scholarly journals 1338. A Pooled Analysis of Patients With Wound Infections in the Phase 3 REVIVE Trials: Randomized, Double-blind Studies to EValuate the Safety and Efficacy of Iclaprim Vs. Vancomycin for trEatment of Acute Bacterial Skin and Skin Structure Infections

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S409-S409
Author(s):  
David Huang ◽  
G Ralph Corey ◽  
Thomas L Holland ◽  
Thomas P Lodise ◽  
William O’Rirodan ◽  
...  
Keyword(s):  
Clinical Response ◽  
Board Member ◽  
Early Time ◽  
Study Drug ◽  
Surgical Site Infections ◽  
Pooled Analysis ◽  
Fixed Dose ◽  
Wound Infections ◽  
Phase 3 ◽  
Double Blind

Abstract Background The objective of this evaluation was to provide an analysis of pooled efficacy data from two parallel Phase 3 trials of iclaprim, a diaminopyrimidine dihydrofolate reducatase inhibitor, compared with vancomycin for the treatment of patients with wound infections including surgical site infections (SSI). Methods A pooled analysis of patients with wound infections was conducted from two parallel Phase 3, double-blind, randomized (1:1), active-controlled, multinational, multicenter trials (REVIVE-1 and REVIVE-2), which included a total of 602 patients with wound infections. The data were analyzed separately and then pooled to determine the efficacy of iclaprim 80 mg fixed dose compared with vancomycin 15 mg/kg. Both drugs were administered intravenously every 12 hours for 5 to 14 days according to the investigator assessment of clinical response. The primary endpoint of these studies was to determine whether iclaprim was noninferior (NI; 10% margin) to vancomycin in achieving a ≥20% reduction in lesion size (early clinical response [ECR] at 48 to 72 hours after initiation of the study drug (early time point [ETP]), compared with baseline in the intent-to-treat (ITT) population. Results Iclaprim had similar ECR rates at ETP compared with vancomycin among the subset of patients with wound infections (see table). The median treatment duration for both iclaprim and vancomycin was 7 days (range 5–14 days). Conclusion In this post-hoc analysis of the REVIVE studies, iclaprim achieved NI to vancomycin in both studies, based on ECR at ETP, in the subgroup of patients with wound infections. These results suggest that iclaprim may be a valuable treatment option for patients with wound infections, including SSI, suspected or confirmed to be due to Gram-positive pathogens. Disclosures D. Huang, Motif BioSciences: Employee, Salary. G. R. Corey, Motif BioSciences: Board Member, Consulting fee. T. L. Holland, Basilea: Consultant, Consulting fee. Motif Bio: Consultant and Scientific Advisor, Consulting fee. Theravance: Consultant, Speaker honorarium. Genentech: Consultant, Consulting fee. T. P. Lodise Jr., Motif BioSciences: Board Member, Consulting fee. W. O’Rirodan, Motif BioSciences: Board Member, Consulting fee. M. Wilcox, Motif BioSciences: Board Member, Consulting fee. T. M. File Jr., Motif BioSciences: Board Member, Consulting fee. M. Dryden, Motif BioSciences: Board Member, Consulting fee. B. Balser, Motif BioSciences: Consultant, Consulting fee. E. Desplats, Motif BioSciences: Consultant, Consulting fee.

scholarly journals A pooled analysis of patients with wound infections in the Phase 3 REVIVE trials: randomized, double-blind studies to evaluate the safety and efficacy of iclaprim versus vancomycin for treatment of acute bacterial skin and skin structure infections

2020 ◽  
Vol 69 (4) ◽  
pp. 625-630
Author(s):  
Stephanie Noviello ◽  
G. Ralph Corey ◽  
Thomas L. Holland ◽  
Thomas Lodise ◽  
William O’Riordan ◽  
...  
Keyword(s):  
Clinical Response ◽  
Safety Profile ◽  
Wound Infections ◽  
Phase 3 ◽  
Gram Positive ◽  
Two Phase ◽  
Double Blind ◽  
Skin Structure ◽  
Treatment Difference ◽  
Vancomycin Treatment

