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BackgroundMarzeptacog alfa (activated) (MarzAA), a novel recombinant activated human factor VII (FVIIa) variant, was developed to provide increased procoagulant activity, subcutaneous (SC) administration, and longer duration of action in people with hemophilia.ObjectivesTo investigate if daily SC administration of MarzAA in subjects with inhibitors can provide effective prophylaxis.MethodsThis multicenter, open-label phase 2 trial (NCT03407651) enrolled men with severe congenital hemophilia with an inhibitor. All subjects had a baseline annualized bleeding rate (ABR) of ≥12 events/year. Subjects received a single 18μg/kg intravenous dose of MarzAA to measure 24-hour pharmacokinetics (PK) and pharmacodynamics (PD), single 30μg/kg SC dose to measure 48-hour PK/PD, then daily SC 30μg/kg MarzAA for 50days. If spontaneous bleeding occurred, the dose was sequentially escalated to 60, 90, or 120μg/kg, with 50days at the final effective dose without spontaneous bleeding to proceed to a 30-day follow-up. The primary end point was reduction in ABR. Secondary end points were safety, tolerability, and antidrug antibody (ADA) formation.ResultsIn the 11subjects, the mean ABR significantly reduced from 19.8 to 1.6, and the mean proportion of days with bleeding significantly reduced from 12.3% to 0.8%. Of a total of 517 SC doses, six injection site reactions in two subjects were reported. No ADAs were detected. One fatal unrelated serious adverse event occurred: intracerebral hemorrhage due to untreated hypertension.ConclusionsThe data demonstrated that MarzAA was highly efficacious for prophylactic treatment in patients with inhibitors by significantly decreasing bleed frequency and duration of bleeding episodes.

AimPhase 2b study to assess efficacy, safety, thrombogenicity, immunogenicity and tolerability with 28days of daily dosing of subcutaneous (SQ) dalcinonacog alfa as prophylaxis for haemophilia B (HB).MethodsAdult males with a confirmed diagnosis of congenital HB (factor IX [FIX] activity

In this paper, we describe progress in via-formation and processing of thin glass substrates. An advanced temporary bonding approach enables easy handling of thin glass substrates through TGV fill, as well as aggressive downstream processes such as CMP. The formation of TGVs in both aluminoborosilicate and fused silica is discussed, and hermetic, filled vias are successfully demonstrated. Promising simulation results on fused silica validate the usefulness of glass structures in millimeter-wave-frequency antennas.

Glass substrates with through-glass vias for electronic packaging and radio-frequency substrate applications have been demonstrated in a variety of formats from wafers to panels, yet adoption has been hindered by difficulty in handling thin glass in the fab. In this paper we describe successful processing of glass wafers on silicon handles, using our polymer-free temporary bonding process. One preferred handle is silicon, so that the glass- on-silicon unit is rigid, opaque, and compatible with existing silicon-processing equipment. With the Mosaic bond approach, no adhesive wicks into the glass vias, allowing good via fill. Furthermore, no solvent is required for post-debond cleaning. In this paper, we demonstrate fundamental process capability for implementation of this technology for volume manufacture of glass solutions.

IntroductionThe rapid clearance of factor IX necessitates frequent intravenous administrations to achieve effective prophylaxis for patients with hemophilia B. Subcutaneous administration has historically been limited by low bioavailability and potency. Dalcinonacog alfa was developed using a rational design approach to be a subcutaneously administered, next-generation coagulation prophylactic factor IX therapy.AimThis study aimed to investigate the pharmacokinetic, pharmacodynamic, and safety profile of dalcinonacog alfa administered subcutaneously in hemophilia B dogs.MethodsTwo hemophilia B dogs received single-dose daily subcutaneous dalcinonacog alfa injections for six days. Factor IX antigen and activity, whole blood clotting time, and activated partial thromboplastin time were measured at various time points. Additionally, safety assessments for clinical adverse events and evaluations of laboratory test results were conducted.ResultsThere was an increase in plasma factor IX antigen with daily subcutaneous dalcinonacog alfa. Bioavailability of subcutaneous dalcinonacog alfa was 10.3% in hemophilia B dogs. Daily subcutaneous dosing of dalcinonacog alfa demonstrated the effects of bioavailability, time to maximal concentration, and half-life by reaching a steady-state activity sufficient to correct severe hemophilia to normal, after four days.ConclusionThe increased potency of dalcinonacog alfa facilitated the initiation and completion of the Phase 1/2 subcutaneous dosing study in individuals with hemophilia B.

Background There are many inherited conditions that present with episodic bleeding effectively treated with Factor VIIa (FVIIa). These include Factor VII deficiency (FVIID), an autosomal recessive disorder caused by ineffective or reduced levels of FVII, Glanzmann thrombasthenia (GT), a rare platelet disorder associated with a deficiency or dysfunction of glycoprotein IIb/IIIa, Hemophilia A with inhibitors (HawI), an X-linked, recessive, bleeding disorder caused by a deficiency of FVIII with development of inhibitors against FVIII, rendering them refractory to replacement treatment. Although emicizumab prophylaxis is available for HAwI (HAwI-E), breakthrough bleeding still occurs. Treatment of episodic bleeding requires technical expertise to gain the requisite intravenous (IV) access and is often associated with pain. This causes delays in administration which results in prolonged bleeding and accumulation of blood in the joint or other bleeding sites. Currently approved FVIIa containing products take 6-24 hours to achieve hemostasis and maintain efficacy. Marzeptacog alfa (activated) (MarzAA), a novel variant activated recombinant FVII (rFVIIa), is being developed for subcutaneous (SQ) administration to address this important unmet need. Data from the Phase 1 study, MAA-102, demonstrated that SQ MarzAA is quickly absorbed and has the potential to achieve and maintain plasma levels in the desired range with an acceptable safety profile. This open-label, multi-center, Phase 1/2 study is designed to evaluate the pharmacokinetics, pharmacodynamics, safety and efficacy of MarzAA for on-demand treatment of spontaneous or traumatic bleeds in adolescents and adults with FVIID (cohort 1), GT (cohort 2) and HAwI-E (cohort 3). It is estimated that 24 subjects will be enrolled across all 3 cohorts at approximately 25 sites in 5 countries. Study Design and Methods Key inclusion criteria:Eligible male or female subjects, ≥ 12 years of age must have confirmed diagnosis of: FVIID (cohort 1), GT (cohort 2) or HAwI treated with the same dose of emicizumab for at least 4 weeks, HAwI-E (cohort 3); history of bleeding with annualized bleeding rate (ABR) of ≥ 8 for cohorts 1 and 2 and ABR of ≥ 1 for cohort 3; investigator-confirmed subject's ability to identify bleeds and administer MarzAA SQ at home. Key exclusion criteria:Subjects should not have previous exposure to SQ administration of rFVIIa or exposure to any other variant rFVIIa; known positive antibody or hypersensitivity to MarzAA , FVIIa, or variants thereof; history of other coagulation disorder(s); platelet count Treatment:In Phase 1, subjects will receive a single dose of IV MarzAA followed by ascending doses of SQ MarzAA for PK assessments. Once the Phase 2 dose for the cohort is confirmed, subjects will be treated for episodic bleeding with SQ MarzAA until ≥30 eligible bleeds in Cohorts 1 and 2, and ≥15 eligible bleeds in Cohort 3 have been treated with MarzAA. Endpoints:Primary endpoints by cohort: Phase 1 includes PK of ascending SC doses of MarzAA and confirmation of the Phase 2 dose; Phase 2 includes the percentage of treated bleeds resulting in effective hemostasis (excellent or good) at 24 hours after the initial dose. Key secondary endpoints by cohort: Phase 1 includes PK and PD of IV and SQ MarzAA and PK dose proportionality; Phase 2 includes time to cessation of bleeding after the initial dose; percentage of treated bleeds resulting in effective hemostasis at fixed timepoints; percentage of bleeds that maintain hemostasis at 48 hours after the initial dose and use and amount of rescue therapy. Key safety endpoints for the study include the incidence of adverse events; occurrence of thrombotic events and binding and/or neutralizing anti-drug antibodies. Key exploratory endpoints for Phase 2 include assessment of patient satisfaction with the Treatment Satisfaction Questionnaire for Medicine- 9; assessment of pain using the Visual Analogue Scale; evaluation of the time required to administer treatment. Statistics:The appropriate statistics of all recorded, measured, and calculated parameters will be reported and include 95% confidence intervals, sample size, mean, standard deviation, and median. These will be reported separately for intent to treat and per protocol subjects in Phase 2. Safety results will be tabulated by cohort and in aggregate. Figure Disclosures Neuman: Catalyst Biosciences:Current Employment, Current equity holder in publicly-traded company.Desai:Catalyst Biosciences:Current Employment, Current equity holder in publicly-traded company.Del Greco:Catalyst Biosciences:Current Employment, Current equity holder in publicly-traded company.Knudsen:Catalyst Biosciences:Current Employment, Current equity holder in publicly-traded company.Levy:Catalyst Biosciences:Current Employment, Current equity holder in publicly-traded company.

