Exacerbations and Real-World Outcomes After Single-Inhaler Triple Therapy of Budesonide/Glycopyrrolate/Formoterol Fumarate, Among Patients with COPD: Results from the EROS (US) Study.

Purpose: Triple therapy to prevent exacerbations from chronic obstructive pulmonary disease (COPD) is associated with improved health compared to single and dual-agent therapy in some populations. This study assessed the benefits of prompt administration of budesonide/glycopyrrolate/formoterol fumarate (BGF) following a COPD exacerbation. Patients and methods: EROS was a retrospective analysis of people with COPD using the MORE2 Registry®. Inclusion required ≥1 severe, ≥2 moderate, or ≥1 moderate exacerbation while on other maintenance treatment. Within 12 months following the index exacerbation, ≥1 pharmacy claim for BGF was required. Primary outcomes were the rate of COPD exacerbations and healthcare costs for those that received BGF promptly (within 30 days of index exacerbation) versus delayed (31-180 days) and very delayed (181-365 days). The effect of each 30-day delay in initiation of BGF was estimated using a multivariable negative binomial regression model. Results: 2409 patients were identified: 434 prompt, 1187 delayed, and 788 very delayed. The rate (95% CI) of total exacerbations post-index increased as time to BGF initiation increased: prompt 1.52 (1.39-1.66); delayed 2.00 (1.92-2.09); and very delayed 2.30 (2.20-2.40). Adjusting for patient characteristics, each 30-day delay in receiving BGF was associated with a 5% increase in the average number of subsequent exacerbations (rate ratio, 95% CI: 1.05, 1.01-1.08; p<0.05). Prompt initiation of BGF was also associated with lower post-index annualized COPD-related costs ($5002 for prompt vs $7639 and $8724 for the delayed and very delayed groups, respectively). Conclusion: Following a COPD exacerbation, promptly initiating BGF was associated with a reduction in subsequent exacerbations and reduced healthcare utilization and costs.

Characteristics of initiators of budesonide/glycopyrrolate/formoterol for treatment of chronic obstructive pulmonary disease (COPD) in the United States: the AURA study.

INTRODUCTION: A twice-daily single inhaler triple therapy consisting of budesonide/glycopyrrolate/formoterol fumarate (BGF) was approved by the US Food and Drug Administration (FDA) in July 2020 as a maintenance treatment for patients with chronic obstructive pulmonary disease (COPD). The objective of this AURA study is to describe patient characteristics, exacerbation and treatment history, and healthcare resource utilization (HCRU) before BGF initiation to better inform treatment decisions for prescribers. METHODS: This retrospective cohort study leveraged data of all payer types from IQVIA's Longitudinal Prescription Data (LRx) linked to Medical Data (Dx). Patients with COPD who had ⩾1 LRx claim for BGF between 1 October 2020 and 30 September 2021 were included. The date of first BGF claim was the index date. Patient demographic and clinical characteristics, history of COPD exacerbation or related event, treatment history, and HCRU were assessed during the 12 months before index (baseline). RESULTS: We identified 30,339 patients with COPD initiating BGF (mean age: 68.2 years; 57.1% female; 67.6% Medicare). Unspecified COPD (J44.9; 74.0%) was the most commonly coded COPD phenotype. The most prevalent respiratory conditions/symptoms were dyspnea (50.8%), lower respiratory tract infection (25.3%), and sleep apnea (19.0%). Uncomplicated hypertension (58.8%), dyslipidemia (43.9%), cardiovascular disease (41.4%), and heart failure (19.9%) were the most prevalent nonrespiratory conditions. During the 12-month baseline, 57.9% of patients had evidence of a COPD exacerbation or related event, and 14.9% had ⩾1 COPD-related emergency department (ED) visit; 21.0% of patients had evidence of prior triple therapy use, while 54.3% had ⩾1 oral corticosteroid (OCS) fill. Among OCS users, 29.9% had cumulative exposures >1000 mg [median [Q1-Q3] exposure: 520 (260-1183) mg]. CONCLUSION: This real-world data analysis indicates that BGF is being initiated in patients with COPD experiencing symptoms and exacerbations despite current therapy, and among patients who have various chronic comorbidities, most often cardiopulmonary-related.

Prompt initiation of triple therapy following hospitalization for a chronic obstructive pulmonary disease exacerbation in the United States: An analysis of the PRIMUS study.

