Difference In Treatment-emergent Adverse Events Research Articles

Effect of local prolonged-release incisional doxycycline on surgical site infection prophylaxis in abdominal colorectal surgery: The SHIELD 1 randomized clinical trial.

Despite advanced infection control practices including preoperative antibiotic prophylaxis, surgical site infection (SSI) remains a challenge. This study aimed to test whether local administration of a novel prolonged-release Doxycycline-Polymer-Lipid Encapsulation matriX (D-PLEX) before wound closure, concomitantly with standard of care (SOC), reduces the incidence of incisional SSI after elective abdominal colorectal surgery. This was a phase 3 randomized, controlled, double-blind, multinational study (SHIELD 1) between June 2020 to June 2022. Patients with at least one abdominal incision length >10cm were randomized 1:1 to the investigational arm (D-PLEX+SOC) or control (SOC) arm . The primary outcome was a composite of incisional SSI, incisional reintervention, and all-cause mortality. A total of 974 patients were analyzed, of whom 579 (59.4%) were male. The mean age (±SD) was 64.2±13.0 years. The primary outcome occurred in 9.3% of D-PLEX patients versus 12.1% (SOC) (risk difference estimate [RDE], -2.8%; 95% CI [-6.7%, 1.0%], P=0.1520). In a pre-specified analysis by incision length, a reduction in the primary outcome was observed in the >20cm subpopulation: 8% (D-PLEX) versus 17.5% (SOC) (RDE, -9.4%; 95% CI [-15.5%, -3.2%], P=0.0032). In the >10 to ≤20cm subgroup, no reduction was observed: 9.9% versus 7.9% (RDE, 2.0%; 95% CI [-2.8%, 6.7%], P=0.4133). Exploratory post-hoc analyses of patients with increased SSI risk (≥1 patient-specific comorbidity) indicated a reduction in the incidence of the primary outcome: 9.0% (D-PLEX) versus 13.7% (SOC) (RDE, -4.8%; 95% CI [-9.5%, -0.1%], P=0.0472). The D-PLEX safety profile was good (no difference in treatment-emergent adverse events between the groups). The SHIELD-1 study did not meet its primary outcome of reduced incisional SSI, incisional reinterventions, or all-cause mortality. Pre-specified and post-hoc analyses suggested that D-PLEX may reduce the incidence of the primary outcome event in patients with increased SSI risk, including lengthy incisions.

Efficacy of ravulizumab in patients with generalized myasthenia gravis by time from diagnosis: A post hoc subgroup analysis of the CHAMPION MG study.

The CHAMPION MG study demonstrated that ravulizumab significantly improved Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) total scores versus placebo in adults with acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR+ gMG). This post hoc analysis aimed to assess these outcomes by time from MG diagnosis. Changes from baseline to week 26 in MG-ADL and QMG total scores were analyzed by time from MG diagnosis to study entry (≤2 vs. >2 years). Within each subgroup, least-squares (LS) mean changes for ravulizumab and placebo were compared using mixed models for repeated measures. In ravulizumab-treated patients, differences in LS mean (standard error of the mean) changes from baseline to week 26 were not statistically significant in the ≤2-years subgroup versus the >2-years subgroup for MG-ADL (-4.3 [0.70] vs. -2.9 [0.37]; p = .0511) or QMG (-4.3 [0.94] vs. -2.5 [0.50]; p = .0822) scores. No clear trends were observed in the placebo group. LS mean changes from baseline were significantly greater for ravulizumab versus placebo in both the ≤2 and >2 years from diagnosis subgroups for MG-ADL and QMG scores (all p < .05). The difference in treatment effect between the ≤2-years and >2-years subgroups was not statistically significant. No clinically meaningful between-subgroup differences in treatment-emergent adverse events were observed in ravulizumab-treated patients. Ravulizumab treatment improved clinical outcomes for patients with AChR+ gMG regardless of time from diagnosis. A numerical trend was observed favoring greater treatment effect with earlier versus later treatment after diagnosis. Further studies are required for confirmation.

Safety and effectiveness of very-high-power, short-duration ablation in patients with atrial fibrillation: Preliminary results

Abstract Funding Acknowledgements Type of funding sources: None. Background Pulmonary vein isolation (PVI) is at the forefront of rhythm control strategies in patients with atrial fibrillation (AF). A very-high-power, short-duration (vHPSD) catheter was designed to improve the effectiveness of AF ablation within a shorter procedure time. We aimed to compare the effectiveness and safety of PVI ablation between this vHPSD ablation mode (90W/4s) and conventional index-guided ablation (up to 40W/indexed). Methods This single-center, retrospective, observational study enrolled 148 patients with AF, referred for catheter ablation between December 16, 2019 and July 29, 2022. In 77 procedures (mean age: 59.7±12.0 years; 61.0% male; 74.0% paroxysmal), a vHPSD catheter was used (vHPSD-group), and 71 patients (mean age: 58.1±11.6 years; 70.4% male; 67.6% paroxysmal) were treated with a ablation index catheter (AI-group). The study assessed the recurrence of AF at 3- and 6-months after ablation. The outcomes also included the amount of opioids administered during the procedure and the incidence of treatment-emergent adverse events. Additionally, procedural factors, such as total procedure time, fluoroscopy time and radiofrequency application time were compared between the groups. Results At 3 months, AF was found to recur in 14.29% (11/77) of patients in the vHPSD-group and in 30.99% (22/71) of patients in the AI-group (p=0.02). At 6 months, 18.31% (13/71) patients reported AF recurrence in the vHPSD-group and 32.73 % (18/55) in the AI-group (p=0.09). There was no difference in treatment-emergent adverse events between the two groups (3.9% vs. 2.8%; p=1.00). One severe adverse event (a cerebral vascular accident) was observed in the vHPSD-group. The mean dose of remifentanil was reported to be lower during vHPSD-based PVI (p&amp;lt;0.0001). The vHPSD-based PVI was associated with shorter radiofrequency application time (p&amp;lt;0.0001), fluoroscopy time (p&amp;lt;0.0001), and total procedure time (p&amp;lt;0.0001). Conclusions This study suggests that the vHPSD-quided PVI is equally effective and safe with reference to short-term clinical observation as conventional ablation. Also, the vHPSD ablation may allow to reduce the dosage of analgesics during significantly shorter procedures.