Background Hemophilia A (HA) and HB are X-linked bleeding disorders caused by a deficiency of Factor VIII (HA) or Factor IX (HB). A significant number of individuals with HA and HB develop inhibitors against the wild-type FVIII or FIX, respectively, and thereby become refractory to factor replacement treatment. Treatment of episodic bleeding in these individuals requires technical expertise to gain the requisite intravenous (IV) access and is often associated with pain. This causes delays in administration, which results in prolonged bleeding and accumulation of blood in the joint or other bleeding site. Currently approved FVIIa containing products take 6-24 hours to achieve hemostasis and maintain efficacy. Marzeptacog alfa (activated) (MarzAA), a novel variant activated recombinant Factor VII (rFVIIa), is being developed for subcutaneous (SQ) administration to address this important unmet need. Data from the Phase 1 study, MAA-102, demonstrated that SQ MarzAA is quickly absorbed and has the potential to achieve and maintain plasma levels in the desired range with an acceptable safety profile. This open-label, global, multi-center, randomized, cross-over Phase 3 study will evaluate the efficacy and safety of MarzAA for on demand treatment of spontaneous or traumatic bleeding episodes in adolescents and adults with congenital HA or HB with inhibitors. MarzAA will be compared to the Standard of Care (SOC). Approximately 60 subjects will be enrolled at 54 sites in 19 countries. Study Design and Methods Key inclusion criteria: Eligible male or female subjects ≥ 12 years of age must have: confirmed diagnosis of HA or HB unresponsive to or intolerant of standard replacement therapy; history of bleeding with annualized bleeding rate of ≥ 8; investigator-confirmed subject's ability to identify bleeding episodes and administer MarzAA SQ and infuse SOC IV at home. Key exclusion criteria: Subjects should not have had previous exposure to SQ administration of rFVIIa or exposure to any other variant rFVIIa; known positive antibody or hypersensitivity to MarzAA, FVIIa, or variants thereof; history of other coagulation disorder(s); platelet count Treatment: Subjects >17 years of age will be randomized in blocks to target treatment of approximately 5 bleeds with MarzAA and an additional 5 bleeds with SOC in either order, Sequence A or Sequence B, with a washout period to assess anti-drug antibodies (ADA) status between treatments. A total of 488 eligible bleeds will be treated, ~244 bleeds with each treatment, until ≥80% of patients have ≥3 bleeds treated with MarzAA and SOC. Pharmacokinetic samples will be collected during the MarzAA treatment period. Subjects 12-17 years of age will be enrolled after a positive DSMB assessment of 30 eligible bleeds treated with MarzAA. Subjects will administer 60 µg/kg SQ dose of MarzAA, at 3-hour intervals, for up to 3 doses as required to achieve hemostasis. Endpoints: Primary endpoint includes percentage of treated bleeds resulting in effective hemostasis (excellent or good) at 24 hours after the initial dose. Key secondary endpoints include time to cessation of bleeding after the initial dose; percentage of treated bleeds resulting in effective hemostasis at fixed timepoints; percentage of those that maintain hemostasis at 48 hours after the initial dose; use and amount of rescue therapy. Key safety endpoints include the incidence of adverse events; occurrence of thrombotic events and binding and/or neutralizing anti-drug antibodies. Key exploratory endpoints include assess patient satisfaction with the Treatment Satisfaction Questionnaire for Medicine- 9; assessment of pain using the Visual Analogue Scale; time required to administer treatment. Statistics: The goal is to demonstrate the true proportion of bleeds effectively treated with MarzAA is not inferior to SOC. Using a baseline efficacy of 85% for SOC, with a -12% margin of non-inferiority, treatment of 244 bleeds in each group provides 90% power with a one-sided 2.5% significance level to substantiate this result. Figure Disclosures Neuman: Catalyst Biosciences: Current Employment, Current equity holder in publicly-traded company. Desai:Catalyst Biosciences: Current Employment, Current equity holder in publicly-traded company. Knudsen:Catalyst Biosciences: Current Employment, Current equity holder in publicly-traded company. Del Greco:Catalyst Biosciences: Current Employment, Current equity holder in publicly-traded company. Levy:Catalyst Biosciences: Current Employment, Current equity holder in publicly-traded company.

We present advances in a back-contact, back-junction metallization strategy using preformed multilayers of aluminum foil with a polymer insulator. The low-cost multilayer foils can be conductively bonded to substrates using nonconducting adhesives. The properties of this bonding process are discussed. We also demonstrate different cell structures based on multilayer foils. One approach leverages features of the multilayer foil to produce a self-aligned base contact, leading to a process with only a single alignment step. A champion silicon heterojunction cell with this foil metallization achieved 19.5% efficiency. We further show first results on a completely alignment-free back contact process enabled by multilayer foil metallization.

Hereditary angioedema (HAE) is a rare autosomal-dominant disease characterized by recurring attacks of nonpruritic, nonpitting edema caused by an inherited deficiency or dysfunction of C1 esterase inhibitor (C1 INH). Symptoms can present years before an accurate diagnosis is made. The objective of this study, the Angioedema Clinical Epidemiology Testing Initiative for the Study of Hereditary Angioedema, was to determine the prevalence and clinical manifestations of HAE in untested first-degree blood relatives of known patients with HAE. Patients with a confirmed diagnosis of HAE recruited first-degree relatives who had not been evaluated for HAE. Enrolled subjects underwent complement testing (C4, C1 INH antigen, and functional C1 INH). If the lab tests were abnormal, the enrolled subjects returned to the site for a follow-up visit and questionnaire. Overall, 31 patients with HAE and 46 first-degree relatives enrolled in the study. Of 46 enrolled relatives, 30 (65%) had lab test results that ruled out a diagnosis of HAE, two (4%) were categorized as “HAE not ruled out,” and 14 (30%) were newly diagnosed with HAE. Of 14 newly diagnosed subjects, nine (64%) reported having experienced symptoms that may have been related to HAE, such as swelling in the throat, face, or extremities or abdominal pain. When reported, median age of symptom onset in these 14 subjects was nine years whereas newly diagnosed asymptomatic subjects had a median chronological age of six years. These 14 subjects reported a historic mean standard deviation rate of 2.51 (5.59) swelling episodes per month with a mean standard deviation duration of 1.6 (0.74) days. This study's findings reinforce the importance of testing family members of patients with HAE to detect this hereditary condition.

Neuroemergency clinical studies in patients with acute neurologic injury/disease who have a complex set of symptoms and signs, require accurate and rapid diagnosis, determination of appropriateness for recruitment, informed consent and randomization, as well as careful clinical follow-up. The Project Medical Officer (PMO) can provide appropriate guidance in the design, implementation, execution of the study, finalization of the database, planning of the statistical analysis plan, and interpretation of the statistical output. Study success depends on PMO leadership and a committed, knowledgeable, and responsive clinical team at the research site. It is essential that the PMO have the appropriate skills and perspectives to perform a wide range of functions with timely response to issues raised by the site personnel and monitoring staff during active patient screening, recruitment, and follow-up.

We present a new back-contact back-junction (BCBJ) cell metallization strategy based upon preformed multilayer laminates. Capable of being produced in low-cost roll-to-roll processes, the laminates consist of aluminum foil bonded to an insulating film of PET. Several methods to produce base contacts were studied. One method to achieve n+ base contacts involved laser firing of phosphorus-treated aluminum foils. Another method utilized carrier selective base contacts, and efficiencies as high as 20.7% were obtained. BCBJ cells with multilayer aluminum foil can lead to the production of low-cost PV modules with high performance.

Sickle Cell Disease (SCD) is a painful, lifelong hemoglobinopathy inherited as a missense point mutation in the hemoglobin (Hb) beta-globin gene. This disease has significant impact on quality of life and mortality, thus a substantial medical need exists to reduce the vaso-occlusive crises which underlie the pathophysiology of the disease. The concept that a gaseous molecule may exert biological function has been well known for over one hundred years. Carbon monoxide (CO), although studied in SCD for over 50 years, has recently emerged as a powerful cytoprotective biological response modifier capable of regulating a host of physiologic and therapeutic processes that, at low concentrations, exerts key physiological functions in various models of tissue inflammation and injury. CO is physiologically generated by the metabolism of heme by the heme oxygenase enzymes and is measurable in blood. A substantial amount of preclinical and clinical data with CO have been generated, which provide compelling support for CO as a potential therapeutic in a number of pathological conditions. Data underlying the therapeutic mechanisms of CO, including in SCD, have been generated by a plethora of in vitro and preclinical studies including multiple SCD mouse models. These data show CO to have key signaling impacts on a host of metallo-enzymes as well as key modulating genes that in sum, result in significant anti-inflammatory, anti-oxidant and anti-apoptotic effects as well as vasodilation and anti-adhesion of cells to the endothelium resulting in preservation of vascular flow. CO may also have a role as an anti-polymerization HbS agent. In addition, considerable scientific data in the non-SCD literature provide evidence for a beneficial impact of CO on cerebrovascular complications, suggesting that in SCD, CO could potentially limit these highly problematic neurologic outcomes. Research is needed and hopefully forthcoming, to carefully elucidate the safety and benefits of this potential therapy across the age spectrum of patients impacted by the host of pathophysiological complications of this devastating disease.