Introduction. Iclaprim is a diaminopyrimidine antibiotic for the treatment of acute bacterial skin and skin structure infections (ABSSSI) due to Gram-positive pathogens. Aim. This analysis evaluates patients with wound infections from two Phase 3 trials of ABSSSI. Methodology. Six-hundred-two patients with wound infections from two Phase 3, double-blinded, randomized, multicenter, active controlled trials (REVIVE-1/–2) were evaluated in a post hoc analysis of iclaprim 80 mg compared with vancomycin 15 mg kg–1 administered intravenously every 12 h for 5–14 days. The primary endpoint was to determine whether iclaprim was non-inferior (10 % margin) to vancomycin in achieving a ≥20 % reduction from baseline in lesion size 48–72 h after starting study drug (early clinical response [ECR]). Safety was assessed. Results. In REVIVE-1, ECR was 83.5 % with iclaprim versus 79.7 % with vancomycin (treatment difference 3.77%, 95 % CI −4.50%, 12.04%). In REVIVE-2, ECR was 82.7 % with iclaprim versus 76.3 % with vancomycin (treatment difference 6.38%, 95 % CI −3.35%, 16.12%). In the pooled dataset, iclaprim had similar ECR rates compared with vancomycin among wound infection patients (83.2 % vs 78.2 %) with a treatment difference of 5.01 % (95 % CI −1.29%, 11.32%). The safety profile was similar in iclaprim- and vancomycin-treated patients, except for a higher incidence of diarrhea with vancomycin (n=17) compared with iclaprim (n=6) and fatigue with iclaprim (n=17) compared with vancomycin (n=8). Conclusion. Based on early clinical response, iclaprim achieved non-inferiority to vancomycin with a similar safety profile in patients with wound infections suspected or confirmed as caused by Gram-positive pathogens. Iclaprim may be a valuable treatment option for wound infections.

scholarly journals OP23 Efficacy and safety of vedolizumab SC in patients with moderately to severely active Crohn’s disease: Results of the VISIBLE 2 study

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S020-S021
Author(s):  
S Vermeire ◽  
W Sandborn ◽  
F Baert ◽  
S Danese ◽  
T Kobayashi ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Clinical Response ◽  
Clinical Remission ◽  
Maintenance Treatment ◽  
Activity Index ◽  
Study Drug ◽  
Open Label ◽  
Phase 3 ◽  
Double Blind

Abstract Background Vedolizumab (VDZ) is a gut-selective, humanised, monoclonal α 4β 7 integrin antibody for the treatment of patients with moderately to severely active ulcerative colitis (UC) or Crohn’s disease (CD). VDZ is currently an intravenous (IV) therapy; a subcutaneous (SC) formulation is under development to provide patients with an alternative route of administration for maintenance treatment for UC and CD. Here we present the first data from the phase 3 study of VDZ SC maintenance treatment in CD. Methods VISIBLE 2 (NCT02611817; EudraCT 2015-000481-58) was a randomised, double-blind, placebo (PBO)-controlled phase 3 trial of VDZ SC as maintenance treatment in adults with moderately to severely active CD. Patients (n = 644) received open-label VDZ 300mg IV induction therapy at Weeks 0 and 2. At Week 6, clinical responders (defined as patients with a ≥70-point decrease in CD Activity Index [CDAI] from baseline) were randomly assigned to receive vedolizumab SC (108 mg every 2 weeks [Q2W]), or placebo (Q2W) for up to 52 weeks. The primary endpoint was clinical remission at Week 52 (defined as CDAI score ≤150). Rank-ordered secondary endpoints were enhanced clinical response at Week 52 (a drop of ≥100 in CDAI score), corticosteroid (CS)-free clinical remission at Week 52, and clinical remission at Week 52 in anti-tumour necrosis factor (TNF)-naïve patients. Finally, VDZ immunogenicity and predefined adverse events of special interest were assessed. Results Patients who responded to VDZ IV induction at Week 6 (n = 409) were randomised to VDZ SC (n = 275) or PBO (n = 134) maintenance and received at least 1 dose of study drug; 61% and 53%, respectively, were previously exposed to anti-TNF therapy. At Week 52, 48.0% of patients on VDZ SC vs. 34.3% on PBO were in clinical remission (p = 0.008, Figure). Enhanced clinical response at Week 52 was reached by 52.0% vs. 44.8% of patients on VDZ SC vs. PBO, respectively (p = 0.167). Among patients on concomitant CS at baseline (VDZ SC, n = 95; PBO, n = 44), 45.3% receiving VDZ SC vs. 18.2% receiving PBO achieved CS-free clinical remission at Week 52. Of anti-TNF-naïve patients (VDZ SC, n = 107; PBO, n = 63), 48.6% vs. 42.9% were in clinical remission at Week 52 in the VDZ SC and PBO arms, respectively. Injection-site reactions were reported for <3% of patients treated with VDZ SC. Serious infections, malignancy, and liver injury were ≤5% for both arms. Anti-VDZ antibodies were detected in 7 (2.5%) patients treated with VDZ SC arm; 4 of 7 patients developed neutralising antibodies. No new safety signals were observed. Conclusion Among VDZ IV induction responders, significantly more patients on maintenance VDZ SC than PBO achieved clinical remission at Week 52. The safety findings with VDZ SC remain in line with the known safety profile of VDZ IV in patients with CD.