(017) At-Home Therapeutic Ultrasound Treatment for Vulvovaginal Atrophy (VVA): A Pilot Study

Abstract Introduction VVA symptoms affect 50% of post-menopausal women and can be progressive without treatment. Hormonal therapies (HT) are the only FDA approved treatments for VVA, but many women prefer not to use or are not candidates for HT. As an alternative, an at-home therapeutic ultrasound system was developed to help women manage their VVA symptoms. Objective To evaluate the effectiveness and safety of therapeutic ultrasound compared with sham after 12 weeks of treatment for VVA. Methods This pilot study was a double-blind, multi-site, randomized, controlled trial (RCT) that assessed the effectiveness and safety of home-use therapeutic ultrasound applied to the vaginal introitus for 8 minutes/day on post-menopausal vaginal symptoms (Clinicaltrials.gov NCT04887701). Thirty-one women were screened between July 2021 and February 2022 at three sites, of which 26 (ages 54-65 yrs.) were randomized 1:1 to active treatment or sham. The intent-to-treat population included women with moderate to severe vaginal dryness and dyspareunia who were ≤15 yrs. postmenopausal. The primary outcome was change from baseline to week 12 in clinician-reported Vaginal Health Index (VHI) giving a numerical score (1-5) for each of the 5 parameters (tissue elasticity, vaginal fluid, pH, mucosa, and vaginal moisture). Women reported change in vaginal symptoms (dryness, soreness, irritation, and dyspareunia) measured by the Vaginal Assessment Scale (VAS), with a 4-level response score ranging from none (0), mild (1), moderate (2), to severe (3). VHI and VAS changes were assessed using mixed model analysis of variance. Women also rated their vaginal symptoms using the Patient Global Impression of Improvement (PGI-I) score with a 7-level response scale ranging from “very much better” (1) to “very much worse” (7). Results VHI increased with ultrasound treatment after the 12-week blinded period (least squares mean change ± SEM) 1.48 ± 0.77 (P=0.06) but less with sham 0.69 ± 0.75 (P=0.37). The empirical cumulative distribution functions for the change from baseline in the VHI score for the baseline severe population revealed that treatment showed a greater positive change in VHI at each percentile than sham (e.g., at the 50th percentile treatment had an improvement in VHI of 2.0 vs 0.0 for sham). Treatment also showed a greater negative change in VAS at each percentile than sham (e.g., at the 50th percentile treatment had an improved symptom reduction in VAS of -0.75 vs 0.0 for sham). The PGI-I showed more women experienced a clinically meaningful improvement to therapeutic ultrasound compared with sham (P=0.04). The ultrasound device was well tolerated without any safety signals. There were no differences in treatment-emergent adverse events between active treatment and sham and no serious adverse events. Conclusions This is the second pilot RCT to support a new and safe, non-HT treatment of VVA with therapeutic ultrasound. Improved vaginal dryness and dyspareunia scores are similar to pharmaceutical treatments (Bachmann 2010; Constantine 2017; Labrie 2016) but did not reach statistical significance due to the small sample size. These pilot RCTs, along with the open-label extension of this study, now form the basis for the anticipated FDA approved pivotal RCT. Disclosure Yes, this is sponsored by industry/sponsor: Madorra, Inc. Clarification: Industry initiated, executed and funded study Any of the authors act as a consultant, employee or shareholder of an industry for: Madorra, Inc.

Safety and effectiveness of a novel home-use therapeutic ultrasound device for the treatment of vaginal dryness in postmenopausal women: a pilot study.

Abstract A home-use, therapeutic ultrasound device was safe and effective for treating vaginal dryness after 12 weeks, and effectiveness was maintained to 1 year. Therapeutic ultrasound could offer a new, nonhormone treatment option for postmenopausal women with vulvovaginal atrophy. Objective To evaluate safety and effectiveness of therapeutic ultrasound for treatment of postmenopausal vaginal dryness. Methods In a pilot study, postmenopausal women with self-reported vaginal dryness were randomized (1:1) to double-blind ultrasound treatment (n = 21) or sham (n = 21) for 12 weeks. Primary effectiveness endpoint was change from baseline to week 12 in Vaginal Assessment Scale symptoms (dryness, soreness, irritation, dyspareunia). Secondary effectiveness endpoint was scoring of clinician-reported Vaginal Health Index (elasticity, fluid, pH, mucosa, moisture). After 12 weeks, participants received open-label ultrasound treatment to 1 year. Safety endpoint was treatment-emergent adverse events. Results In the modified intent-to-treat population, women showed (mean ± standard error) reduction in Vaginal Assessment Scale with ultrasound treatment versus sham (n = 15, −0.5 ± 0.2 vs n = 15, −0.4 ± 0.3; P = 0.9) and improved Vaginal Health Index (n = 9, 2.7 ± 0.9 vs n = 9, 0.6 ± 1.4; P = 0.3). In the per-protocol analysis population, ultrasound treatment (n = 9) versus sham (n = 8) significantly reduced symptoms score (−0.6 ± 0.3 vs −0.0 ± 0.4; P = 0.05) and significantly improved Vaginal Health Index (2.7 ± 0.9 vs −0.4 ± 1.2; P = 0.03). Improvement in effectiveness endpoints were seen at 1 year compared with baseline. There were no differences in treatment-emergent adverse events between ultrasound treatment versus sham and no serious adverse events. Conclusions Home-use ultrasound was safe and effective for treating vaginal dryness after 12 weeks. Effectiveness was maintained to 1 year. Therapeutic ultrasound could offer a new, nonhormonal treatment option for postmenopausal women with vulvovaginal atrophy.

