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Sickle cell disease (SCD) is a genetic disorder, characterized by hemolytic anemia and vaso‐occlusive crises (VOCs). Data on the global SCD impact on quality of life (QoL) from the patient viewpoint are limited. The international Sickle Cell World Assessment Survey (SWAY) aimed to provide insights into patient‐reported impact of SCD on QoL. This cross‐sectional survey of SCD patients enrolled by healthcare professionals and advocacy groups assessed disease impact on daily life, education and work, symptoms, treatment goals, and disease management. Opinions were captured using a Likert scale of 1‐7 for some questions; 5‐7 indicated “high severity/impact.” Two thousand one hundred and forty five patients (mean age 24.7 years [standard deviation (SD) = 13.1], 39% ≤18 years, 52% female) were surveyed from 16 countries (six geographical regions). A substantial proportion of patients reported that SCD caused a high negative impact on emotions (60%) and school achievement (51%) and a reduction in work hours (53%). A mean of 5.3 VOCs (SD = 6.8) was reported over the 12 months prior to survey (median 3.0 [interquartile range 2.0‐6.0]); 24% were managed at home and 76% required healthcare services. Other than VOCs, fatigue was the most commonly reported symptom in the month before survey (65%), graded “high severity” by 67% of patients. Depression and anxiety were reported by 39% and 38% of patients, respectively. The most common patient treatment goal was improving QoL (55%). Findings from SWAY reaffirm that SCD confers a significant burden on patients, epitomized by the high impact on patientsʼ QoL and emotional wellbeing, and the high prevalence of self‐reported VOCs and other symptoms.

Background: VOCs are the hallmark of SCD and can lead to serious complications and organ damage. P-selectin, a cell adhesion protein, plays a central role in the multicellular interactions that can lead to VOCs. Crizanlizumab, a first-in-class humanized monoclonal antibody that targets P-selectin, is approved in several regions to prevent/reduce VOC burden for patients (pts) with SCD aged ≥16 years. Pts in some countries can obtain early access to crizanlizumab before health authority approval via a MAP (NCT03720626); first pt enrolled in June 2018. Aim: To describe the proportions of pts with 0 home- or 0 healthcare-managed VOCs after 6 months of treatment with crizanlizumab in the MAP (in countries where publication of these data is allowed). Methods: The MAP was designed to provide access to crizanlizumab for SCD pts with serious or life-threatening disease for which no comparable or satisfactory alternative to crizanlizumab was available as treatment in their country. Other eligibility criteria included: aged 16-70 years (18-70 years in Italy); history of VOCs as assessed by the treating physician (including recurrent VOCs while receiving hydroxyurea [HU], L-glutamine or other therapies); and not eligible for a crizanlizumab clinical trial. At baseline, treating physicians were asked about their pts' disease burden in the 12 months prior to requesting access to crizanlizumab (eg frequency of home- or healthcare-managed VOCs and opioid use for VOC management). The proportions of pts with 0 home- or 0 healthcare-managed VOCs after 6 months of treatment with crizanlizumab are described overall and stratified by SCD genotype and history of HU use. Results: Treating physicians made requests for initial access to crizanlizumab for 146 pts eligible for this analysis. Most of these pts were from Brazil (n=105; 72%), with the remainder residing in Italy, Spain, Israel, Canada, Portugal and Switzerland. Of the 144 pts with baseline data (missing, n=2), 142 (99%) had ≥1 home-managed VOC (median [interquartile range; IQR] of 6 [4‒8.5] VOCs) and 137 (95%) had ≥1 healthcare-managed VOC (median [IQR] of 3 [2‒5] VOCs) in the 12 months before entry into the MAP. Opioids were taken for VOC management by 92% of pts in the 12 months prior to baseline (n=132/144); the most common was morphine (n=57/132; 43%). As of June 2021, 102 of the 146 pts with initial requests had received crizanlizumab for ≥6 months and had resupply requests submitted by their physicians. For these 102 pts, median (IQR) age was 33 (25-40) years, 62% were female, 47% were of African American ethnicity, the genotype was HbSS in 79%, and a history of HU use was reported in 45% of these pts. Eleven pts (5%) discontinued crizanlizumab during the 6 months of treatment reported in this analysis. Of the 102 pts with data available 6 months post-crizanlizumab initiation, 46 (45%) reported 0 home-managed VOCs (median [IQR] of 1 [0‒2] VOC) and 62 (61%) reported 0 healthcare-managed VOCs (median [IQR] of 0 [0‒1] VOCs) during this time period. The proportions of pts with 0 home- or 0 healthcare-managed VOCs after 6 months of treatment with crizanlizumab stratified by SCD genotype and history of HU use are shown in Figure 1. Clinicians participating in the MAP anecdotally reported improvement in certain clinical complications (eg leg ulcers and priapism), reduced frequency of hospitalizations, shorter lengths of hospital stay and reduced use of opioids in some pts after crizanlizumab treatment. Adverse events were consistent with those reported in other crizanlizumab studies. Limitations: The difference in time periods for which data are available (ie 12 months for baseline data vs 6 months for post-treatment initiation data) precludes a comparison of data pre- and post-initiation of crizanlizumab in this analysis. Information about HU use was not provided for all pts, therefore the proportion of pts with a history of HU use in this analysis could be higher than reported. Conclusion: Pts participating in the crizanlizumab MAP had a high burden of home- and healthcare-managed VOCs at baseline despite many pts reporting a history of HU use; almost all required opioids for VOC management. Findings from this analysis looking at the proportion of pts with 0 home- or 0 healthcare-managed VOCs after 6 months of treatment with crizanlizumab are promising, although additional data with ≥12 months of exposure are required to compare VOC burden on treatment with that reported here at baseline. Figure 1 Figure 1. Disclosures Cançado: Novartis: Consultancy. Colombatti: NovoNordisk: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees. Quarta: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; Speaker at conferences; Celgene: Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; Sanofi - Genzyme: Membership on an entity's Board of Directors or advisory committees, Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; Speaker at conferences; Blue Bird Bio: Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; Takeda: Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; speaker at conferences; Bristol Meyer Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Speaker at conferences. DeBonnett: Novartis Pharmaceuticals Corporation: Current Employment. Soliman: Novartis: Current Employment. Sarkar: Novartis: Current Employment. Pinto: Novartis: Consultancy; Global Blood therapeutics (GBT): Consultancy; EMS, Brazil: Consultancy.

