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2839. Efficacy, Pharmacokinetics (PK), and Safety Profile of Suvratoxumab (MEDI4893), a Staphylococcus aureus Alpha Toxin (AT)-Neutralizing Human Monoclonal Antibody in Mechanically Ventilated Patients in Intensive Care Units; Results of the Phase 2 SAATELLITE Study Conducted by the Public-Private COMBACTE Consortium

ABSTRACT: Abstract Background Staphylococcus aureus (SA) pneumonia imposes significant morbidity and mortality in mechanically ventilated, intensive care unit (MV ICU) patients despite best clinical care. We assessed efficacy, PK, AT-neutralizing antibodies (AT NAbs), and safety of suvratoxumab (suvra) in MV ICU subjects in the placebo-controlled, randomized Phase 2 SAATELLITE study (NCT02296320; EudraCT 2014-001097-34). Methods Subjects with PCR-confirmed SA colonization of the lower respiratory tract were randomized to either a single intravenous infusion of 5,000 mg suvra (n = 96) or placebo (n = 100) and followed for 190 days post dose. Efficacy endpoints were Endpoint Adjudication Committee-determined relative risk reduction (RRR) of SA pneumonia incidence in suvra vs. placebo recipients within 30 days post dose (primary endpoint, tested at 2-sided ? = 0.1), incidence of all-cause pneumonia, and all-cause pneumonia or death. Serum suvra PK and levels of AT NAbs were measured through 90 days post dose and analyzed for statistical correlation. Treatment-emergent adverse events (TEAEs) and serious AEs (SAEs) were assessed through 190 days post dose. Results Baseline characteristics were similar between groups. Suvra provided 31.9% RRR in incidence of SA pneumonia vs. placebo (17.7% vs. 26%; P = 0.166), 30% RRR (P = 0.146) in incidence of all-cause pneumonia, and 23% RRR (P = 0.164) in incidence of all-cause pneumonia or death. Suvra reduced mean hospital stay and ICU duration by 3.0 and 2.4 days, resp. vs. placebo. Mean serum ± SD suvra level was 296 ± 131 µg/mL at 30 days post dose. Serum AT Nab ± SD levels reached 156.03 ± 72.48 IU/mL at 2 days post dose, declining slowly to 33.74 ± 16.04 IU/mL by 90 days post dose. AT NAbs correlated with PK (r2 = 0.7), thereby confirming functional activity of suvra over time. Proportion of subjects with TEAEs or SAEs was similar between groups: ?1 TEAE (93.8% suvra; 93.0% placebo); ?1 serious; and/or ?grade 3 severity SAE (66.7% suvra; 58.0% placebo). Conclusion A single intravenous dose of suvra produced a trend toward reduced incidence of SA pneumonia, health resource savings, sustained functional exposure in serum, and an acceptable safety profile. These results support continued development of suvra in MV ICU patients. Disclosures All Authors: No reported Disclosures.