Background: Hemophilia patients treated prophylactically with emicizumab (Hemlibra®) may experience break-through bleeds or require additional hemostatic coverage for procedures or surgery. Currently available therapies including rFVIIa (Eptacog Alfa (Activated); NovoSeven®) and aPCC (FEIBA®) have been used with Hemlibra to treat bleeding or when additional coverage is required. While NovoSeven appears safe in combination with Hemlibra (HAVEN 1 to 4 clinical trials), thrombotic events have been observed with concurrent use of FEIBA and Hemlibra. While safe and efficacious when used as directed, NovoSeven must be infused intravenously. Ideally, for patients on subcutaneous (SC) prophylaxis with Hemlibra adjunct rFVIIa could be dosed SC too. Marzeptacog alfa (activated) (MarzAA) is a novel rFVIIa differentiated by increased potency and the ability to be administered SC to achieve pharmacologically relevant plasma concentrations. Thus, MarzAA provides a potential solution to address this unmet need in hemophilia therapy. Objective: Demonstrate the procoagulant potential of MarzAA, NovoSeven or FEIBA alone or in combination with Hemlibra using the thrombin generation assay in platelet poor hemophilia A (HA) plasma. The thrombin generation potential will therefore provide a surrogate marker to assess the potential safety and efficacy of SC MarzAA in combination with Hemlibra. Methods: A thrombin generation assay was performed using the PPP-Low Tissue Factor and phospholipid containing thrombin generation assay reagent (#TS31.00, Thrombinoscope, Stago). Citrated hemophilia A plasma was spiked with increasing concentrations (0, 25, 50, and 100 µg/mL) of Hemlibra together with various concentrations of each bypassing agent: MarzAA at 0, 0.1, 0.5, 1, 2.5, 5, and 10 µg/mL, NovoSeven at 1, 2.5, 5, 10, and 50 µg/mL or FEIBA at 0.25, and 0.50 IU/ml. Statistical significance was set at α = 0.05. Results: We assessed the relative potencies of MarzAA and NovoSeven in HA plasma. As expected, MarzAA demonstrated an approximate ten-fold increased potency vs NovoSeven. Both rFVIIa compounds increased peak thrombin generation in the HA plasma to the level of normal plasma and beyond. The effect of adding normalizing levels of MarzAA (1 µg/mL), NovoSeven (10 µg/mL) or FEIBA (0.5 IU/mL) to HA plasma containing clinically relevant concentrations of Hemlibra was evaluated (Fig 1). When correcting for the effect of Hemlibra alone, the increase in peak thrombin generation induced by FEIBA was significantly greater than that observed for both MarzAA and NovoSeven (P Conclusion: As assessed by in vitro thrombin generation, equipotent concentrations of MarzAA and NovoSeven exhibit comparable characteristics when spiked into HA plasma containing Hemlibra at clinically relevant concentrations. Based on these data, MarzAA and NovoSeven are expected to behave similarly in combination with Hemlibra when dosed to achieve equipotent plasma concentrations. Figure 1 Disclosures Knudsen: Catalyst Biosciences: Employment, Equity Ownership. Kumar:Catalyst Biosciences: Employment, Equity Ownership. Del Greco:Catalyst Biosciences: Consultancy, Equity Ownership. Neuman:Catalyst Biosciences: Employment, Equity Ownership. Levy:Catalyst Biosciences: Employment, Equity Ownership. Blouse:Catalyst Biosciences: Employment, Equity Ownership.

Background: Patients with Hemophilia A or B with and without inhibitors lack treatment options that are fast and easy to use for treating acute bleeding. Currently, their only options are intravenous administration of replacement or bypass therapies. Marzeptacog alfa (activated) (MarzAA) is a novel increased potency recombinant FVIIa in clinical development. We hypothesized that, in addition to its clinically demonstrated efficacy in SC prophylaxis, MarzAA could potentially be used SC on-demand to control acute hemorrhage after bleeding has started. Objective: To demonstrate the procoagulant effect of dosing MarzAA subcutaneously at timepoints both before and after injury using a tail clip bleeding model in hemophilia A mice. Methods: Each mouse was initially weighed and briefly anesthetized with isoflurane for collection of 5 µL blood to assess baseline hemoglobin levels. Later, anaesthetized (100 mg/kg ketamine + 10 mg/kg xylazine) F8-/- (Haem A, B6;129S4-F8tm1Kaz/J) mice were submitted to a tail clip injury model completely transecting the tail at a diameter of 1.25 mm from the tip using a sharp razor blade. Following injury, blood loss was monitored with the tail submerged in warm saline for 20 minutes and quantified by hemoglobin content. Mice were dosed with MarzAA SC (1.5 mg/kg) or vehicle at 15, 30, 60, or 90 minutes before or one minute after injury (1.5 and 4.5 mg/kg). An ED50 for MarzAA was determined using various doses ranging from 0.15 mg/kg to 3.0 mg/kg. Statistical significance was set at α = 0.05. Results: SC administration of MarzAA resulted in a dose dependent reduction in bleeding when administered to hemophilia A mice 15 minutes before injury. At the highest dose of MarzAA, full efficacy was achieved as bleeding in the treated mice was comparable to the blood loss observed in normal hemostatically competent mice. The ED50 for MarzAA was calculated to be 387 µg/kg after SC administration in this model. More importantly, when dosed as a rescue therapy one minute after injury, SC MarzAA significantly reduced bleeding to 350±46 µL from 635±50 µL (vehicle), p = 0.02. Conclusion: MarzAA demonstrated efficacy when administered SC both before and after injury. Taken together these data suggest that SC MarzAA could potentially be used on-demand to treat patients with acute bleeding. These results provide a basis for further clinical investigation of the acute treatment of a bleed with SC MarzAA in hemophilia patients. Disclosures Del Greco: Catalyst Biosciences: Consultancy, Equity Ownership. Neuman:Catalyst Biosciences: Employment, Equity Ownership. Levy:Catalyst Biosciences: Employment, Equity Ownership. Reckless:RxCelerate: Employment. Knudsen:Catalyst Biosciences: Employment, Equity Ownership. Blouse:Catalyst Biosciences: Employment, Equity Ownership.

Background Bioabsorbable cardiac matrix (BCM) is a novel device that attenuates adverse left ventricular (LV) remodeling after large myocardial infarctions in experimental models. Objectives This study aimed to analyze whether BCM, compared with saline control, would result in less LV dilation and fewer adverse clinical events between baseline and 6 months. Methods In an international, randomized, double-blind, controlled trial, 303 subjects with large areas of infarction despite successful primary percutaneous coronary intervention (PCI) of ST-segment elevation myocardial infarction (STEMI) were randomized 2:1 to BCM or saline injected into the infarct-related artery 2 to 5 days after primary PCI. The primary outcome was mean change from baseline in LV end-diastolic volume index (LVEDVI) at 6 months. Secondary outcomes included change in Kansas City Cardiomyopathy Questionnaire score, 6-minute walk time, and New York Heart Association functional class at 6 months. The primary safety endpoint was a composite of cardiovascular death, recurrent MI, target-vessel revascularization, stent thrombosis, significant arrhythmia requiring therapy, or myocardial rupture through 6 months. Results In total, 201 subjects were assigned to BCM and 102 to saline control. There was no significant difference in change in LVEDVI from baseline to 6 months between the groups (mean change ± SD: BCM 14.1 ± 28.9 ml/m 2 vs. saline 11.7 ± 26.9 ml/m 2 ; p = 0.49). There was also no significant difference in the secondary endpoints. The rates of the primary safety outcome were similar between the 2 groups (BCM 11.6% vs. saline 9.1%; p = 0.37). Conclusions Intracoronary deployment of BCM 2 to 5 days after successful reperfusion in subjects with large myocardial infarction did not reduce adverse LV remodeling or cardiac clinical events at 6 months. (IK-5001 for the Prevention of Remodeling of the Ventricle and Congestive Heart Failure After Acute Myocardial Infarction [PRESERVATION I]; NCT01226563 )