scholarly journals 1230. Clinical and Microbiologic Outcomes by Causative Pathogen in Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia (HABP/VABP) Treated with Imipenem/Cilastatin (IMI)/Relebactam (REL) Versus Piperacillin/Tazobactam (PIP/TAZ)

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S635-S635
Author(s):  
Maria C Losada ◽  
Alok Maniar ◽  
Jiejun Du ◽  
Michelle L Brown ◽  
Katherine Young ◽  
...  
Keyword(s):  
Clinical Response ◽  
Study Drug ◽  
Empiric Therapy ◽  
Causative Pathogen ◽  
Phase 3 ◽  
Double Blind ◽  
Mitt Population ◽  
Secondary Endpoints ◽  
Intent To Treat ◽  
Hospital Acquired

Abstract Background IMI/REL is a combination of IMI and the novel class A and class C β-lactamase inhibitor REL. Here we present per-pathogen outcomes from a recent phase 3 clinical trial (RESTORE-IMI 2), in which IMI/REL was shown to be non-inferior to piperacillin/tazobactam (PIP/TAZ) for empiric therapy of HABP/VABP, in both primary and key secondary endpoints. Methods Randomized, controlled, double-blind, multinational, phase 3, non-inferiority trial in adults with HABP/VABP. Lower respiratory tract specimens were obtained ≤48 hours prior to screening. Participants (pts) were randomized 1:1 to IMI/REL 500 mg/250 mg or PIP/TAZ 4 g/500 mg, given intravenously every 6 h for 7-14 d. Pts also received empiric linezolid until baseline cultures confirmed absence of MRSA. This analysis evaluated outcomes by causative LRT pathogen in modified intent to treat (MITT) pts (randomized pts with ≥1 dose of study drug, excluding pts with only gram-positive cocci present on baseline Gram stain) who had ≥1 baseline LRT pathogen susceptible (according to CLSI criteria) to both study drugs. Outcomes assessed were microbiologic response at end of therapy (EOT), clinical response at early follow-up (EFU; 7-14 d after EOT), and Day 28 all-cause mortality (ACM). Results Of 531 MITT pts, 51.4% (130 IMI/REL, 143 PIP/TAZ) had ≥1 baseline LRT pathogen susceptible to both study drugs. The most common causative pathogens in this analysis population were Klebsiella spp (30.4% of patients), Pseudomonas aeruginosa (22.3%), Escherichia coli (22.0%), and Haemophilus influenzae (9.2%), consistent with other recent trials in HABP/VABP and with surveillance data. Outcomes by pathogen were generally comparable between IMI/REL and PIP/TAZ (Table). In a separate subgroup analysis of the microbiologic MITT population, in pts with ≥1 ESBL-positive LRT pathogen (45 IMI/REL, 35 PIP/TAZ), microbiologic response at EOT was 82.2% (IMI/REL) vs 68.6%% (PIP/TAZ), clinical response at EFU was 64.4% vs 60.0%, and Day 28 ACM was 20.0% and 22.9%, respectively. In the IMI/REL arm, 8 pts had ≥1 confirmed KPC-positive baseline LRT pathogen; KPC status was not assessed in the PIP/TAZ arm. Conclusion IMI/REL is an efficacious treatment option for HABP/VABP, regardless of causative pathogen. Table. Primary and secondary efficacy outcomes in patients who were in the MITT population and had at least 1 baseline LRT pathogen susceptible to both study drugs Disclosures Maria C. Losada, BA, Merck & Co., Inc. (Employee, Shareholder) Jiejun Du, PhD, Merck & Co., Inc. (Employee, Shareholder) Michelle L. Brown, BS, Merck & Co., Inc. (Employee, Shareholder) Katherine Young, MS, Merck & Co., Inc. (Employee, Shareholder)Merck & Co., Inc. (Employee, Shareholder) Robert Tipping, MS, Merck & Co., Inc. (Employee, Shareholder) C. Andrew DeRyke, PharmD, Merck & Co., Inc. (Employee, Shareholder) Joan R. Butterton, MD, Merck & Co., Inc. (Employee, Shareholder) Amanda Paschke, MD MSCE, Merck & Co., Inc. (Employee, Shareholder) Luke F. Chen, MBBS MPH MBA FRACP FSHEA FIDSA, Merck & Co., Inc. (Employee, Shareholder)Merck & Co., Inc. (Employee, Shareholder)

