The burden of illness in patients with paroxysmal nocturnal hemoglobinuria receiving treatment with the C5-inhibitors eculizumab or ravulizumab: results from a US patient survey.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening disease with symptoms of hemolysis and thrombosis. Current therapies for this complement-mediated disease rely predominantly on inhibition of the C5 complement protein. However, data on treatment responses and quality of life in C5-inhibitor (C5i)-treated PNH patients are scarce. The objective of this study was to determine C5i treatment effects on clinical parameters, PNH symptoms, quality of life, and resource use for PNH patients. This cross-sectional study surveyed 122 individuals in the USA receiving treatment for PNH with C5-targeted monoclonal antibodies, eculizumab (ECU) or ravulizumab (RAV). Despite most patients receiving C5i therapy for ≥ 3 months (ECU 100%, n = 35; RAV 95.4%, n = 83), many patients remained anemic with hemoglobin levels ≤ 12 g/dL in 87.5% (n = 28/32) and 82.9% (n = 68/82) of ECU and RAV recipients, respectively. A majority of patients on ECU (88.6%; n = 31/35) and RAV (74.7%; n = 65/87) reported fatigue symptoms. Among PNH patients receiving C5i therapy for ≥ 12 months, some still reported thrombotic events (ECU, 10.0%, n = 1/10; RAV, 23.5%, n = 4/17) and required transfusions within the past year (ECU, 52.2%, n = 12/23; RAV, 22.6%, n = 7/31). Other patient-reported PNH symptoms included breakthrough hemolysis, shortness of breath, and headaches. Patients reported scores below the average population norms on the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) scales. Overall, this study found that PNH patients receiving ECU or RAV therapy demonstrated a significant burden of illness, highlighting the need for improved PNH therapies.

Changes in hemoglobin and clinical outcomes drive improvements in fatigue, quality of life, and physical function in patients with paroxysmal nocturnal hemoglobinuria: post hoc analyses from the phase III PEGASUS study.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, acquired, hematologic, life-threatening disease characterized by thrombosis, impaired bone marrow function, and complement-mediated hemolysis. The PEGASUS phase III clinical trial demonstrated superiority of pegcetacoplan over eculizumab regarding improvements in hemoglobin levels in patients with suboptimal response to prior eculizumab treatment. The objective of this post hoc analysis was to compare the patient-reported outcome (PRO) response rates observed among PEGASUS participants and the relationships between their PRO scores with clinical and hematological parameters. Data from the 16-week randomized, controlled (1:1 to pegcetacoplan or eculizumab) period of the PEGASUS trial included comparisons of weekly PRO measurements taken using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) scales. A clinically meaningful FACIT-F response was defined as an increase from baseline of ≥5 points. Convergent validity was assessed using conventional threshold correlations between FACIT-F, EORTC QLQ-C30, and laboratory parameters. A clinically meaningful improvement in FACIT-F score was seen in 72.2% of pegcetacoplan-treated patients compared to 22.9% of eculizumab-treated patients. At week 16, the FACIT-F total score correlated with hemoglobin levels (r=0.47, p< 0.0001), absolute reticulocyte count (r=-0.37, p<0.01), and indirect bilirubin levels (r=-0.25, p<0.05). Clinically meaningful improvements in pegcetacoplan-treated patients were also observed for multiple EORTC scales. Fatigue and other self-reported outcomes were correlated with clinically meaningful improvements in clinical and hematological parameters. Clinical trial registration: NCT03500549.

Global incidence of intraventricular hemorrhage among extremely preterm infants: a systematic literature review.

OBJECTIVES: To conduct a systematic literature review to evaluate the global incidence of intraventricular hemorrhage grade 2-4 among extremely preterm infants. METHODS: We performed searches in MEDLINE and Embase for intraventricular hemorrhage and prematurity cited in English language observational studies published from May 2006 to October 2017. Included studies analyzed data from infants born at ≤28 weeks' gestational age and reported on intraventricular hemorrhage epidemiology. RESULTS: Ninety-eight eligible studies encompassed 39 articles from Europe, 31 from North America, 25 from Asia, five from Oceania, and none from Africa or South America; both Europe and North America were included in two publications. The reported global incidence range of intraventricular hemorrhage grade 3-4 was 5-52% (Europe: 5-52%; North America: 8-22%; Asia: 5-36%; Oceania: 8-13%). When only population-based studies were included, the incidence range of intraventricular hemorrhage grade 3-4 was 6-22%. The incidence range of intraventricular hemorrhage grade 2 was infrequently documented and ranged from 5-19% (including population-based studies). The incidence of intraventricular hemorrhage was generally inversely related to gestational age. CONCLUSIONS: Intraventricular hemorrhage is a frequent complication of extremely preterm birth. Intraventricular hemorrhage incidence range varies by region, and the global incidence of intraventricular hemorrhage grade 2 is not well documented.