Safety and effectiveness of very-high-power, short-duration ablation in patients with atrial fibrillation: Preliminary results.

Pulmonary vein isolation (PVI) is at the forefront of rhythm control strategies in patients with atrial fibrillation (AF). A very-high-power, short-duration (vHPSD) catheter, QDot MicroTM (Biosense Webster) was designed to improve the effectiveness of AF ablation within a shorter procedure time. The aim of this study was to compare the effectiveness and safety of PVI ablation between this vHPSD ablation mode and conventional ablation-index-guided ablation (ThermoCool Smarttouch SF catheter). This single-center, retrospective, observational study enrolled 108 patients with AF, referred for catheter ablation between December 16, 2019 and December 3, 2021. In 54 procedures (mean age: 58.0 ± 12.3; 66.67% male), a QDot MicroTM catheter was used (vHPSD-group), and 54 patients (mean age: 57.2 ± 11.8; 70.37% male) were treated with a ThermoCool SmarttouchTM SF catheter (AI-group). The primary endpoint was freedom from AF 3 months after ablation. Atrial fibrillation was found to recur in 14.81% of patients in the vHPSD-group and in 31.48% of patients in the AI-group (p = 0.07). There was no difference in treatment-emergent adverse events between the two groups (6.3% vs. 0%; p = 0.10). One severe adverse event (a cerebral vascular accident) was observed in the vHPSD-group. The mean dose of remifentanil was reported to be lower during QDot MicroTM catheter-based PVI (p < 0.01). The vHPSD-based PVI was associated with shorter radiofrequency application time (p < 0.001), fluoroscopy time (p < 0.0001), and total procedure time (p < 0.0001). This study suggests vHPSD ablation is safe, can reduce the dosage of analgesics during significantly shorter procedures and may enhance the success rate of catheter-based PVI.

PMON166 Safety Comparison of 40- vs 60-mg/day Doses of Oral Octreotide Capsules for Treatment of Acromegaly in the CHIASMA OPTIMAL Trial

Abstract Background Oral octreotide capsules (OOC) are a treatment option for patients with acromegaly in the United States who have previously responded to injectable somatostatin receptor ligands (iSRLs, octreotide or lanreotide). In previous phase 3 studies, the safety of OOC was shown to be consistent with iSRLs, without dose-dependent adverse reactions. In the double-blind, placebo-controlled period (DPC) of the CHIASMA OPTIMAL trial (NCT03252353), patients were randomized to twice-daily OOC at 40-mg/day, with the option for up-titration to 80-mg/day. In contrast, patients entered the open-label extension (OLE) at a 60-mg/day dose. Objective Examine the safety of 40-mg/day versus 60-mg/day OOC doses. Methods Eligible patients had the option to enroll in the OLE following the core trial. All patients received OOC 60-mg/day upon entering the OLE regardless of prior treatment in the DPC, including patients who received placebo in the DPC. OOC doses were up- or down-titrated based on insulin-like growth factor I (IGF-I) level and/or acromegaly signs or symptoms. The current analysis compared the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), TEAE-related study drug discontinuation, and acromegaly-related TEAEs (defined as new or worsening signs or symptoms of acromegaly). Results Twenty-eight patients randomized to OOC in the DPC (40-mg/day dose) and 19 who were originally randomized to placebo and continued into the OLE (60-mg/day dose) were included in the analysis. Biochemical control was similar in both groups as demonstrated by mean IGF-I levels over the respective periods. Ninety-six percent of patients on 40-mg/day and 57.9% on 60-mg/day experienced ≥1 TEAEs. Two patients on 60-mg/day reported a total of 2 SAEs, both deemed unrelated to study drug. Two patients on 40-mg/day experienced TEAEs leading to study drug discontinuation (headache and gastrointestinal symptoms). The incidence of acromegaly-related TEAEs was generally lower in those on 60-mg/day versus 40-mg/day. Conclusions This is the first analysis exploring differences in OOC doses. The nature and incidence of TEAEs occurring with an OOC dose of 60-mg/day versus 40-mg/day were similar, though this analysis was limited by differences in TEAE reporting across sequential phases of a lengthy trial. A trend was observed for decreased incidence of acromegaly-related TEAEs with the 60-mg/day dose. This finding is in line with previous analyses showing no dose-related TEAEs with OOC. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Safety and effectiveness of very high-power short duration ablation in patients with atrial fibrillation: early results

Abstract Background Pulmonary vein isolation (PVI) is at the forefront of treatment methods of rhythm control in patients with atrial fibrillation (AF) (1). The novel contact-force sensing catheter, QDot MicroTM (Biosense Webster) was designed to improve effectiveness of AF ablation and allow better time management due to shorter procedure time. It is a very high power-short duration (vHP-SD) catheter optimized for high density mapping and temperature control, which enables the application of high energy (up to 90W, 4s) (2). Purpose The aim of the study was to compare the QDot MicroTM catheter with the ThermoCool SmarttouchTM SF catheter with regard to the effectiveness and safety of PVI ablation. Methods It is a single center, cross-sectional, observational study enrolling 101 consecutive patients suffering from symptomatic paroxysmal or persistent AF, referred for first catheter ablation between 16 December 2019 and 03 December 2021. In 47 procedures (mean age 54 years; 70% male; 77% paroxysmal) the QDot Micro catheter was used (vHP-SD group; Qmode+ 90W, 4s), whereas the remaining 54 patients (mean age 57 years; 70% male; 67% paroxysmal) were treated with the ThermoCool SmarttouchTM SF catheter (control group, Ablation Index guided ablation). The primary endpoint was freedom from AF at 3-months after ablation. The secondary endpoints included the amount of opioids administered as well as the incidence of early-onset treatment-emergent adverse events (TEAEs). Results AF recurrence was documented in 14.9% patients in vHP-SD group and in 31.5% patients in control group (p=0.06). The mean dose of remifentanil was reported to be lower during Qmode+ catheter-based PVI (0.50 (0.40–0.60) vs. 0.70 (0.55–0.90) mg; p&amp;lt;0.001). There was no statistically significant difference in TEAEs between both groups (6.3 vs. 0%; p=0.10). One severe adverse event (cerebral vascular incident 2 days after PVI – due to thrombus in the left ventricle) was observed in vHP-SD group. Conclusions This study suggests that the vHP-SD ablation is safe and enables sedative-analgesic medications demand reduction during procedure. vHP-SD mode may enhance the success rate of catheter-based PVI, however further research is needed to provide additional evidence of its superiority. Funding Acknowledgement Type of funding sources: None.