BACKGROUND: Severe exacerbations requiring hospitalization contribute a substantial portion of the morbidity and costs of chronic obstructive pulmonary disease (COPD). Triple therapy (inhaled corticosteroid + long-acting ß-agonist + long-acting muscarinic antagonist) is a recommended option for patients who experience recurrent COPD exacerbations or persistent symptoms. Few real-world studies have specifically examined the effect of prompt initiation of triple therapy, specifically among patients hospitalized for a COPD exacerbation. OBJECTIVE: To assess whether prompt initiation of triple therapy following a severe COPD exacerbation was associated with lower risk of subsequent exacerbations and lower health care use and costs and the effects of each 30-day delay of initiation. METHODS: Adults aged 40 years or older with COPD were identified in the Merative MarketScan Databases between January 1, 2010, and December 31, 2019, and were required to meet the following criteria: open or closed triple therapy (date of first closed prescription or last component of open=index treatment date), more than 1 inpatient admission with a primary COPD diagnosis (ie, severe exacerbation) in the prior 12 months (index exacerbation), 12 months of continuous enrollment before (baseline) and after (follow-up) index exacerbation, and absence of select respiratory diseases and cancer. Patients were stratified based on timing of open or closed triple therapy after the index exacerbation: prompt (≤30 days), delayed (31-180 days), or very delayed (181-365 days). Multivariable regression controlled for baseline characteristics (age, sex, insurance type, index year, comorbidities, prior treatment, and prior exacerbations) and estimated the odds of subsequent exacerbations, change in the number of exacerbations, and change in health care costs during 12-month follow-up associated with each 30-day delay of triple therapy initiation. RESULTS: A total of 6,772 patients met inclusion criteria (2,968 [43.8%] prompt, 1,998 [29.5%] delayed, and 1,806 [26.7%] very delayed). The adjusted odds of any exacerbation and a severe exacerbation during 12-month follow-up increased by 13% (odds ratio [95% CI]: 1.13 [1.11-1.15]) and 10% (1.10 [1.08-1.12]), respectively, for each 30-day delay in triple therapy initiation, and the mean number of exacerbations increased by 5.4% (95% CI = 4.7%-6.1%). There was a 3.0% increase (95% CI = 2.2%-3.8%) in mean all-cause costs and a 3.7% increase (95% CI = 2.9%-4.6%) in total COPD-related costs for each 30-day delay of triple therapy initiation. CONCLUSIONS: Longer delays in triple therapy initiation after a COPD hospitalization result in greater risk of subsequent exacerbations and higher health care resource use and costs. Adequate post-discharge follow-up care and earlier consideration of triple therapy may improve clinical and economic outcomes among patients with COPD. DISCLOSURES: This study was funded by AstraZeneca. Dr Evans is employed by Merative, formerly IBM Watson Health, and Mr Tkacz was employed by IBM Watson Health at the time of this study; Merative/IBM Watson Health received funding from AstraZeneca to conduct this study. Mr Pollack, Dr Staresinic, Dr Feigler, and Dr Patel are employed by AstraZeneca. Dr Touchette, Dr Portillo, and Dr Strange are paid consultants to AstraZeneca. Dr Strange also participates in research grants paid to the Medical University of South Carolina by AstraZeneca, CSA Medical, and Nuvaira, and is a consultant to GlaxoSmithKline, Morair, and PulManage regarding COPD.

PRIMUS - Prompt Initiation of Maintenance Therapy in the US: A Real-World Analysis of Clinical and Economic Outcomes Among Patients Initiating Triple Therapy Following a COPD Exacerbation.

