scholarly journals 2228. Treatment of Community-Acquired Bacterial Pneumonia (CABP) in Patients with Diabetes: Outcomes from a Global Phase 3 Study of Delafloxacin (DLX)

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S761-S761
Author(s):  
Igor Kaidashev ◽  
Mimi Nitu ◽  
Monica Popescu ◽  
Laura Lawrence ◽  
Megan Quintas ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Clinical Success ◽  
Signs And Symptoms ◽  
Patient Characteristics ◽  
Qt Prolongation ◽  
Phase 3 ◽  
Double Blind ◽  
Challenge Study ◽  
Patients With Diabetes ◽  
Intent To Treat

Abstract Background Delafloxacin (DLX) is an IV/oral anionic fluoroquinolone with no QT restrictions. It is approved for the treatment of serious skin infections including those due to MRSA and Gram-negative pathogens. A Phase 3 trial of patients with CABP was recently completed comparing DLX to moxifloxacin (MOX), including patients with diabetes (DM). Methods Multicenter, randomized, double-blind trial of adults with CABP with at least 2 clinical symptoms; physical signs; and radiographic evidence of pneumonia. Patients were randomized 1:1 to DLX or MOX treatment for 5–10 days. Patients received a minimum of 3 days of IV treatment, then were switched to oral at MD discretion. Key endpoints were the Early Clinical Response (ECR) at 96 ±24h and the investigator assessment of response at Test of Cure (TOC) 5–10 days after last dose in the Intent to Treat population. Clinical success was defined as complete or near resolution of signs and symptoms and no further antibiotics needed per investigator assessment. Results 131 DM patients were randomized. Patient characteristics: 59% male; mean age 66 (26% ≥ age 75); 40% PORT class IV/V; 29% multi-lobar pneumonia. Bacterial pathogens were identified in 59% at baseline. Patients received treatment ~8.5 days. DLX was comparable to MOX in patients with DM, with response at ECR 90% DLX vs. 88.5% MOX [1.5 (95% CI -9.6, 13.2)] as well as Clinical Success at TOC 87.1% DLX vs. 86.9% MOX [0.3 (95% CI −11.6, 12.7)]. The overall % of DM patients with at least one treatment-related adverse event (AE) was 18.6% DLX and 11.7% MOX. The most frequent treatment-related adverse events were gastrointestinal in nature including diarrhea seen in 6 DLX and 2 MOX patients.There were 3 DLX and 2 MOX deaths of patients with DM during the study (up to Day 28), unrelated to treatment. There were no cases of C diff in these patients. There were no reports of hypoglycemia on DLX. There was one discontinuation of treatment due to a related AE in each treatment group. Conclusion IV/oral DLX was comparable to IV/oral MOX for treatment of CABP in patients with diabetes. DLX has no preclinical signals for QT prolongation and has no QT prolongation in a validated challenge study. There were no events of hypoglycemia. DLX appears effective and well tolerated in patients with diabetes and CABP. Disclosures All authors: No reported disclosures.

scholarly journals 2234. Outcomes by Age and Gender from a Global Phase 3 Study of Delafloxacin (DLX) in Community-Acquired Bacterial Pneumonia (CABP)

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S763-S763
Author(s):  
Andrzej Madej ◽  
John Pullman ◽  
Monica Popescu ◽  
Megan Quintas ◽  
Laura Lawrence ◽  
...  
Keyword(s):  
Clinical Success ◽  
Signs And Symptoms ◽  
The United States ◽  
Qt Prolongation ◽  
Phase 3 ◽  
Double Blind ◽  
Age And Gender ◽  
Promising Alternative ◽  
And Gender ◽  
Intent To Treat