SUBMITTER: Francois B

PROVIDER: S-EPMC6809370 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Project description:Abstract Background Pseudomonas aeruginosa (PA) pneumonia is associated with morbidity and mortality in mechanically ventilated, intensive care unit (MV ICU) patients despite best clinical care. We assessed efficacy, PK, and safety of MEDI3902 in MV ICU subjects in the placebo-controlled, randomized Phase 2 EVADE study (NCT02696902; EudraCT 2015-001706-34). Methods Subjects with PCR-confirmed PA colonization of the lower respiratory tract were randomized to either a single IV infusion of 1,500 mg MEDI3902 (n = 85) or placebo (n = 83). Primary Efficacy endpoint was Endpoint Adjudication Committee-determined relative risk reduction (RRR) of PA pneumonia incidence in MEDI3902 vs. placebo recipients within 21 days post dose (2-sided α = 0.2). Serum MEDI3902 PK levels were measured through 49 days post dose. Treatment-emergent adverse events (TEAEs) and serious AEs (SAEs) were assessed through 49 days post dose. Results Baseline characteristics were similar between groups. MEDI3902 did not meet the primary endpoint of PA pneumonia vs. placebo (22.4% vs. 18.1%; RRR -23.7%, P = 0.491). Mean serum MEDI3902 level was 9.46 µg/mL (target 1.7µg/mL) at 21 days post dose, with a t½ 5.6 days. Proportion of subjects with TEAEs was similar between groups: ≥1 TEAE (98.8% MEDI3902; 97.6% placebo); ≥1 serious; and/or ≥grade 3 severity SAE (70.6% MEDI3902; 66.3% placebo). Deaths were numerically higher, although not statistically significant (24 (28.2%) MEDI3902 vs 19 (22.9%) Placebo; RRR -23.3%, P 0.429). Post-hoc analyses suggested RRR 47% among ~70% of the study population who had baseline Procalcitonin levels < 0.55 µg/L (12.5% MEDI3902 vs 23.7% placebo; 80%CI 6.1%-69.9%; P 0.135). Similarly, RRR 83% was observed among 50% of study subjects with baseline absolute neutrophil count (ANC) of < 8170 /µL (2.8% MEDI3902 vs 17.0% placebo; 80%CI 39.5%-95.5%; P 0.038). Subjects with Procalcitonin < 0.55 µg/L and ANC < 8170/ µL also had higher serum PK exposure. Conclusion A single IV dose of MEDI3902 provided PK exposure above the target level but did not achieve primary efficacy endpoint of reduction in PA pneumonia. Efficacy trends were observed in subjects with lower levels of baseline inflammatory biomarkers. MEDI3902 may have a path forward in certain patient populations such as ICU patients with lower baseline inflammation. Disclosures Jean Chastre, MD, AstraZeneca (Scientific Research Study Investigator) Marc Bourgeois, MD, AstraZeneca (Scientific Research Study Investigator) Apostolos Komnos, MD, PhD, AstraZeneca (Scientific Research Study Investigator) Ricard Ferrer, MD, PhD, Shionogi B.V. (Advisor or Review Panel member) Galia Rahav, MD, AstraZeneca (Scientific Research Study Investigator) Nicolas De Schryver, MD, AstraZeneca (Scientific Research Study Investigator) Alain Lepape, MD, AstraZeneca (Scientific Research Study Investigator) Miguel Sanchez Garcia, MD, PhD, AstraZeneca (Scientific Research Study Investigator) Antoni Torres, MD, PhD, AstraZeneca (Scientific Research Study Investigator) Omar Ali, PhD, AstraZeneca (Employee) Kathryn Shoemaker, MS, AstraZeneca (Employee) Alexey Ruzin, PhD, AstraZeneca (Employee, Shareholder) Yu Jiang, PhD, AstraZeneca (Employee) Susan Colbert, BSN, AstraZeneca (Employee) Drieke Vandamme, PhD, AstraZeneca (Scientific Research Study Investigator) Terramika Bellamy, n/a, AstraZeneca (Employee) Colin Reisner, MD, AstraZeneca (Employee) Filip Dubovsky, MD, MPH, AstraZeneca (Employee) Hasan S. Jafri, MD, FAAP, AstraZeneca (Employee)

Project description:BackgroundIn recent years, the number of elderly patients receiving mechanical ventilation (MV) in intensive care units (ICUs) has increased. However, the evidence on the outcomes of elderly mechanically ventilated patients is scant in China. Our objective was to evaluate the characteristics and outcomes in elderly patients (≥65 years) receiving MV in the ICU.MethodsWe performed a multicentre retrospective study involving adult patients who were admitted to the ICU and received at least 24 hours of MV. Patients were divided into three age groups: under 65, 65-79, and ≥80 years. The primary outcome was hospital mortality. We performed univariate and multivariate logistic regression analysis to identify factors associated with hospital mortality.ResultsA total of 853 patients were analysed. Of those, 61.5% were ≥65 years of age, and 26.0% were ≥80 years of age. There were significant differences in the principal reason for MV among the three age groups (P<0.001). Advanced age was significantly associated with total duration of MV, ICU length of stay (LOS), and ICU costs (all P<0.001), but not with hospital LOS and hospital costs (P>0.05). In addition, mortality rates in the ICU, hospital, and at 60 days significantly increased with age (all P<0.001). In the age group of 80 years and older, the mortality rates were 47.7%, 49.5%, and 50.0%, respectively. Multivariate logistic regression analysis had found that age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO2/FiO2) ratio, total duration of MV, ICU LOS, and the decision to withhold/withdraw life-sustaining treatments were independent influence factors for mortality rates.ConclusionsMechanically ventilated elderly patients (≥65 years) have a higher ICU and hospital mortality, but the hospital LOS and hospital costs are similar to younger patients. Advanced age should be considered as a significant independent risk factor for hospital mortality of mechanically ventilated ICU patients.

