after 8 weeks of treatment with quetiapine, symptom improvements were similar between bipolar I and II disorder subtypes.

Impact of concomitant low-dose aspirin on the safety and tolerability of naproxen and esomeprazole magnesium delayed-release tablets in patients requiring chronic nonsteroidal anti-inflammatory drug therapy: an analysis from 5 Phase III studies.

Patients receiving chronic nonsteroidal anti-inflammatory drugs (NSAIDs) and concomitant low-dose aspirin (LDA) are at increased risk of gastrointestinal (GI) toxicity. A fixed-dose combination of enteric-coated (EC) naproxen and immediate-release esomeprazole magnesium (NAP/ESO) has been designed to deliver a proton-pump inhibitor followed by an NSAID in a single tablet. To examine safety data from 5 Phase III studies of NAP/ESO in LDA users (≤ 325 mg daily, administered at any time during the study), and LDA non-users, data were analyzed from 6-month studies assessing NAP/ESO versus EC naproxen in patients with osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis (n = 2), 3-month studies assessing NAP/ESO vs celecoxib or placebo in patients with knee osteoarthritis (n = 2), and a 12-month, open-label, safety study of NAP/ESO (n = 1). In an analysis of two studies, incidences of endoscopically confirmed gastric ulcers (GUs) and duodenal ulcers (DUs) were summarized by LDA subgroups. In the pooled analysis from all five studies, incidences of treatment-emergent adverse events (AEs) (including prespecified NSAID-associated upper GI AEs and cardiovascular AEs), serious AEs, and AE-related discontinuations were stratified by LDA subgroups. Overall, 2,317 patients received treatment; 1,157 patients received NAP/ESO and, of these, 298 received LDA. The cumulative incidence of GUs and DUs in the two studies with 6-month follow-up was lower for NAP/ESO vs EC naproxen in both LDA subgroups [GUs: 3.0 vs 27.9%, respectively, for LDA users, 6.4 vs 22.4%, respectively, for LDA non-users (both P < 0.001); DUs: 1.0 vs 5.8% for LDA users, 0.6 vs 5.3% for LDA non-users]. The incidence of erosive gastritis was lower in NAP/ESO- vs EC naproxen-treated patients for both LDA users [18.2 vs 36.5%, respectively (P = 0.004)] and LDA non-users [19.8 vs 38.5%, respectively (P < 0.001)]. Among LDA users, incidences of NSAID-associated upper GI AEs were: NAP/ESO, 16.1%; EC naproxen, 31.7%; celecoxib, 22.1%; placebo, 23.2%. Among LDA non-users, incidences of NSAID-associated upper GI AEs were: NAP/ESO, 20. %; EC naproxen, 36.6%; celecoxib, 18.5%; placebo, 18.9%. For LDA users, incidences of cardiovascular AEs were: NAP/ESO, 3.0%; EC naproxen, 1.0%; celecoxib, 0%; placebo, 0%. For LDA non-users, incidences of cardiovascular AEs were: NAP/ESO, 1.0%; EC naproxen, 0.6%; celecoxib, 0.3%; placebo, 0%. NAP/ESO appears to be well-tolerated in patients receiving concomitant LDA. For LDA users, AE incidence was less than that observed for EC naproxen. For most AE categories, incidences were similar among NAP/ESO, celecoxib and placebo groups. The safety of NAP/ESO appeared similar regardless of LDA use.

Treating moderate-to-severe atopic dermatitis with benralizumab: results from the HILLIER study, a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: Atopic dermatitis (AD) is a chronic (long-lasting) skin disease that leads to dry, itchy, and swollen red spots, which can also be painful and flare up at any time. Some people with AD have a high number of eosinophils, a type of white blood cell, which are associated with worse disease. Medicated creams and lotions, prescribed by health care providers, are meant to reduce the symptoms of AD. For some people, these creams and lotions do not work. Benralizumab injection is a medication that reduces and removes eosinophils. A clinical trial called HILLER tested benralizumab to see if there was a difference in symptoms of AD after reducing or removing eosinophils. This article explains how benralizumab reduced eosinophils and the effect it had on AD symptoms in the HILLIER study. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: Benralizumab reduced blood eosinophil numbers. However, benralizumab showed no evidence of treatment benefit on signs, symptoms, or severity of AD, as measured by three skin assessments compared with placebo. Benralizumab was well tolerated and had a safety profile that was consistent with previous studies. The five most commonly reported side effects were COVID-19 infection, upper respiratory tract infection, headache, swelling of the lymph nodes, and pink eye (conjunctivitis) in patients who received either benralizumab or placebo. WHAT ARE THE KEY TAKEAWAYS?: Benralizumab lowered the number of blood eosinophils without improving AD symptoms and was well tolerated.