PURPOSE: Patients with chronic obstructive pulmonary disease (COPD) may experience moderate (requiring outpatient care) or severe (requiring hospitalization) disease exacerbations. Guidelines recommend escalation from dual to triple therapy (inhaled corticosteroid + long-acting beta agonist + long-acting muscarinic antagonist) after two moderate or one severe exacerbation in a year. This study examined whether prompt initiation of triple therapy lowers risk of future exacerbations and reduces healthcare costs, compared to delayed/very delayed triple therapy after an exacerbation. PATIENTS AND METHODS: This retrospective observational study of US healthcare claims included patients ≥40 years old with COPD who initiated triple therapy (1/1/2011-3/31/2020) after ≥2 moderate or ≥1 severe exacerbation in the prior year. The earliest of the second moderate or first severe exacerbation was the index date. Patients were stratified by triple therapy timing: prompt (≤30 days post-index), delayed (31-180 days), very delayed (181-365 days). COPD exacerbations, all-cause and COPD-related healthcare utilization and costs were assessed during 12 months post-index (follow-up). Multivariable regression estimated the effect of each 30-day delay in triple therapy on the odds of exacerbations, number of exacerbations, and costs during follow-up, controlling for patient characteristics. RESULTS: A total of 24,770 patients were included: 7577 prompt, 9676 delayed, 7517 very delayed. Each 30-day delay of triple therapy was associated with 11% and 7% increases in the odds of any exacerbation and a severe exacerbation, respectively (odds ratio [95% CI]: 1.11 [1.10-1.13] and 1.07 [1.05-1.08]), a 4.3% (95% CI: 3.9-4.6%) increase in the number of exacerbations, a 1.8% (95% CI: 1.3-2.3%) increase in all-cause costs, and a 2.1% (95% CI: 1.6-2.6%) increase in COPD-related costs during follow-up. CONCLUSION: Promptly initiating triple therapy after two moderate or one severe exacerbation is associated with decreased morbidity and economic burden in COPD. Proactive disease management may be warranted to prevent future exacerbations and lower costs among patients with COPD.

Lipid-based emulsion drug delivery systems - a comprehensive review.

Lipid-based emulsion system - a subcategory of emulsion technology, has emerged as an enticing option to improve the solubility of the steadily rising water-insoluble candidates. Along with enhancing solubility, additional advantages such as improvement in permeability, protection against pre-systemic metabolism, ease of manufacturing, and easy to scale-up have made lipid-based emulsion technology very popular among academicians and manufacturers. The present article provides a comprehensive review regarding various critical properties of lipid-based emulsion systems, such as microemulsion, nanoemulsion, SMEDDS (self microemulsifying drug delivery system), and SNEDDS (self nanoemulsifying drug delivery system). The present article also explains in detail the similarities and differences between them, the stabilization mechanism, methods of preparation, excipients used to prepare them, and evaluation techniques. Subtle differences between nearly related terminologies such as microemulsion and nanoemulsion, SMEDDS, and SNEDDS are also explained in detail to clarify the basic differences. The present article also gives in-depth information regarding the chemical structure of various lipidic excipients, various possible chemical modifications to modify their inherent properties, and their regulatory status for rational selection.

Patient-reported outcomes in individuals with hepatitis C virus infection treated with elbasvir/grazoprevir.

PURPOSE: People chronically infected with hepatitis C virus (HCV) have diminished patient-reported outcomes (PROs). This study aimed to compare the impact of elbasvir/grazoprevir (EBR/GZR) treatment versus sofosbuvir with pegylated interferon and ribavirin (SOF/PR) on changes in PROs: 1) during the treatment period and 2) at posttreatment follow-up. PATIENTS AND METHODS: PRO data collected during the Phase III C-EDGE Head-2-Head (H2H) open-label study was analyzed. In this trial, patients infected with HCV were randomized 1:1 to receive either EBR/GZR or SOF/PR for 12 weeks. Patients self-administered the Short Form-36 version 2 (SF-36v2®) Health Survey Acute (1-week recall) Form and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale at baseline, during treatment, and posttreatment. Between-group differences in mean change of PRO scores from baseline were estimated during the treatment period and also at the posttreatment follow-up. Effect sizes were calculated to evaluate if the detected change in mean PRO scores is clinically meaningful between groups. RESULTS: There were 255 patients (99.2% White, 54.1% female, 74.9% treatment naïve) included in the analysis. During the treatment period, significant declines in SF-36v2 scores were observed across all domains for the SOF/PR group. Compared to the SOF/PR group, the EBR/GZR group reported more improvement in scores across all SF-36v2 domain scores at the end of the treatment period. At treatment week 12, the between-group differences for 6 out of the 8 domain scores for these patients reflected at least moderate effects (effect sizes >0.5). No significant between-group differences in change in SF-36v2 scores from baseline were detected posttreatment. The decline in SF-36v2 scores observed during the treatment period for the SOF/PR group returned to near baseline scores or above posttreatment. Treatment with EBR/GZR did not impact fatigue scores, but treatment with SOF/PR led to increased fatigue scores during treatment which resolved by posttreatment follow-up week 12. CONCLUSION: This study demonstrated that HCV treatment with EBR/GZR resulted in a significantly better PRO profile as compared to SOF/PR. PROs are an important consideration as worsening PROs experienced during treatment may negatively influence adherence and ultimately contribute to an unfavorable clinical outcome. CLINICALTRIALSGOV IDENTIFIER: NCT02358044.

