Phase II, Randomized, Double-Blind, Multicenter Study Comparing the Safety and Pharmacokinetics of Tefibazumab to Placebo for Treatment of Staphylococcus aureus Bacteremia

ABSTRACT Tefibazumab (Aurexis), a humanized monoclonal antibody that binds to the surface-expressed adhesion protein clumping factor A, is under development as adjunctive therapy for serious Staphylococcus aureus infections. Sixty patients with documented S. aureus bacteremia (SAB) were randomized and received either tefibazumab at 20 mg/kg of body weight as a single infusion or a placebo in addition to an antibiotic(s). The primary objective of the study was determining safety and pharmacokinetics. An additional objective was to assess activity by a composite clinical end point (CCE). Baseline characteristics were evenly matched between groups. Seventy percent of infections were healthcare associated, and 57% had an SAB-related complication at baseline. There were no differences between the treatment groups in overall adverse clinical events or alterations in laboratory values. Two patients developed serious adverse events that were at least possibly related to tefibazumab; one hypersensitivity reaction was considered definitely related. The tefibazumab plasma half-life was 18 days. Mean plasma levels were <100 μg/ml by day 14. A CCE occurred in six patients (four placebo and two tefibazumab patients) and included five deaths (four placebo and one tefibazumab patient). Progression in the severity of sepsis occurred in four placebo and no tefibazumab patients. Tefibazumab was well tolerated, with a safety profile similar to those of other monoclonal antibodies. Additional trials are warranted to address the dosing range and efficacy of tefibazumab.

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Interleukin (IL)-1β and IL-10 Host Responses in Patients With Staphylococcus aureus Bacteremia Determined by Antimicrobial Therapy

Clinical Infectious Diseases ◽

10.1093/cid/ciz686 ◽

2019 ◽

Vol 70 (12) ◽

pp. 2634-2640 ◽

Cited By ~ 7

Author(s):

Cecilia F Volk ◽

Sarah Burgdorf ◽

Graham Edwardson ◽

Victor Nizet ◽

George Sakoulas ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Antimicrobial Therapy ◽

Ex Vivo ◽

Host Responses ◽

Enzyme Linked Immunosorbent Assay ◽

Treatment Groups ◽

Staphylococcus Aureus Bacteremia ◽

Medical Centers ◽

Persistent Bacteremia

Abstract Background Patient interleukin (IL)-1β and IL-10 responses early in Staphylococcus aureus bacteremia (SaB) are associated with bacteremia duration and mortality. We hypothesized that these responses vary depending on antimicrobial therapy, with particular interest in whether the superiority of β-lactams links to key cytokine pathways. Methods Three medical centers included 59 patients with SaB (47 methicillin-resistant S. aureus [MRSA], 12 methicillin-sensitive S. aureus [MSSA]) from 2015–2017. In the first 48 hours, patients were treated with either a β-lactam (n = 24), including oxacillin, cefazolin, or ceftaroline, or a glyco-/lipopeptide (n = 35), that is, vancomycin or daptomycin. Patient sera from days 1, 3, and 7 were assayed for IL-1β and IL-10 by enzyme-linked immunosorbent assay and compared using the Mann-Whitney U test. Results On presentation, IL-10 was elevated in mortality (P = .008) and persistent bacteremia (P = .034), while no difference occurred in IL-1β. Regarding treatment groups, IL-1β and IL-10 were similar prior to receiving antibiotic. Patients treated with β-lactam had higher IL-1β on days 3 (median +5.6 pg/mL; P = .007) and 7 (+10.9 pg/mL; P = .016). Ex vivo, addition of the IL-1 receptor antagonist anakinra to whole blood reduced staphylococcal killing, supporting an IL-1β functional significance in SaB clearance. β-lactam–treated patients had sharper declines in IL-10 than vancomycin or daptomycin –treated patients over 7 days. Conclusions These data underscore the importance of β-lactams for SaB, including consideration that the adjunctive role of β-lactams for MRSA in select patients helps elicit favorable host cytokine responses.