Content validity of a novel patient-reported and observer-reported outcomes assessment to evaluate ocular symptoms associated with infectious conjunctivitis in both adult and pediatric populations.

BACKGROUND: Acute infectious conjunctivitis is a common condition most frequently caused by viruses or bacteria. Clinical outcome assessments have been used to assess signs and symptoms of bacterial and viral conjunctivitis, but have not been evaluated for content validity. We aimed to develop content-valid patient- (PRO) and observer-reported outcome (ObsRO) instruments to assess symptoms of ocular discomfort associated with viral or bacterial conjunctivitis in adult and pediatric patients. METHODS: Draft items were developed from a previous review of published studies from 2001 to 2015. Patients and caregivers of patients with a diagnosis of viral or bacterial conjunctivitis within the past 6 months were recruited. Concept elicitation with open-ended questions explored signs and symptoms, followed by cognitive interviewing to assess clarity and relevance of the draft items. Patients aged ≥8 years were interviewed for the PRO; parents/caregivers of children aged 1-10 years were interviewed for the ObsRO. Interviews were conducted in three rounds to allow changes. Concept saturation was documented using a saturation grid. Cognitive interview data were analyzed iteratively and focused on clarity, relevance and inconsistent interpretation of the instrument's content. RESULTS: Overall, 23 patients or parents/caregivers participated (round 1, n = 10; round 2, n = 6; round 3, n = 7). Data saturation was reached by the 16th interview. The most frequent spontaneously reported signs/symptoms were: discharge, red/pink eyes, itchiness, swelling/puffiness, watery eyes, pain, burning and foreign body sensation. Itching, pain/burning/stinging and foreign body sensation were most commonly reported as the top three most bothersome symptoms. Interview results indicated that items on pain, itching and foreign body sensation for the PRO and pain or discomfort for the ObsRO were relevant to the patients' experience of conjunctivitis and were clear and easy to understand. CONCLUSIONS: PRO and ObsRO items were found to be clear, relevant and appropriate in assessing key viral and bacterial conjunctivitis symptoms in adult and pediatric patients.

Effects of BG-12 (dimethyl fumarate) on health-related quality of life in patients with relapsing-remitting multiple sclerosis: findings from the CONFIRM study.

Multiple sclerosis (MS) has a significant impact on health-related quality of life (HRQoL) with symptoms adversely affecting many aspects of everyday living. BG-12 (dimethyl fumarate) demonstrated significant efficacy in the phase III studies DEFINE and CONFIRM in patients with relapsing-remitting MS. In CONFIRM, HRQoL was worse in patients with greater disability at baseline, and who relapsed during the study, and improved with BG-12 treatment. Mean Short Form-36 Physical Component Summary scores for BG-12 increased over 2 years and scores for placebo decreased. Coupled with clinical and neuroradiological benefits, these HRQoL results further support BG-12 as an effective oral treatment for relapsing MS.

Quality of life outcomes with BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: the DEFINE study.

BACKGROUND: Oral BG-12 (dimethyl fumarate), approved for the treatment of the relapsing forms of MS, has demonstrated clinical efficacy with an acceptable safety profile in the Phase III "Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (RRMS)" (DEFINE) and "Comparator and an Oral Fumarate in RRMS" (CONFIRM) studies. OBJECTIVES: To evaluate the health-related quality of life (HRQoL) impairment that is associated with RRMS and to assess the effects of BG-12 on HRQoL in the DEFINE study. METHODS: Patients with RRMS were randomized to BG-12 240 mg twice (BID) or three times (TID) daily, or placebo, for 2 years. HRQoL was assessed by the Short Form-36 (SF-36), global assessment of well-being visual analog scale and the EuroQol-5D. RESULTS: In the 1237 patients from DEFINE, HRQoL impairment was greatest in patients who had higher disability scores and in those who had experienced relapse. Change in SF-36 physical component summary scores during 2 years' treatment significantly favored BG-12 over placebo (both doses: p < 0.001). We saw similar benefits in other measures of functioning and general well-being as early as Week 24. These benefits were maintained during the study. CONCLUSIONS: Our results add to evidence for a negative impact of RRMS on HRQoL and they demonstrate the benefits of BG-12 on HRQoL measures, which coupled with significant clinical efficacy, further support its use as a new treatment for RRMS.

