scholarly journals 2289. Bacterial Causes of Acute Bacterial Skin and Skin Structure Infections (ABSSSI) in Patients with Intravenous Drug Use (IVDU): Phase 3 REVIVE Studies

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S784-S785
Author(s):  
David B Huang ◽  
Stephanie S Noviello ◽  
Barbara Balser ◽  
Amy E Scaramucci ◽  
Eve Desplats ◽  
...  
Keyword(s):  
Surgical Intervention ◽  
Signs And Symptoms ◽  
The United States ◽  
Lesion Size ◽  
Intravenous Drug Use ◽  
Wound Edge ◽  
Phase 3 ◽  
Double Blind ◽  
Baseline Characteristics ◽  
Post Hoc

Abstract Background Opioid addiction in the United States has reached epidemic proportions threatening public health. This analysis evaluates the baseline characteristics and bacterial causes of ABSSSI in patients who were IVDU from two parallel Phase 3 trials comparing the treatment of iclaprim with vancomycin. Methods A total of 621 patients who were IVDU from two parallel Phase 3, double-blind, randomized (1:1), active-controlled, multinational, multicenter trials (REVIVE-1 and REVIVE-2) were analyzed both separately and pooled. This post-hoc analysis summarizes the baseline bacterial causes of ABSSSI identified among IVDU. Per protocol, ABSSSI (major abscesses, cellulitis, or wound infections) were defined as having either the presence of purulent or seropurulent drainage before or after surgical intervention of the wound or at least 3 of the following signs and symptoms: discharge, erythema (extending at least 2 cm beyond the wound edge in any direction), swelling and/or induration, heat and/or localized warmth, and/or pain and/or tenderness to palpation. IVDU was defined based on subjected-reported medical history. At the baseline visit, ABSSSI were sampled for microbiological culture. Cultures were performed locally, and isolates were submitted to the central microbiology laboratory. Results Among IVDU with ABSSSI, average age was 44 years, 67.6% were male, average lesion size was 322 cm2, 10.8% had abnormal renal function (CrCl ≤ 90 mL/minute), and 3.9% had bacteremia. The bacterial causes of ABSSSI among IVDU are shown in the Table. Conclusion IVDU, a growing population, are vulnerable to ABSSSI. S. aureus, including MRSA, and S. anginosus group were the most commonly identified bacterial causes of ABSSSI in patients who are IVDU. Therefore, antibiotic selection should cover these bacteria among IVDU who present with an ABSSSI. Disclosures All authors: No reported disclosures.

scholarly journals 470. Treatment of Acute Bacterial Skin and Skin Structure Infections (ABSSSI) in Patients with Significant Drug Abuse: Outcomes from Global Phase 3 Studies of Delafloxacin (DLX)

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S230-S230 ◽  
Author(s):  
J Scott Overcash ◽  
William O’Riordan ◽  
Megan Quintas ◽  
Laura Lawrence ◽  
Carol Tseng ◽  
...  
Keyword(s):  
Substance Abuse ◽  
Objective Response ◽  
The United States ◽  
Lesion Size ◽  
Fixed Dose ◽  
Phase 3 ◽  
Double Blind ◽  
Intent To Treat ◽  
To Receive

