scholarly journals A Phase 3, Randomized, Double-Blind, Multicenter Study To Evaluate the Safety and Efficacy of Intravenous Iclaprim versus Vancomycin for Treatment of Acute Bacterial Skin and Skin Structure Infections Suspected or Confirmed To Be Due to Gram-Positive Pathogens (REVIVE-2 Study)

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Thomas L. Holland ◽  
William O'Riordan ◽  
Alison McManus ◽  
Elliot Shin ◽  
Ali Borghei ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Controlled Trial ◽  
Study Drug ◽  
Lesion Size ◽  
Skin Infections ◽  
Phase 3 ◽  
Gram Positive ◽  
Double Blind ◽  
Skin Structure ◽  
Safe Treatment

ABSTRACTIclaprim is a novel diaminopyrimidine antibiotic that may be an effective and safe treatment for serious skin infections. The safety and effectiveness of iclaprim were assessed in a global phase 3, double-blind, randomized, active-controlled trial. Six hundred thirteen adults with acute bacterial skin and skin structure infections (ABSSSIs) suspected or confirmed to be due to Gram-positive pathogens were randomized to iclaprim (80 mg) or vancomycin (15 mg/kg of body weight), both of which were administered intravenously every 12 h for 5 to 14 days. The primary endpoint was a ≥20% reduction in lesion size compared with that at the baseline at 48 to 72 h after the start of administration of study drug in the intent-to-treat population. Among patients randomized to iclaprim, 78.3% (231 of 295) met this primary endpoint, whereas 76.7% (234 of 305) of those receiving vancomycin met this primary endpoint (difference, 1.58%; 95% confidence interval, −5.10% to 8.26%). This met the prespecified 10% noninferiority margin. Iclaprim was well tolerated, with most adverse events being categorized as mild. In conclusion, iclaprim was noninferior to vancomycin in this phase 3 clinical trial for the treatment of acute bacterial skin and skin structure infections. On the basis of these results, iclaprim may be an efficacious and safe treatment for skin infections suspected or confirmed to be due to Gram-positive pathogens. (This trial has been registered at ClinicalTrials.gov under identifier NCT02607618.)

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 1347. Omadacycline for Acute Bacterial Skin and Skin Structure Infections: Integrated Analysis of Randomized Clinical Trials

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S412-S412 ◽  
Author(s):  
Fredrick M Abrahamian ◽  
George Sakoulas ◽  
Evan Tzanis ◽  
Amy Manley ◽  
Judith N Steenbergen ◽  
...  
Keyword(s):  
Clinical Response ◽  
Randomized Clinical Trials ◽  
Treatment Initiation ◽  
Study Drug ◽  
Lesion Size ◽  
Integrated Analysis ◽  
Drug Discontinuation ◽  
Gram Positive ◽  
Skin Structure ◽  
Infection Types

Abstract Background Skin infections are a significant medical burden for affected individuals and the healthcare system. The purpose of this investigation was to integrate the findings of two randomized studies of omadacycline (OMC) in ABSSSI. Methods OMC in Acute Skin and Skin Structure Infections Study (OASIS)-1 initiated patients on intravenous (IV) OMC or linezolid (LZD) with a possible transition to oral formulation after at least 3 days of IV therapy. OASIS-2 investigated oral-only OMC. Treatment duration in both studies was 7–14 days. Early clinical response (ECR) in the mITT population, the primary endpoint in both studies, was defined as a ≥20% reduction in lesion size at 48–72 hours after treatment initiation. The secondary endpoint was investigator assessment of clinical response (IACR) at post-therapy evaluation (PTE) in the mITT and CE populations, 7–14 days after treatment initiation. Results A total of 691 patients receiving OMC and 689 patients receiving LZD were included. The mean age of patients was 45 years, 64% were male, and 83% enrolled at US sites. Infection types: wound infections (46.8%), cellulitis/erysipelas (30.5%), major abscess (22.7%). Median lesion size was 316 cm2 and 304 cm2 in OMC and LZD patients, respectively. S. aureus was detected in 74.6% of patients, of which 43.4% had MRSA. 71% were mono-microbial Gram-positive infections, 15% were poly-microbial Gram-positive infections. OMC showed similar efficacy to LZD for the primary and secondary endpoints, as well as for mono-microbial and poly-microbial infections (figure). Clinical responses were similar across different infection types, lesion sizes, and baseline pathogens. Treatment-emergent adverse events (TEAEs), most mild or moderate, were reported by 51% and 41% of patients receiving OMC or LZD, respectively. Nausea and vomiting were more frequent for OMC patients in the OASIS-2 oral-only study while receiving the loading dose on Day 1 and 2. Serious AEs were reported by 2.3% and 1.9%, respectively. TEAEs leading to study drug discontinuation were reported by 1.7% and 1.5%, respectively. Conclusion The integrated analysis of OASIS trials showed that oral and IV omadacycline was effective in the treatment of ABSSSI and was safe and generally well-tolerated by patients. Disclosures F. M. Abrahamian, Allergan: Speaker’s Bureau, Speaker honorarium. Melinta: Speaker’s Bureau, Speaker honorarium. Merck: Speaker’s Bureau, Speaker honorarium. Nabriva: Scientific Advisor, Consulting fee. Paratek: Scientific Advisor, Consulting fee. G. Sakoulas, Allergan: Consultant and Speaker, Consulting fee and Speaker honorarium. Sunovion Pharmaceuticals: Speaker, Speaker honorarium. The Medicines Company: Speaker, Speaker honorarium. Paratek Pharmaceuticals: Consultant, Consulting fee. Cidara Therapeutics: Scientific Advisor, Consulting fee. Arsanis Pharmaceuticals: Scientific Advisor, Consulting fee. E. Tzanis, Paratek Pharmaceuticals: Employee, Salary. A. Manley, Paratek Pharmaceuticals: Employee and Shareholder, Salary. J. N. Steenbergen, Paratek Pharmaceuticals: Employee and Shareholder, Salary. A. Das, Achaogen: Consultant, Consulting fee. Cempra: Consultant, Consulting fee. Contrafect: Consultant, Consulting fee. Nabriva: Consultant, Consulting fee. Paratek: Consultant, Consulting fee. Tetraphase: Consultant, Consulting fee. Theravance: Consultant, Consulting fee. Wockhardt: Consultant, Consulting fee. P. Eckburg, Paratek: Consultant, Consulting fee. P. McGovern, Paratek Pharmaceuticals: Employee, Salary.