Randomized, double-blind study of the efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) monotherapy in elderly patients with major depressive disorder.

OBJECTIVES: This study assessed the efficacy and tolerability of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in elderly patients with major depressive disorder (MDD). DESIGN: An 11-week (9-week randomized; 2-week posttreatment phase), double-blind, placebo-controlled, Phase III study (D1448C00014). SETTING: A total of 53 centers in Argentina, Estonia, Finland, Russia, Ukraine, and the United States. PARTICIPANTS: A total of 338 patients (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of MDD, age ≥66 years, Hamilton Rating Scale for Depression [HAM-D] total score ≥22, HAM-D Item 1 [depressed mood] score ≥2) were randomized (mean age: 71.3 years). INTERVENTION: Patients were randomized to quetiapine XR (n = 166; flexible-dosing 50-300 mg/day) or placebo (n = 172). MEASUREMENTS: Primary outcome was Montgomery Åsberg Depression Rating Scale (MADRS) total score change from randomization at Week 9. RESULTS: At Week 9, quetiapine XR (least squares [LS] means: -16.33, standard error [SE]: 0.95; mean change: -16.0, standard deviation [SD]: 9.3) significantly reduced MADRS total score from randomization versus placebo (LS means [SE]: -8.79 [0.94]; mean [SD]: -9.0 [9.9]); significant improvements were also seen at Week 1 (LS means [SE]: -4.65 [0.53] versus -2.56 [0.53], respectively; mean [SD]: -4.3 [5.1] versus -2.4 [3.7], respectively). At Week 9, secondary outcome variables significantly improved with quetiapine XR versus placebo, including MADRS response (≥50% reduction in total score); MADRS remission (total score ≤8); HAM-D total, HAM-A total, HAM-A psychic and somatic cluster, and Clinical Global Impressions-Severity of Illness (CGI-S) total scores; proportion of patients with CGI-Improvement score of 2 or less; Q-LES-Q-SF% maximum total, Pittsburgh Sleep Quality Index global, and pain Visual Analog Scale scores. Common adverse events (>10% patients with quetiapine XR) were somnolence, headache, dry mouth, and dizziness. CONCLUSION: In elderly patients with MDD, quetiapine XR monotherapy (50-300 mg/day, flexibly dosed) is effective at improving depressive symptoms, with symptom improvement observed as early as Week 1. Overall tolerability and safety were consistent with the known profile of quetiapine.

Double-blind, randomized study of extended release quetiapine fumarate (quetiapine XR) monotherapy in older patients with generalized anxiety disorder.

OBJECTIVE: The objective of the study was to evaluate once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in older patients with generalized anxiety disorder (GAD). METHODS: An 11-week (9-week treatment; 2-week posttreatment), randomized, double-blind, placebo-controlled study (D1448C00015) of flexibly-dosed quetiapine XR (50-300 mg/day) or placebo conducted at 47 sites (Estonia, Poland, Russia, Ukraine, and USA) between September 2006 and April 2008. Patients (≥66 years) with DSM-IV diagnosis of GAD, Hamilton Anxiety Rating Scale (HAM-A) total score of ≥20 with item 1 (anxious mood) and 2 (tension) scores of ≥2, Clinical Global Impressions-Severity of Illness (CGI-S) score of ≥4, and Montgomery Åsberg Depression Rating Scale (MADRS) total score of ≤16 were eligible for inclusion. Primary endpoint: week 9 change from randomization in HAM-A total score. RESULTS: Patients were randomized to quetiapine XR (n = 223) or placebo (n = 227). At week 9, quetiapine XR significantly reduced HAM-A total score versus placebo (least squares mean -14.97 versus -7.21; p < 0.001); symptom improvement with quetiapine XR versus placebo was significant at week 1 (p < 0.001). At week 9, quetiapine XR demonstrated significant benefits over placebo for HAM-A response and remission rates, HAM-A psychic and somatic cluster, MADRS total, CGI-S, Pittsburgh Sleep Quality Index global, pain visual analog scale, and Quality of Life, Enjoyment and Satisfaction Questionnaire short form % maximum total scores and Clinical Global Impressions-Improvement (% patients with a score of 1/2) (all p < 0.001). Adverse events (>5% in either treatment group) included somnolence, dry mouth, dizziness, headache, and nausea. CONCLUSIONS: Quetiapine XR (50-300 mg/day) monotherapy is effective in the short term in improving symptoms of anxiety in older patients with GAD, with symptom improvement seen as early as week 1. Tolerability findings were generally consistent with the known profile of quetiapine.