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Efficacy of Early Oral Switch with β-Lactams for Low-Risk Staphylococcus aureus Bacteremia

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02345-19 ◽

2020 ◽

Vol 64 (7) ◽

Cited By ~ 1

Author(s):

Olivia Bupha-Intr ◽

Tim Blackmore ◽

Max Bloomfield

Keyword(s):

Staphylococcus Aureus ◽

Deep Infection ◽

Primary Treatment ◽

Low Risk ◽

Prosthetic Material ◽

Beta Lactam ◽

Related Complication ◽

Content Type ◽

Staphylococcus Aureus Bacteremia ◽

Oral Switch

ABSTRACT The aim of this study was to assess the safety of early oral switch (EOS) prior to 14 days for low-risk Staphylococcus aureus bacteremia (LR-SAB), which is the primary treatment strategy used at our institution. The usual recommended therapy is 14 days of intravenous (i.v.) antibiotics. All patients with SAB at our hospital were identified between 1 January 2014 and 31 December 2018. Those meeting low-risk criteria (health care-associated, no evidence of deep infection or demonstrated involvement of prosthetic material, and no further positive blood cultures after 72 h) were included in the study. The primary outcome was occurrence of a SAB-related complication within 90 days. There were 469 SAB episodes during the study period, 100 (21%) of whom met inclusion criteria. EOS was performed in 84 patients. In this group, line infection was the source in 79%, methicillin-susceptible S. aureus caused 95% of SABs and 74% of patients received i.v. flucloxacillin. The median durations of i.v. and oral antibiotics in the EOS group were 5 days (interquartile range [IQR], 4 to 6) and 10 days (IQR, 9 to 14), respectively. A total of 71% of patients received flucloxacillin as their EOS agent. Overall, 86% of oral step-down therapy was with beta-lactams. One patient (1%) undergoing EOS had SAB relapse within 90 days. No deaths attributable to SAB occurred within 90 days. In this low-MRSA-prevalence LR-SAB cohort, EOS was associated with a low incidence of SAB-related complications. This was achieved with oral beta-lactam therapy in most patients. Larger prospective studies are needed to confirm these findings.

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Pomaglumetad Methionil (LY2140023 Monohydrate) and Aripiprazole in Patients with Schizophrenia: A Phase 3, Multicenter, Double-Blind Comparison

Schizophrenia Research and Treatment ◽

10.1155/2014/758212 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 24

Author(s):

David H. Adams ◽

Lu Zhang ◽

Brian A. Millen ◽

Bruce J. Kinon ◽

Juan-Carlos Gomez

Keyword(s):

Weight Gain ◽

Adverse Events ◽

Term Treatment ◽

Phase 3 ◽

Serious Adverse Events ◽

Double Blind ◽

Treatment Groups ◽

Long Term Treatment ◽

Blind Comparison

We tested the hypothesis that long-term treatment with pomaglumetad methionil would demonstrate significantly less weight gain than aripiprazole in patients with schizophrenia. In this 24-week, multicenter, randomized, double-blind, Phase 3 study, 678 schizophrenia patients were randomized to either pomaglumetad methionil (n=516) or aripiprazole (n=162). Treatment groups were also compared on efficacy and various safety measures, including serious adverse events (SAEs), discontinuation due to adverse events (AEs), treatment-emergent adverse events (TEAEs), extrapyramidal symptoms (EPS), and suicide-related thoughts and behaviors. The pomaglumetad methionil group showed significantly greater weight loss at Week 24 (Visit 12) compared with the aripiprazole group (−2.8 ± 0.4 versus 0.4 ± 0.6;P<0.001). However, change in Positive and Negative Syndrome Scale (PANSS) total scores for aripiprazole was significantly greater than for pomaglumetad methionil (−15.58 ± 1.58 versus −12.03 ± 0.99;P=0.045). The incidences of SAEs (8.2% versus 3.1%;P=0.032) and discontinuation due to AEs (16.2% versus 8.7%;P=0.020) were significantly higher for pomaglumetad methionil compared with aripiprazole. No statistically significant differences in the incidence of TEAEs, EPS, or suicidal ideation or behavior were noted between treatment groups. In conclusion, long-term treatment with pomaglumetad methionil resulted in significantly less weight gain than aripiprazole. This trial is registered with ClinicalTrials.govNCT01328093.