The MOSAIC Study: A Mixed-Methods Study of the Clinical, Emotional, and Financial Burden of Geographic Atrophy Among Patients and Caregivers in the US.

Purpose: Geographic atrophy (GA) impacts both patients and caregivers, yet little is understood about their respective burdens. The MOSAIC study aimed to identify the clinical, emotional, and financial burden among patients with GA and caregivers. Methods: A total of 28 patients with GA and 17 caregivers from the United States (US), the United Kingdom, and Australia participated in individualized qualitative interviews followed by a cross-sectional quantitative survey of 102 patients and 102 caregivers in the US. Interview transcripts were analyzed to develop conceptual models, which were then used to guide the design of quantitative surveys. Data were described at the item level and score level when appropriate (National Eye Institute Visual Function Questionnaire [NEI VFQ]-39 and Zarit Burden Interview [ZBI]). For the patient/caregiver dyad sample, the association between the NEI VFQ-39 scores and ZBI score was explored through correlation coefficients and scatterplots. Results: GA had a substantial impact on patients' vision-related quality of life, activities of daily living, and instrumental activities of daily living. There was considerable overlap between perspectives and key concerns identified by patients and caregivers. Eighty-three percent of caregivers reported having to drive patients to appointments due to limited patient mobility, for example, and 41% reported a change in their employment status after becoming a caregiver, with 50% of them unable to work due to caregiving. The burden of patients and caregivers had a correlation ranging from -0.63 to -0.21 between NEI VFQ-39 subscale and composite scores and ZBI score. Conclusion: This study confirms the paucity of support for both patients with GA and caregivers. Both groups require expanded access to financial, social, and mental health resources.

What is this summary about? People with geographic atrophy, also called GA, can lose their eyesight and have a hard time driving, reading, and recognizing faces. This can worsen their quality of life. Often, people with GA need someone to care for them. The MOSAIC study was done to find out how GA affects health, happiness, and finances of people with GA and their caregivers. What were the results? One hundred and two people with GA and 102 caregivers in the United States were interviewed. The average age of people with GA was 68 years and of caregivers was 46 years. The findings showed that most people with GA did not drive because of their poor eyesight and instead counted on their caregivers to drive them to doctor appointments and other places. They also had a reading and doing things around their home because of their worsened eyesight. Both people with GA and caregivers said they felt stressed. They both worried about spending money on things they need to make living with GA easier. They also felt stressed about their finances because they could not work as much. People with GA worried most about losing their independence and caregivers worried most about the future of their loved one with GA. What do the results mean? This study showed that GA has a serious effect on people's health and quality of life while also having a major impact on their caregivers.

Geographic atrophy: Mechanism of disease, pathophysiology, and role of the complement system.

Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD), characterized by atrophic lesions that first start in the outer retina and progressively expand to cover the macula and the fovea, the center of the macula, leading to irreversible loss of vision over time. GA is distinct from wet or neovascular AMD (nAMD), the other form of advanced AMD. Neovascular AMD is characterized by new invading leaky blood vessels in the macula that can lead to acute vision loss. GA and nAMD may coexist in the same eye. The underlying pathophysiology of GA is complex and thought to involve chronic inflammation due to overactivation of the complement system that leads to the loss of photoreceptors, retinal pigment epithelium (RPE), and the underlying choriocapillaris. The disappearance of these structures appears as sharply demarcated atrophic lesions that are typical of GA. Researchers have reported about 1 million reported cases of GA in the United States, and about 160,000 cases occur per year. The most important risk factors for GA are increasing age and family history. Diagnosis of GA is usually made by using multimodal imaging techniques. Lesions associated with GA are highly heterogeneous, and the growth rate may differ from patient to patient. Despite the progressive nature of GA, the fovea may be spared until much later in the disease, thereby retaining central vision in patients. With time, atrophic lesions may progressively grow to involve the fovea, thereby severely impairing central vision. Vision loss can happen rapidly once the lesions reach the fovea. However, even without the involvement of the fovea, ongoing vision impairment impacting daily life may be present. Median time from GA not involving the center of the fovea (without subfoveal involvement) to GA with lesion boundary affecting the foveal center (subfoveal involvement) ranges from 1.4 to 2.5 years. GA can greatly impact patients' functioning and quality of life and limit their independence by interfering with activities of daily living, including difficulties with reading, driving, watching television, recognizing faces, and being unable to do household chores. No treatments have been available until intravitreal pegcetacoplan was recently approved by the US Food and Drug Administration for GA secondary to AMD. DISCLOSURES: Dr Bakri serves as a consultant to Apellis Pharmaceuticals, as well as AbbVie, Adverum, Eyepoint, iLumen, Iveric Bio, Genentech, Novartis, Outlook Therapeutics, Pixium, Regeneron, Roche, and Regenxbio. Drs Sharp, Luo, and Sarda are employees of Apellis Pharmaceuticals. Dr Bektas and Ms Khan are employees of RTI Health Solutions. Apellis developed and led the concept design of this publication, review and interpretation, approval, and decision to publish. This research was developed under a research contract between RTI Health Solutions and Apellis Pharmaceuticals and was funded by Apellis Pharmaceuticals. This supplement is to describe the disease of geographic atrophy and was funded by Apellis. Apellis Pharmaceuticals has developed Syfovre (pegcetacoplan), the first and only treatment for geographic atrophy.