Characteristics, treatment patterns, health care resource utilization and costs in patients with bullous pemphigoid: A retrospective analysis of US health insurance claims data.

Background: Real-world data describing the impact of incident bullous pemphigoid (BP) on patients and health care resource utilization (HCRU) are limited. Objective: To examine characteristics, treatment patterns, HCRU, and costs for incident BP. Methods: Retrospective analysis of 2015 to 2019 US health insurance claims for patients ≥18 years with an incident BP diagnosis. Patients with BP were matched to those without on demographic and clinical characteristics. Statistics were descriptive. Results: The mean Charlson Comorbidity Index score was higher for patients with BP (n = 1108) than without (n = 4621) at baseline (mean [SD]: 3.3 [2.7] vs 2.8 [2.4]) and during follow-up (5.0 [4.9] vs 3.7 [3.0]). Hypertension, diabetes, skin ulcers, chronic pulmonary disease, dyslipidemia, sleep disorders, and congestive heart failure were higher with BP. Most patients with BP received antibiotics (>80%) and/or corticosteroids (>90%). Hospitalizations were more common (44.0% vs 17.1%) and monthly all-cause health care costs more than double ($3214 vs $1353) in patients with BP than without. Limitations: Diagnoses were based on billing codes. HCRU claims data may not reflect the true number of encounters. Conclusion: Incident BP is associated with considerable morbidity, HCRU, and costs. More effective, targeted treatments are needed to improve quality of life, while minimizing exposure to systemic corticosteroids.

Trends for incidence of hospitalization and death due to GI complications in the United States from 2001 to 2009.

OBJECTIVES: Studies from the 1990s through mid-2000s report variable decreases in upper gastrointestinal (UGI) complications and differ regarding changes in lower gastrointestinal (LGI) complications. We determined incidence and case fatality of hospitalizations for GI complications in the United States over the past decade. METHODS: We used a national inpatient database to calculate yearly projections from 2001-2009 for incidence and case fatality of hospitalizations with primary discharge diagnoses of UGI and LGI complications (bleeding, perforation, and obstruction) and of undefined GI bleeding. RESULTS: Age/sex-adjusted incidence of GI complications decreased non-significantly from 236.1 to 223.7/100,000 population from 2001-2009. Components were UGI complications (85.0 to 66.0/100,000), LGI complications (100.3 to 104.4/100,000), and undefined bleeding (50.8 to 53.3/100,000). Decreases were seen in UGI bleeding (78.4 to 60.6/100,000), peptic ulcer bleeding (48.7 to 32.1/100,000), LGI bleeding (41.8 to 35.7/100,000), and colonic diverticular bleeding (30.4 to 23.9/100,000), whereas LGI obstruction increased (55.0 to 66.0/100,000). Age/sex-adjusted case fatality decreased from 3.78 to 2.70%. 2009 case fatality rates were 2.45% for UGI bleeding, 3.00% for undefined bleeding, 1.47% for LGI bleeding, 2.30% for LGI obstruction, 10.7% for UGI perforation, and 16.0% for LGI perforation. Case fatality increased with age, but was 3.54% in patients >75 years with bleeding or obstruction. CONCLUSIONS: Hospitalizations for UGI complications are decreasing in the United States owing to a decrease in UGI bleeding. LGI complications are relatively stable, with a decrease in LGI bleeding and a larger increase in LGI obstruction. Case fatality owing to bleeding or obstruction is low, increasing with age but remaining <5% even in the elderly.

Development and content validation of a symptom assessment for eosinophilic gastritis and eosinophilic gastroenteritis in adults and adolescents.

BACKGROUND: A patient reported outcome (PRO) instrument with evidence of validity and reliability for assessing symptoms of eosinophilic gastritis (EG) and eosinophilic gastroenteritis (EGE) is needed to measure treatment benefit in clinical trials. The aim of this research is to develop an EG/EGE symptom PRO instrument for patients aged 12 and above. METHODS: The Symptom Assessment for Gastrointestinal Eosinophilic Diseases (SAGED) was developed through a literature review, discussions with expert clinicians, and concept elicitation and cognitive debriefing interviews with patients. Patients (n = 28) were recruited based on confirmed diagnosis and self-reported symptoms. The final instrument was translated and linguistically validated with additional cognitive debriefing interviews (n = 105). RESULTS: SAGED is a 24-h recall questionnaire consisting of eight items evaluating the core symptoms of EG and EGE (abdominal pain, nausea, bloating, early satiety, loss of appetite, vomiting, and diarrhea). Seven of the eight items are evaluated on an 11-point numerical rating scale ranging from 'none' to 'worst imaginable'. Cognitive debriefing interviews showed that adults and adolescents understand the content and are able to select a response that reflects their experience. The linguistic validation process produced 21 translations that are understandable to patients and conceptually equivalent to the source version. CONCLUSIONS: SAGED is suitable for measuring symptom improvement in adult and adolescent patients with EG and/or EGE. The content validity of SAGED has been established through best practices in qualitative research for PRO instrument development. The psychometric properties of SAGED will be evaluated in a future study.