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Preoperative Antithrombin Supplementation in Patients at Risk for Antithrombin Deficiency After Cardiac Surgery.

Antithrombin (AT) activity is reduced during cardiac operations with cardiopulmonary bypass (CPB), which is associated with adverse outcomes. Preoperative AT supplementation, to achieve >58% and <100% AT activity, may potentially reduce postoperative morbidity and mortality in cardiac operations with CPB. This prospective, multicenter, randomized, double-blind, placebo-controlled study was designed to evaluate the safety and efficacy of preoperative treatment with AT supplementation in patients at risk for low AT activity after undergoing cardiac surgery with CPB. A total of 425 adult patients were randomized (1:1) to receive either a single dose of AT (n = 213) to achieve an absolute increase of 20% above pretreatment AT activity or placebo (n = 212) before surgery. The study duration was approximately 7 weeks. The primary efficacy end point was the percentage of patients with any component of a major morbidity composite (postoperative mortality, stroke, acute kidney injury [AKI], surgical reexploration, arterial or venous thromboembolic events, prolonged mechanical ventilation, and infection) in the 2 groups. Secondary end points included AT activity, blood loss, transfusion requirements, duration of intensive care unit (ICU), and hospital stays. Safety was also assessed. Overall, 399 patients (men, n = 300, 75.2%) with a mean (standard deviation [SD]) age of 66.1 (11.7) years, with the majority undergoing complex surgical procedures (n = 266, 67.9%), were analyzed. No differences in the percentage of patients experiencing morbidity composite outcomes between groups were observed (AT-treated 68/198 [34.3%] versus placebo 58/194 [29.9%]; P = .332; relative risk, 1.15). After AT infusion, AT activity was significantly higher in the AT group (108% [42-143]) versus placebo group (76% [40-110]), and lasted up to postoperative day 2. At ICU, the frequency of patients with AT activity ≥58% in the AT group (81.5%) was significantly higher ( P < .001) versus placebo group (43.2%). Secondary end point analysis did not show any advantage of AT over placebo group. There were significantly more patients with AKI ( P < .001) in the AT group (23/198; 11.6%) than in the placebo group (5/194, 2.6%). Safety results showed no differences in treatment-emergent adverse events nor bleeding events between groups. AT supplementation did not attenuate adverse postoperative outcomes in our cohort of patients undergoing cardiac surgery with CPB.

Kimyrsa, An Oritavancin-Containing Product: Clinical Study and Review of Properties.

BackgroundThere is a need for improved antibiotic formulations for the treatment of acute bacterial skin and soft structure infection (ABSSSI), especially with the rise of antimicrobial resistance among Gram-positive bacteria. A new formulation of oritavancin was developed to reduce intravenous infusion volume (from 1000 mL to 250 mL), shorten infusion time (from 3 hours to 1 hour), and provide pharmacies with flexibility in oritavancin preparation (from 5% dextrose in sterile water to either normal saline or 5% dextrose in sterile water) compared with the current formulation.MethodsA total of 102 adult patients with a diagnosis of ABSSSI suspected or confirmed to be caused by a Gram-positive pathogen were randomized 1:1 to receive either the new formulation of oritavancin or the current formulation. After a single 1200-mg intravenous infusion of oritavancin, the relative area-under-the-curve exposure of the new formulation and current formulation groups were compared. Safety and tolerability of the new formulation were assessed for treatment-emergent adverse events, serious adverse events, and changes to laboratory parameters.ResultsThe area under the curve for 0 hour to 72 hours postdose was very similar in the new formulation group compared with the current formulation group. No differences in treatment-emergent adverse events were observed between the current and new formulation groups, and all treatment-emergent adverse events were consistent with the known safety profile of the current formulation.ConclusionsThe new formulation of oritavancin with reduced volume and duration of intravenous infusion demonstrates a safety profile and pharmacokinetics similar to that of the original formulation.

Abstract B055: Phase 1b/2 study of rebastinib (DCC-2036) in combination with paclitaxel: Preliminary safety, efficacy, pharmacokinetics and pharmacodynamics in patients with advanced or metastatic solid tumors