Burden of Treatments for Respiratory Complications in Extremely Premature Infants: Interviews with Caregivers.

Introduction: Extremely premature (EP) infants (<28 weeks gestational age) with respiratory conditions after discharge from the neonatal intensive care unit (NICU) impose a significant burden on caregivers. This study explored caregiver burden post-NICU discharge and perceptions of meaningful change in infant chronic respiratory morbidity. Methods: Adult primary caregivers of EP infants 3-14 months corrected age were recruited through patient advocacy organizations or hospital centers in the USA, Northern Ireland, Germany, and Japan and interviewed by phone. Interviews explored caregiver experiences with infants with respiratory conditions, associated treatment burden, and meaningful change in infant respiratory morbidity as measured by treatment use. Qualitative analysis of interview data was performed using MAXQDA software. Sociodemographic data were summarized using descriptive statistics. Results: Forty-five caregivers (95.6% female) of EP infants were interviewed. Respiratory morbidities post-NICU discharge included coughing (78%), breathing difficulties (76%), wheezing (58%), and bronchopulmonary dysplasia/chronic lung disease of prematurity (56%). Respiratory medications were required by 87% of infants, 80% used home respiratory technology support (e.g., supplemental oxygen), 38% were re-hospitalized, and 33% had emergency department visits. Caregivers considered visits to the emergency department to be the most burdensome treatment requirement they experienced, and reduction in the number of emergency department visits was considered the most meaningful change in treatment use. Conclusion: These findings underscore the significant burden faced by caregivers of EP infants with respiratory morbidities. Development of treatments for respiratory complications should take into consideration the concerns and preferences of caregivers in order to provide a meaningful benefit.

A multicenter chart review of patient characteristics, treatment, and outcomes in hereditary angioedema: unmet need for more effective long-term prophylaxis.

BACKGROUND: Hereditary angioedema (HAE) is a rare disease characterized by unpredictable, recurring subcutaneous or submucosal swelling. Without effective therapy, HAE can negatively impact patients' quality of life. Management of HAE includes on-demand treatment of attacks and short- and long-term prophylaxis (LTP) to prevent attacks. Newer therapies may be more tolerable and effective in managing HAE; however, therapies such as androgens are still widely used in some countries owing to their relative ease of access and adequate disease control for some patients. This study evaluated the characteristics, treatment patterns, clinical outcomes, and healthcare resource utilization of a multinational cohort of patients with HAE, with a focus on understanding reasons for recommending or discontinuing available therapies. METHODS: A retrospective chart review was conducted at 12 centers in six countries and included data from patients with HAE type 1 or 2 who were ≥ 12 years of age at their first clinical visit. The relationship between LTP use and attack rates was evaluated using a multivariable Poisson regression model. Data were collected between March 2018 and July 2019. RESULTS: Data from 225 patients were collected (62.7% female, 86.2% White, 90.2% type 1); 64.4% of patients had their first HAE-related visit to the center prior to or during 2014. Treatment patterns varied between countries. Overall, 85.8% of patients were prescribed on-demand treatment and 53.8% were prescribed LTP, most commonly the androgen danazol (53.7% of patients who used LTP). Plasma-derived C1 inhibitor (Cinryze®) was used by 29.8% of patients for LTP. Patients who received LTP had a significantly lower rate of HAE attacks than patients who did not receive any LTP (incidence rate ratio (95% confidence interval) 0.90 (0.84-0.96)). Androgens were the most commonly discontinued therapy (51.3%), with low tolerability cited as the most frequent reason for discontinuation (50.0%). CONCLUSIONS: Overall, findings from this study support the use of LTP in the prevention of HAE attacks; a lower rate of attacks was observed with LTP compared with no LTP. However, the type of LTP used varied between countries, with tolerability and accessibility to specific treatments playing important roles in management decision-making.