Project description:BackgroundAssessment of preparedness of weaning has been recommended before extubation for mechanically ventilated patients. We aimed to understand the association of a structured assessment of weaning preparedness with successful liberation.MethodsWe retrospectively investigated patients with acute respiratory failure who experienced an extubation trial at the medical intensive care units of a medical center and compared the demographic and clinical characteristics between those patients with successful and failed extubation. A composite score to assess the preparedness of weaning, the WEANSNOW score, was generated consisting of eight components, including Weaning parameters, Endotracheal tube, Arterial blood gas analysis, Nutrition, Secretions, Neuromuscular-affecting agents, Obstructive airway problems and Wakefulness. The prognostic ability of the WEANSNOW score for extubation was then analyzed.ResultsOf the 205 patients included, 138 (67.3%) patients had successful extubation. Compared with the failure group, the success group had a significantly shorter duration of MV before the weaning attempt (11.2 ± 11.6 vs. 31.7 ± 26.2 days, p < 0.001), more with congestive heart failure (42.0% vs. 25.4%, p = 0.020), and had different distribution of the types of acute respiratory failure (p = 0.037). The failure group also had a higher WEANSNOW score (1.22 ± 0.85 vs. 0.51 ± 0.71, p < 0.001) and worse Rapid Shallow Breathing Index (93.9 ± 63.8 vs. 56.3 ± 35.1, p < 0.001). Multivariate logistic regression analysis showed that a WEANSNOW Score = 1 or higher (OR = 2.880 (95% CI [1.291-6.426]), p = 0.010) and intubation duration >21 days (OR = 7.752 (95% CI [3.560-16.879]), p < 0.001) were independently associated with an increased probability of extubation failure.ConclusionAssessing the pre-extubation status of intubated patients in a checklist-based approach using the WEANSNOW score might provide valuable insights into extubation failure in patients in a medical ICU for acute respiratory failure. Further prospective studies are warranted to elucidate the practice of assessing weaning preparedness.

Project description:ObjectivesThe determinants of decisions to limit life support (withholding or withdrawal) in ventilated stroke patients have been evaluated mainly for patients with intracranial hemorrhages. We aimed to evaluate the frequency of life support limitations in ventilated ischemic and hemorrhagic stroke patients compared with a nonbrain-injured population and to determine factors associated with such decisions.DesignMulticenter prospective French observational study.SettingFourteen ICUs of the French OutcomeRea network.PatientsFrom 2005 to 2016, we included stroke patients and nonbrain-injured patients requiring invasive ventilation within 24 hours of ICU admission.InterventionNone.Measurements and main resultsWe identified 373 stroke patients (ischemic, n = 167 [45%]; hemorrhagic, n = 206 [55%]) and 5,683 nonbrain-injured patients. Decisions to limit life support were taken in 41% of ischemic stroke cases (vs nonbrain-injured patients, subdistribution hazard ratio, 3.59 [95% CI, 2.78-4.65]) and in 33% of hemorrhagic stroke cases (vs nonbrain-injured patients, subdistribution hazard ratio, 3.9 [95% CI, 2.97-5.11]). Time from ICU admission to the first limitation was longer in ischemic than in hemorrhagic stroke (5 [3-9] vs 2 d [1-6] d; p < 0.01). Limitation of life support preceded ICU death in 70% of ischemic strokes and 45% of hemorrhagic strokes (p < 0.01). Life support limitations in ischemic stroke were increased by a vertebrobasilar location (vs anterior circulation, subdistribution hazard ratio, 1.61 [95% CI, 1.01-2.59]) and a prestroke modified Rankin score greater than 2 (2.38 [1.27-4.55]). In hemorrhagic stroke, an age greater than 70 years (2.29 [1.43-3.69]) and a Glasgow Coma Scale score less than 8 (2.15 [1.08-4.3]) were associated with an increased risk of limitation, whereas a higher nonneurologic admission Sequential Organ Failure Assessment score was associated with a reduced risk (per point, 0.89 [0.82-0.97]).ConclusionsIn ventilated stroke patients, decisions to limit life support are more than three times more frequent than in nonbrain-injured patients, with different timing and associated risk factors between ischemic and hemorrhagic strokes.

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