Abstract Background: Rebastinib is an orally administered, kinase inhibitor targeting the switch pocket of tunica interna endothelial cell kinase (TIE2). TIE2 is primarily expressed in endothelial cells, playing a role in angiogenesis. In addition, TIE2 is expressed in a subset of macrophages, TIE2 expressing macrophages (TEMs), which have pro-angiogenic, pro-metastatic, and immunosuppressive properties. Accumulating evidence suggests that chemotherapies, such as paclitaxel, increase the recruitment and activity of TEMs, leading to chemotherapy resistance. This study aims to investigate the efficacy of anti-TIE2 therapy against chemo-resistant advanced solid tumors. Methods: This is an open-label, Phase 1b/2, multicenter study with two parts. Part 1 evaluated two doses of rebastinib at 50 and 100 mg twice daily (BID) with paclitaxel administered weekly at 80 mg/m2 to determine the recommended phase 2 dose (RP2D) by enrolling at least 15 pts in each arm. The objective of Part 1 is to identify a recommended Phase 2 dose. Pts with locally advanced or metastatic solid tumors for which paclitaxel was considered appropriate treatment were enrolled. Part 2 has four disease-specific cohorts: triple-negative breast cancer, inflammatory breast cancer, platinum-resistant ovarian cancer and metastatic endometrial cancer to further evaluate the safety, tolerability and efficacy of the RP2D. This abstract focuses on data from Part 1. Results: A total of 43 pts were enrolled in Part 1 (24 pts at 50 mg BID and 19 pts at 100 mg BID) as of June 21, 2019. The median age was 61 years; 79% were female. Most frequent diagnoses were ovarian (11 pts), breast (8 pts) and endometrial cancer (7 pts). The median number of prior anti-cancer therapies was four (4). Median duration of treatment is 56 days. Treatment-emergent adverse events (TEAEs) were reported for 41 pts. Most TEAEs were previously observed in the rebastinib first-in-human study or were known AEs of paclitaxel. TEAEs &amp;gt;10% include mostly Grade (Gr) 1 or 2 fatigue (30%), constipation (21%), dry mouth (21%), nausea and alopecia (19% each), anemia and UTI (16%), hypokalemia, hypomagnesemia, peripheral neuropathy, and dyspnea (14% each), diarrhea, stomatitis, vomiting, sepsis, dysgeusia, rash and ALT elevation (12% each). Twenty-four pts experienced at least one ≥Gr 3 TEAE. Six pts had ≥Gr 3 AEs related to rebastinib. No significant difference in TEAEs was observed between the two dose levels. The RP2D was determined for rebastinib at 100 mg BID in combination with weekly paclitaxel at 80 mg/m2. Exposure of rebastinib was dose-proportional. Plasma TIE2 and its ligand, ANG2, were induced in a dose-dependent manner. Evidence of observed preliminary clinical activity in heavily pre-treated patients will be presented. Conclusion: Preliminary results demonstrated that the combination of rebastinib and paclitaxel was generally well tolerated. This combination is currently under evaluation in four disease-specific cohorts in Part 2. Clinical trial information: NCT03601897. Citation Format: Filip Janku, Michael Birrer, Debra Richardson, Christina Chu, Sanjay Goel, Ying Su, Bahar Matin, Keisuke Kuida, Rodrigo Ruiz-Soto, Erika Paige Hamilton. Phase 1b/2 study of rebastinib (DCC-2036) in combination with paclitaxel: Preliminary safety, efficacy, pharmacokinetics and pharmacodynamics in patients with advanced or metastatic solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B055. doi:10.1158/1535-7163.TARG-19-B055

1562. Safety and Efficacy of High-Dose Cefazolin Therapy in Obesity

BackgroundObesity leads to altered pharmacokinetics through changes in volume of distribution and clearance, which can impact antimicrobial dosing. Although there is data to support higher cefazolin pre-operative dosing for surgical prophylaxis, data evaluating treatment doses of cefazolin in obese patients is lacking. This study was designed to assess the safety and efficacy of high-dose (HD) cefazolin compared with traditional-dose (TD) cefazolin in obesity.MethodsThis was a multicenter, retrospective, cohort study of patients admitted from September 1, 2013 to August 31, 2018. Obese adults, defined as a BMI > 30 kg/m2, receiving cefazolin for at least 48 hours for bacteremia or skin and soft-tissue infection were eligible for inclusion. Patients with creatinine clearances <30 mL/minute or positive MRSA cultures were excluded. TD cefazolin was defined as 1–2 g IV every 8 hours and HD cefazolin was defined as 2 g every 4–6 hours. Patients were matched 1:1 based on indication, severity of illness, and BMI. Primary objective was to compare rates of treatment-emergent adverse events (TEAE). Secondary outcomes included comparison of treatment failure rates and 30-day readmission.ResultsA total of 332 patients (166 matched pairs) were included in this analysis. Baseline demographics were similar between groups with the exception of higher age in the TD group (61.8 TD vs 55.1 HD; P < 0.001) and more males in the HD group (39.2% TD vs. 65.6% HD; P < 0.001). Median Charlson comorbidity index was also higher in the TD group [4 (2–6) TD vs. 3 (1–4) HD; P < 0.001]. There were no differences in TEAE between groups (24.1% TD vs. 16.9% HD; P = 0.103). Treatment failure occurred more frequently in the TD group (24.7% TD vs. 15.1% HD; P = 0.028), driven primarily by rates of readmission secondary to recurrence or relapse of the index infection (18.7% vs. 11.5%; P = 0.07).ConclusionThere were no differences in TEAE in patients who received TD cefazolin vs. HD cefazolin therapy. Obese patients receiving TD therapy experienced higher treatment failure than those receiving HD therapy. Dose-optimization strategies with cefazolin in obese patients should be further explored. Disclosures All authors: No reported disclosures.

Efficacy of naldemedine for the treatment of opioid-induced constipation: A meta-analysis.