Burden of Comorbidities and Healthcare Resource Utilization Among Medicaid-Enrolled Extremely Premature Infants.

Background: The effect of gestational age (GA) on comorbidity prevalence, healthcare resource utilization (HCRU), and all-cause costs is significant for extremely premature (EP) infants in the United States. Objectives: To characterize real-world patient characteristics, prevalence of comorbidities, rates of HCRU, and direct healthcare charges and societal costs among premature infants in US Medicaid programs, with respect to GA and the presence of respiratory comorbidities. Methods: Using International Classification of Diseases, Ninth/Tenth Revision, Clinical Modification codes, diagnosis and medical claims data from 6 state Medicaid databases (1997-2018) of infants born at less than 37 weeks of GA (wGA) were collected retrospectively. Data from the index date (birth) up to 2 years corrected age or death, stratified by GA (EP, ≤28 wGA; very premature [VP], >28 to <32 wGA; and moderate to late premature [M-LP], ≥32 to <37 wGA), were compared using unadjusted and adjusted generalized linear models. Results: Among 25 573 premature infants (46.1% female; 4462 [17.4%] EP; 2904 [11.4%] VP; 18 207 [71.2%] M-LP), comorbidity prevalence, HCRU, and all-cause costs increased with decreasing GA and were highest for EP. Total healthcare charges, excluding index hospitalization and all-cause societal costs (US dollars), were 2 to 3 times higher for EP than for M-LP (EP $74 436 vs M-LP $27 541 and EP $28 504 vs M-LP $15 892, respectively). Conclusions: Complications of preterm birth, including prevalence of comorbidities, HCRU, and costs, increased with decreasing GA and were highest among EP infants during the first 2 years in this US analysis.

The clinical burden of extremely preterm birth in a large medical records database in the United States: Mortality and survival associated with selected complications.

BACKGROUND: Preterm birth is a leading cause of infant mortality, particularly for those born extremely prematurely (EP; <28 weeks' gestational age [GA]). Survivors are predisposed to complications such as bronchopulmonary dysplasia (BPD), chronic lung disease (CLD), intraventricular hemorrhage (IVH), and retinopathy of prematurity (ROP). AIMS: To examine the epidemiology, complications, and mortality/survival among EP infants. STUDY DESIGN: Retrospective analysis of electronic medical records from the Kaiser Permanente Northern California database. SUBJECTS: EP infants live-born between 22 and <28 weeks' GA from 1997 to 2016. OUTCOME MEASURES: Cumulative all-cause mortality/survival were analyzed and stratified by GA (22 to <24, 24 to <26, 26 to <28 weeks), complications (BPD/CLD, IVH, ROP), and birth period (1997 to 2003, 2004 to 2009, 2010 to 2016). Cox proportional hazard models were constructed to assess the mortality risk associated with BPD/CLD or IVH. RESULTS: 2154 EP infants were identified; of these, 916 deaths were recorded. Mortality was highest during the first 3 months (41.7 % cumulative mortality), and few were reported after 2 years (42.5 % cumulative mortality). Mortality decreased with higher GA and over more recent birth periods. BPD/CLD and IVH grade 3/4 were associated with increased mortality risk versus no complications (adjusted hazard ratios 1.41 and 1.78, respectively). CONCLUSIONS: The risk of mortality is high during the first few months of life for EP infants, and is even higher for those with BPD and IVH. Despite an overall trend toward increased survival for EP infants, strategies targeting survival of EP infants with these complications are needed.

The clinical burden of extremely preterm birth in a large medical records database in the United States: complications, medication use, and healthcare resource utilization.