Background: Sickle cell disease (SCD) is an inherited group of red blood cell disorders with a complex pathophysiology largely driven by vaso-occlusion and hemolytic anemia. Vaso-occlusive crises (VOCs) are the hallmark of SCD. VOCs and continuing silent vaso-occlusion are associated with cycles of inflammation and tissue injury that can lead to acute and chronic organ complications. Sickle cell nephropathy (SCN) is the term used to describe kidney-related complications of SCD; manifestations include hyperfiltration, albuminuria and progressive loss of kidney function. Endothelial dysfunction may play a role in the development of albuminuria in SCD. Increased plasma endothelin-1 (ET-1), a biomarker of endothelial dysfunction, is significantly associated with an increase in the urine albumin-to-creatinine ratio (ACR) (Ataga et al. PLoS One 2016). Patients (pts) with SCN may develop chronic kidney disease (CKD; diagnosed when abnormalities in kidney structure or function persist for >3 mo). Pts with SCD and baseline (BL) albuminuria ≥100 mg/g can develop persistent albuminuria, which is associated with a rapid decline in estimated glomerular filtration rate (eGFR) (Niss et al. Blood Adv 2020). No treatments are approved for CKD due to SCN; current SoC usually consists of angiotensin-converting enzyme inhibitors (ACEI), angiotensin-receptor blockers (ARBs) and/or hydroxyurea/hydroxycarbamide (HU/HC). P-selectin is one of the drivers of multicellular adhesion leading to vaso-occlusion. Preclinical studies have shown that P-selectin expression increases in response to renal ischemia-reperfusion injury (Zizzi et al. J Pediatr Surg 1997). Crizanlizumab, a humanized monoclonal antibody that binds to P-selectin, significantly reduced the median annualized VOC rate vs placebo (Ataga et al. NEJM 2017). The aim of the Phase II STEADFAST study (NCT04053764) is to determine the effect of P-selectin inhibition with crizanlizumab on kidney function in pts with SCD and early-stage CKD. Methods: The STEADFAST trial aims to enroll 148 pts aged ≥16 yrs with CKD due to SCD; pts eligible for inclusion are detailed in the figure. Pts will be randomized 1:1 to receive crizanlizumab 5.0 mg/kg (intravenous infusion over 30 min on Day 1 of Wk 1, Day 1 of Wk 3, then every 4 wks for 1 yr) and their usual SoC or their usual SoC alone. Pts will be stratified based on CKD risk category (moderate risk or high/very high risk, based on eGFR and albuminuria assessed by ACR) and if they are receiving HU/HC. Exclusion criteria include pts with a history of stem cell transplant, evidence of acute kidney injury within 3 mo of study entry, or those receiving renal replacement therapy. The primary endpoint is the proportion of pts with ≥30% decrease from BL in ACR at 12 mo. A logistic regression model including treatment effects and stratification factors will be utilized; the test (based on the log-odds ratio estimated by the model) will be performed at a 1-sided significance level of 0.025. Secondary endpoints include mean change in ACR from BL to 3, 6, 9 and 12 mo, the percentage change in eGFR from BL to 3, 6, 9 and 12 mo, the proportion of pts with a protein-to-creatinine ratio (PCR) improvement (≥20% decrease) or stable PCR (within ±20%) at 12 mo compared with BL and the proportion of pts with progression of CKD (based on pre-defined eGFR decline and ACR increase) from BL to 12 mo. To minimize variability of ACR measurements, 3 urine samples (2/3 samples collected as morning voids) will be collected at all designated timepoints. Exploratory endpoints include assessments of renal and cardiac biomarkers, including ET-1 and soluble P-selectin, at BL, 3, 6, 9 and 12 mo, echocardiography at BL and 12 mo and renal MRI at BL, 6 and 12 mo (at selected sites). Results: As of July 2021, 31 pts have been enrolled, with 36 sites in 10 countries currently open to enrollment. Open sites by country include USA (9 sites), Brazil (5 sites), Spain (4 sites), Italy, Turkey and the UK (3 sites each), France, Greece and Panama (2 sites each), Lebanon, the Netherlands and South Africa (1 site each). Study sites in Bahrain, Egypt, Ghana and Kenya are planned and Ireland, Tanzania and Saudi Arabia have been recently added as new participating countries. Conclusion: The Phase II STEADFAST study has been designed to evaluate whether crizanlizumab, in combination with SoC, can provide a potentially targeted disease-modifying benefit for pts with SCD and CKD. The trial is open for enrollment. Figure 1 Figure 1. Disclosures Saraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ataga: Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees. Derebail: Travere Therapeutics: Consultancy; Novartis: Consultancy; Bayer: Consultancy; UpToDate: Patents & Royalties. Sharpe: Napp Pharmaceuticals: Speakers Bureau; Novartis Pharmaceuticals: Consultancy. Lebensburger: Novartis: Consultancy; Bio Products Laboratory: Consultancy. DeBonnett: Novartis Pharmaceuticals Corporation: Current Employment. Zhang: Novartis: Current Employment. Bartolucci: INNOVHEM: Other: Co-founder; Hemanext: Consultancy; AGIOS: Consultancy; Jazz Pharma: Other: Lecture fees; GBT: Consultancy; Emmaus: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy; Bluebird: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Fabre Foundation: Research Funding; Addmedica: Consultancy, Other: Lecture fees, Research Funding. OffLabel Disclosure: The presentation will discuss use of crizanlizumab as an investigational therapy in patients with sickle cell disease and sickle cell nephropathy