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 Results of a Double-Blind, Randomized Trial of Ceftobiprole Treatment of Complicated Skin and Skin Structure Infections Caused by Gram-Positive Bacteria

2007 ◽  
Vol 52 (1) ◽  
pp. 37-44 ◽  
Author(s):  
Gary J. Noel ◽  
Richard S. Strauss ◽  
Karen Amsler ◽  
Markus Heep ◽  
Rienk Pypstra ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Study Drug ◽  
Primary Objective ◽  
Gram Positive ◽  
Taste Disturbance ◽  
Double Blind ◽  
Skin Structure ◽  
Gram Positive Bacteria ◽  
Complicated Skin ◽  
Cure Rates

ABSTRACT Ceftobiprole is the first broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) to be assessed in late-stage clinical trials. As a pivotal step in the clinical development of ceftobiprole, a multicenter, global, randomized, double-blind trial was conducted to compare the efficacy of ceftobiprole to that of vancomycin in patients with complicated skin and skin structure infections (cSSSIs) caused by gram-positive bacteria. The primary objective was to assess noninferiority on the basis of the cure rates 7 to 14 days after the completion of therapy in patients administered ceftobiprole 500 mg every 12 h or vancomycin 1 g every 12 h. Of 784 patients randomized, 282 receiving ceftobiprole and 277 receiving vancomycin were clinically evaluable. Of these patients, 93.3% treated with ceftobiprole and 93.5% treated with vancomycin were cured (95% confidence interval of difference, −4.4%, 3.9%). The cure rates for patients with MRSA infections were 91.8% (56/61) with ceftobiprole treatment and 90.0% (54/60) with vancomycin treatment (95% confidence interval of difference, −8.4%, 12.1%). At least one adverse event (AE) was reported by 52% of the ceftobiprole-treated patients and 51% of the vancomycin-treated patients. The most common AEs reported by the ceftobiprole-treated patients were nausea (14%) and taste disturbance (8%). Discontinuation of the study drug because of treatment-emergent AEs occurred in 4% (n = 17) of the ceftobiprole-treated patients and 6% (n = 22) of the vancomycin-treated patients. The results of this trial support the use of ceftobiprole as an effective and well-tolerated treatment option for patients with cSSSIs caused by a spectrum of gram-positive bacteria.

IP 1184. ZX008 (Fenfluramine) in Dravet’s Syndrome: First Results of a Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial

2018 ◽  
Author(s):  
Tilman Polster ◽  
Lieven Lagae ◽  
Joseph Sullivan ◽  
Ulrich Brandl ◽  
Arne Herting ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Phase 3 ◽  
Double Blind ◽  
Double Blind Placebo ◽  
First Results

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 Randomized, controlled trial of lasmiditan over four migraine attacks: Findings from the CENTURION study

Cephalalgia ◽  
2021 ◽  
Vol 41 (3) ◽  
pp. 294-304 ◽  
Author(s):  
Messoud Ashina ◽  
Uwe Reuter ◽  
Timothy Smith ◽  
Judith Krikke-Workel ◽  
Suzanne R Klise ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Study Drug ◽  
Statistical Testing ◽  
Control Group ◽  
Double Blind ◽  
Treatment Groups ◽  
Primary Endpoints ◽  
Registration Number ◽  
Secondary Endpoints ◽  
Common Teaes

Background We present findings from the multicenter, double-blind Phase 3 study, CENTURION. This study was designed to assess the efficacy of and consistency of response to lasmiditan in the acute treatment of migraine across four attacks. Methods Patients were randomized 1:1:1 to one of three treatment groups – lasmiditan 200 mg; lasmiditan 100 mg; or a control group that received placebo for three attacks and lasmiditan 50 mg for either the third or fourth attack. The primary endpoints were pain freedom at 2 h (first attack) and pain freedom at 2 h in ≥2/3 attacks. Secondary endpoints included pain relief, sustained pain freedom and disability freedom. Statistical testing used a logistic regression model and graphical methodology to control for multiplicity. Results Overall, 1471 patients treated ≥1 migraine attack with the study drug. Both primary endpoints were met for lasmiditan 100 mg and 200 mg ( p < 0.001). All gated secondary endpoints were met. The incidence of treatment-emergent adverse events (TEAEs) was highest during the first attack. The most common TEAEs with lasmiditan were dizziness, paresthesia, fatigue, and nausea; these were generally mild or moderate in severity. Conclusions These results confirm the early and sustained efficacy of lasmiditan 100 mg and 200 mg and demonstrate consistency of response across multiple attacks. Trial Registration Number: NCT03670810

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