INTRODUCTION: Approximately 5% of global preterm births are extremely premature (EP), defined as occurring at less than 28 weeks gestational age. Advances in care have led to an increase in the survival of EP infants during the neonatal period. However, EP infants have a higher risk of developing complications such as bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), and retinopathy of prematurity (ROP). BPD and other respiratory morbidities are particularly prevalent among this population. To understand the healthcare resource utilization (HRU) of EP infants in the United States, the clinical and economic burden of extreme prematurity was examined in this retrospective study of data extracted from electronic medical records in the Kaiser Permanente Northern California (KPNC) health system. METHODS: The analysis included data from EP infants live-born between January 1997 and December 2016, and focused on complications and HRU up to 3 years corrected age (CA), covering the period up to December 2018. Stillbirths, infants born at <22 weeks gestational age, and infants with major congenital malformations were excluded. Complications of interest (BPD, IVH, and ROP) and medication use were compared by age group (≤1 year, >1 year and ≤2 years, and >2 years and ≤3 years CA). Analysis of HRU included hospital readmissions, ambulatory visits, and emergency room (ER) visits. RESULTS: A total of 2154 EP births (0.32% of total live births and 4.0% of preterm births that met the inclusion/exclusion criteria) were analyzed. The prevalence of EP birth showed a declining trend over time. ROP was the most commonly recorded complication during the birth hospitalization (37.1% any stage; 2.9% Stages 3 and 4). BPD was recorded in 34.3% of EP infants. IVH (any grade) was recorded in 22.7% of EP infants (6.4% Grades III and IV). A majority (78.7%) of EP infants were diagnosed with at least one respiratory condition during the first year CA, the most common being pneumonia (68.9%); the prevalence of respiratory conditions decreased over the second and third years CA. During the first 3 years CA, the most common medications prescribed to children born EP were inhaled bronchodilators (approximately 30% of children); at least 15% of children received systemic corticosteroids and inhaled steroids during this period. During the first 3 years CA, at least one hospital readmission was recorded for 16.4% of children born EP; 57.1% of these readmissions were related to respiratory conditions. At least one ER visit was recorded for 33.8% of children born EP, for which 53.1% were due to a respiratory condition. Ambulatory visits were recorded for 54.2% of EP children, for which 82.9% were due to a respiratory condition. CONCLUSIONS: The short- and long-term clinical burden of EP birth was high. The onset of BPD, IVH, and ROP was common during the birth hospitalization for EP infants. Medication use, hospital readmission, and clinic visits (ER and ambulatory) occurred frequently in these children during the first 3 years CA, and were commonly due to respiratory conditions. Strategies prioritizing the reduction of risk and severity of respiratory conditions may alleviate the clinical burden of EP birth over the long term.

Long-term burden of respiratory complications associated with extreme prematurity: An analysis of US Medicaid claims.

BACKGROUND: Infants born extremely premature (EP) (<28 weeks gestational age) are at high risk of complications, particularly bronchopulmonary dysplasia (BPD), which can develop into chronic lung disease (CLD). METHODS: The burden of respiratory complications in EP infants up to 2 years corrected age (CA) was evaluated using real-world data from the US Medicaid program. Data recorded between 1997 and 2018 on EP infants without major congenital malformations were collected from Medicaid records of six states. EP infants were divided into three cohorts: BPD, CLD, and without BPD or CLD. The incidence of respiratory conditions, respiratory medication use, and healthcare resource utilization were compared between the BPD cohort and CLD cohort versus the cohort without BPD or CLD, using unadjusted and adjusted generalized linear models. RESULTS: A total of 4462 EP infants were identified (17.4% of all premature infants in the database). Of these, BPD and CLD were diagnosed in 61.9% and 72.1%, respectively, and 14.5% were diagnosed with neither BPD nor CLD. Compared with infants without BPD or CLD, infants with BPD or CLD had more complications and a longer length of birth hospitalization stay. Respiratory distress syndrome was the most frequently reported complication (94.6%, 92.5%, and 82.3% of EP infants in the BPD, CLD, and without BPD or CLD cohorts, respectively). After the birth hospitalization, respiratory conditions, respiratory medication use, and incidence rates of rehospitalizations, emergency room visits, and outpatient visits were higher for infants with BPD or CLD. Rehospitalization occurred in 50.5%, 51.6%, and 27.3% of EP infants with BPD, CLD, or without BPD or CLD, respectively; most hospitalizations occurred for respiratory-related reasons. CONCLUSION: In this analysis of a large population of EP infants up to 2 years CA, respiratory conditions were prevalent after the birth hospitalization and were associated with high rates of medication and healthcare resource utilization.

The cost-effectiveness, of pegcetacoplan compared with ravulizumab for the treatment of paroxysmal nocturnal hemoglobinuria, in a UK setting.