Background MP4OX (oxygenated polyethylene glycol-modified hemoglobin) is an oxygen therapeutic agent with potential applications in clinical settings where targeted delivery of oxygen to ischemic tissues is required. The primary goal of this study was to investigate MP4OX for preventing hypotensive episodes. An additional goal was to establish the safety profile of MP4OX in a large surgical population. Methods Patients (n = 367) from 18 active study sites in six countries, undergoing elective primary hip arthroplasty with spinal anesthesia, were randomized to receive MP4OX or hydroxyethyl starch 130/0.4. Patients received a 250-ml dose at induction of spinal anesthesia and a second 250-ml dose if the protocol-specified trigger (predefined decrease in systolic blood pressure) was reached. The primary end point was the proportion of patients who developed one or more hypotensive episodes. Results The proportion of patients with one or more hypotensive episodes was significantly lower (P < 0.0001) in the MP4OX group (66.1%) versus controls receiving hydroxyethyl starch 130/0.4 (90.2%). More MP4OX-treated patients experienced adverse events compared with controls (72.7% vs. 61.4%; P = 0.026). Transient elevations in laboratory values (e.g., alanine aminotransferase, aspartate aminotransferase, lipase, and troponin concentrations) occurred more frequently in the MP4OX group. There were no significant differences in the incidence of serious adverse events or in the composite morbidity and ischemia outcome end points, but nausea and hypertension were reported more often in MP4OX-treated patients. Conclusion MP4OX significantly reduced the incidence of hypotensive episodes in patients undergoing hip arthroplasty, but the adverse event profile does not support use in routine low-risk surgical patients for the indication evaluated in this study.

MP4OX (oxygenated polyethylene glycol-modified hemoglobin) is a novel oxygen therapeutic agent specifically developed to perfuse and oxygenate tissue at risk for ischemia and hypoxia. In this study, we investigated the ability of MP4OX to treat hypotensive episodes. In addition, the tolerability profile of MP4OX in a large surgical population was established.Patients from 21 study sites in 5 countries, scheduled to undergo primary hip arthroplasty under spinal anesthesia, were randomized in a double-blind manner to receive MP4OX or hydroxyethyl starch (HES) solution (Voluven®; HES 130/0.4). Patients received the first 250-mL dose of investigational product when systolic blood pressure decreased to the predefined dosing trigger. A second 250-mL dose was given only if the systolic blood pressure decreased to the same trigger level after administration of the first dose. The primary efficacy outcome was total duration of all hypotensive episodes during surgery and the first 6 hours after skin closure.Of the 474 patients randomized, 405 reached the dosing trigger and received at least 1 dose. The mean total duration of all hypotensive episodes was significantly shorter (P0.0001) in the MP4OX group (52.4 ± 71.50 minutes; range, 3-442 minutes) compared with the HES group (137.6 ± 120.21 minutes; range, 5-435 minutes). The overall incidence of adverse events (AEs) in the intent-to-treat population was similar between the MP4OX and HES groups (75.2% vs 73.4%; P = 0.733). Transient increases in laboratory values were reported in more patients in the MP4OX group versus HES controls for aspartate aminotransferase (13.4% vs 7.4%; P = 0.052), alanine aminotransferase (6.9% vs 4.9%; P = 0.409), lipase (9.7% vs 3.6%; P = 0.015), and troponin (8.1% vs 2.0%; P = 0.006). There was no significant difference in the incidence of serious AEs reported (6.4% in MP4OX group vs 3.0% in HES controls; P = 0.106). Certain AEs did occur more frequently in the MP4OX group, including nausea (23.8% vs 14.3%; P = 0.016), bradycardia (14.9% vs 5.9%; P = 0.003), hypertension (8.4% vs 2.5%; P = 0.009), and oliguria (5.9% vs 1.5%; P = 0.019). The composite morbidity and ischemia end points did not reveal any differences between the 2 treatment groups.Administration of MP4OX achieved the end point of treating perioperative hypotension in patients undergoing primary hip arthroplasty under spinal anesthesia. The study was not powered to demonstrate clinical benefit based on the composite morbidity or ischemia outcomes. Although efficacy end points with sufficient power were met, MP4OX is not being proposed for use in routine surgery where the risk-benefit profile would not be favorable based on the safety profile demonstrated in this study.

Background: Patients with community-acquired pneumonia (CAP) comprised 35.6% of the overall phase 3 Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study and 33.1% of the placebo arm. We investigated the use of CURB-65, the Pneumonia Severity Index (PSI), and Acute Physiology and Chronic Health Evaluation II (APACHE II) prediction scores to identify the CAP population from the PROWESS placebo arm at the greatest mortality risk. Methods: Patients were classified as having CAP if the lung was the primary infection site and the patient originated from home. The abilities of CURB-65, PSI, and APACHE II scores to determine the 28-day and in-hospital mortality were compared using receiver operator characteristic (ROC) curves and the associated areas under the curve. Results: PROWESS enrolled 278 patients with CAP in the placebo arm. The areas under the ROC curves for PSI = 5, CURB-65 ≥3, and APACHE II ≥25 for predicting 28-day (c = 0.65, 0.66, and 0.64, respectively) and in-hospital mortality (c = 0.65, 0.65, and 0.64, respectively) were not statistically different from each other. The 28-day mortality of patients with a PSI score of 5, CURB-65 ≥3, and APACHE II ≥25 was 41.6%, 37.9%, and 43.5%, respectively. Conclusions: Despite early diagnosis and appropriate antibiotic therapy, conventionally treated CAP with PSI = 5, CURB-65 ≥3, or APACHE II ≥25 has an unacceptably high mortality. In this study, PSI, CURB-65, and APACHE II scoring systems perform similarly in predicting the 28-day and in-hospital mortality; however, differences in the categorization of severe CAP were observed and there was a significant mortality in patients with a CURB-65

Background: In hemophilia patients with inhibitors, hemostasis can be achieved using bypass agents: activated plasma-derived prothrombin complex concentrates (aPCC), recombinant Factor VIIa (FVIIa), or emicizumab - that can only manage hemophilia A. Marzeptacog alfa (activated) (MarzAA), an engineered recombinant FVIIa with enhanced biological properties enabling subcutaneous (SQ) delivery was developed using a rational protein design approach. It has 7-fold increased catalytic activity and prolonged duration of effect demonstrated in a single-dose intravenous (IV) study that documented safety. Daily SQ dosing in dogs demonstrated achievement of stable trough levels of MarzAA that are believed to be effective for prophylaxis. Aims: Phase 2/3 Study MAA-201 (NTC03407651) will determine if SQ MarzAA can provide effective prophylaxis. This study complies with the Declaration of Helsinki and is approved by recognized research ethics committees. Up to 12 subjects with inhibitors, who have an annualized bleeding rate ≥12 (ABR), and sign informed consent, will participate. Methods: After an 18 mg/kg MarzAA IV bolus, pharmacokinetics and coagulation parameters were measured for 24 hours followed by 30 mg/kg MarzAA SQ with pharmacokinetics and coagulation parameters measured for a further 48 hours to calculate bioavailability. Subjects then received daily 30 mg/kg MarzAA SQ for 50 days. If no spontaneous bleeding events occurred the subject proceeded to safety follow-up 3 weeks after the last dose. If spontaneous bleeding occurred, dose escalation occurred sequentially to 60, 90 or 120 mg/kg for 50 daily doses as needed (fig 1). Subjects were monitored for treatment-related changes in Quality of Life measures and tested for anti-drug antibodies to MarzAA and FVII weekly. ABR was compared to the subjects prior ABR. Results: 5 participants have been enrolled (Median ABR 16.6; Range 12.2-26.7) (fig 2). One participant with historical ABR 26.7 has completed the study with no bleeding at 60 mg/kg MarzAA but had a spontaneous bleed 16 days into the follow-up period when no longer receiving study drug. In a participant with previously-treated but currently-untreated and uncontrolled hypertension, a fatal hemorrhagic stroke deemed unrelated to study drug occurred on Day 11. Pharmacokinetics are shown in fig 3. IV half-life of 3.5 hours was increased to SQ half-life of 9.5 hours. Levels of MarzAA at Tmax 5 hours after SQ injection were similar to levels at 6 hours after IV infusion. Median subcutaneous bioavailability was 35%; Range 32.4-37.5%. Prothrombin Time baseline of 12-12.7 seconds fell to 8-9 seconds after 18 µg/kg IV infusion (normal 9.4-12.5 seconds). Prothrombin Time gradually declined to 8.7 seconds after 7 days of 30 µg/kg SQ injection. No anti-drug antibodies have been detected to date. Conclusion: This study demonstrates that an individualized dose of daily SQ MarzAA can provide effective prophylaxis in hemophilia patients with inhibitors. Supported by Catalyst Biosciences Disclosures Levy: Catalyst Biosciences: Employment, Equity Ownership. Mahlangu:Sanofi: Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Chugai: Consultancy; Catalyst Biosciences: Consultancy, Research Funding; Biomarin: Research Funding, Speakers Bureau; Biogen: Research Funding, Speakers Bureau; Bayer: Research Funding; Amgen: Consultancy; Alnylam: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; Spark: Consultancy, Research Funding. Del Greco:Catalyst Biosciences: Employment, Equity Ownership. Booth:Catalyst Biosciences: Consultancy.