Background: SCD is an inherited blood disorder that for many patients (pts) has a high clinical burden, results in poor quality of life (QoL), and reduces life expectancy. Gaining a deeper understanding of pt and HCP experiences of SCD is important to improve pt management. Aims: SWAY was a cross-sectional survey that assessed pt and HCP experiences of SCD. Here we focus on the experiences of HCPs from various regions on SCD symptoms and complications, impact of SCD on QoL, treatment goals and treatment satisfaction. Methods: SWAY was developed by international SCD expert physicians, pt advocates and Novartis. HCPs completed the survey between Apr and Oct 2019. Eligible HCPs had qualified in their primary specialty by 2014 and were managing ≥10 SCD pts at the time of survey (≥5 pts per HCP in Canada; ≥2 pts in the Netherlands). Responses to questions on how much SCD impacts pt QoL, and on HCP treatment satisfaction, were ranked on a Likert scale (1-7, where 1=not at all/strongly dissatisfied, 7=a great deal/strongly satisfied; 5-7 indicated high impact/satisfaction). The data reflect only the experiences of the surveyed HCPs in each region (recruited by Adelphi Real World fieldwork). A limitation is that Asia and South America (SA) were represented by single countries (India and Brazil, respectively). Results: SWAY was completed by 365 HCPs from 6 regions (Table). In all regions HCPs recognized the prevalence of acute and chronic pain, however acute pain was reported less frequently by HCPs in Africa than in other regions (Table). Acute chest syndrome and joint issues were among the top 5 most frequently mentioned complications by HCPs in all regions. Globally, HCPs recognized the high impact of SCD symptoms and complications on pt QoL and the high negative impact of SCD on pt emotional wellbeing (Likert score 5-7 reported by 79-100% and 71-97%, respectively). Fewer HCPs in the Middle East (ME) reported a high impact of SCD on physical and sexual activity, compared with HCPs in other regions. Around 40% of HCPs in the ME and Asia thought SCD has a high impact on daily activities, compared with 79-90% of HCPs in other regions. In Asia, fewer HCPs reported that SCD has a high impact on pts' education and ability to maintain a job compared with HCPs in other regions (Figure). Hydroxyurea (HU) was among the top 3 most common therapies ever initiated and was the therapy most likely to be initiated in any age group by HCPs in almost all regions. In Africa, the most common therapy ever initiated and the therapy most likely to be initiated in any age group was opioids (Table). Fewer HCPs in North America (NA; 32%) and SA (27%) were highly satisfied with current SCD treatments, compared with HCPs in other regions (46-72%). The main reason for dissatisfaction was limited treatment options in all regions except Asia, where HCPs said they were unable to reach their treatment goals with current therapies. Improving pts' QoL was among the top 3 treatment goals for 51-84% of HCPs across all regions. For HCPs in NA and the ME, the most important goal when treating vaso-occlusive crises was to improve QoL; in SA, Europe and Asia it was to avoid organ damage; and in Africa it was to eliminate pain completely. Discussion: The top 5 most frequent SCD symptoms and complications that HCPs reported were similar across all regions. There were regional differences in HCP experiences of how SCD impacts aspects of pts' daily life, with fewer HCPs in the ME reporting a high impact on physical and sexual activity, and fewer HCPs in Asia and the ME reporting a high impact on daily activities compared with other regions. This may be due to cultural variations, with pts in these regions being less comfortable discussing these topics with HCPs. There was a difference in the reported impact of SCD on school and work between HCPs in Asia and other regions, which could be due to varying expectations regarding school/work productivity. HU was one of the top 3 most common treatments ever initiated by HCPs for pts of any age, except in Africa, which may be due to an educational knowledge gap about HU, high cost, or poor access in this region. HCPs in almost all regions, except Asia, were dissatisfied with current SCD treatments because of limited therapeutic options, indicating a global unmet need for additional treatment choices. Improving QoL was the most important treatment goal for HCPs in all regions, demonstrating the high negative impact that SCD has on pt QoL and the ongoing need for methods to address this. Figure 1 Figure 1. Disclosures Osunkwo: Novartis Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; FORMA Therapeutics: Consultancy; Global Blood Therapeutics: Consultancy, Speakers Bureau; Chiesi: Consultancy; Acceleron: Consultancy; Cyclerion: Consultancy; Emmaus: Consultancy. Minniti: Roche: Consultancy, Honoraria; NovoNordisk: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; GBT: Consultancy, Research Funding. Nur: Roche: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Nero: Global Blood Therapeutics: Consultancy; Editas Medicine: Consultancy; bluebird bio: Consultancy; Novartis: Consultancy. Colombatti: Global Blood Therapeutics: Research Funding; Addmedica: Consultancy; Forma Therapeutics: Consultancy; Novartis: Consultancy; NovoNordisk: Consultancy; BlueBirdBio: Consultancy; Global Blood Therapeutics: Consultancy; BlueBirdBio: Research Funding. de Montalembert: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Addmedica: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees; Vertex: Membership on an entity's Board of Directors or advisory committees. Abboud: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research Support and Advisory Board, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Other: Reserach support and advisory board , Research Funding; GBT: Other: Research Support, Research Funding; Vertex Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: DSMB. Arlet: Addmedica: Research Funding; Pfizer: Honoraria; Novartis company: Consultancy, Honoraria, Research Funding. Jastaniah: Novartis: Consultancy, Honoraria, Research Funding. Pita: GLOBAL ALLIANCE OF SCD: Membership on an entity's Board of Directors or advisory committees; LUA VERMELHA SCD ASSOCIATION: Membership on an entity's Board of Directors or advisory committees. Francis-Gibson: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sickle Cell Disease Association of America: Current Employment; ASH: Membership on an entity's Board of Directors or advisory committees; Alliance for Regenerative Medicine Foundation for Cell and Gene Medicine: Membership on an entity's Board of Directors or advisory committees; Global Alliance of SCD Organizations: Membership on an entity's Board of Directors or advisory committees. Trimnell: Novartis: Consultancy; Cyclerion: Consultancy; Global Blood Therapeutics: Consultancy. DeBonnett: Novartis Pharmaceuticals Corporation: Current Employment. Bailey: Novartis Pharmaceuticals: Other: I am an employee of Adelphi Real World, which received payment from Novartis Pharmaceuticals for this research. Rajkovic-Hooley: Novartis Pharmaceuticals: Other: I am an employee of Adelphi Real World, which received payment from Novartis Pharmaceuticals for this research. James: GBT: Honoraria; Novartis: Honoraria.