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Inhibition of Interleukin-6 (IL-6) Reverses Anemia In Patients with Advanced Non Small Cell Lung Cancer (NSCLC): Results of a Phase II, Randomized, Double-Blind, Placebo-Controlled Trial

Blood ◽

10.1182/blood.v116.21.640.640 ◽

2010 ◽

Vol 116 (21) ◽

pp. 640-640 ◽

Cited By ~ 1

Author(s):

Michael W. Schuster ◽

James R Rigas ◽

Sergey V Orlov ◽

Branislav Milovanovic ◽

Kumar Prabhash ◽

...

Keyword(s):

Adverse Events ◽

Clinical Chemistry ◽

Controlled Trial ◽

Safety Data ◽

Primary Objective ◽

Serious Adverse Events ◽

Double Blind ◽

Reactive Protein ◽

Grade 3 ◽

Cancer Related Anemia

Abstract Abstract 640 Background: ALD518 is a humanized, desialyated anti-IL-6 antibody being developed for the treatment of cancer-related anemia, cachexia and fatigue. The primary objective of the study was to determine the efficacy and safety of ALD518 in patients with advanced NSCLC. Secondary objectives examined hematologic parameters. Methods: 124 patients with NSCLC, ECOG 0–3, weight loss in the preceding 3 months of >5% body weight, hemoglobin (Hb) >7g/dL, and C-reactive protein (CRP) >10mg/L were dosed. Patients were randomized to 1 of 4 groups (n~30/group). Placebo or ALD518 80mg, 160mg, or 320mg was administered intravenously every 8 weeks. Pts were followed up for 24 weeks. Data included hematologic parameters, clinical chemistry, CRP, D-dimer, lean body mass and adverse events (AEs). Quality of life data included the FACIT-F, FACT-L, and FAACT questionnaires. Data presented in this abstract relates to the safety and hematology results. Results: 29 pts completed the study treatments and evaluations, 38 failed to complete every visit, 52 died of progressive disease, and 5 withdrew because of adverse events. There were no dose limiting toxicities (DLTs), infusion reactions, or anti-idiotypic antibody responses to ALD518 observed in the study. 84 pts had serious AEs of which 1 was deemed to be possibly related to administration of ALD518 (rectal hemorrhage). The majority of the serious adverse events were due to progression of the NSCLC. Six patients had a CTC grade 4 change in laboratory safety data during the study. Four patients experienced a grade 4 hypercalcemia: 1 (3.6%), 2 (6.1%), and 1 (3.2%) in the ALD518 80mg, 160mg and placebo groups, respectively, and there was 1 patient with grade 4 GGT elevation (placebo) and 1 patient with grade 4 hypokalemia (ALD518 160mg). There were no treatment related differences in vitals sign or 12-lead ECG data. The mean (±SD) values for Hb, hematocrit (Hct), mean corpuscular Hb (MCH) and platelet counts are listed below: 38/93 pts treated with ALD518 and 10/31 given placebo had a pre-dose Hb =< 11g/dL. 24 of these pts on ALD518 and 7 of these pts on placebo remained in the study at week 4. 14/24 pts on ALD518 and 0/7 on placebo had raised their Hb from =< 11g/dL to >= 12g/dL. Conclusions: ALD518 increased Hb, Hct, MCH in NSCLC pts and raised Hb to >= 12g/dL in 58% of pts with a Hb =< 11g/dL at baseline. There was also a modest fall in platelet count observed in patients treated with ALD518 but no patients had a CTC grade 4 thrombocytopenia and only one patient (ALD518 160mg group) had a grade 3 thrombocytopenia at one time point. There were no major safety signals related to the administration of ALD518. Further study of ALD518 as a novel non-erythropoietic stimulating agent for cancer-related anemia is warranted. Disclosures: Schuster: Alder Biopharmaceuticals Inc: Honoraria. Rigas: Alder Biopharmaceuticals inc: Honoraria. Smith:Alder Biopharmaceuticals Inc: Employment.