Extended-release quetiapine fumarate (quetiapine XR) as adjunctive therapy in major depressive disorder (MDD) in patients with an inadequate response to ongoing antidepressant treatment: a multicentre, randomized, double-blind, placebo-controlled study.

This study evaluated once-daily extended-release quetiapine fumarate (quetiapine XR) as adjunctive therapy in patients with major depressive disorder (MDD) with inadequate response to ongoing antidepressant treatment. In this 8-wk (6-wk active treatment/2-wk post-treatment drug-discontinuation/follow-up), multicentre, double-blind, placebo-controlled, Phase III study, 446 patients were randomized to quetiapine XR 150 mg/d, 300 mg/d, or placebo adjunct to ongoing antidepressant treatment. The primary endpoint was the change from randomization to week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) total score. At week 6, MADRS total scores significantly improved with quetiapine XR 300 mg/d vs. placebo (-14.7 vs. -11.7, p<0.01). Quetiapine XR 300 mg/d showed significant improvements vs. placebo for: MADRS total score from week 1 onwards; MADRS response [(> or = 50% total score reduction) 58.9% vs. 46.2%, p<0.05] and remission [(total score < or = 8) 42.5% vs. 24.5%, p<0.01] rates; Hamilton Depression Rating Scale (HAMD) (-13.53 vs. -10.80, p<0.01) and Clinical Global Impression-Severity of illness (CGI-S) change (-1.52 vs. -1.23, p<0.05) at week 6. For quetiapine XR 150 mg/d, improvements were not significantly different vs. placebo, except for MADRS (weeks 1 and 2) and HAMD (week 6) total scores. Withdrawal rates due to adverse events (AEs) were: quetiapine XR 150 mg/d 11.5%, 300 mg/d 19.5%, and placebo 0.7%. The most common AEs (>10%) with quetiapine XR were dry mouth, somnolence, sedation, dizziness, constipation, nausea, insomnia, headache, and fatigue. In this study, quetiapine XR 300 mg/d as adjunctive therapy in patients with MDD with an inadequate response to ongoing antidepressant treatment was effective at week 6. However, the difference from placebo for quetiapine XR 150 mg/d at week 6 was not statistically significant. Both doses studied (150 and 300 mg/d) were effective at week 1 and generally well tolerated.

Efficacy and tolerability of extended release quetiapine fumarate monotherapy as maintenance treatment of major depressive disorder: a randomized, placebo-controlled trial.

PRIMARY OBJECTIVE: evaluate the efficacy (time to recurrence of depressive symptoms) of once daily extended release quetiapine fumarate (quetiapine XR) as maintenance monotherapy treatment to prevent relapse for major depressive disorder (MDD). METHODS: Time-to-event (maximum 52 weeks), double-blind, multicenter, randomized withdrawal, placebo-controlled study of quetiapine XR (50-300 mg/day) comprising four treatment phases: enrollment (up to 28 days), open-label run-in (4-8 weeks), open-label stabilization (12-18 weeks), and randomization (up to 52 weeks). Seven hundred and seventy-six patients stabilized on quetiapine XR were eligible for randomization (Montgomery-Åsberg Depression Rating Scale [MADRS] score ≤12 and Clinical Global Impression-Severity of Illness [CGI-S] score ≤3); 391 received quetiapine XR and 385 received placebo (same dose as last open-label visit). Primary endpoint: time to recurrence of depressive event from randomization. Secondary outcomes included changes from randomization in MADRS total, CGI-S, Pittsburgh Sleep Quality Index (PSQI) global, and Hamilton Anxiety Rating Scale (HAM-A) total scores. Adverse events were recorded throughout. RESULTS: Risk of recurrence of depressive event was significantly (P<.001) reduced by 66% (HR=.34; 95% CI: .25, .46) in patients randomized to continue with quetiapine XR versus patients randomized to switch to placebo. During the randomized phase, quetiapine XR maintained improvements in secondary outcomes (P<.001 for all): MADRS (0.15 versus 2.03), CGI-S (-0.03 versus 0.23); PSQI global (0.06 versus 1.35), and HAM-A total score (0.20 versus 1.58), respectively. The most common AEs (>10% any group) during the randomized period were headache and insomnia. CONCLUSIONS: Quetiapine XR maintenance therapy significantly reduced the risk of a depressive event in patients with MDD stabilized on quetiapine XR, with a safety and tolerability profile consistent with the known profile of quetiapine.