Abstract Background Delafloxacin (DLX) is a fluoroquinolone, approved in the United States for treatment of ABSSSI. DLX has no preclinical signals for QT prolongation and has no QT prolongation in a validated challenge study. Risk of QT prolongation is a consideration in antibiotic selection for elderly hospitalized CABP patients. A Phase 3 CABP trial with DLX was analyzed with a focus on age and gender. Methods Data on age and gender were reviewed from a multicenter, randomized, double-blind trial of adults with CABP. Patients were randomized 1:1 to DLX or moxifloxacin (MOX) treatment for 5–10 days. Patients received a minimum of 3 days of IV treatment, then were switched to oral at MD discretion. A key clinical endpoint was the investigator-assessment at Test of Cure (TOC) 5–10 days after the end of treatment. Clinical success was defined as complete or near resolution of signs and symptoms and no further antibiotics needed Results In the overall study, 859 patients were randomized with a mean age of 60 years (55.5% <65, 44.5% ≥65, 21.2% ≥75; range 18–93); 58.7% were male; 25.4% and 1.4% were PORT class IV and V; 28.6% multi-lobar pneumonia. Table shows the comparison of DLX and MOX clinical response at TOC in the Intent to Treat (ITT) population. Overall, DLX was well tolerated, with similar related adverse events (AE) between treatment groups regardless of age (< 65: 16.7% DLX, 13.3% MOX; ≥ 65: 13.4% DLX, 11.7% MOX) or gender (male: 16.0% DLX, 11.1% MOX; female 14.0% DLX, 14.9% MOX). The most common treatment-related AEs for DLX were diarrhea and transaminase elevations which were mild-to-moderate and did not routinely lead to discontinuation. There were no reports of potential QT prolongation on DLX. Conclusion Based on age and gender, DLX had comparable outcomes to MOX in clinical success at TOC. DLX was also well tolerated regardless of age or gender. DLX may offer a promising alternative in the treatment of CABP including elderly patients. Disclosures All authors: No reported disclosures.

scholarly journals 2232. A Global Phase 3 Study of Delafloxacin (DLX) Compared with Moxifloxacin (MOX) in Patients with Community-acquired Bacterial Pneumonia (CABP)

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S762-S762 ◽  
Author(s):  
Robert Salata ◽  
Rodolfo Alvarez-Sala ◽  
Juan P Horcajada ◽  
Laura Lawrence ◽  
Megan Quintas ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Study Drug ◽  
Patient Characteristics ◽  
Antibiotic Use ◽  
Qt Prolongation ◽  
Phase 3 ◽  
Double Blind ◽  
Gram Negative ◽  
Atypical Pathogens ◽  
Evaluable Population

Abstract Background DLX is an IV/oral fluoroquinolone with no QT restrictions, and activity against Gram-positive, Gram-negative and atypical pathogens. DLX is approved for treatment of ABSSSI including those due to MRSA and Gram-negative pathogens. A Phase 3 trial of patients with CABP was recently completed. Methods Global active-comparator double-blind trial; adults with CABP with at least 2 clinical symptoms, physical signs, and radiographic evidence of pneumonia. Randomized 1:1 to DLX or MOX treatment for 5–10 days. Randomization stratified by PORT Class, history of COPD/asthma, and prior single-dose antibiotic use (limit 25%). Patients received a minimum of 3 days IV treatment, then were switched to oral at MD discretion. The primary endpoint for FDA was the Early Clinical Response (ECR): improvement at 96 hours after first dose of study drug in at least 2 of the baseline symptoms in the Intent to Treat (ITT) population. Results 859 patients were randomized; both groups were comparable. Patient characteristics: mean age 60 (range 18–93, 21% ≥ age 75); 58.7% male; 28.6% multi-lobar pneumonia; 26.8% PORT class IV/V. Bacterial pathogens were identified in 60.5% at baseline; most commonly S. pneumoniae, as well as S. aureus, atypicals and Gram-negatives. Patients received treatment ~ 8.5 days (6.3 days of IV, 2.2 days oral). DLX was non-inferior to MOX in ECR 88.9% DLX vs. 89.0% MOX [∆−0.2 (CI -4.4, 4.1)] in the ITT population; ECR in the evaluable population was 91.1% DLX vs. 91.8% MOX [∆−0.6 (CI -4.5, 3.2)]. Day 28 Mortality was 1.9% DLX vs. 1.4% MOX. In the micro evaluable population, DLX was comparable to MOX in eradication, 92.5% DLX vs. 93.5% MOX at Test of Cure 5–10 days after treatment, [∆ −1.0 (CI -5.8, 3.6)]. 30.5% DLX and 26.2% MOX patients had ≥1 treatment-emergent adverse events (AEs). The most common DLX AEs were diarrhea and transaminase elevations, which were mild-to-moderate and did not routinely lead to discontinuation (DC). Treatment DC due to treatment-related AEs was seen in 9 DLX and 4 MOX patients. There were no potential QT AEs with DLX. Conclusion IV/oral DLX was comparable to IV/oral MOX for treatment of CABP in patients. DLX has no preclinical signals for QT prolongation and has no QT prolongation in a validated challenge study. DLX appears effective and well tolerated in patients with CABP. Disclosures All authors: No reported disclosures.