Opioid induced constipation (OIC) is the most common side effect of opioid therapy. It can lead to a decreased quality of life. Naldemedine is a peripherally acting μ-opioid receptor antagonist that has been recently studied in randomized controlled trials (RCTs) for the management of OIC. The aim of this study is to perform a meta-analysis of existing clinical trials to estimate the efficacy and safety of naldemedine in opioid-induced constipation. A systematic search of PubMed, CINAHL, Scopus, Cochrane database of systematic reviews, and ClinicalTrials.gov registry was performed in March 2018. Two independent reviewers systematically identified prospective RCTs published in the English language that compared the effect of oral naldemedine versus placebo in adults with OIC. Meta-analysis was performed using a random effects model to assess the primary outcome: spontaneous bowel movement (SBM) responder rates. Assessed secondary outcomes were: a change in SBM frequency per week from baseline during the treatment period, change from baseline in the frequency of complete SBM and incidence of treatment-emergent adverse events. Review Manager 5.3 software program was utilized for statistical analysis. Six RCTs met the inclusion criteria. A total of 2,762 patients were included in the meta-analysis. The proportion of SBM responders was significantly higher in the naldemedine group compared to the placebo group (56.4%, vs. 34.7%, p<0.00001). There was no statistically significant difference in treatment-emergent adverse events between naldemedine group and placebo group (mean odds ratio=1.18, p = 0.25, 95% CI: 0.89-1.55). Change in SBM frequency was higher in the naldemedine group versus placebo group (p<0.00001), as well as the change in complete SBM frequency. Naldemedine 0.2 mg daily significantly improved symptoms in patients with opioid-induced constipation and was generally well tolerated. These results support the use of naldemedine for the treatment of opioid-induced constipation.

Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): a randomised, double-blind, placebo-controlled, phase 2 trial

Multipotent adult progenitor cells are a bone marrow-derived, allogeneic, cell therapy product that modulates the immune system, and represents a promising therapy for acute stroke. We aimed to identify the highest, well-tolerated, and safest single dose of multipotent adult progenitor cells, and if they were efficacious as a treatment for stroke recovery. We did a phase 2, randomised, double-blind, placebo-controlled, dose-escalation trial of intravenous multipotent adult progenitor cells in 33 centres in the UK and the USA. We used a computer-generated randomisation sequence and interactive voice and web response system to assign patients aged 18-83 years with moderately severe acute ischaemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 8-20 to treatment with intravenous multipotent adult progenitor cells (400 million or 1200 million cells) or placebo between 24 h and 48 h after symptom onset. Patients were ineligible if there was a change in NIHSS of four or more points during at least a 6 h period between screening and randomisation, had brainstem or lacunar infarct, a substantial comorbid disease, an inability to undergo an MRI scan, or had a history of splenectomy. In group 1, patients were enrolled and randomly assigned in a 3:1 ratio to receive 400 million cells or placebo and assessed for safety through 7 days. In group 2, patients were randomly assigned in a 3:1 ratio to receive 1200 million cells or placebo and assessed for safety through the first 7 days. In group 3, patients were enrolled, randomly assigned, and stratified by baseline NIHSS score to receive 1200 million cells or placebo in a 1:1 ratio within 24-48 h. Patients, investigators, and clinicians were masked to treatment assignment. The primary safety outcome was dose-limiting toxicity effects. The primary efficacy endpoint was global stroke recovery, which combines dichotomised results from the modified Rankin scale, change in NIHSS score from baseline, and Barthel index at day 90. Analysis was by intention to treat (ITT) including all patients in groups 2 and 3 who received the investigational agent or placebo. This study is registered with ClinicalTrials.gov, number NCT01436487. The study was done between Oct 24, 2011, and Dec 7, 2015. After safety assessments in eight patients in group 1, 129 patients were randomly assigned (67 to receive multipotent adult progenitor cells and 62 to receive placebo) in groups 2 and 3 (1200 million cells). The ITT populations consisted of 65 patients who received multipotent adult progenitor cells and 61 patients who received placebo. There were no dose-limiting toxicity events in either group. There were no infusional or allergic reactions and no difference in treatment-emergent adverse events between the groups (64 [99%] of 65 patients in the multipotent adult progenitor cell group vs 59 [97%] of 61 in the placebo group). There was no difference between the multipotent adult progenitor cell group and placebo groups in global stroke recovery at day 90 (odds ratio 1·08 [95% CI 0·55-2·09], p=0·83). Administration of multipotent adult progenitor cells was safe and well tolerated in patients with acute ischaemic stroke. Although no significant improvement was observed at 90 days in neurological outcomes with multipotent adult progenitor cells treatment, further clinical trials evaluating the efficacy of the intervention in an earlier time window after stroke (<36 h) are planned. Athersys Inc.

Placebo Effect and Efficacy of Nebivolol in Patients with Hypertension not Controlled with Lisinopril or Losartan: A Phase IV, Randomized, Placebo-Controlled Trial