Efficacy and safety of elbasvir/grazoprevir and sofosbuvir/pegylated interferon/ribavirin: A phase III randomized controlled trial.

BACKGROUND & AIMS: Direct-acting antiviral agents have improved treatment outcomes for patients with hepatitis C virus (HCV) infection; however, head-to-head comparisons are limited. The C-EDGE Head-2-Head Study compared the safety and efficacy of elbasvir/grazoprevir (EBR/GZR) with sofosbuvir plus pegylated interferon/ribavirin (SOF/PR) in patients with HCV infection. METHODS: This was a randomized, open-label, phase III trial. Two hundred fifty-seven patients with HCV genotype (GT)1 or 4 infection and baseline viral load >10,000IU/ml were randomized to receive 12weeks of EBR/GZR 50mg/100mg once daily (n=129) or sofosbuvir (400mg once daily) plus PR (n=128). Primary efficacy objective was sustained virologic response 12weeks after the end of therapy (SVR12, HCV RNA <15IU/ml). The primary safety objective was the proportion of patients experiencing a tier 1 safety event. RESULTS: The majority of patients were non-cirrhotic (83.1%), treatment-naïve (74.9%) and had HCV GT1b infection (82.0%). SVR12 rates were 99.2% (128/129) and 90.5% (114/126) in the EBR/GZR and SOF/PR groups, respectively. The estimated adjusted difference in SVR12 was 8.8% (95% confidence interval [CI], 3.6-15.3%). Because the lower bound of the 1-sided 1-sample exact test was greater than -10% and greater than zero, both non-inferiority and superiority of EBR/GZR vs. SOF/PR were established. The frequency of tier 1 safety events was lower among patients receiving EBR/GZR than SOF/PR (0.8% vs. 27.8%, between group difference, 27.0% [95% CI, -35.5% to -19.6%; p<0.001]). CONCLUSIONS: EBR/GZR has a superior efficacy and safety profile in patients with HCV GT1 or 4 infection compared with SOF/PR. LAY SUMMARY: The combination of elbasvir/grazoprevir for 12weeks was highly effective in treating patients with chronic hepatitis C, genotypes 1 or 4 infection. This regimen was more effective than sofosbuvir/pegylated interferon/ribavirin for 12weeks, and was notably superior in patients regarded as difficult to treat, including those with previous treatment failure, cirrhosis, or a high baseline viral load. The combination of elbasvir/grazoprevir also demonstrated a superior safety and tolerability profile based on fewer serious adverse events, no serious drug-related adverse events, and no treatment discontinuations. CLINICAL TRIAL REGISTRATION: Clinical trials.gov Identifier: NCT02358044.