scholarly journals A Phase-3 Study to Compare Delafloxacin to Moxifloxacin for the Treatment of Adults with Community-acquired Bacterial Pneumonia (DEFINE-CABP)

2019 ◽  
Author(s):  
Juan P Horcajada ◽  
Robert A Salata ◽  
Rodolfo Álvarez-Sala ◽  
Floarea Mimi Nitu ◽  
Laura Lawrence ◽  
...  
Keyword(s):  
Clinical Response ◽  
Bacterial Pneumonia ◽  
Study Drug ◽  
The United States ◽  
Efficacy And Safety ◽  
Success Rates ◽  
Phase 3 ◽  
Double Blind ◽  
Atypical Pathogens ◽  
Intent To Treat

Abstract Background The clinical and economic burden of community-acquired bacterial pneumonia (CABP) is significant and is anticipated to increase as the population ages and pathogens become more resistant. Delafloxacin is a fluoroquinolone antibiotic approved in the United States for the treatment of adults with acute bacterial skin and skin structure infections. Delafloxacin’s shape and charge profile uniquely impacts its spectrum of activity and side effect profile. This phase 3 study compared the efficacy and safety of delafloxacin to moxifloxacin for the treatment of CABP. Methods A randomized, double-blind, comparator-controlled, multicenter, global Phase 3 study compared the efficacy and safety of delafloxacin 300 mg BID or moxifloxacin 400 mg QD in adults with CABP. The primary endpoint was early clinical response (ECR) defined as improvement at 96 (± 24) hours after first dose of study drug. Clinical response at test of cure (TOC) and microbiologic response were also assessed. Results In the intent-to-treat analysis population (ITT), ECR rates were 88.9% in the delafloxacin group and 89.0% in the moxifloxacin group. Noninferiority of delafloxacin compared with moxifloxacin was demonstrated. At TOC in the ITT population, the success rates were similar between groups. Treatment-emergent adverse events considered at least possibly related to the study drug occurred in 65 subjects (15.2%) in the delafloxacin group and 54 (12.6%) in the moxifloxacin group. Conclusions IV/oral delafloxacin monotherapy is effective and well tolerated in the treatment of adults with CABP, providing coverage for grampositive, gramnegative, and atypical pathogens.

scholarly journals 704. Incidence and Patient Outcomes of S. aureus Isolates from Acute Bacterial Skin and Skin Structure Infections (ABSSSI) with High Iclaprim MIC values in Phase 3 REVIVE Trials

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S318-S318
Author(s):  
David B Huang ◽  
Cedric Charrier ◽  
Chloe Le Bras ◽  
Stephen Hawser ◽  
Stephanie S Noviello
Keyword(s):  
Therapy Response ◽  
Early Time ◽  
Study Drug ◽  
Signs And Symptoms ◽  
Lesion Size ◽  
Fixed Dose ◽  
Phase 3 ◽  
Two Phase ◽  
Vancomycin Mics ◽  
Double Blinded