Most patients with hypertension require more than one antihypertensive to achieve blood pressure (BP) control. The purpose of this trial was to assess the efficacy and tolerability of add-on nebivolol, a vasodilatory β-blocker, in patients with untreated or poorly controlled hypertension, receiving stable therapy with lisinopril (an angiotensin-converting enzyme inhibitor) or losartan (an angiotensin II receptor blocker). This was a phase IV double-blind, placebo-controlled trial conducted from August 2008 to March 2010 (ClinicalTrials.gov identifier: NCT00734630). Patients entered a 2-week, single-blind, placebo-only washout phase, followed by a 3- to 4-week open-label lead-in phase (lisinopril, 10-20 mg/day, or losartan, 50-100 mg/day), and a 12-week randomized, double-blind add-on treatment phase with placebo or nebivolol (5-40 mg/day). This study was conducted at 76 outpatient centers in the United States. Participants were men and women aged 18-85 years with a diagnosis of primary hypertension and seated trough systolic BP (SBP) at screening in the range of 170-200 mmHg if untreated, 155-180 mmHg if taking 1 antihypertensive medication, or 140-170 mmHg if taking 2 antihypertensive medications. The intervention was 12 weeks' treatment with nebivolol 5-40 mg/day added to a background therapy of lisinopril 10-20 mg/day or losartan 50-100 mg/day. Primary and secondary efficacy parameters were changes from baseline in seated trough cuff SBP and diastolic BP (DBP) at Week 12, respectively. Tolerability was assessed by monitoring treatment-emergent adverse events (TEAEs). A total of 491 patients were randomized to receive nebivolol (n=258) or placebo (n=233). Efficacy analyses were conducted for 256 nebivolol and 232 placebo patients (intent-to-treat population); completion rates were 88.8% and 85.8%, respectively. Mean baseline SBP/DBP values were 163.1/98.2 mmHg (nebivolol) and 162.4/96.8 mmHg (placebo). Nebivolol was associated with a non-significant mean±SD reduction in SBP (-10.1±16.9 mmHg) versus placebo (-7.3±15.9 mmHg, P=0.093) and significant mean DBP reduction (-7.8±10.1 mmHg vs -3.5±10.6 mmHg, P<0.001). Subgroup analysis suggested a significant effect on DBP for patients receiving background losartan treatment (-8.1±9.2 mmHg vs -3.1±9.4 mmHg, P<0.001), but not for those receiving lisinopril (-7.6±10.8 mmHg vs -3.8±11.6 mmHg, P=0.076). A total of 28% nebivolol-treated and 22% placebo-treated patients reported a TEAE, the most frequent being upper respiratory tract infection (4.3% and 2.1%, respectively), bradycardia (2.7% and 0%), headache (2.3% and 2.1%), and nasopharyngitis (2.3% and 0.9%). These data suggest that nebivolol, when added to lisinopril or losartan, results in an additional BP reduction; however, only the effect on DBP reached statistical significance. A subanalysis suggests that the effect on DBP may be stronger in losartan-treated than lisinopril-treated patients. A relatively strong placebo effect may limit data interpretation. Nebivolol was well tolerated, as there was no difference in TEAEs between nebivolol and placebo. This trial (NCT00734630) was funded by Forest Laboratories, Inc.

Capsaicin Instillation for Postoperative Pain following Total Knee Arthroplasty

Pain following total knee arthroplasty (TKA) interferes with rehabilitation. Capsaicin applied in high concentration to nociceptors can cause relatively selective C-fibre desensitization for a period of weeks to months. Resultant long-lasting analgesia might facilitate rehabilitation. The objective of this study was to determine if direct instillation of a high-concentration capsaicin preparation into the wound following TKA would provide pain relief, improve physical functioning and rehabilitation, and reduce opioid requirements. This was a randomized, double-blind, parallel-group, placebo-controlled, multicentre, phase II trial carried out in a teaching hospital system. Non-opioid-tolerant males or females aged 18-85 years with a body mass index (BMI) ≤45 kg/m2, American Society of Anesthesiologists (ASA) physical status 1-3 and end-stage osteoarthritis who were scheduled for primary unilateral TKA were included. Patients received placebo vehicle or capsaicin 15 mg (Anesiva 4975) by instillation immediately prior to wound closure. Surgery was conducted under spinal anaesthesia and femoral nerve block. Postoperative rescue analgesia consisted of intravenous patient-controlled analgesia with morphine for 24 hours; oral oxycodone was provided thereafter as needed. It was hypothesized prior to data collection that capsaicin instillation would reduce postoperative pain scores and result in improved patient satisfaction and ambulation. The primary outcome was the area under the numerical rating scale (NRS) for pain score-time curve from 4 to 24 hours (AUC(4-24)). NRS for pain scores were obtained every 4 hours for 24 hours then daily with ambulation and physical therapy for 3 days. Function and patient satisfaction were assessed at 14, 28 and 42 days. Data from 14 patients (seven per group) from a single centre (data were not available from other sites because of sponsor bankruptcy) were available for this preliminary report. AUC(4-24) was not significantly different clinically (placebo 70.3; capsaicin 65.7) in this sample; however, a significant opioid-sparing effect was seen in the capsaicin group despite the fact that patients in this group had higher BMIs. Pain scores tended to be lower in the capsaicin group, despite the fact that patients in this group received significantly less rescue opioid medication. Morphine use from 12-24 hours was lower (capsaicin group mean 13.4 mg; 95% confidence interval [CI] 7.4, 19.5; range 10-21 mg vs placebo group mean 25.9 mg; 95% CI 19.8, 32.0; range 15-36 mg; p = 0.009). Total intravenous and oral opioid in morphine equivalents over 72 hours was also lower with capsaicin compared with placebo (p = 0.03). Active range of motion (ROM) was also significantly improved at day 14 in the capsaicin group compared with the placebo group (p = 0.0014). A higher percentage of patients in the capsaicin group reported being extremely satisfied with their treatment. The only statistically significant difference in treatment-emergent adverse events was for pruritus, which was more frequent in the placebo group (p = 0.03). Despite having higher BMIs, patients in the capsaicin group achieved comparable or better pain scores with significantly less opioid use in the first 3 postoperative days. They also had less pruritus, which may have been a consequence of the opioid-sparing effect. The effects of capsaicin with respect to function, however, appeared to be longer lasting, with improved active ROM reported at 14 days.