scholarly journals Efficacy and Safety of Dalbavancin for the Treatment of Acute Bacterial Skin and Skin Structure Infection (ABSSSI) in Patients with Diabetes Mellitus

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S95-S95 ◽  
Author(s):  
Michael Nowak ◽  
Urania Rappo ◽  
Pedro L Gonzalez ◽  
Jie Chen ◽  
Jennifer S McGregor ◽  
...  
Keyword(s):  
Single Dose ◽  
Clinical Success ◽  
Signs And Symptoms ◽  
Lesion Size ◽  
Categorical Variables ◽  
Continuous Variables ◽  
Double Blind ◽  
Exact Test ◽  
Increased Risk ◽  
Patients With Diabetes

Abstract Background ABSSSIs are common in patients with diabetes and have an increased risk of complications. Dalbavancin is a long-acting lipoglycopeptide with potent activity against Gram-positive pathogens responsible for ABSSSI, including methicillin-resistant Staphylococcus aureus (MRSA), and has demonstrated activity in ABSSSI with single-dose administration. We assessed outcomes in patients with and without diabetes in a clinical trial evaluating the efficacy of dalbavancin for ABSSSI. Methods In a double-blind, phase 3 trial, adult patients with ABSSSI involving deeper soft tissue or requiring significant surgical intervention, defined as major abscess, cellulitis, and traumatic wound/surgical site infection were randomized 1:1 to dalbavancin as a single-dose (1500 mg) or as a two-dose regimen (1000 mg on Day 1 and 500 mg on Day 8). The primary endpoint was ≥20% reduction in erythema at 48–72 hours; clinical success on Days 14 and 28 was defined as improvement in lesion size and signs and symptoms. P-values were obtained using Fisher’s exact test for categorical variables and Wilcoxon rank-sum test for continuous variables. In a post-hoc subgroup analysis, outcomes were compared among the subgroups of participants with and without diabetes. Results There were 76/698 (10.9%) participants with diabetes and 622/698 (89.1%) participants without diabetes. Participants with diabetes were more likely to be older or obese, and had higher rates of cellulitis, while participants without diabetes had higher rates of abscess (Figure 1). At Days 14 and 28, clinical success was achieved in ≥84% of participants with diabetes, and investigator assessment of cure was achieved in ≥95% of participants with diabetes (Figure 2). Drug-related adverse events were observed in 7 (9.2%) patients with and 44 (7.1%) participants without diabetes. Conclusion Dalbavancin has similar rates of clinical response and success for the treatment of ABSSSI in patients with or without diabetes. Disclosures M. Nowak, Allergan plc: Employee, Salary. U. Rappo, Allergan plc: Employee and Shareholder, Salary. P. L. Gonzalez, Allergan plc: Employee and Shareholder, Salary. J. Chen, Allergan plc: Employee, Salary. J. S. McGregor, Allergan plc: Employee, Salary. J. Bryowsky, Allergan plc: Employee and Shareholder, Salary.

scholarly journals 2841. A Phase 3, Randomized, Double-Blind Study Comparing Tedizolid Phosphate (TZD) and Linezolid (LZD) for Treatment of Ventilated Gram-Positive (G+) Nosocomial Pneumonia