Abstract Background Delafloxacin (DLX), an IV/oral anionic fluoroquinolone antibiotic, is approved for the treatment of ABSSSI including those due to MRSA and Gram-negative pathogens including P. aeruginosa. Two global phase 3 ABSSSI trials included patients with substance abuse including IV drugs. Methods Two multicenter, double-blind, double-dummy trials of adults with ABSSSI randomized patients 1:1 to receive either DLX monotherapy or vancomycin 15 mg/kg + aztreonam (VANAZ) for 5–14 days. Study 302 used DLX 300 mg BID IV only; study 303 used DLX 300 mg BID IV for 3 days with a mandatory blinded switch to DLX 450 mg oral BID. Key endpoints were Objective Response at 48–72 hours with ≥20% reduction in lesion size, and Investigator assessment of outcome at Follow-up (FU, Day 14), both in the Intent To Treat population. Results In the 2 studies, 620 patients with substance abuse, excluding alcoholism, including heroin, cocaine and methamphetamine abuse, were randomized in the United States. 71% were male with mean age 44 years. Average erythema area at baseline was ~230 cm2. 16% percent had cellulitis, 30% abscesses, and 53% wound. S. aureus (SA) was the most frequent pathogen. DLX was non-inferior to VANAZ for the Objective Response: 85.9% DLX vs. 84.4% VANAZ [∆2.6 (95% CI −2.9, 8.1)] as well as the assessment of outcome at FU: 82.0% DLX vs. 79.3% VANAZ [∆3.2 95% (CI −3, 9.4)]. Micro success in evaluable patients with SA was seen in 99.1% DLX vs. 100% VANAZ as well as 98.2% DLX vs. 100% VANAZ in patients with MRSA. The overall % of patients with at least one adverse event (AE) was comparable for DLX (49.0%) compared with VANAZ (56.1%). The most frequent treatment-related AEs were gastrointestinal in nature, including nausea seen in 9.7% DLX and 5.8% VANAZ patients, primarily mild to moderate in severity. There were no cases of C.difficile diarrhea. Discontinuations due to treatment-related AEs were lower with DLX (0.3%) compared with VANAZ (2.2%). Conclusion Fixed-dose monotherapyDLX was comparable to VANAZ in treatment of ABSSSI in patients with substance abuse based on the Objective Response as well as investigator-assessed outcome. DLX was also comparable to VANAZ in treating patients with SA and MRSA. DLX appears effective and well tolerated in patients with ABSSSI and significant substance abuse. 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 090 The effect of cladribine tablets on delaying the time to conversion to clinically definite multiple sclerosis (MS) or McDonald MS is consistent across subgroups in the ORACLE-MS study

2019 ◽  
Vol 90 (e7) ◽  
pp. A29.1-A29
Author(s):  
James Bowen ◽  
Alan Gillett ◽  
Doris Damian ◽  
Yann Hyvert ◽  
Fernando Dangond ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Phase 3 ◽  
Double Blind ◽  
T2 Lesions ◽  
Definite Multiple Sclerosis ◽  
Clinically Definite Multiple Sclerosis ◽  
Baseline Characteristics ◽  
Post Hoc ◽  
Delayed Time ◽  
Patient Subgroups

IntroductionIn the Phase 3 ORACLE-MS trial in 616 subjects with a first demyelinating event at high risk of converting to multiple sclerosis (MS), treatment with cladribine tablets 10 mg (3.5 mg/kg or 5.25 mg/kg cumulative dose over 2 years [CT3.5 and CT5.25, respectively]) significantly delayed time to conversion to clinically definite multiple sclerosis (CDMS) according to Poser criteria (67% or 62% risk reduction [RR], respectively) and time to conversion to 2005 McDonald MS (50% or 57% RR, respectively), versus placebo. The objective was to analyze the effect of cladribine tablets vs placebo on converstion to CDMS and McDonald MS across ORACLE-MS patient subgroups based on baseline characteristics.MethodsIn this post-hoc analysis, time-to-conversion to CDMS or McDonald MS over the double-blind period was analyzed for patients treated with CT5.25 (N=204), CT3.5 (N=206) or placebo (N=206) across different subgroups. Subgroups were defined by baseline characteristics which have been investigated as potential predictors of CDMS conversion (age [<30 or ≥30 years], gender, first classification demyelinating event [monofocal or multifocal], presence of T1 Gd+ lesions and number of T2 lesions [<9 or ≥9]).ResultsTreatment with CT3.5 or CT5.25 was consistently efficacious across the subgroups examined on conversion to CDMS versus placebo for most comparisons (RR range: CT3.5, 39%–72%; CT5.25, 36%–79%). Similarly, treatment effect of both doses on conversion to 2005 McDonald MS was consistent across subgroups (CT3.5,40%–59%;CT5.25,42%–79%).ConclusionsThe effect of cladribine tablets on delaying the time-to-conversion to CDMS, or to McDonald MS, is consistent across subgroups.