Abstract Background The incidence and outcomes of patients with S. aureus isolates with an iclaprim MIC >8 µg/mL, a concentration that is not systemically achievable, were determined among patients from two Phase 3 studies for the treatment of ABSSSI, REVIVE-1 and -2. Methods REVIVE-1 and REVIVE-2 studies were 600-patient, double-blinded, randomized (1:1), active-controlled trials among patients with ABSSSI that compared the safety and efficacy of iclaprim 80 mg fixed dose with vancomycin 15 mg/kg (adjusted for renal function), both administered intravenously over 2 hours every 12 hours for 5–14 days. Patients had a bacterial skin infection suspected or confirmed to be due to a Gram-positive pathogen with a lesion size ≥75 cm2. An early clinical response (ECR) was defined as a ≥20% reduction in lesion size compared with baseline at the early time point (ETP) 48–72 hours after the start of administration of the study drug in the intent-to-treat (ITT) population. A clinical cure, defined as complete resolution of all signs and symptoms of ABSSSI was measured at the end of therapy (EOT) and test of cure (TOC) visit, 7–14 days after the last dose of study drug. At baseline, EOT and TOC visits, ABSSSIs were sampled for microbiological culture and broth microdilution susceptibility testing conducted in accordance with CLSI M7. Results The incidence of culture confirmed S. aureus isolates among patients with ABSSSI with an iclaprim MIC >8 µg/mL was 2.0% (16/790). Six were MSSA and 10 were MRSA. The clinical outcomes of these infections included ECR of 63% (10/16), EOT response of 81.3% (13/16) and the TOC response of 75% (12/16). For microbiological outcomes of these infections, the end of therapy response was 92.9% (13/14) and the test of cure response was 92.3% (12/13). In comparison, there was less variation in vancomycin MICs among the S. aureus isolates. For patients who were randomized to vancomycin and had a pathogen identified from their ABSSSI, the pooled ECR was 82.6% (242 of 293) at a vancomycin MIC of 0.5–1 µg/mL and one isolate from a patient with ECR had a MIC of 2 µg/mL. Conclusion Patients receiving iclaprim had good clinical and microbiological responses against S. aureus isolates with an iclaprim MIC >8 µg/mL, which are uncommon (2.0%). Disclosures All authors: No reported disclosures.

scholarly journals A Phase 3, Randomized, Double-Blind Study Comparing Tedizolid Phosphate and Linezolid for Treatment of Ventilated Gram-Positive Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia

2021 ◽  
Author(s):  
Richard G Wunderink ◽  
Antoine Roquilly ◽  
Martin Croce ◽  
Daniel Rodriguez Gonzalez ◽  
Satoshi Fujimi ◽  
...  
Keyword(s):  
Clinical Response ◽  
Bacterial Pneumonia ◽  
Double Blind Study ◽  
Phase 3 ◽  
Gram Positive ◽  
Double Blind ◽  
Intention To Treat ◽  
The Difference ◽  
Hospital Acquired ◽  
Noninferiority Margin

Abstract Background Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are associated with high mortality rates. We evaluated the efficacy and safety of tedizolid (administered as tedizolid phosphate) for treatment of gram-positive ventilated HABP/VABP. Methods In this randomized, noninferiority, double-blind, double-dummy, global phase 3 trial, patients were randomized 1:1 to receive intravenous tedizolid phosphate 200 mg once daily for 7 days or intravenous linezolid 600 mg every 12 hours for 10 days. Treatment was 14 days in patients with concurrent gram-positive bacteremia. The primary efficacy end points were day 28 all-cause mortality (ACM; noninferiority margin, 10%) and investigator-assessed clinical response at test of cure (TOC; noninferiority margin, 12.5%) in the intention-to-treat population. Results Overall, 726 patients were randomized (tedizolid, n = 366; linezolid, n = 360). Baseline characteristics, including incidence of methicillin-resistant Staphylococcus aureus (31.3% overall), were well balanced. Tedizolid was noninferior to linezolid for day 28 ACM rate: 28.1% and 26.4%, respectively (difference, –1.8%; 95% confidence interval [CI]: –8.2 to 4.7). Noninferiority of tedizolid was not demonstrated for investigator-assessed clinical cure at TOC (tedizolid, 56.3% vs linezolid, 63.9%; difference, –7.6%; 97.5% CI: –15.7 to 0.5). In post hoc analyses, no single factor accounted for the difference in clinical response between treatment groups. Drug-related adverse events occurred in 8.1% and 11.9% of patients who received tedizolid and linezolid, respectively. Conclusions Tedizolid was noninferior to linezolid for day 28 ACM in the treatment of gram-positive ventilated HABP/VABP. Noninferiority of tedizolid for investigator-assessed clinical response at TOC was not demonstrated. Both drugs were well tolerated. Clinical Trials Registration NCT02019420.