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S67-S67
Author(s):  
Richard G Wunderink ◽  
Antoine Roquilly ◽  
Martin Croce ◽  
Daniel Rodriguez Gonzalez ◽  
Satoshi Fujimi ◽  
...  
Keyword(s):  
Clinical Response ◽  
Clinical Laboratory ◽  
Clinical Success ◽  
Incidence Rates ◽  
Double Blind Study ◽  
Phase 3 ◽  
Double Blind ◽  
Intent To Treat ◽  
Hospital Acquired

Abstract Background Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are frequently caused by G+ cocci; TZD has potent in vitro activity against these pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). The VITAL study compared the efficacy and safety of TZD vs. LZD for the treatment of ventilated patients with G+ HAP/VAP. Methods Randomized, double-blind, double-dummy, global, phase 3 study in mechanically ventilated adult patients with presumed G+ HAP/VAP (clinicaltrials.gov NCT02019420). Patients were stratified by region, age, and trauma/nontrauma, then randomized 1:1 to intravenous (IV) TZD 200 mg once daily for 7 days or IV LZD 600 mg every 12 h for 10 d (patients with concurrent G+ bacteremia received 14 d of treatment). The primary efficacy endpoint was day 28 all-cause mortality (ACM) in the intent to treat (ITT) population (all randomized patients; noninferiority [NI] margin, 10%). Secondary endpoints included investigator-assessed clinical response at test of cure (TOC; NI margin, 12.5%). Results In total, 726 patients were randomized (TZD n = 366; LZD n = 360). Baseline characteristics were well balanced between arms. TZD was noninferior to LZD for day 28 ACM in the ITT (table). Noninferiority was not demonstrated for TZD vs. LZD for investigator-assessed clinical success at TOC in the ITT. Stratification factors, analysis population, baseline clinical/laboratory signs of HAP/VAP, G+ only vs. mixed G+/gram-negative (G–) HAP/VAP, adjunctive G– therapy, MRSA vs. methicillin-susceptible S. aureus, and HAP vs. VAP were evaluated, and no single factor accounted for the observed imbalance in clinical response between treatment arms. Greater than 90% of patients experienced treatment-emergent adverse events (TEAEs). Anemia, hypokalemia, and diarrhea were the most frequently reported (TEAEs) in both arms. Types and incidence rates of TEAEs overall, and of drug-related TEAEs specifically, were comparable between TZD and LZD. Conclusion TZD was noninferior to LZD for day 28 ACM in the treatment of ventilated G+ HAP/VAP. However, TZD was not noninferior to LZD based on the investigator-assessed clinical response at TOC. Both drugs were similarly well tolerated and TEAEs were well balanced between groups, with no new safety signals identified. Disclosures All Authors: No reported Disclosures.

scholarly journals Clinical Trial of Efficacy and Toxicity of Disoproxil Tenofovir Fumarate and Emtricitabine for Mild to Moderate SARS-CoV-2 Infections

2021 ◽  
Author(s):  
Aldo A M Lima ◽  
Erico A G Arruda ◽  
Roberto J Pires-Neto ◽  
Melissa S Medeiros ◽  
J Quirino-Filho ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Vitamin C ◽  
Respiratory Infection ◽  
Clinical Symptoms ◽  
Clinical Signs ◽  
Signs And Symptoms ◽  
Clinical Suspicion ◽  
Pharmacological Intervention ◽  
Controlled Clinical Trial ◽  
Double Blind