scholarly journals Telavancin for Acute Bacterial Skin and Skin Structure Infections, aPost HocAnalysis of the Phase 3 ATLAS Trials in Light of the 2013 FDA Guidance

2015 ◽  
Vol 59 (10) ◽  
pp. 6170-6174 ◽  
Author(s):  
Richard Pushkin ◽  
Steven L. Barriere ◽  
Whedy Wang ◽  
G. Ralph Corey ◽  
Martin E. Stryjewski
Keyword(s):  
Clinical Response ◽  
Lesion Size ◽  
Phase 3 ◽  
Two Phase ◽  
Skin Structure ◽  
Fda Guidance ◽  
Complicated Skin ◽  
Clinical Responses ◽  
Cure Rates ◽  
Post Hoc

ABSTRACTTwo phase 3 ATLAS trials demonstrated noninferiority of telavancin compared with vancomycin for complicated skin and skin structure infections. Data from these trials were retrospectively evaluated according to 2013 U.S. Food and Drug Administration (FDA) guidance on acute bacterial skin and skin structure infections. Thispost hocanalysis included patients with lesion sizes of ≥75 cm2and excluded patients with ulcers or burns (updated all-treated population;n= 1,127). Updated day 3 (early) clinical response was defined as a ≥20% reduction in lesion size from baseline and no rescue antibiotic. Updated test-of-cure (TOC) clinical response was defined as a ≥90% reduction in lesion size, no increase in lesion size since day 3, and no requirement for additional antibiotics or significant surgical procedures. Day 3 (early) clinical responses were achieved in 62.6% and 61.0% of patients receiving telavancin and vancomycin, respectively (difference, 1.7%, with a 95% confidence interval [CI] of −4.0% to 7.4%). Updated TOC visit cure rates were similar for telavancin (68.0%) and vancomycin (63.3%), with a difference of 4.8% (95% CI, −0.7% to 10.3%). Adopting current FDA guidance, this analysis corroborates previous noninferiority findings of the ATLAS trials of telavancin compared with vancomycin.

Early onset of effect of onabotulinumtoxinA for chronic migraine treatment: Analysis of PREEMPT data

Cephalalgia ◽  
2019 ◽  
Vol 39 (8) ◽  
pp. 945-956 ◽  
Author(s):  
David W Dodick ◽  
Stephen D Silberstein ◽  
Richard B Lipton ◽  
Ronald E DeGryse ◽  
Aubrey Manack Adams ◽  
...  
Keyword(s):  
Chronic Migraine ◽  
Migraine Treatment ◽  
Phase 3 ◽  
Double Blind ◽  
Registration Number ◽  
Treatment Analysis ◽  
Prophylaxis Therapy ◽  
Probable Migraine ◽  
Multiple Treatments ◽  
Post Hoc

Background The Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials demonstrated efficacy/tolerability of onabotulinumtoxinA for headache prevention in adults with chronic migraine. This post hoc analysis assessed time of onset of onabotulinumtoxinA after the first treatment in total and responder populations and consistency weekly through five treatment cycles. Methods In the 24-week, double-blind, placebo-controlled phase of PREEMPT, individuals were randomized 1:1 to onabotulinumtoxinA (155-195 U) or placebo every 12 weeks for two cycles. The primary pooled efficacy variable was change in headache days per 28 days at week 24. We assessed change in headache and migraine/probable migraine (hereafter migraine) days/week compared with baseline week 4. Results Baseline mean (SD) headache days/week (week 4 of baseline) for onabotulinumtoxinA (n = 688) and placebo (n = 696) were similar (4.8 [1.6] vs. 4.8 [1.6] days/week, respectively), as were migraine days/week (4.6 [1.7] vs. 4.6 [1.7] days/week). The effect of onabotulinumtoxinA on change in headache and migraine days/week was significantly greater than placebo at week 1, persisting from week 3 after the first treatment (−1.6 [2.2] vs. −1.1 [2.2] headache days/week [  p < 0.001] and −1.6 [2.2] vs. −1.1 [2.2] migraine days/week [  p < 0.001]). Headache and migraine days decreased in onabotulinumtoxinA responders beginning 1 week after treatment 1. Conclusions Treatment with onabotulinumtoxinA is associated with significant reductions in headache and migraine days/week at week 1, persisting after week 3, compared with placebo. Combined with earlier reports showing onabotulinumtoxinA treatment results in a persistent and progressive reduction in headache days over 56 weeks, it is suggested peak benefit may require multiple treatments. Trial registration number ClinicalTrials.gov: NCT00156910 and NCT00168428.