INTRODUCTION: Hemophilia A or B carries significant morbidity - progressive throughout life. The mainstay of treatment is regular factor replacement to treat or prevent bleeding episodes. Up to 30% of Hemophilia A and up to 5% of Hemophilia B develop neutralizing antibodies (inhibitors) rendering factor replacement therapy ineffective. Hemophilia patients with inhibitors are managed with bypassing agents for treatment or prevention of bleeds. Prophylaxis is not adequate in inhibitor patients using currently available bypassing products due to their very short half-life (2-3 hours for rFVIIa; 5-6 hours for aPCC) so they are treated on an episodic basis for bleeds. On-demand treatment results in poor quality of life, significantly higher mortality and inferior musculoskeletal outcomes in inhibitor patients when compared to patients without inhibitors. The quality of life of hemophilia has been evaluated using EQ-5D and Haem-A-QOL and impaired activity has been measured with Haemophilia Activity List (HAL). The EQ-5D is a widely used internationally validated general-purpose quality of life instrument however it lacks granularity and is not specific to Hemophilia. Haem A-QOL (Mackensen et al 2004) and Hemophilia Activities List (HAL) (Van Genderen FR et al 2006.) were developed and validated specifically to address the typical disabilities and life issues faced by patients with Hemophilia. Marzeptacog alfa (activated) (MarzAA) was created using a structure-based rational protein design and has 4 amino acid substitutions to enhance the biological properties of FVIIa. This variant molecule has substantially (6-7x) greater potency than wild-type FVIIa, a greater half-life and sufficient bioavailability when given subcutaneously (SQ). There is currently a paucity of data on quality of life (QoL) of inhibitor patients. We evaluated the baseline QoL and functional activity of inhibitor patients enrolled in the MAA-201 study using the EQ-5D , Haem-A-QoL and HAL compared the results to those of reference hemophilia patients without inhibitors. METHODS A phase 2 / 3 open-label study evaluating safety and efficacy of MarzAA in hemophilia patients with inhibitors is underway MAA-201, (NCT03407651) Subject eligibility required an annualized bleeding rate of >12 and documented inhibitor to replacement factor. The primary aim of the trial was the complete prevention of breakthrough bleeding for 50 days by the daily administration of a fixed SQ dose of MarzAA. If breakthrough bleeding occurred, up to three dose escalations were permitted. At baseline and study conclusion, each subject completed quality of life assessment tools the EQ-5D, Haem-A-QOL and the Hemophilia Activities List Haem-A-QOL assesses subjects across ten domains and provides a summarized score. Subjects in the present trial (MARZAAPOP) were compared to baseline values for subjects with severe hemophilia but without inhibitors recruited into a long-term prophylaxis trial (The A-LONG trial - ALONGREFPOP). Mean baseline Haem-A-QOL summed score in the A-LONG trial was 29.3 ±15.7 contrasting sharply with a mean baseline summed score of 42 ±15.2 for subjects in the present trial (Table 1) HAL is more motor function oriented and assesses patients across ten domains of which seven assess basic functionality and three are composites intended to assess disability in performing complex tasks. HAL provides both raw and normalized scores. Normalized scores provide meaningful output in the case of missing data elements. For each domain and for the sum score, a raw score of 0 and a normalized score of 100 indicates no functional deficit. Figure 1 provides a visual comparison between recruited subjects (MARZAAPOP) in the present trial and the population used to validate the HAL tool. (HALREFPOP). CONCLUSION: In examining recruits into the present trial, it is clear that inhibitor patients have generally worse functional scores than either of two reference groups. Effective long-term prophylaxis is expected to produce measurable improvement in QOL scores in this hard-to-treat population. Disclosures Booth: Catalyst Biosciences: Consultancy. Mahlangu:Sanofi: Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Chugai: Consultancy; Catalyst Biosciences: Consultancy, Research Funding; Biomarin: Research Funding, Speakers Bureau; Biogen: Research Funding, Speakers Bureau; Bayer: Research Funding; Amgen: Consultancy; Alnylam: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; Spark: Consultancy, Research Funding. Levy:Catalyst Biosciences: Employment, Equity Ownership.

Acute kidney injury (AKI) is common in critically ill patients with severe sepsis (SS), and the predictors of AKI in this population have not been well characterized. The study group was the placebo group of the Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) data set. PROWESS is a prospective, randomized, controlled study of the use of drotrecogin alpha (activated) for the treatment of SS. Placebo patients who had an admission renal sepsis organ failure score of 2 or more were excluded. AKI was defined as an increase in serum creatinine of 25% or 0.3 mg/dl during the first week postbaseline. The incidence of relevant parameters was then compared in patients with and without AKI. Half of the patients were randomly assigned to a model-building data set, and multivariable Cox regression was used to determine risk factors. Factors that remained significant in the remaining "model validation" data set were considered significant. Of the 840 patients in the placebo group, 547 met inclusion criteria. Of the 547 patients, 127 (23.2%) patients met criteria for AKI. The mean age of the 547 patients was 59.8 +/- 17.0, and 43.3% of the cohort were female. The ethnicity breakdown was as follows: White 83.2%, black 5.9%, and other 11%. Univariate analyses indicated that patients with AKI had a higher incidence of a dependence on the basis of activity of daily living scale (38.6 versus 26.7%; P = 0.01), a lower baseline platelet count (193,000 versus 222,000; P = 0.02), a higher baseline respiratory Sepsis Organ Failure Assessment score (2.9 versus 2.7; P = 0.02), higher preinfusion Acute Physiology and Chronic Health Evaluation II (APACHE II) score (24.8 versus 22.0; P = 0.0002), older age (63.7 versus 58.7 yr; P = 0.008), and higher log IL-6 (6.6 versus 5.8; P = 0.0006). In a multivariable Cox regression, the predictors of AKI were log IL-6 (P < 0.0001) and APACHE II (P = 0.0008). Increased log IL-6 and APACHE II score are significant risk factors of AKI in patients with SS. IL-6 data and the absence of correlation with measures of hypotension (e.g., mean arterial pressure, dosage of vasopressors) support the notion that inflammation is a significant component of AKI in SS.

Objective. To gather additional 28-day all-cause mortality data and safety information for pediatric patients with severe sepsis who received drotrecogin alfa (activated) (DrotAA).Design and Setting. Single-arm, open-label, multicentered study conducted in 59 study sites in 15 countries.Patients: One-hundred eighty-eight children (term newborn to

In November 2001, the Food and Drug Administration (FDA) approved drotrecogin alfa (activated) (DrotAA) for adults who had severe sepsis and a high risk of death. The FDA required a study to evaluate the efficacy of DrotAA for adults who had severe sepsis and a low risk of death.We randomly assigned adult patients with severe sepsis and a low risk of death (defined by an Acute Physiology and Chronic Health Evaluation [APACHE II] score25 or single-organ failure) to receive an intravenous infusion of placebo or DrotAA (24 microg per kilogram of body weight per hour) for 96 hours in a double-blind, placebo-controlled, multicenter trial. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. In-hospital mortality within 90 days after the start of the infusion was measured, and safety information was collected.Enrollment in the trial was terminated early because of a low likelihood of meeting the prospectively defined objective of demonstrating a significant reduction in the 28-day mortality rate with the use of DrotAA. The study enrolled 2640 patients and collected data on 2613 (1297 in the placebo group and 1316 in the DrotAA group) at the 28-day follow-up. There were no statistically significant differences between the placebo group and the DrotAA group in 28-day mortality (17.0 percent in the placebo group vs. 18.5 percent in the DrotAA group; P=0.34; relative risk, 1.08; 95 percent confidence interval, 0.92 to 1.28) or in in-hospital mortality (20.5 percent vs. 20.6 percent; P=0.98; relative risk, 1.00; 95 percent confidence interval, 0.86 to 1.16). The rate of serious bleeding was greater in the DrotAA group than in the placebo group during both the infusion (2.4 percent vs. 1.2 percent, P=0.02) and the 28-day study period (3.9 percent vs. 2.2 percent, P=0.01).The absence of a beneficial treatment effect, coupled with an increased incidence of serious bleeding complications, indicates that DrotAA should not be used in patients with severe sepsis who are at low risk for death, such as those with single-organ failure or an APACHE II score less than 25.