This study aimed to evaluate the efficacy and toxicity of tenofovir (TDF) and TDF combined with emtricitabine (TDF/FTC) in patients with mild to moderate COVID-19 infections. We conducted a randomized, double-blind, placebo-controlled clinical trial in patients with clinical suspicion of mild to moderate respiratory infection caused by SARS-CoV-2 who were treated at an outpatient clinic. Patients were randomly recruited to take 10 days of TDF (300 mg/day), TDF (300 mg/day) combined with FTC (200 mg/day) or placebo Vitamin C (500 mg/day). The primary parameter was the score of symptoms and predictive signs of COVID-19, assessed on the seventh day of patient follow-up. From a total of 309 patients with clinical suspicion of SARS-CoV-2, 227 met the inclusion criteria and were randomly distributed into the following groups: (a) 75 (one did not initiate treatment) in the TDF group; (b) 74 in the TDF combined with FTC group; and (c) 77 in the Vitamin C group (placebo). Of the 226 patients, 139 (62%) were positive for SARS-CoV-2. Fever (37.8oC), ageusia or dysgeusia, anosmia or dysosmia, and two or more clinical symptoms or signs were significantly associated with SARS-CoV-2 infection. There was no significant change in clinical score based on clinical symptoms and signs between treatment groups. Patients with mild to moderate infection by SARS-CoV-2 had higher concentrations of G-CSF, IL-1β, IL-6 and TNF-α compared to patients without infection. Patients with mild to moderate respiratory infection, with fever (37.8oC), loss of smell, loss of taste and two or more symptoms, have a better prediction for the diagnosis of COVID-19. Patients with SARS-CoV-2 showed higher and more persistent proinflammatory cytokines profile compared to patients not infected with SARS-CoV-2. Pharmacological intervention with TDF or TDF combined with FTC did not change the clinical signs and symptoms score in mild to moderate respiratory infection in patients with SARS-CoV-2 compared to the Vitamin C group (placebo).

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) &gt;−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 700. Safety and Efficacy of Omadacycline in Patients with Diabetes in Phase 3 Clinical Studies

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S316-S317
Author(s):  
Manjunath P Pai ◽  
Mark H Wilcox ◽  
Marla Curran ◽  
Surya Chitra ◽  
Lynne Garrity-Ryan ◽  
...  
Keyword(s):  
Clinical Response ◽  
Medical History ◽  
Clinical Success ◽  
Oral Medication ◽  
Phase 3 ◽  
Safety And Efficacy ◽  
Skin Structure ◽  
Patients With Diabetes ◽  
Poor Treatment ◽  
History Of

Abstract Background The risk of serious infections and poor treatment outcomes is reported to be higher in patients with diabetes compared with the general population. Omadacycline (OMC) is an intravenous (IV) and oral aminomethylcycline antibiotic approved in the US to treat acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) in adults. Here we assessed safety and efficacy results from OMC Phase 3 studies (ABSSSI: Omadacycline in Acute Skin and skin structure Infections Study [OASIS]-1 and OASIS-2; CABP: Omadacycline for Pneumonia Treatment In the Community study [OPTIC]), by diabetes history. Methods In OASIS-1 (IV to optional oral medication) and OASIS-2 (oral only), patients were randomized to OMC or linezolid (LZD) for 7–14 days. In OPTIC, patients were randomized to IV OMC or moxifloxacin (MOX) for 7–14 days, with optional transition to oral medication. Data from OASIS-1 and OASIS-2 were pooled, and patient subgroups were defined by any medical history of diabetes (type 1, type 2, or unspecified), or no medical history of diabetes. Efficacy outcomes were early clinical response (ECR) and investigator’s assessment of clinical response at post-treatment evaluation (PTE), as defined for each indication. Safety was assessed by treatment-emergent adverse events (TEAEs) and laboratory measures, and data were pooled across the three studies. Results A total of 2,150 patients were included, of whom 238 (11.1%) had any history of diabetes (n = 105 for ABSSSI, n = 133 for CABP). In the pooled ABSSSI studies and the CABP study, clinical success at ECR and PTE was similar between patients with or without diabetes, and between OMC and the respective comparator (figure). TEAEs and serious TEAEs, respectively, were reported in similar numbers of OMC-, LZD-, and MOX-treated patients with diabetes (41.8–49.3%, 4.5–7.0%) and without (41.2–48.3%, 1.6–6.9%). Rates of nausea and vomiting, respectively, in patients with diabetes were similar across treatment arms: OMC (5.0%, 5.0%), LZD (7.5%, 6.0%), MOX (7.0%, 2.8%). Conclusion Omadacycline efficacy and safety were similar and consistent in patients with or without diabetes. Disclosures All authors: No reported disclosures.

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