Ceftobiprole versus daptomycin in Staphylococcus aureus bacteremia: a novel protocol for a double-blind, Phase III trial

Abstract

Although Staphylococcus aureus is a common cause of bacteremia, treatment options are limited. The need for new therapies is particularly urgent for methicillin-resistant S. aureus bacteremia (SAB). Ceftobiprole is an advanced-generation, broad-spectrum cephalosporin with activity against both methicillin-susceptible and -resistant S. aureus. This is a Phase III, randomized, double-blind, active-controlled, parallel-group, multicenter, two-part study to establish the efficacy and safety of ceftobiprole compared with daptomycin in the treatment of SAB, including infective endocarditis. Anticipated enrollment is 390 hospitalized adult patients, aged ≥18 years, with confirmed or suspected complicated SAB. The primary end point is overall success rate. Target completion of the study is in the second half of 2021. Clinicaltrials.gov identifier: NCT03138733.

Keywords: Phase III; Staphylococcus aureus; bacteremia; ceftobiprole; daptomycin; double-blind; infective endocarditis; noninferiority; protocol; randomized.

Conflict of interest statement

Financial & competing interests disclosure

The study is funded in part with federal funds from the Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response and Biomedical Advanced Research and Development Authority (BARDA), under Contract No. HHSO100201600002C, and in part by Basilea Pharmaceutica International Ltd, Basel, Switzerland. K Hamed, M Engelhardt, ME Jones and M Saulay are employees of Basilea Pharmaceutica International Ltd. TL Holland is a scientific advisory board member for Motif Bio, and consultant for Basilea Pharmaceutica, Genentech, Motif Bio, Roivant and Theravance. H Seifert has received grants or research support from Accelerate, Cubist, Entasis, German Research Foundation (DFG), German Centre for Infection Research (DZIF), Novartis and Tetraphase; is a consultant for Basilea Pharmaceutica, Entasis, Genentech, MSD, Roche, Shionogi and Tetraphase; and has received payments for lectures from Gilead and Merck/MSD. VG Fowler Jr has received grants or research support from Advanced Liquid Logics, Affinergy, Basilea Pharmaceutica, Cerexa/Forest/Actavis/Allergan, ContraFect, Cubist/Merck, Genentech, Karius, Locus, Medical BioSurfaces, MedImmune, Novartis, Pfizer, Regeneron and Theravance; is a consultant for Achaogen, Affinergy, Affinium, Basilea Pharmaceutica, Bayer, Cerexa, ContraFect, Cubist, Debiopharm, Destiny, Durata, Galderma, Genentech, Janssen, Medicines Co., MedImmune, NovaDigm, Novartis, Pfizer, Regeneron, Tetraphase, Theravance, Trius and xBiotech; is Merck Co-Chair for V710 Vaccine; and has received educational fees from Cerexa, Cubist, Debiopharm, Durata, Green Cross and Theravance. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Medical writing support, under the direction of the authors, was provided by Stephanie Carter of Spirit Medical Communications Group Ltd, funded by Basilea Pharmaceutica International Ltd.

Figures

Figure 1.. Study design.

†Patients in Part 1 (N = 80) will receive active treatment for 21–28 days. For Part 2, maximum duration of therapy may be extended to 42 days, pending the outcome of the interim safety analysis and implementation of a protocol amendment. ‡Patients in the ceftobiprole group with Gram-negative infections receive placebo to maintain blinding. §EOT visit to be conducted within 72 h of last study-drug administration. EOT: End of treatment; IE: Infective endocarditis; PTE: Post-treatment evaluation; R: Randomization; SAB: Staphylococcus aureus bacteremia.

Figure 2.. Random effects meta-analysis of clinical outcome (all-cause mortality) in untreated patients with Staphylococcus aureus bacteremia.

Seven original articles [36–42] were identified that described outcomes in case series of SAB in patients who did not receive antibacterial treatments. These studies were included in a random effects meta-analysis, which suggests an all-cause mortality of 76%. The lower bound of the 95% CI for this mortality estimate is 0.71, suggesting a conservative estimate of 71% mortality for patients with SAB who did not receive antibacterial treatment. CIs were calculated using the Clopper Pearson formula. SAB: Staphylococcus aureus bacteremia.

Figure 3.. Random effects meta-analysis of clinical outcome (all-cause mortality) in patients with Staphylococcus aureus bacteremia who receive antibacterial treatment.

Three original articles [8,43,44] were identified that described outcomes of SAB patients treated with antibacterial treatment in randomized controlled trials published since 1985. These studies were included in a random effects meta-analysis, which suggests an all-cause mortality of 16%. The upper bound of the 95% CI for this mortality estimate is 0.20, suggesting a conservative estimate of 20% mortality for patients with SAB who receive antibacterial treatment. CIs were calculated using the Clopper Pearson formula. SAB: S. aureus bacteremia.