BACKGROUND: Drotrecogin alfa (activated) [DrotAA] is approved for the reduction of mortality in adults with severe sepsis (sepsis with acute organ dysfunction) and high risk of death. Patients whose actual body weight was >135 kg were excluded from the Phase III PROWESS trial. OBJECTIVE: To compare exposure to DrotAA in patients with severe sepsis weighing >135 kg with those weighing ⩽135 kg in an open-label, Phase IV trial, and quantify the elimination half-life (t1/2) of DrotAA in these patients. METHODS: PROWESS inclusion/exclusion criteria were used, except that patients >135 kg were enrolled. Blood samples were collected for steady-state plasma concentration (Css) analysis of activated protein C once each day and for t1/2 analysis after infusion. Weight-normalized clearance (Clp) and t1/2 estimates for DrotAA were calculated and compared between weight groups. RESULTS: Patient weight range was 59–227 kg. There were 32 patients ⩽135 kg and 20 patients >135 kg enrolled. Median Clp was 0.45 L/h/kg (interquartile range [IQR] 0.37–0.54) for patients ⩽135 kg and 0.42 L/h/kg (IQR 0.33–0.54) for patients >135 kg (p = 0.692). Median estimates of Css were 51.9 ng/mL (IQR 43.4–62.0) and 56.5 ng/mL (IQR 44.9–71.1; p = 0.570). In patients ⩽135 kg, DrotAA had a median t1/2 of 16.7 minutes (IQR 13.9–20.0) compared with 16.0 minutes (IQR 12.9–19.8) in patients >135 kg (p = 0.767), for a composite median t1/2 of 16.3 minutes (IQR 14.2–18.8). CONCLUSIONS: There is no statistically significant difference in Css concentrations or t1/2 of DrotAA between patients weighing ⩽135 kg and >135 kg. DrotAA should be dosed by actual body weight.

OBJECTIVE: To compare differences in hospital mortality and resource use in adult severe sepsis subjects randomized to receive drotrecogin alfa (activated) (DrotAA) or placebo in the PROWESS trial. DESIGN: Retrospective, cross-sectional, blinded follow-up of subjects enrolled in a previous randomized, controlled trial. SETTING: One hundred sixty-four tertiary care institutions in 11 countries. PARTICIPANTS: The 1,690 subjects with severe sepsis enrolled and treated with study drug in PROWESS, of whom 1,220 were alive at 28 days (the end of the original PROWESS follow-up). INTERVENTIONS: DrotAA (n = 850), 24 microg/kg/hr for 96 hrs, or placebo (n = 840). MEASUREMENTS AND MAIN RESULTS: New follow-up data through hospital discharge were merged with existing 28-day follow-up data. Hospital mortality was calculated for designated subgroups. Intensive care unit and hospital length of stay and Simplified Therapeutic Intervention Scoring System-28 (TISS-28) scores were calculated overall and in designated subgroups. Hospital discharge location was recorded. The 95% confidence interval of most subgroups contained the relative risk estimate for overall 28-day and hospital mortality. Median hospital length of stay and intensive care unit length of stay were similar in both treatment groups: 16 vs. 17 days (p = .22) and 9 vs. 9 days (p = .7) for placebo vs. DrotAA. No significant difference in TISS-28 scores was observed between treatment groups overall or in subgroups of disease severity. In subjects for whom discharge destination was reported, 42.8% of placebo subjects and 46.8% of DrotAA subjects (two thirds of survivors in each group) were discharged directly to home. CONCLUSIONS: Reduction in hospital mortality with DrotAA in most of the subgroups of PROWESS is consistent with the reduction in 28-day and hospital mortality observed in the overall PROWESS population. Additional survivors created with DrotAA treatment did not increase per-patient resource use or intensive care unit or hospital length of stay.

Study objective To gather additional 28-day all-cause mortality and safety data among adult patients with severe sepsis who were treated with drotrecogin alfa (activated). Design Prospective, single-arm, multicenter clinical trial. Setting Eighty-five study sites in the United States and two in Puerto Rico. Participants Adult patients (273 patients) with a diagnosis of severe sepsis, which was defined as a systemic inflammatory response due to acute infection and one or more sepsis-induced organ dysfunctions present for ≤ 48 h, as in the recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial. Interventions Drotrecogin alfa (activated) [Xigris; Eli Lilly and Company; Indianapolis, IN], 24 μg/kg/h, as a continuous IV infusion for a duration of 96 ± 1 h. Measurements and results The primary end point was all-cause mortality, which was assessed 28 days after the start of the infusion of drotrecogin alfa (activated). Serious bleeding was monitored to day 28. Comparisons of mortality were made to treatment groups from two double-blind, placebo-controlled clinical trials (PROWESS United States and the Secretory Phospholipase A2 Inhibitor [sPLA2I] in Severe Sepsis trial) that used similarly defined patient populations from the United States. For the 273 adult patients enrolled in this study, the 28-day all-cause mortality rate was 26.4%. This mortality rate was 6% lower than that observed in the placebo groups in the PROWESS US trial (32.9%) and the sPLA2I trial (33.2%), and was similar to that of the group treated with drotrecogin alfa (activated) in the PROWESS US trial (24.4%). One nonfatal intracranial hemorrhage was reported in the Extended Evaluation of Recombinant Human Activated Protein C United States trial (ENHANCE US) [0.35%]. Serious bleeding events during the infusion period occurred in 11 patients (4.0%) compared to 10 patients (2.8%) in the PROWESS US drotrecogin alfa (activated) treatment group. Conclusions Despite the limitations associated with comparisons across trials, this study provides confirmatory evidence of the efficacy and safety of drotrecogin alfa (activated) documented in the PROWESS trial.

Study objectives Transpyloric feeding is desirable in critically ill patients who often have gastroparesis; however, correct placement is difficult, requiring fluoroscopy, endoscopy, or time-consuming blind attempts. This study evaluated the success rate and time required to place transpyloric tubes using erythromycin infusion and GI electromyogram (EMG) signal. Design Observational trial. Setting University hospital medical ICU. Patients Thirty-nine patients receiving mechanical ventilation for respiratory failure (n = 13), pancreatitis (n = 9), ARDS (n = 8), neurologic disease (n = 4), major surgery (n = 3), and GI disease (n = 2) were enrolled (25 men and 14 women; mean age, 48.4 years; range, 21 to 82 years). Interventions Unweighted Flexiflo 10F feeding tubes were modified by the placement of an electrode 4 to 8 cm from the tip to record electromyogram (EMG) signals (Ross Products Division; Columbus, OH). Gastric signals are high amplitude with a frequency of 3 cycles per minute, while the duodenum and jejunum are low amplitude and 11 to 13 cycles per minute. Erythromycin was infused at a dose of 3 mg/kg to enhance gastric motor activity and emptying. The transpyloric tube was placed in the stomach, and its position was confirmed by EMG, then slowly advanced until duodenal EMG was detected. Tube position was determined by abdominal radiography. Measurements and results Thirty-one of 39 placements were immediately successful (initial success rate, 80%), 23 jejunal and 8 duodenal, requiring an average 7.8 min (range, 3 to 31 min). Six attempts in five patients were initial failures but were repeated, reaching the duodenum in one patient and the jejunum in four patients. Conclusion Erythromycin infusion and EMG guidance can facilitate rapid transpyloric feeding tube placement in critically ill patients at the bedside.

Objective: In the multinational PROWESS trial, drotrecogin alfa (activated) significantly reduced mortality rate in patients with severe sepsis compared with placebo. The use of large multiple-enter trials can potentially complicate interpretation of results in severe sepsis populations because of variability in medical attitudes and practices and the frequency of confounding events such as protocol violations. The objective of this study was to perform a blinded, critical, integrated review of data from the 1,690 severe sepsis patients from 164 medical centers enrolled in the PROWESS trial using a Clinical Evaluation Committee. Design: Blinded, critical, integrated review of data. Setting: Participating sites. Patients: The 1,690 severe sepsis patients from 164 medical centers enrolled in the PROWESS trial. Interventions: We performed analyses of the optimal cohort, defined as patients who had full compliance with the protocol, had evidence of an infection, and received adequate anti-infective therapy. We also performed other analyses, including significant underlying disorders, life support measures, and causes of death. Measurements and Main Results: The optimal cohort of 81.4% of the intention-to-treat population [drotrecogin alfa (activated), n = 695; placebo, n = 680] had similar baseline severity of illness between the two groups, a similar pharmacodynamic effect, and a relative risk of death estimate consistent with that observed in the overall PROWESS trial (0.83, 95% confidence interval 0.69-0.99 vs. 0.806, 95% confidence interval 0.69-0.94). A beneficial effect of drotrecogin alfa (activated) similarly was observed in patients with significant underlying disorders (0.73, 95% confidence interval 0.57-0.93) who were more severely ill and had a higher percentage of patients forgoing life-sustaining therapy. In contrast with the original investigator determinations, a benefit associated with drotrecogin alfa (activated) treatment in urinary tract infection adjudicated by the Clinical Evaluation Committee was observed. Conclusions: The survival benefit associated with drotrecogin alfa (activated) use was consistent with the results of the overall trial regardless of whether patients met criteria of the optimal cohort or had a significant underlying disorder.