scholarly journals Ceftobiprole Compared With Vancomycin Plus Aztreonam in the Treatment of Acute Bacterial Skin and Skin Structure Infections: Results of a Phase 3, Randomized, Double-blind Trial (TARGET)

2020 ◽  
Author(s):  
J Scott Overcash ◽  
Charles Kim ◽  
Richard Keech ◽  
Illia Gumenchuk ◽  
Borislav Ninov ◽  
...  
Keyword(s):  
Clinical Response ◽  
Clinical Success ◽  
Laboratory Data ◽  
European Medicines Agency ◽  
Success Rates ◽  
Phase 3 ◽  
Gram Positive ◽  
Double Blind ◽  
Gram Negative ◽  
Skin Structure

Abstract Background The development of novel broad-spectrum antibiotics, with efficacy against both gram-positive and gram-negative bacteria, has the potential to enhance treatment options for acute bacterial skin and skin structure infections (ABSSSIs). Ceftobiprole is an advanced-generation intravenous cephalosporin with broad in vitro activity against gram-positive (including methicillin-resistant Staphylococcus aureus) and gram-negative pathogens. Methods TARGET was a randomized, double-blind, active-controlled, parallel-group, multicenter, phase 3 noninferiority study that compared ceftobiprole with vancomycin plus aztreonam. The Food and Drug Administration-defined primary efficacy endpoint was early clinical response 48–72 hours after treatment initiation in the intent-to-treat (ITT) population and the European Medicines Agency-defined primary endpoint was investigator-assessed clinical success at the test-of-cure (TOC) visit. Noninferiority was defined as the lower limit of the 95% CI for the difference in success rates (ceftobiprole minus vancomycin/aztreonam) >−10%. Safety was assessed through adverse event and laboratory data collection. Results In total, 679 patients were randomized to ceftobiprole (n = 335) or vancomycin/aztreonam (n = 344). Early clinical success rates were 91.3% and 88.1% in the ceftobiprole and vancomycin/aztreonam groups, respectively, and noninferiority was demonstrated (adjusted difference: 3.3%; 95% CI: −1.2, 7.8). Investigator-assessed clinical success at the TOC visit was similar between the 2 groups, and noninferiority was demonstrated for both the ITT (90.1% vs 89.0%) and clinically evaluable (97.9% vs 95.2%) populations. Both treatment groups displayed similar microbiological success and safety profiles. Conclusions TARGET demonstrated that ceftobiprole is noninferior to vancomycin/aztreonam in the treatment of ABSSSIs, in terms of early clinical response and investigator-assessed clinical success at the TOC visit. Clinical Trials Registration NCT03137173.

scholarly journals 268Clinical Response of Tedizolid vs Linezolid in Acute Bacterial Skin and Skin Structure Infections by Severity Measure: Pooled Analysis of 2 Phase 3 Double-Blind Trials

2014 ◽  
Vol 1 (suppl_1) ◽  
pp. S114-S114
Author(s):  
Taylor Sandison ◽  
Carisa De Anda ◽  
Edward Fang ◽  
Anita Das ◽  
Philippe Prokocimer
Keyword(s):  
Pooled Analysis ◽  
Phase 3 ◽  
Double Blind ◽  
Skin Structure ◽  
Blind Trials
Sign in / Sign up

Export Citation Format

Share Document