Background Chronic lung infection with Pseudomonas aeruginosa occurs in approximately 50% of patients with cystic fibrosis (CF). This infection further compromises lung function, and significantly contributes to the increased healthcare costs. Objectives Inhaled tobramycin, used to manage P. aeruginosa infection in CF patients, is available as powder (tobramycin inhalation powder, TIP) and solution (tobramycin inhalation solution, TIS). Evidence suggests increased adherence with the use of TIP over TIS. Hence, this analysis aimed to evaluate the potential pharmacoeconomic benefit of increased adherence with TIP over TIS in the US setting. Methods A patient-level simulation model was developed to compare TIP with TIS. Both costs and benefits were predicted over a 10-year time horizon from a payer’s perspective, and were discounted annually at 3%. All costs were presented in 2016 US dollars. Results TIP was associated with greater quality-adjusted life-years (by 0.27) and lower total costs (by US$36,168) as compared with TIS over a 10-year time horizon. TIP-treated patients experienced a decreased mean number of exacerbations than TIS-treated patients (39.24 vs 50.20). Furthermore, administration of TIP via the T-326 Inhaler was associated with significant cost savings per patient, because of the nebulizer required for administering TIS (by US$1596) and exacerbation costs (by US$76,531). Probabilistic sensitivity analysis showed that TIP was dominant over TIS in 100% of the simulations. Conclusion TIP is likely to be a more cost-effective treatment than TIS, and therefore may reduce the economic burden of CF.

Chronic airway infection with Pseudomonas aeruginosa is a major cause of increased morbidity and mortality in patients with cystic fibrosis (CF). The development and widespread use of nebulized antibacterial therapies, including tobramycin inhalation solution (TIS), has led to improvements in lung function and quality of life. However, the use of nebulizers is associated with various challenges, including extended administration times and the need for frequent device cleaning and disinfection. Multiple therapies are required for patients with CF, which poses a considerable burden to patients, and adherence to the recommended treatments remains a challenge. Tobramycin inhalation powder (TIP), delivered via the T-326 Inhaler, has been shown to have similar clinical efficacy and safety as compared to TIS, with improved patient convenience, satisfaction, and treatment adherence. Long-term safety studies have shown that TIP was well tolerated with no unexpected adverse events in patients with CF. This review of the TIP pivotal and postmarketing studies reinforces the well-established efficacy and safety profile of TIP and its ease of use.

Summary Introduction TOBI® Podhaler™ is a capsule-based drug-device combination (tobramycin inhalation powder [TIP] 28 mg capsules via unit-dose dry powder T-326 Inhaler [Podhaler™]) developed for treatment of Pseudomonas aeruginosa infection in cystic fibrosis (CF). We explored how inspiratory flow profiles and mouth-throat geometries affect drug delivery with the T-326 Inhaler. Methods Inspiratory flow profiles were recorded from 38 subjects aged 6–71 who had CF and varying degrees of lung function impairment. Ten of the inspiratory flow profiles were simulated in the laboratory using a custom breath simulator to determine delivered dose (DD) from the T-326 Inhaler. In vitro total lung dose (TLDin vitro) was measured using four anatomical throat models, ranging from a child to a large adult. Results Aerosol performance was assessed across a range of inspiratory flow profiles. Mean DD ranged from 88.8% to 97.0% of declared capsule content. TLDin vitro ranged from 54.8% to 72.4% of capsule content between the flow profile/throat options tested, and the mean TLDin vitro across the range of flow profiles and anatomical throats tested was 63 ± 5%. Conclusions Our findings indicate that the T-326 Inhaler provides reliable drug delivery at flow rates likely to be achieved by a broad spectrum of patients with CF. Importantly, forceful inhalation was not required to achieve a robust TLDin vitro. Pediatr Pulmonol. © 2016 Wiley Periodicals, Inc.

Summary This is an integrated analysis of data from patients with cystic fibrosis (CF) aged 6–21 years who were treated with up to seven cycles of tobramycin powder for inhalation (TIPTM) over a period of at least 1 year. Safety and key efficacy endpoints were analyzed. Results: The improvement in lung function and decrease in sputum P. aeruginosa (Pa) density from baseline were sustained over the 1-year treatment period. The number of adverse events (AEs) was low and did not increase with additional cycles of TIP treatment. Some increase in tobramycin minimum inhibitory concentration (MIC) was observed, but there was no significant increase in emergence of resistant strains based on the parenteral breakpoint for tobramycin. Conclusion: Efficacy of TIP was maintained for up to seven cycles. Long-term treatment with TIP was generally safe and well tolerated with no increase in AEs. Pediatr Pulmonol. 2016;51:372–378. © 2015 Wiley Periodicals, Inc.

Objectives Erythropoiesis-stimulating agents (ESAs) remain first-choice to treat symptomatic anemia and delay transfusion dependence in most patients with lower-risk myelodysplastic syndromes (MDS) without del(5q). Deferasirox increased erythroid responses in some lower-risk MDS patients in clinical trials, and adding low-dose deferasirox to ESA treatment may further improve erythroid response. Methods KALLISTO (NCT01868477) was a randomized, open-label, multicenter, phase II study. Lower-risk MDS patients received deferasirox at 10 mg/kg/d (dispersible tablets) or 7 mg/kg/d (film-coated tablets) plus erythropoietin (n = 11), or erythropoietin alone (n = 12) for 24 weeks. The primary endpoint was the between-group difference in erythroid response within 12 weeks. Results Erythroid response occurred in 27.3% of patients receiving deferasirox plus erythropoietin vs 41.7% of patients receiving erythropoietin alone within 12 weeks (difference 14.4%; 95% CI -24.0, 48.16). Within 24 weeks, the hematologic response rate was 27.3% with deferasirox plus erythropoietin vs 50% with erythropoietin alone, and hematologic improvement rates were 45.5% vs 100%. Deferasirox plus erythropoietin was generally well tolerated. Conclusions In this small pilot study, combining low-dose deferasirox with erythropoietin did not improve erythroid response. It remains of interest to investigate early chelation approaches with even lower deferasirox doses plus erythropoietin in lower-risk MDS patients before the onset of transfusion dependence.