Aim: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by hemolytic anemia, bone marrow failure and thrombosis. We evaluated, the cost-effectiveness of pegcetacoplan, a novel proximal C3 inhibitor, versus ravulizumab in patients with PNH and hemoglobin levels <10.5 g/dl despite eculizumab treatment in the UK healthcare and social services setting. Materials & methods: A Markov cohort framework model, based on the data from the pivotal trial of pegcetacoplan (PEGASUS/NCT03500549), evaluated lifetime costs and outcomes. Patients transitioned through 3 PNH hemoglobin level/red blood cell transfusion health states. Results: Pegcetacoplan provides lower lifetime costs/greater quality-adjusted life years (£6,409,166/14.694QALYs, respectively) versus ravulizumab (£6,660,676/12.942QALYs). Conclusion: Pegcetacoplan is associated with enhanced anemia control, greater QALYs and reduced healthcare costs versus ravulizumab in the UK healthcare and social services setting.

Real-World Eculizumab Dosing Patterns Among Patients with Paroxysmal Nocturnal Hemoglobinuria in a US Population.

Purpose: Current pharmacologic management of paroxysmal nocturnal hemoglobinuria (PNH) consists of C5 inhibitors, eculizumab and ravulizumab; however, because patients experience incomplete symptom control, off-label doses may be utilized. We conducted a retrospective, longitudinal cohort study of provider-based claims data to assess the real-world eculizumab dosing patterns in PNH patients. Patients and Methods: Patients were ≥12 years, received ≥2 eculizumab infusions between January 1, 2015 and September 30, 2019, and had ≥3 months of continuous clinical activity prior to index. The index date was the first claim for eculizumab. Patients with ≥1 diagnosis of another indication for eculizumab were excluded. Treatment patterns including the proportion with high, label-recommended, and low dosages during induction (first 28 days) and maintenance (beginning day 29) phases were described. The proportion and time-to-first dose escalation, defined as an increase in dose or frequency of infusion, were assessed among a subset of patients (ie, escalation analysis cohort). Results: A total of 707 patients were examined. Mean (standard deviation [SD]) starting dose was 862mg (412mg) and was higher than label-recommended 600mg for 64% of the patients. Mean (SD) dose per infusion was 859mg (391mg) during the induction phase; average dose was higher than label-recommended 600mg for 68%. Mean (SD) dose per infusion during the maintenance phase was 1005mg (335mg); average dose was higher than label-recommended 900mg for 43%. Dose escalation occurred in 40/121 escalation analysis cohort patients. Median time-to-first dose escalation was ~12 months. Conclusion: Results suggest that deviations from label-recommended dosing patterns were common. Future budget impact assessments of eculizumab should account for real-world dosing patterns to comprehensively assess costs and benefits.

Development of the PREMature Infant Index (PREMII™), a clinician-reported outcome measure assessing functional status of extremely preterm infants.

BACKGROUND: Comprehensive measures to evaluate the effectiveness of medical interventions in extremely preterm infants are lacking. Although length of stay is used as an indicator of overall health among preterm infants in clinical studies, it is confounded by nonmedical factors (e.g. parental readiness and availability of home nursing support). OBJECTIVES: To develop the PREMature Infant Index (PREMII™), an electronic content-valid clinician-reported outcome measure for assessing functional status of extremely preterm infants (<28 weeks gestational age) serially over time in the neonatal intensive care unit. We report the development stages of the PREMII, including suggestions for scoring. METHODS: We developed the PREMII according to US Food and Drug Administration regulatory standards. Development included five stages: (1) literature review, (2) clinical expert interviews, (3) Delphi panel survey, (4) development of items/levels, and (5) cognitive interviews/usability testing. Scoring approaches were explored via an online clinician survey. RESULTS: Key factors reflective of functional status were identified by physicians and nurses during development of the PREMII, as were levels within each factor to assess functional status. The resulting PREMII evaluates eight infant health factors: respiratory support, oxygen administration, apnea, bradycardia, desaturation, thermoregulation, feeding, and weight gain, each scored with three to six gradations. Factor levels are standardized on a 0-100 scale; resultant scores are 0-100. No usability issues were identified. The online clinician survey identified optimal scoring methods to capture functional status at a given time point. CONCLUSIONS: Our findings support the content validity and usability of the PREMII as a multifunction outcome measure to assess functional status over time in extremely preterm infants. Psychometric validation is ongoing.

Clinical and economic impact of vagus nerve stimulation therapy in patients with drug-resistant epilepsy.