Efficacy and Safety of Tadalafil Once Daily in the Treatment of Men With Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia: Results of an International Randomized, Double-Blind, Placebo-Controlled Trial

BackgroundTadalafil is being investigated for the treatment of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH-LUTS). ObjectiveTo assess efficacy, including onset, and safety of tadalafil on BPH-LUTS and the subject's and clinician's perception of changes in urinary symptoms. Design, setting, and participantsThis randomized, double-blind, placebo-controlled, 12-week trial enrolled men ≥45 yr of age with BPH-LUTS for >6 mo, International Prostate Symptom Score (IPSS) ≥13, and maximum urine flow rate (Qmax) ≥4 to ≤15ml/s. InterventionTadalafil 5mg (n=161) or placebo (n=164), once daily. MeasurementsAnalysis of covariance (ANCOVA) modeling evaluated change from baseline in continuous efficacy variables. Categoric efficacy variables were analyzed with the Cochran-Mantel-Haenszel test, and between-group differences in treatment-emergent adverse events (TEAEs) were assessed using the Fisher exact test. Results and limitationTadalafil significantly improved IPSS results, from baseline to endpoint, compared to placebo (−5.6 vs −3.6; p=0.004). Reduction in IPSS results was apparent after 1 wk and significant after 4 wk (tadalafil −5.3 vs placebo −3.5; p=0.003). The BPH Impact Index (BII) was not assessed at week 1; however, BII improvement was apparent at 4 wk (tadalafil −1.8 vs placebo −1.2; p=0.029) and continued at 12 wk (tadalafil −1.8 vs placebo −1.3; p=0.057). Tadalafil significantly improved the International Index of Erectile Function–Erectile Function score in sexually active men with erectile dysfunction (ED; 6.7 vs 2.0; p<0.001) at 12 wk (not assessed at week 1). Few subjects reported one TEAE or more (p=0.44). For tadalafil, the most common TEAEs were headache (3.7%) and back pain (3.1%). Tadalafil did not significantly improve Qmax or reduce postvoid residual volume. ConclusionsTadalafil 5mg once daily for 12 wk resulted in a clinically meaningful reduction in total IPSS results as early as 1 wk and achieved statistical significance at 4 wk in men with BPH-LUTS. The adverse event profile was consistent with that previously reported in men with ED. Trial registrationThis clinical trial is registered on the clinicaltrials.gov website (http://www.clinicaltrials.gov). The registration number is NCT00827242.

Efficacy and safety of a single intrathecal methylprednisolone bolus in chronic complex regional pain syndrome

Activated immune cells in the spinal cord may play an important role in the development and maintenance of neuropathic pain, such as occurs in response to peripheral inflammation or tissue injury. Immune activation may therefore serve as a therapeutic target for immune modulating drugs like corticosteroids. This double-blind randomized placebo-controlled parallel-group trial aimed to investigate the efficacy and safety of a single intrathecal administration of 60 mg methylprednisolone (ITM) in chronic patients with complex regional pain syndrome (CRPS). The primary outcome measure was change in pain (pain intensity numeric rating scale; range 0–10) after 6 weeks. With 21 subjects per group the study had a 90% power to detect a clinically relevant difference (⩾2 points). After 21 patients (10 on ITM) were included, the trial was stopped prematurely after the interim analysis had shown that ITM had no effect on pain (difference in mean pain intensity numeric rating scale at 6 weeks 0.3, 95% confidence interval −0.7 to 1.3) or any other outcome measure. We did not find any difference in treatment-emergent adverse events between the ITM and placebo group. We conclude that a single bolus administration of ITM is not efficacious in chronic CRPS patients, which may indicate that spinal immune activation does not play an important role in this phase of the syndrome.

Effects of Atomoxetine and Methylphenidate on Sleep in Children With ADHD

This study compared the effects of atomoxetine and methylphenidate on the sleep of children with attention-deficit/hyperactivity disorder (ADHD). This study also compared the efficacy of these medications for treating ADHD in these children. Randomized, double-blind, crossover trial. Two sleep disorders centers in the United States; 1 in a private-practice setting and 1 in a hospital setting. 85 children diagnosed with ADHD. Twice-daily atomoxetine and thrice-daily methylphenidate, each for approximately 7 weeks. Relative to baseline, the actigraphy data indicated that methylphenidate increased sleep-onset latency significantly more than did atomoxetine (39.2 vs 12.1 minutes, p < .001). These results were consistent with the polysomnography data. Child diaries indicated that it was easier to get up in the morning, it took less time to fall asleep, and the children slept better with atomoxetine, compared with methylphenidate. Parents reported that it was less difficult getting their children up and getting them ready in the morning and that the children were less irritable, had less difficulty getting ready for bed, and had less difficulty falling asleep with atomoxetine, compared with methylphenidate. There were no significant differences between medications using the main measures of efficacy for ADHD treatment. Atomoxetine was superior on some secondary ADHD treatment-efficacy measures, based on parent reports. The only significant differences in treatment-emergent adverse events were greater incidence of decreased appetite and greater incidence of insomnia with methylphenidate. Patients receiving twice-daily atomoxetine had shorter sleep-onset latencies, relative to thrice-daily methylphenidate, based on objective actigraphy and polysomnography data. Although both medications decreased nighttime awakenings, the decrease was greater for methylphenidate.

Tolerability of levetiracetam in elderly patients with CNS disorders

The purpose of this analysis was to compare treatment-emergent adverse events (TEAE) related to use of levetiracetam (LEV) reported by young and elderly patients with anxiety and cognitive disorders, and young epilepsy patients. The LEV database includes reports of TEAE from trials of patients with diagnoses of a cognitive disorder ( N=719), an anxiety disorder ( N=1510), or localization-related epilepsy ( N=1023) who participated in clinical trials lasting up to 16 weeks. Patients were grouped as young (<65 years) or elderly (≥65 years). The most common TEAE occurring most frequently in the LEV-treated groups were abdominal pain, asthenia, headache, anorexia, weight loss, dizziness, insomnia, somnolence, and tremor. The only significant differences in TEAE were seen between young and elderly groups with anxiety disorders (>3% higher for LEV than for placebo-treated patients) in headache (5.2% elderly, −0.9% young, P=0.041), and tremor (5.2 and −0.5%, respectively, P=0.022) and between young anxiety patients and young epilepsy patients for somnolence (−0.7 and 5.4%, respectively, P=0.036). For the other TEAEs there was no evidence for consistent differences between young and elderly patients and between patients with different CNS disorders. Overall, LEV was well tolerated by all patient groups. The favorable adverse event profile suggests that LEV might be suitable for use by elderly patients.