Background: This study assessed the ease of use of tobramycin inhalation powder (TIP) administered via T-326 inhaler versus tobramycin inhalation solution (TIS) and colistimethate sodium (COLI), both administered via nebulizers, for the treatment of chronic pulmonary Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF). Methods: A real-world, open-label, crossover, interventional phase IV study was conducted in CF patients aged ⩾6 years with forced expiratory volume in 1 second (FEV1) ⩾25% to ⩽90% predicted. Patients were assigned to one of the three treatment arms in Cycle 1; all patients received TIP in Cycle 2. Each cycle consisted of 28 days on and 28 days off the treatment. Results: A total of 60 patients [mean (standard deviation) age, 27.6 (8.4) years] were allocated to three treatment arms [TIS/TIP ( n = 14); COLI/TIP ( n = 28); TIP/TIP ( n = 18)] in Cycle 1. The mean total administration time, which included device setup and cleaning, in Cycle 1 versus Cycle 2 for TIS/TIP, COLI/TIP, and TIP/TIP arms were 37.0 versus 5.0 min, 16.4 versus 3.8 min, and 4.2 versus 3.4 min, respectively. The difference in mean total administration time was significantly shorter in Cycle 2 than in Cycle 1 for TIS/TIP ( p = 0.0112) and COLI/TIP ( p = 0.0016) arms. Overall, 12 patients were found to have contaminated devices across the two treatment cycles. In the TIP/TIP arm, no contamination of the T-326 inhaler was observed in either cycle. Treatment satisfaction, assessed by the Treatment Satisfaction Questionnaire for Medication and ACCEPT® questionnaire, was better overall for TIP compared with TIS and COLI. There were no unexpected adverse events and most were mild or moderate in intensity. Conclusion: The T-326 inhaler used to deliver TIP was easy to use, required shorter total administration time, and was much less frequently contaminated than the nebulizers. The safety findings observed for TIP were generally consistent with its established safety profile.