We evaluated long-term medical and economic benefits of vagus nerve stimulation (VNS) therapy in drug-resistant epilepsy. A pre-post analysis was conducted using multistate Medicaid data (January 1997-June 2009). One thousand six hundred fifty-five patients with one or more neurologist visits with epilepsy diagnoses (ICD-9 345.xx, 780.3, or 780.39), one or more procedures for vagus nerve stimulator implantation, one or more antiepileptic drugs (AEDs), and 6 or more months of continuous Medicaid enrollment pre- and post-VNS were selected. The pre-VNS period was 6 months. The post-VNS period extended from implantation to device removal, death, Medicaid disenrollment, or study end (up to 3 years). Incidence rate ratios (IRRs) and cost differences ($2009) were estimated. Mean age was 29.4 years. Hospitalizations decreased post-VNS compared with pre-VNS (adjusted IRR=0.59, P<0.001). Grand mal status events decreased post-VNS compared with pre-VNS (adjusted IRR=0.79, P<0.001). Average total health care costs were lower post-VNS than pre-VNS ($18,550 vs $19,945 quarterly, P<0.001). VNS is associated with decreased resource utilization and epilepsy-related clinical events and net cost savings after 1.5 years.

Global prevalence of long-term neurodevelopmental impairment following extremely preterm birth: a systematic literature review.

OBJECTIVE: Neurodevelopmental impairment (NDI) is a major complication of extreme prematurity. This systematic review was conducted to summarize the worldwide long-term prevalence of NDI associated with extreme prematurity. METHODS: Embase and MEDLINE databases were searched for epidemiologic and observational/real-world studies, published in English between 2011 and 2016, reporting long-term prevalence of NDI (occurring from 1 year) among extremely preterm infants born at gestational age (GA) ≤28 weeks. RESULTS: Of 2406 articles identified through searches, 69 met the protocol NDI definition (24 North America, 25 Europe, 20 Rest of World). Prevalence of any severity NDI in North America was 8%-59% at 18 months to 2 years, and 11%-37% at 2-5 years; prevalence of moderate NDI in Europe was 10%-13% at 18 months to 2 years, 3% at 2-5 years, and 9%-19% at ≥5 years; prevalence of any NDI in Rest of World was 15%-61% at 18 months to 2 years, and 42% at 2-5 years (no North America/Rest of World studies reported any NDI at ≥5 years). A trend toward higher prevalence of NDI with lower GA at birth was observed. CONCLUSIONS: Extreme prematurity has a significant long-term worldwide impact on neurodevelopmental outcomes.

Respiratory morbidity, healthcare resource use, and cost burden associated with extremely preterm birth in The Netherlands.

BACKGROUND: Extremely preterm (EP) infants have high rates of respiratory morbidity and correspondingly high healthcare resource utilization. OBJECTIVES: Data from the PHARMO Perinatal Research Network were analyzed to quantify the burden of EP birth in the Netherlands. METHODS: A retrospective analysis included infants <28 weeks gestational age with a birth record in the Perinatal Registry (1999-2015) and data in the PHARMO Database Network. Outcomes of interest included select comorbidities, hospital readmissions, and costs of hospitalization and medication up to 1- and 2-years corrected age. Outcomes were stratified by birth period (1999-2005, 2000-2009, 2010-2015) and by diagnosis of bronchopulmonary dysplasia (BPD) and chronic lung disease (CLD). RESULTS: The cohort included 168 EP infants (37 born 1999-2005, 51 born 2006-2009, 80 born 2010-2015). Median (Q1-Q3) birth weights decreased by birth period from 970 (840-1,035) g in 1999-2005 to 853 (695-983) g in 2010-2015. Overall, BPD and CLD were reported during the birth hospitalization in 40% and 29% of infants, respectively; rates of BPD increased and rates of CLD decreased by birth period. Eighty-four percent of EP infants had an additional comorbidity. Mean (standard deviation) costs of birth hospitalization were €110,600 (€73,000) for 1999-2005, €119,350 (€60,650) for 2006-2009, and €138,800 (€130,100) for 2010-2015. Birth hospitalization and total costs for up to 1- and 2-years corrected age were higher for infants with BPD and/or CLD than for those without either complication. CONCLUSION: Healthcare resource utilization and costs for EP infants, especially for those with respiratory morbidities, increased between 1999 and 2015. Future cost-effectiveness analyses are essential to determine the economic impact of this change and underscore the need for new therapeutic interventions to decrease clinical sequelae in this vulnerable population.