Study Objectives. To evaluate whether a dose-response curve exists for erythromycin, determine the lowest effective dose of erythromycin needed to improve gastric motility, and compare erythromycin's effectiveness with that of metoclopramide in improving gastric emptying. Design. Randomized, crossover, multiintervention trial. Setting. Inpatient clinical research center. Subjects. Ten healthy volunteers (four men, six women) from the general population. Intervention. On each study day, the subjects were infused with erythromycin 0.75 mg/kg, 1.5 mg/kg, or 3.0 mg/kg; metoclopramide 10 mg; or placebo, in random order. Subjects then drank Ensure 200 ml mixed with acetaminophen 1.5 g. Gastric emptying was estimated by comparing the area under the curve after 60 minutes for acetaminophen absorption using four timed blood draws. Measurements and Main Results. Erythromycin increased gastric emptying in a dose-response manner. Erythromycin 3.0 mg/kg and metoclopramide 10 mg were associated with statistically significant increases in liquid gastric emptying compared with placebo. During infusion, nausea and stomach cramping were associated with the 3.0-mg/kg dose of erythromycin; drowsiness was associated with metoclopramide. Conclusion. In patients requiring intravenous erythromycin for gastric motility, the 3.0-mg/kg dose seems the most effective, with a reasonable side effect profile.

Marketed factor IX (FIX) products require intravenous (IV) administration to achieve effective prophylaxis for patients with hemophilia B. Subcutaneous (SQ) administration is a preferred route of administration but has been limited by low bioavailability and potency of the marketed FIX products. CB2679d/ISU304 with enhanced biological properties was developed using a rational protein design approach and has resistance to inhibition by ATIII, increased affinity for FVIIIa, increased catalytic activity, which result in 22-fold enhanced potency in vitro (clotting activity) and in vivo (the tail clip model) and 8-fold increased duration of aPTT activity in vivo compared with recombinant wild-type FIX dosed at the same mass and may allow SQ administration to provide prophylaxis. Methods: The trial design is provided below. IV pharmacokinetics (PK) (antigen and activity) was sampled at predose, 0, 0.25, 0.5, 1, 3, 6, 9, 24, 48 and 72 hours. SQ PK was sampled at predose, 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72 hours. Cohort 5 has PK sampled before each injection, 6 hours after first and 6th injection and 24 hours after 6th daily injection. Hematology, chemistry and coagulation was measured at Seoul Clinical Laboratories (Yongin-si, South Korea). FIX antigen and FIX activity, anti-drug antibody to BeneFIX and ISU304 and neutralizing antibody were measured at Haematologic Technologies Inc (Essex Junction, VT). A safety follow-up was done 2 weeks after last visit. FIX antigen was measured using VisuLizeTM Factor IX Antigen KitAG (Affinity Biologicals, Inc, Ancaster, ON, Canada) and FIX activity was measured using a one-stage clotting assay using ACL TOP 700 and Instrumentation Laboratories (Bedford, MA) reagents. The calculation of AUC was based on the trapezoidal rule. To calculate the additional area for AUC0-inf, the log-linear regression line for the last three time points was fit and extrapolated to the x-intercept. The calculation of half-life was based on the use of Demitasse 2000 (version 1.1.3, M. Lee, 2000) which uses an iterative piecewise fitting algorithm based on a robust (M-regression) log-linear model (Lee, 1990, 1997). All activity data were adjusted for baseline before analysis, assuming exponential falloff after IV administration and a half-life of 20 hours. Bioavailability was calculated from the AUC0-t for the IV and SQ data using FIX activity data. Subject safety was reviewed by an external Data Safety Monitoring Board and also an internal Data Monitoring Committee. Results: PK and activity of ISU304 demonstrate the 22-fold greater potency over BeneFIX and longer mean residence time (Cohort 1 figure, Table 1). Bioavailability of 18.2-23.6%, SQ beta half-life 66-103 hours and Tmax 6-24 hours (Cohort 2 figure, Table 2) One subject reported transient fever and a mild SQ injection site reaction. Conclusion: Interim study results support the aim of achieving normal or high mild hemophilia FIX levels in individuals with hemophilia B with repeated SQ dosing. Complete PK and activity and steady-state levels after 6 daily doses will be reported from this phase 1/2 subcutaneous dosing study. Figure Figure. Disclosures Levy: Catalyst Biosciences: Employment, Equity Ownership. Lee: Catalyst Biosciences: Consultancy. Hong: ISU Abxis: Employment. Siegel: Catalyst Biosciences: Consultancy. Park: ISU Abxis: Employment.

Tricyclic overdose can be a medical emergency, and therapy with intravenous bicarbonate is not always successful in preventing cardiac toxicity or coma. Mortality in patients developing these complications is from 1% to 15%. Extracorporeal detoxification with sorbents has been used in treatment of patients with very high drug levels and declining clinical condition. Ten patients with serious drug overdose caused by tricyclics failed to respond quickly to standard therapy and were in stage 3-4 encephalopathy. Nine of these patients were on respirator support, 5 had hypotension, and 6 had QRS widening. Average level was 1,423 microg/L at presentation. Enteral activated charcoal and intravenous (IV) bicarbonate were initiated in the emergency room. The patients were treated for 3 to 4 hours with the Liver Dialysis Unit, a hemodiabsorption device using a cellulosic plate dialyzer and sorbent suspension as dialysate. Inflow and outflow blood levels indicated that the hemodetoxifier removed modest amounts of the tricyclics, metabolites, and other consumed drugs. The clinical improvement of the patients was dramatic, with patients reaching stage 0 or 1 encephalopathy during the treatment. Ventilator support was removed at the end of treatment for 3 patients who had not already developed pneumonia, and for others was prolonged up to 48 hours because of pneumonia, rather than mental status. Average length of stay in the intensive care unit (ICU) was 4.8 days (range 1 to 7 days). None of the patients died despite their high risk for ventricular arrhythmias, seizures, and death. Clinical improvement may have been attributable to removal of free drug from the blood or to removal of drug metabolites.

Introduction Measuring functional C1 inhibitor (C1 INH) with chromogenic or ELISA methods can confirm a diagnosis of hereditary angioedema (HAE) due to C1 INH deficiency. Previous studies found differences in the agreement of these assays. Objective To evaluate the agreement between chromogenic or ELISA methods in the context of an observational study. Methods Patients with previously confirmed HAE underwent functional C1 INH testing. These patients contacted first-degree relatives (parents, siblings, or offspring) not previously evaluated for HAE, who underwent a panel of complement testing, including for functional C1 INH. Results Overall, 31 patients with HAE and 46 untested relatives enrolled. Of 46 relatives, 14 (30.4%) were newly diagnosed with HAE based on their laboratory results. Among the 31 patients previously confirmed with HAE, all had low functional C1 INH according to the chromogenic method, whereas 22 (71.0%) had low, 7 (22.6%) had equivocal, and 2 (6.5%) had normal functional C1 INH according to the ELISA method. In the 14 newly diagnosed relatives, all had low functional C1 INH according to the chromogenic method, whereas 11 (78.5%) had low and 3 (21.4%) had equivocal results according to the ELISA method. Conclusion Despite the apparent discordance in the ELISA and chromogenic assays in a small number of patients, both were useful in measuring functional C1 INH. To establish the diagnosis of HAE due to C1 INH deficiency, functional C1 INH results should be interpreted in combination with family and clinical history, and with other complement tests.

An FDA-approved Phase 1 feasibility study was performed in two centers to determine the safety of the BioLogic-DTPF (detoxifier/plasma filter) system for the treatment of patients with systemic inflammatory response syndrome (SIRS). This device combines hemodiabsorption (dialysis of blood against powdered sorbents with the BioLogic-DT system) with push-pull sorbent-based pheresis (the PF add-on module). Eight adult ICU patients with both SIRS and multiple organ failure participated in the study. One 6 h treatment was planned for each patient with powdered charcoal as sorbent for 4 patients and a combination of charcoal/silica in the PF sorbent bag for 4 patients. The treatments appeared to have no negative effects in 7 patients, but 1 patient died during treatment due to progressive cardiac failure. Sepsis was resolved in 5 of the 8 patients. However, there were only 2 long-term survivors of the group. The addition of the PF module should improve the chemical function of the BioLogic-DT by allowing removal of protein-bound toxins such as cytokines. The selected patients tolerated treatment by the DTPF system well, but proof of benefit of the device remains to be proven in a Phase 2 clinical trial with randomized controls.