Background: Sickle cell disease (SCD) is an inherited genetic disorder that results in the formation of sickle hemoglobin (HbS). HbS polymerizes when deoxygenated, deforming erythrocytes and leading to chronic hemolysis, anemia and vaso-occlusion. Sickle cell nephropathy (SCN) is the term used to describe the renal complications of SCD. Renal vaso-occlusion and hemolysis contribute to the manifestations of SCN which include hyperfiltration and progressive renal impairment. Chronic kidney disease (CKD) is diagnosed if abnormalities in kidney structure or function are present for >3 months. The prevalence of CKD in patients with SCD increases with age, and ~12% of patients progress to end-stage renal disease (Gosmanova et al. J Investig Med 2014; Powars et al. Medicine 2005). There are no treatments approved for CKD caused by SCD. Standard of care (SoC) typically consists of angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs) and/or hydroxyurea (HU). Evidence for the clinical effectiveness of ARBs and ACE inhibitors has been generated mainly from trials in other causes of kidney disease or short-term studies in SCD. P-selectin contributes to vaso-occlusion by mediating adhesion of sickled erythrocytes and leukocytes to the endothelium. Crizanlizumab is a humanized monoclonal antibody that binds to P-selectin with high affinity and specificity. In SUSTAIN, crizanlizumab significantly reduced the median annual rate of vaso-occlusive crises compared with placebo (Ataga et al. N Engl J Med 2017). Preclinical data show P-selectin expression in the kidneys and upregulation in response to renal ischemia-reperfusion injury (Singbartl et al. FASEB J 2000; Zizzi et al. J Pediatr Surg 1997). Crizanlizumab may have a beneficial effect in patients with SCD and CKD by blocking P-selectin-mediated multicellular adhesion, reducing the effects of vaso-occlusion in the renal vasculature and slowing the decline in renal function. The aim of the STEADFAST study is to determine if crizanlizumab can slow the progression of CKD due to SCD (EUDRACT no. 2018-003608-38). Methods: Approximately 170 patients aged ≥16 years with CKD due to SCD will be enrolled. Eligible patients will have HbSS or HbSβ0-thalassemia genotypes, an estimated glomerular filtration rate (eGFR) ≥45 to ≤120 mL/min/1.73 m2, an albumin-to-creatinine ratio (ACR) ≥100 to Patients will be randomized to receive crizanlizumab 5.0 mg/kg plus SoC or SoC alone. Patients in the combination arm will receive crizanlizumab 5.0 mg/kg by IV infusion over 30 minutes on day 1 of week 1, followed by a second dose 2 weeks later, after which it will be administered every 4 weeks. The total treatment period is 12 months. Primary endpoint: proportion of patients with a ≥30% decrease from baseline in ACR at 12 months, based on the intent-to-treat population. A logistic regression model including treatment effects and stratification factors will be utilized and the test (based on the log-odds ratio estimated by the model) will be carried out at the 1-sided significance level of 0.025. Secondary endpoints include mean change in ACR from baseline to 3, 6, 9, and 12 months, proportion of patients with ≥30% decrease in ACR at 6 months, proportion of patients with ≥20% improvement of protein-to-creatinine ratio (PCR) at 12 months, percentage change in eGFR from baseline to 3, 6, 9, and 12 months, and the proportion of patients with progression of CKD (based on decline in eGFR category accompanied by a ≥25% drop in eGFR from baseline) from baseline to 12 months. Exploratory endpoints include improvement in renal and cardiac biomarkers at 3, 6, 9, and 12 months and tricuspid regurgitation velocity (TRV) Conclusion: CKD is a common complication of SCD. The STEADFAST study will evaluate whether crizanlizumab, in combination with SoC, can reduce albuminuria and slow CKD progression, thus providing evidence of a reno-protective effect of crizanlizumab. Figure Disclosures Ataga: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Emmaus Life Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Modus Therapeutics: Honoraria. Saraf:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding. Derebail:RTI: Honoraria; Novartis: Consultancy; Retrophin: Consultancy. Sharpe:Novartis: Consultancy. Inati:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novonordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Global Blood Therapeutics: Research Funding. Lebensburger:Pfizer: Research Funding; Novartis: Consultancy. DeBonnett:Novartis Pharmaceuticals Corporation: Employment. Zhang:Novartis: Employment. Bartolucci:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; HEMANEXT: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AddMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Background: Sickle cell disease (SCD) is characterized by the presence of sickle hemoglobin (HbS), chronic hemolysis, recurrent pain episodes called vaso-occlusive crises (VOCs), multiorgan dysfunction and early death. VOCs decrease quality of life, are the main cause of healthcare encounters in SCD, and increase the risk of death. New therapies that reduce SCD hospitalizations are desirable given the potential to impact healthcare utilization, but also to reduce disease burden and decrease mortality and morbidity. The SUSTAIN study (Ataga et al. NEJM 2017), was a Phase 2, multicenter, randomized, placebo-controlled, double-blind, 12-month study to assess safety and efficacy of crizanlizumab (2.5 and 5 mg/kg) with or without hydroxyurea therapy, in patients with SCD and a history of 2-10 VOCs in the previous 12 months (NCT01895361). The primary efficacy endpoint was annual rate of SCD-related pain crises (VOCs) leading to healthcare visit. The key secondary endpoint was annual rate of days hospitalized, regardless of cause. There was a statistically significant 45.3% reduction in median annual rate of VOCs leading to healthcare visit with crizanlizumab 5 mg/kg compared with placebo (1.63 vs 2.98 VOCs/year, P=0.01). There was a 41.8% reduction in median rate of days hospitalized with crizanlizumab 5 mg/kg compared with placebo (4.00 vs 6.87 days/year). Although this difference was not statistically significant (P=0.45), it appears to be clinically relevant. Methods: A post-hoc analysis of the SUSTAIN data was performed to better characterize the difference in the annual rate of days hospitalized between the crizanlizumab 5 mg/kg and placebo arms, and to compare the distribution of hospitalizations and time to first hospitalization. Results: As illustrated in Figure 1, a greater proportion of patients in the crizanlizumab arm (46%) were not hospitalized during the trial period (up to end of treatment) than in the placebo arm (35%). Correspondingly, the percentage of patients with ≥1 hospitalization was lower in the crizanlizumab (54%) than the placebo arm (65%). In addition, a trend for delayed time to first hospitalization shown in Figure 1 was further explored with a Kaplan-Meier (KM) analysis (Figure 2). Figure 2 shows clear separation of the curves, evident from Month 1 of treatment. The median time to first hospitalization was greater with crizanlizumab 5 mg/kg than with placebo (6.3 vs 3.2 months; hazard ratio [HR] 0.683 [95% CI 0.437-1.066]). The apparent improvement in time to first hospitalization is consistent with previously published SUSTAIN results regarding median time to first VOC leading to healthcare visit. Patients treated with crizanlizumab 5 mg/kg were found to experience a longer median time to first VOC leading to healthcare visit than patients on placebo (4.07 vs 1.38 months; HR 0.50 [95% CI 0.33-0.74]). Conclusions: The primary SUSTAIN results showed that crizanlizumab reduced VOCs leading to a healthcare visit. This analysis demonstrates additional positive trends associated with crizanlizumab treatment compared to placebo, regarding the percentage of patients with no hospitalizations and a delayed time to first hospitalization. Together, these findings provide further evidence that crizanlizumab may have a beneficial impact on reducing hospitalizations. Disclosures Ataga: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Emmaus Life Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Modus Therapeutics: Honoraria. Kutlar:Micelle Biopharma: Other: DSMB Chair; Novartis: Consultancy; Global Blood Therapeutics, Inc. (GBT): Research Funding; Novo Nordisk: Research Funding; Bluebird Bio: Other: DSMB Member. DeBonnett:Novartis Pharmaceuticals Corporation: Employment. Lincy:NOVARTIS PHARMA AG: Employment. Kanter:Novartis: Consultancy, Honoraria; Imara: Consultancy; Sangamo: Consultancy, Honoraria; Modus: Consultancy, Honoraria; Guidepoint Global: Consultancy; GLG: Consultancy; Cowen: Consultancy; Jeffries: Consultancy; Medscape: Honoraria; Rockpointe: Honoraria; Peerview: Honoraria; SCDAA: Membership on an entity's Board of Directors or advisory committees; NHLBI: Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Consultancy.