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Impact of Prior Healthcare-Associated Exposure on Clinical and Molecular Characterization of Methicillin-Susceptible Staphylococcus aureus Bacteremia

Medicine ◽

10.1097/md.0000000000000474 ◽

2015 ◽

Vol 94 (5) ◽

pp. e474 ◽

Cited By ~ 6

Author(s):

Pao-Yu Chen ◽

Yu-Chung Chuang ◽

Jann-Tay Wang ◽

Shan-Chwen Chang

Keyword(s):

Staphylococcus Aureus ◽

Molecular Characterization ◽

Staphylococcus Aureus Bacteremia ◽

Healthcare Associated

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Classification of Healthcare-Associated Staphylococcus aureus Bacteremia: Influence of Different Definitions on Prevalence, Patient Characteristics, and Outcome

Infection Control and Hospital Epidemiology ◽

10.1017/ice.2015.259 ◽

2015 ◽

Vol 37 (2) ◽

pp. 208-211 ◽

Cited By ~ 8

Author(s):

Jesper Smit ◽

Mette Søgaard ◽

Henrik Carl Schønheyder ◽

Henrik Nielsen ◽

Reimar Wernich Thomsen

Keyword(s):

Staphylococcus Aureus ◽

Patient Characteristics ◽

Infect Control Hosp ◽

Healthcare Associated Infection ◽

Staphylococcus Aureus Bacteremia ◽

Healthcare Associated

We investigated whether different definitions of healthcare-associated infection influenced the prevalence, characteristics, and mortality of patients with Staphylococcus aureus bacteremia. With different definitions, the proportion of patients classified as having healthcare-associated S. aureus bacteremia varied substantially and the distribution of patient characteristics was influenced, whereas 30-day mortality remained robust.Infect. Control Hosp. Epidemiol. 2016;37(2):208–211

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Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2015-207628 ◽

2015 ◽

Vol 75 (6) ◽

pp. 1081-1091 ◽

Cited By ~ 99

Author(s):

Gerd R Burmester ◽

William F Rigby ◽

Ronald F van Vollenhoven ◽

Jonathan Kay ◽

Andrea Rubbert-Roth ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Randomised Controlled Trial ◽

Adverse Events ◽

Physical Function ◽

Controlled Trial ◽

Health Assessment ◽

Serious Adverse Events ◽

Double Blind ◽

Treatment Groups ◽

Randomised Controlled

ObjectivesThe efficacy of tocilizumab (TCZ), an anti-interleukin-6 receptor antibody, has not previously been evaluated in a population consisting exclusively of patients with early rheumatoid arthritis (RA).MethodsIn a double-blind randomised controlled trial (FUNCTION), 1162 methotrexate (MTX)-naive patients with early progressive RA were randomly assigned (1:1:1:1) to one of four treatment groups: 4 mg/kg TCZ+MTX, 8 mg/kg TCZ+MTX, 8 mg/kg TCZ+placebo and placebo+MTX (comparator group). The primary outcome was remission according to Disease Activity Score using 28 joints (DAS28–erythrocyte sedimentation rate (ESR) <2.6) at week 24. Radiographic and physical function outcomes were also evaluated. We report results through week 52.ResultsThe intent-to-treat population included 1157 patients. Significantly more patients receiving 8 mg/kg TCZ+MTX and 8 mg/kg TCZ+placebo than receiving placebo+MTX achieved DAS28-ESR remission at week 24 (45% and 39% vs 15%; p<0.0001). The 8 mg/kg TCZ+MTX group also achieved significantly greater improvement in radiographic disease progression and physical function at week 52 than did patients treated with placebo+MTX (mean change from baseline in van der Heijde–modified total Sharp score, 0.08 vs 1.14 (p=0.0001); mean reduction in Health Assessment Disability Index, −0.81 vs −0.64 (p=0.0024)). In addition, the 8 mg/kg TCZ+placebo and 4 mg/kg TCZ+MTX groups demonstrated clinical efficacy that was at least as effective as MTX for these key secondary endpoints. Serious adverse events were similar among treatment groups. Adverse events resulting in premature withdrawal occurred in 20% of patients in the 8 mg/kg TCZ+MTX group.ConclusionsTCZ is effective in combination with MTX and as monotherapy for the treatment of patients with early RA.Trial registration numberClinicalTrials.gov, number NCT01007435

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