Impact of opioid use on patients undergoing screening colonoscopy according to the quality of bowel preparation.

AIMS: Constipation associated with opioid therapy for chronic pain may negatively impact colonoscopy success. This retrospective, observational study using administrative data and electronic medical records evaluated the impact of opioid use on colonoscopy outcomes. METHODS AND RESULTS: Procedural codes were used to identify patients who had a screening colonoscopy at two Henry Ford Health System centers (January 2015-December 2016). All patients had completed a standard uniform bowel preparation protocol. Medication orders and filled prescriptions were used to identify patients with a history of opioid use during the 28 days preprocedure (exposed) and a matched random sample of presumptive opioid nonusers (unexposed). Electronic medical records were reviewed for colonoscopy procedure data and outcomes.The exposed and unexposed groups included 964 and 1054 patients, respectively. Inadequate bowel preparation was significantly more common in the exposed versus unexposed group (18.5% vs 12.7%; P < 0.001). In the exposed and unexposed groups, 97.1 and 98.0% of colonoscopy procedures were completed, respectively (P = nonsignificant). Total procedure time was slightly increased for the exposed versus unexposed group (23.8 vs 22.5 min; P = 0.039). Polyp identification and cancer diagnosis were similar between groups. Prolonged sedation occurred in three patients in the exposed group and none in the unexposed group. Procedural complications were rare, but the incidence was significantly greater in the exposed versus unexposed group (1.3% vs 0.2%; P < 0.01). CONCLUSIONS: Opioid exposure was associated with significant reductions in the quality of preprocedure bowel preparation and an increased risk of complications in patients undergoing colonoscopy.

Self-reported sedation profile of immediate-release quetiapine fumarate compared with extended-release quetiapine fumarate during dose initiation: a randomized, double-blind, crossover study in healthy adult subjects.

OBJECTIVES: The primary study objective was to assess the time course and intensity of sedation after administration of immediate-release (IR) and extended-release (XR) quetiapine fumarate in healthy subjects during dose initiation. The tolerability of the 2 formulations was also evaluated. METHODS: This was a randomized, double-blind, double-dummy, 2-period crossover study in healthy adult (age 18-50 years) subjects. It employed the dose-initiation schedule used in studies of the 2 quetiapine formulations in patients with bipolar depression: 50 mg on day 1, 100 mg on day 2, 200 mg on day 3, and 300 mg on days 4 and 5. Doses were administered in the morning. The primary end point was the level of sedation 1 hour after dosing on day 1, as rated by subjects using a visual analog scale (VAS) ranging from 0 = alert to 100 = drowsy. Secondary VAS end points included sedation over a 14-hour period on day 1, and on days 2 through 5. Blood was drawn on day 5 of both periods for determination of plasma drug concentrations by a liquid chromatography method with tandem mass-spectrometric detection. Adverse events (AEs) were recorded throughout the study. RESULTS: Sixty-three subjects were enrolled in the study, comprising the safety population. The perprotocol population consisted of 58 subjects (79.0% male, 21.0% female; 67.2% black, 24.1% white; mean age, 31.8 years; mean weight, 80.7 kg). One hour after dosing on day 1, sedation was significantly greater with quetiapine IR than with quetiapine XR (mean VAS score, 33.2 vs 11.3, respectively; P < 0.001). There were no significant differences in sedation between formulations at 7 hours after dosing (64.5 and 53.6), 8 hours after dosing (46.9 and 50.8), or 14 hours after dosing (both, 12.7). On day 1, numerically more subjects had a VAS score>75 (substantial sedation) 1 hour after dosing in the quetiapine IR group than in the quetiapine XR group (14 vs 4 subjects). On day 5, the mean (95% CI) quetiapine C(max) for the IR and XR formulations was 689.19 (605.83-784.02) and 381.70 (341.40-426.76) ng/mL; the mean was AUC(0-11) was 2835.89 (2517.92-3194.02) and 2515.21 (2281.76--2772.55) ng . h/mL; and the median T(max) was 2.0 and 5.0 hours. The incidence of any AEs was 21.7% with quetiapine IR and 9.8% with quetiapine XR. CONCLUSION: In these healthy subjects, quetiapine XR was associated with a lower intensity of self-reported sedation compared with quetiapine IR. ClinicalTrials.gov Identifier: NCT00702676; Astra Zenecaclinicaltrials.com Identifier: D1443C00033.