Background: Sickle cell disease (SCD) is a multi-system disease affecting millions of people. The disease is characterized by vaso-occlusive crises (VOCs), resulting in acute and chronic pain, end-organ damage and life-threatening complications. The symptoms experienced by patients, caused largely by multi-cellular adhesion leading to vaso-occlusion and vasculopathy, significantly affect their quality of life (QoL) and ability to work/study. Understanding the effect of SCD on patients' daily lives can inform management of the disease and improve patients' QoL. Aims: To assess the impact of SCD on patients' daily lives, including physical symptoms, emotional wellbeing and economic burden, based on the worldwide SWAY survey. Methods: SWAY is an ongoing multi-country, cross-sectional survey of SCD patients, caregivers and treating physicians. Data are collected using self-completed or proxy surveys and categories include demographics, symptoms and impact of disease (physical, emotional and financial) and need for a caregiver. Where relevant, questions include a 7-point severity scale for each statement, with a score of 5 to 7 indicating 'high severity/impact'. Patient enrollment is via treating physicians and patient association groups. The enrollment target is approximately 2000 patients. Results: To date, 1513 SCD patients (48% male, mean age 24.1 years, 63% HbSS and 30% SC disease) have been surveyed from countries across the world, including the USA (365), UK (299), Nigeria (264), Ghana (255), Brazil (160) and Germany (91). The most commonly experienced symptoms of SCD were bone aches (63%), difficulty concentrating (49%), difficulty gaining weight (49%) and joint stiffness (41%). For these symptoms, 67%, 53%, 70% and 59% of patients rated them as 'high severity' on the 7-point scale, respectively. Background pain was present on an average of 2.9 days per week (standard deviation [SD]=2.2). Commonly experienced complications of SCD include fever (65%), joint issues (55%) and infections (55%). Patients reported a total of 7829 VOCs, with a mean of 5.2 VOCs per patient (SD=5.07) in the 12 months before survey completion; 38% of these VOCs resulted in overnight hospitalization, 24% were managed at home, 19% were treated in the emergency room and 19% of patients sought medical assistance in the community. A high impact on emotional wellbeing was reported by 61% of patients. The highest impact was caused by frustration with symptoms (60%), worry about disease worsening (59%) and worry about family/friends/children who care for them (54%). Only 42% of patients have received professional emotional support (eg psychiatrist, psychologist, counseling), but 67% reported a desire to receive this support. A high impact on household daily activities (eg food preparation, housework, childcare) and on family or social life was reported by 39% and 43% of patients, respectively, with 34% stating a high impact in terms of sexual desire/activity and 35% a high impact on relationships with spouse/partner. Physical activity was also affected in patients with SCD, with 60% reporting they avoid intense physical activity and 30% avoiding even mild physical activity, most commonly because of concerns about pain, exhaustion and dehydration (58%, 57% and 50%, respectively). Of the patients surveyed, 32% were employed, 8% not working but seeking employment, 6% not working and not seeking employment, 36% students, 1% retired, 13% on disability pay and 1% long-term sick leave. Employed patients reported SCD had a high impact on their ability to work, with 57% reducing their hours and 47% considering leaving their job. An average of 6.3 hours missed from work was reported in the 7 days prior to survey completion due to SCD. Half of patients believe that their income would be higher if they did not have SCD, 60% reported often missing school in the past and 52% felt that their disease has had a negative impact on their academic achievements. Conclusions: The acute and chronic symptoms associated with SCD have a substantial impact on patients' daily lives, including emotional and physical wellbeing, relationships and school/work. In addition, the acute symptoms associated with VOCs occur several times a year, resulting in frequent hospitalizations. Improved management of SCD would enhance patients' quality of life both at home and at school/work, likely leading to improved emotional wellbeing and a positive economic effect. Disclosures Osunkwo: Micella Biopharma: Other: DSMB Member ; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; Terumo: Speakers Bureau. Andemariam:Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Other: DSMB Member; Imara: Research Funding; NovoNordisk: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Terumo BCT: Membership on an entity's Board of Directors or advisory committees; Cyclerion: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Emmaus: Membership on an entity's Board of Directors or advisory committees; New Health Sciences: Membership on an entity's Board of Directors or advisory committees; Community Health Network of Connecticut: Consultancy. El-Rassi:Novartis Pharmaceuticals: Research Funding. Francis-Gibson:Sickle Cell Disease Association of America: Employment. Nero:Novartis: Consultancy. Minniti:Doris Duke Foundation: Research Funding. Trimnell:Global Blood Therapeutics: Consultancy; Novartis: Consultancy; Cyclerion: Consultancy. Abboud:AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; CRSPR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Modus: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; GBT: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Other: Travel support; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Colombatti:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Addmedica: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees. de Montalembert:AddMedica: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jastaniah:Novartis Pharmaceuticals: Consultancy, Honoraria. Nur:Novartis Pharmaceuticals: Consultancy. DeBonnett:Novartis Pharmaceuticals Corporation: Employment. James:Sickle Cell Society: Employment; Novartis: Honoraria.

Background: Sickle cell disease (SCD) is a complex genetic disorder affecting mainly people of African origin. A hallmark of SCD is vaso-occlusive crisis (VOC) - this event is acutely painful and the primary cause of hospitalization in SCD patients. VOC can lead to life-threatening complications such as acute chest syndrome. SCD is also associated with chronic complications including pulmonary hypertension, damage to organs and shortened life expectancy. Therefore, effective management and treatment strategies are essential to reduce burden of illness and ensure high quality of life for the patient. Aim: To survey the treatment and management strategies used by patients with SCD, and to determine patient satisfaction levels. Methods: SWAY is an ongoing multi-country, cross-sectional survey of SCD patients, caregivers and treating physicians. The survey, conducted online and in print, includes 6 categories: demographics, symptoms, impact of disease and use of a caregiver, impact on work and finances, disease management/treatment approaches, and patient-physician relationship. Where relevant, questions include a 7-point severity scale for each statement; a score of 5−7 indicates 'high severity/impact'. Patient enrollment is via treating physicians and patient association groups. The enrollment target is approximately 2000 patients. Results: To date, 1513 SCD patients (48% male, mean age 24.1 years, 63% HbSS and 30% HbSC disease) have been surveyed from 11 countries across North and South America, Europe and Africa. When considering the main person responsible for SCD treatment and management, patients primarily reported management by an SCD specialist (59% of patients) or GP/family doctor (20%). Most patients were satisfied with the frequency of interaction with their doctor (78%) and reported they are confident they are being assessed and treated properly (66%; based on high-impact scores 5−7). Accordingly, 60% of patients (scoring 5−7) reported sharing the same goals for SCD management and treatment as their doctor. The most common treatment goals for patients are to improve quality of life (80% of patients), prevent SCD worsening (59%), improve long-term survival (42%) and improve overall symptoms (40%). Patients reported receiving ongoing treatment with folic acid (58%), antibiotics (37%), anti-inflammatories (37%), over-the-counter pain medication (37%), opioids (35%), hydroxyurea (23%), blood transfusions (10%) and L-glutamine (4%). Having surgery or a medical procedure to manage their SCD was reported by 47% of patients, with gall bladder removal (16%), port placement (15%) and splenectomy (11%) being the most frequent. Although 63% of patients (scoring 5−7) indicated satisfaction with their treatment received to manage their SCD, 75% of patients (scoring 5−7) agreed they would like an alternative treatment to their current pain management medication, and 67% of patients would like additional professional emotional support. In the 12 months before survey completion, 7829 VOCs were reported (mean of 5.2 VOCs per patient); 8% of patients experienced 0 VOCs, 51% experienced 1−4 VOCs and 40% experienced ≥5 VOCs. Of these, 38% of VOCs led to overnight hospitalization, 24% were managed at home and 19% were treated in the emergency room. The main reasons that patients chose to manage their VOCs at home include a previous poor experience at hospital (40%), the opinion that medical assistance was not required (28%), the perception that medical professionals do not understand SCD (27%) and the cost of hospital treatment (22%; 41% of patients have no health insurance). Patients who self-managed their VOCs primarily did so with rest/sleep (73%), by drinking fluids (72%) and with opioid-based analgesia (58%). Conclusions: This interim analysis of the SWAY survey suggests that although many patients report satisfaction with their current level of management and treatment, there is still a need for additional healthcare support and alternative treatments. Underlining this, many patients experiencing VOCs do not seek medical assistance despite the potential for life-threatening complications, and >75% of patients surveyed are not receiving hydroxyurea even though the majority are cared for by SCD specialists. Further data collection and analysis will highlight any geographic differences in SCD management strategies and help identify any region-specific unmet patient needs. Disclosures James: Novartis: Honoraria; Sickle Cell Society: Employment. Andemariam:NovoNordisk: Membership on an entity's Board of Directors or advisory committees; New Health Sciences: Membership on an entity's Board of Directors or advisory committees; Emmaus: Membership on an entity's Board of Directors or advisory committees; Cyclerion: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Imara: Research Funding; Global Blood Therapeutics: Other: DSMB Member; Community Health Network of Connecticut: Consultancy; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Terumo BCT: Membership on an entity's Board of Directors or advisory committees. El-Rassi:Novartis Pharmaceuticals: Research Funding. Francis-Gibson:Sickle Cell Disease Association of America: Employment. Nero:Novartis: Consultancy. Minniti:Doris Duke Foundation: Research Funding. Trimnell:Novartis: Consultancy; Global Blood Therapeutics: Consultancy; Cyclerion: Consultancy. Abboud:Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Modus: Research Funding; CRSPR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Other: Travel support; Eli Lilly: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; GBT: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Colombatti:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Addmedica: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees. de Montalembert:AddMedica: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jastaniah:Novartis: Consultancy, Honoraria. Nur:Novartis: Consultancy. DeBonnett:Novartis Pharmaceuticals Corporation: Employment. Osunkwo:Micella Biopharma: Other: DSMB Member ; Terumo: Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau.