Objective: To determine whether adding erythromycin to a gastric feeding regimen could render it as effective in meeting nutritional needs as transpyloric feeding. Design: Randomized, controlled study. Setting: University hospital medical, surgical, and neurologic care intensive care units. Patients: Critically ill patients, requiring a projected 96 hrs of enteral feeding, who had no specific indication for tube location (gastric or transpyloric). Eighty patients were randomized. Interventions: Patients were randomized to gastric feeding with erythromycin (200 mg IV) given every 8 hrs or feeding through a transpylorically placed feeding tube. Goal rate and feeding advancement were determined by protocol. Measurements and Main Results: During the 96-hr period, the gastric group received 74% of their goal calories and the transpyloric group received 67%. The only day on which gastric feedings were superior was the first study day, where the gastric group attained 55% of their goal, compared with 44% in the ...

Study objectives: To describe the clinical features and laboratory abnormalities of 16 adults with confirmed Hantavirus pulmonary syndrome (HPS) due to Andes virus in Temuco, Chile. Design: A retrospective chart review abstracting clinical, radiologic, laboratory, and epidemiologic data. Setting: ICU of the university teaching hospital in Temuco, Chile. Patients: Sixteen patients with HPS treated between 1997 and 1999. Results: Patients were aged from 19 to 45 years, 82% were men, and 88% were farm or timber workers with occupational acquisition of HPS. After an incubation period ranging from 5 to 25 days, a prodromal influenza-like phase frequently was accompanied by abdominal symptoms. From 1 to 7 days later, respiratory insufficiency and hemodynamic instability suddenly appeared. In 81%, hemorrhage was evident; in 63%, moderate-to-severe bleeding occurred. The most prominent laboratory abnormalities were hemoconcentration, leukocytosis, thrombocytopenia, altered partial thromboplastin time (PTT), creatine kinase, transaminases, and hyponatremia. Creatinine elevation was common, with clinical importance in two patients. All patients had severe hypoxemia and pulmonary edema. Fifteen patients received supportive treatment, and 5 patients were treated with corticosteroids. The mortality rate was 43.8%. Conclusions: Bad prognostic factors appeared to be severe hypotension, lower PaO2/fraction of inspired oxygen values, prolonged PTT, hemorrhage, greater volume load, and profuse bronchorrhea. The effects of treatment with corticosteroids could not be determined. Hemorrhage and renal involvement were common in our patients, features not often described in the North American literature of Sin Nombre virus HPS. (CHEST 2001; 120:548 ‐554)

Study Objectives. To determine the validity and reliability of the Sedation-Agitation scale (SAS) when administered by intensive care unit (ICU) nurses with no experience in its use. Design. Prospective, psychometric evaluation. Setting. Adult medical-cardiac ICU. Patients. Sixty patients. Intervention. Sedation and agitation were observed simultaneously but independently by nurses and two investigators, and patients were rated with the SAS. The assessment of an experienced clinical nurse specialist was recorded on visual analog scales (VAS) for sedation (VAS-S) and agitation (VAS-A). Measurements and Main Results. The SAS scores of ICU staff nurses were compared with VAS scored by the clinical nurse specialist using Pearson correlation coefficient. The SAS correlated well with VAS-S (Spearman's ρ = −0.77, p 0.5), but there were few observations of agitated patients. The SAS interrater agreement was excellent between the two trained investigators (weighted κ = 0.93, p

Background: Placement of feeding tubes in the transpyloric position can be helpful in the management of enterally fed patients with pancreatitis, gastric atony, enterocutaneous fistulae, or pulmonary aspiration risk. The attainment of transpyloric position is difficult, and numerous techniques have been proposed to help in achieving this location. Recently, the use of a magnet-tipped feeding tube, dragged into proper position with an external magnet, has been described with an excellent success rate. Methods: At 10 participating institutions, practitioners were trained in the use of the device. Successful tube placement was determined by abdominal radiograph. Results: One hundred fifty-six tube placements were attempted. Transpyloric position was obtained in 60%. Placement into the third portion of the duodenum or distal was obtained in only 32%. Analysis of the data did not reveal a learning curve at the institutions, and 7 of 10 had a 50% or lower success rate. Conclusions: Placement of feeding tubes wi...

Objective To evaluate the safety and efficacy of an intravenous liposomal dispersion of prostaglandin E1 as TLC C-53 in the treatment of patients with acute respiratory distress syndrome (ARDS). Design Randomized, prospective, multicenter, double-blind, placebo-controlled, phase III clinical trial. Setting Forty-seven community and university-affiliated hospitals in the United States. Patients A total of 350 patients with ARDS were enrolled in this clinical trial. Intervention Patients were prospectively randomized in a 1:1 ratio to receive either liposomal prostaglandin E1 or placebo. The study drug was infused intravenously for 60 mins every 6 hrs for 7 days starting with a dosage of 0.15 [micro sign]g/kg/hr. The dose was increased every 12 hrs until the maximal dose (3.6 [micro sign]g/kg/hr) was attained or intolerance to further increases developed. Patients received standard aggressive medical/surgical care during the infusion period. Outcome Measures The primary outcome measure was the time it took to wean the patient from the ventilator. Secondary end points included time to improvement of the PaO2/FIO2 ratio (defined as first PaO2/FIO2 >300 mm Hg), day 28 mortality, ventilator dependence at day 8, changes in PaO2/FIO2, incidence of and time to development/resolution of organ failure other than ARDS. Results A total of 348 patients could be evaluated for efficacy. The distribution of variables at baseline describing gender, lung injury scores, Acute Physiology and Chronic Health Evaluation II scores, PaO2/FIO2, pulmonary compliance, and time from onset of ARDS or from institution of mechanical ventilation to the first dose of study drug was similar among patients in the liposomal prostaglandin E1 (n = 177) and the placebo (n = 171) treatment arms. There was no significant difference in the number of days to the discontinuation of ventilation in the liposomal prostaglandin E1 group compared with the placebo group (median number of days to off mechanical ventilation, 16.9 in patients receiving liposomal prostaglandin E1 and 19.6 in those administered placebo; p = .94). Similarly, mortality at day 28 was not significantly different in the two groups (day 28 mortality, 57 of 176 (32%) in the liposomal prostaglandin E1 group and 50 of 170 (29%) in patients receiving placebo; p = .55). In contrast, treatment with liposomal prostaglandin E1 was associated with a significantly shorter time to reach a PaO2/FIO (2) ratio of >300 mm Hg (median number of days to reaching a PaO2/FIO2 ratio >300 mm Hg: 9.8 days in the liposomal prostaglandin E1 group and 13.7 days in patients receiving the placebo; p = .02). Among the subgroups examined, time to off mechanical ventilation was significantly reduced in patients who received at least 85% of a full dose (i.e., >45.9 [micro sign]g/kg) of liposomal prostaglandin E1 (median number of days to discontinuation of ventilation, 10.3 in the liposomal prostaglandin E1 group and 16.3 days in patients receiving placebo; p = .05). The overall incidence of serious adverse events was not significantly different in the liposomal prostaglandin E1 (40%) or placebo-treated (37%) groups. Drug-related adverse events of all kinds were reported in 69% of the patients receiving liposomal prostaglandin E1 compared with 33% of the placebo group, with hypotension and hypoxia (occurring in 52% and 24% of the liposomal prostaglandin E1-treated patients, respectively, and 17% and 5% of the placebo-treated patients, respectively) being noted most frequently. Conclusions In the intent-to-treat population of patients with ARDS, treatment with liposomal prostaglandin E1 accelerated improvement in indexes of oxygenation but did not decrease the duration of mechanical ventilation and did not improve day 28 survival. (Crit Care Med 1999; 27:1478-1485)

The rates of spontaneous passage of a self-propelling tube, a weighted nasoenteric tube (Ross Products Division, Columbus, OH), and a new unweighted transpyloric tube (Ross Products Division) were compared. This prospective, randomized comparison of outcome was performed at five medical centers and included 129 critically ill patients. Placement was confirmed radiologically at 6, 12, 24, 48, and 72 hours. There was no significant difference between group demographics and clinical characteristics. No significant differences in location of the tubes at any time point were found when comparing the self-propelling vs weighted tubes and self-propelling vs unweighted transpyloric tubes. A significant difference was noted in transpyloric location for the unweighted transpyloric tubes vs weighted tubes at 48 hours (58% vs 29%; p = .014) and at 72 hours (62% vs 32%; p = .011).