scholarly journals 128 Effect of DR/ER-MPH on Early Morning and Late Afternoon/Evening Functioning in Children With ADHD: Analysis of PREMB-R Items From a Phase 3 Trial

CNS Spectrums ◽  
2018 ◽  
Vol 23 (1) ◽  
pp. 80-81
Author(s):  
Steven R. Pliszka ◽  
Valerie K. Arnold ◽  
Andrea Marraffino ◽  
Norberto J. DeSousa ◽  
Bev Incledon ◽  
...  
Keyword(s):  
Early Morning ◽  
Functional Impairments ◽  
Individual Item ◽  
Parent Rating ◽  
Phase 3 ◽  
Double Blind ◽  
Children With Adhd ◽  
Late Afternoon ◽  
Item Scores ◽  
Post Hoc

AbstractObjectiveIn a phase 3 trial of children with ADHD, DR/ER-MPH (formerly HLD200), a delayed-release and extended-release methylphenidate, improved ADHD symptoms and reduced at-home early morning and late afternoon/evening functional impairments versus placebo, as measured by the validated Parent Rating of Evening andMorning Behaviors-Revised, Morning (PREMB-R AM) and Evening (PREMB-R PM) subscales. This post hoc analysis evaluated the effect of DR/ER-MPH versus placebo onindividual PREMB-R AM/PM item scores.MethodData were analyzed from a pivotal, randomized, double-blind, multicenter, placebo-controlled, parallel-group, phase 3 trial of DR/ER-MPH in children (6-12 years) withADHD (NCT02520388). Using the 3-item PREMB-R AM and 8-item PREMB-R PM, both key secondary endpoints, investigators evaluated early morning and lateafternoon/evening functional impairment by scoring each item on a severity scale from 0 (none) to 3 (a lot). For post hoc analyses, treatment comparisons between DR/ER-MPH and placebo at endpoint were determined by using least squares mean changes from baseline on individual PREMB-R AM/PM items score derived from an analysis ofcovariance (ANCOVA) model with treatment as the main effect, and study center and baseline score as covariates.ResultsOf 163 children enrolled across 22 sites, 161 were included in the intent-to-treat population (DR/ER-MPH, n=81; placebo, n=80) and 138 completed the study. The mean DR/ER-MPH dose achieved after 3 weeks of treatment was 68.1 mg. Following 3 weeks of treatment, DR/ER-MPH significantly reduced mean individual item scores from baseline versus placebo on all PREMB-R AM items (all P≤0.002; “getting out of bed”, “getting ready”, and “arguing or struggling in the morning”). Additionally, DR/ER-MPH significantly reduced mean individual item scores from baseline on 5 out of 8 PREMB-R PM items (P<0.01 in 2 items [“sitting through dinner” and “playing quietly”] and P<0.05 in 3 items [“inattentive/distractible”, “transitioning between activities”, and “settling down/getting ready for bed”]). There was a trend towards a reduction on 2 other items of the PREMB-R PM (P<0.09). Distributions of the ratings for each item will be presented. No serious TEAEs were reported; TEAEs were consistent withmethylphenidate.ConclusionsPost hoc analyses revealed that DR/ER-MPH significantly reduced all PREMB-R AM item scores, including “getting out of bed”, and many PREMB-R PM items, including “getting ready for bed” in children with ADHD. These findings are worth further exploration.Funding AcknowledgementsIronshore Pharmaceuticals & Development, Inc.

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