Objective: Long-term treatment with inhaled antibiotics is recommended for chronic Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) patients. The ETOILES study (Clinicaltrials.gov identifier: NCT01519661) evaluated the safety of tobramycin inhalation powder (TIP) for 1 year. Research design and methods: This single-arm, open-label, multicenter, phase IV trial, enrolled CF patients aged ≥6 years, with baseline FEV1 ≥25%–≤75% predicted and Pa infection, and assessed the safety of TIP over six cycles in terms of the incidence of treatment-emergent adverse events (AEs) and serious AEs (SAEs). Secondary endpoints included presence of airway reactivity, relative change in FEV1% predicted, and change in sputum Pa density (log10 colony forming units/g sputum). Results: A total of 157 patients were enrolled, and 96 patients (61.1%) completed the study. The most commonly reported AE was infective pulmonary exacerbation of CF (55.4%). Cough was reported as an AE in 23.6% of patients; a majority were mild or moderate and two were severe (1.3%). SAEs were reported by 31.2% of patients. No deaths were reported during the study. There were no clinically meaningful changes reported in airway reactivity. Most frequently reported post-inhalation event was cough at all time points; however, it was of short duration (1% predicted remained stable from Cycles 1 to 4 and tended to decrease thereafter, although it was not statistically significant (change from baseline to study end mean [SD] = −1.9% [14.55]; P = 0.199). Conclusions: This was one of the largest studies with long-term TIP exposure. The majority of patients enrolled were adults with more advanced CF lung disease than those in previous TIP studies. No new emerging safety signals were seen and efficacy was sustained during the year.

Objective To examine cystic fibrosis (CF) physician adherence to the 2007 CF Foundation (CFF) Pulmonary Guidelines for Chronic Medications. Specifically adherence and barriers to prescribing level A medication recommendations (i.e., inhaled tobramycin and dornase alfa) and level B medication recommendations (i.e., macrolide antibiotics and hypertonic saline) were studied. Methods During Spring 2010, the CFF emailed survey invitations to directors of 136 accredited CF care centers treating 50+ CF patients. Directors were asked to forward the invitations to their physician colleagues. One hundred thirty-three surveys were included in the analyses, representing 92 centers. Barriers were conceptualized based on Cabana et al.'s framework for adherence to guidelines. Adherence was assessed via a case vignette. Results Logistic regression analysis revealed that higher outcome expectancy (OR = 1.099, CI 1.010–1.196) and fewer environmental/system barriers (OR = 1.484, CI 1.158–1.902) were significantly associated with Vignette Adherence. A trend for an association between Familiarity and Vignette Adherence (OR = 1.642, CI 0.953–2.828) was evident, while no demographic variables were significantly associated with Vignette Adherence. Conclusion Targeting outcome expectancy and external barriers with multifaceted, ongoing interventions may improve guideline adherence. Pulmonologists are clearly looking for empirical evidence that these medications benefit their patients over the long-term and offset patient treatment burden with improved health. Pediatr Pulmonol. 2012; 47:434–440. © 2012 Wiley Periodicals, Inc.

TOBIInspiratory flow profiles were recorded from 38 subjects aged 6-71 who had CF and varying degrees of lung function impairment. Ten of the inspiratory flow profiles were simulated in the laboratory using a custom breath simulator to determine delivered dose (DD) from the T-326 Inhaler. In vitro total lung dose (TLDAerosol performance was assessed across a range of inspiratory flow profiles. Mean DD ranged from 88.8% to 97.0% of declared capsule content. TLDOur findings indicate that the T-326 Inhaler provides reliable drug delivery at flow rates likely to be achieved by a broad spectrum of patients with CF. Importantly, forceful inhalation was not required to achieve a robust TLD