Description of the outcomes of prior authorization of palivizumab for prevention of respiratory syncytial virus infection in a managed care organization.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of upper and lower respiratory tract infections in infants and young children. Most children are exposed to the virus before they are 2 years old and experience such symptoms as cough, fever, and irritability. In a select population of infants, the virus can cause hypoxemia and hospitalization. To avoid hospitalization, good infection control practices should be employed, and for those infants at high risk, prophylaxis with palivizumab is indicated. Palivizumab has been shown to reduce hospitalization rates in high-risk infants by 50%. Because of the high cost of palivizumab, it is prudent to use this medication in the population in which it will be most effective. The American Academy of Pediatrics (AAP) established the criteria for those infants who would benefit the most from palivizumab prophylaxis, and these criteria were the foundation for a prior authorization (PA) program to determine coverage of palivizumab in a health plan of approximately 500,000 members. OBJECTIVE: To (a) analyze the appropriateness of this PA program for palivizumab used prophylactically for RSV, and (b) determine the financial cost associated with the medication and disease for this health plan. METHODS: A 3-year, retrospective study was conducted from the 2005- 2006 RSV season through the 2007-2008 season. The primary endpoint outcome was the hospitalization rate associated with RSV infection. Secondary endpoints included the cost of palivizumab and RSV-related emergency room (ER) utilization. Infants were placed into 2 groups: those who received PA approval for use of palivizumab and those who were denied coverage in the PA process. Disease-related hospitalization and ER visits were identified by at least 1 administrative claim containing either a primary or secondary ICD-9-CM code for any of the following: RSV (079.6), acute bronchiolitis caused by RSV (466.11), or pneumonia caused by RSV (480.1). Drug cost was defined as the health plan's allowed amount, which is based on a predefined fee schedule for the Current Procedural Terminology (CPT) code 90378 for palivizumab. Hospital and ER costs are the health plan allowed amounts (health plan plus member cost) based on the reimbursement rates determined by diagnosis related group (DRG) and other coding, and the plan-allowed amount based on DRGs includes all services and drugs provided in the specific encounter. Drug cost avoided was calculated as the average cost of palivizumab treatment per episode multiplied by the number of infants denied coverage of palivizumab over the 3-year study period. RESULTS: Over 3 RSV seasons through May 2008, the PA program received 1,090 requests for coverage of palivizumab, of which 348 (31.9%) were denied. Of 742 PA-approved infants, 629 received at least 1 dose of palivizumab. The mean (SD) gestational age of the PA-denied group was 34.4 (2.5) weeks versus 32.5 (4.0) weeks for the PA-approved group (P < 0.001). In the PA-denied group, 14 infants (4.0%) were subsequently hospitalized with an RSV infection, and 5 (1.4%) had an RSV-related ER visit versus 40 (6.4%) hospitalized and 14 (2.2%) with ER visits for infants in the PA-approved group (P = 0.055 and P = 0.019, respectively); 15 (4.3%) of the PA-denied group had either a hospitalization or an ER visit versus 42 (6.6%) in the PA-approved group (P = 0.060). One patient in the palivizumab PA-approved group died. Over the 3 RSV seasons, the mean number of palivizumab doses and mean allowed palivizumab cost per treatment episode (per infant per season) were 3.64 and $6,950, respectively, and the average allowed palivizumab cost was $7,702 per utilizing infant. Total per infant costs for palivizumab, RSV hospitalizations, and RSV-related ER visits were $8,534 for infants receiving palivizumab compared with $223 for those denied palivizumab coverage (P = 0.002). Drug cost avoidance associated with the PA program was estimated to be $2,418,600 (348 infants times $6,950 palivizumab cost per episode) over the 3 RSV seasons. CONCLUSION: In a 500,000-member health plan, a PA program to restrict palivizumab use in accordance with AAP recommendations was associated with estimated palivizumab drug cost avoidance of more than $2.4 million over 3 years. There was no significant difference in the RSV-related hospitalization rate for the PA-denied versus the PA-approved groups, but the PA-denied group had a slightly lower rate of RSV-related ER visits.

Deficiency in sPLA(2) does not affect HDL levels or atherosclerosis in mice.

Secretory non-pancreatic phospholipase A(2) (sPLA(2)) has been implicated in inflammation and has been found in human atherosclerotic lesions. To test the effect of sPLA(2) deficiency on atherosclerosis, C57BL/Ks mice (apoE(+/+) and PLA(2)(++) were bred with C57BL/6 apoE knockout mice which are sPLA(2)(--) due to a spontaneous mutation. Sibling pairs of mice (apoE(--)/sPLA(2)(++) and apoE(--)/sPLA(2)(--)) on high fat Western diets were dissected at 22 weeks. In vitro enzyme assays confirmed higher serum sPLA(2) activity in the sPLA(2)(++) compared to sPLA(2)(--) for both sexes, while sPLA(2)(--) males had slightly higher serum cholesterol and phospholipids. Analysis of lipoprotein profiles by FPLC showed no effect of sPLA(2) genotype on any measured parameters. Atherosclerosis was quantitated by assaying cholesterol in aortic extracts. Male sPLA(2) trended slightly higher than sPLA(2)(++) with no statistical significance. Female sPLA(2)(++) and sPLA(2)(--) mice showed no significant differences in any of the measured parameters. These results suggest that the endogenous mouse sPLA(2) gene does not significantly affect HDL or atherosclerosis in mice.