Comparison of Intravenous Lignocaine and Esmolol in Attenuating Hemodynamic Response and Cough Reflex during Extubation in Hypertensive Patients under General Anaesthesia

Tracheal extubation carries higher complication rates compared to intubation during general anaesthesia (GA). Thus, various drugs are used to attenuate hemodynamic responses and cough reflex during extubation. We investigated if intravenous (IV) lignocaine and esmolol, given prior extubation, was able to achieve that in hypertensive patients under GA. In this prospective, double-blinded, randomised controlled study, 68 hypertensive patients on treatment undergoing GA were analysed. Group L received IV lignocaine 1 mg/kg while Group E received IV esmolol 1.5 mg/kg, 2 minutes before extubation. Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) were recorded at the following interval: before study drug administration (T-0), prior extubation (T-1), 1 minute (T-2), 3 minutes (T-3), 5 minutes (T-4) and 10 minutes (T-5) post-extubation. Group L showed significantly increase in HR at T-2 while SBP and MAP increased significantly from T-1 until T-5. Group E showed a significant reduction in HR at T-1 up to T-5 and significantly lower HR at T-1 and T-2 compared to Group L. Group E showed stable SBP, DBP and MAP at all intervals. In conclusion, IV esmolol at 1.5 mg/kg was able to attenuate the hemodynamic response more pronounced when compared to IV lignocaine at 1 mg/kg from extubation stress in patients with hypertension on treatment. Both lignocaine and esmolol were equally effective in suppressing cough reflex during extubation.

Abstract 11817: The Effect of Time to Treatment With Antiarrhythmic Drugs on Return of Spontaneous Circulation in Shock Refractory Out-of-Hospital Cardiac Arrest: A Secondary Analysis of the ALPS Randomized Controlled Trial

Purpose: The effects of amiodarone and lidocaine on the return of spontaneous circulation (ROSC), relative to time to treatment in out of hospital cardiac arrest (OHCA) patients is unknown. We conducted a post-hoc analysis of the Resuscitation Outcomes Consortium Amiodarone, Lidocaine, Placebo (ROC ALPS) randomized trial examining the association of time to treatment with ROSC at emergency department (ED) arrival. Method: In the ROC ALPS trial, adults with non-traumatic OHCA with initial VF/pVT after ≥ 1 shock were randomized to receive amiodarone, lidocaine or placebo. We used logistic regression to examine the association of time to treatment (911 call to study drug administration interval) with ROSC at ED arrival. Results: Overall, 1112 (36.7%) patients had ROSC at ED arrival. Time to treatment data were available for 2994 (99%) of the patients. The proportion of patients with ROSC at ED arrival decreased as time to drug administration increased, in amiodarone (OR 0.92, 95% CI 0.90-0.94 per min increase), lidocaine (OR 0.95, 95% CI: 0.93-0.96) and placebo (OR 0.95, 95% CI: 0.93-0.96) arms. The odds of ROSC at ED in the amiodarone group (versus placebo) changed in relation to the time of drug administration (OR 0.96, 95% CI: 0.93-0.99). With short times to drug administration, ROSC was higher in amiodarone versus placebo recipients, whereas ROSC was higher with placebo at later times. Comparing lidocaine to placebo, ROSC rate increased at all times (OR 1.29, 95% CI: 1.07-1.59); there was no time to drug administration effect (OR 1.00, 95% CI: 0.97-1.03). Among all patients, survival at hospital discharge was 21.0%, 24.4%, and 23.7% for placebo, amiodarone and lidocaine respectively. Conclusion: Amiodarone’s efficacy in restoring ROSC declined with longer duration of arrest, potentially due to its adverse hemodynamic effects. Overall, amiodarone and lidocaine had similar effects on mortality; in this study, ROSC at ED arrival trend did not reflect the overall survival rate

110. A Phase 3, Multicenter, Double-blind, Randomized Clinical Trial to Evaluate the Efficacy and Safety of Ceftolozane/Tazobactam Plus Metronidazole Versus Meropenem in Chinese Participants With Complicated Intra-abdominal Infections

Background In China, the prevalence of infections due to multidrug-resistant gram-negative bacteria is high and additional treatment options for complicated intra-abdominal infections (cIAI) are needed. This study compared the efficacy and safety of ceftolozane/tazobactam (C/T) + metronidazole (MTZ) versus meropenem (MEM) + placebo (pbo) for the treatment of cIAI in adult Chinese participants. Methods This was a phase 3, double-blind study conducted at 21 centers in China (NCT03830333). Participants aged 18-75 years with cIAI requiring surgical intervention within 24 hours of study drug administration were stratified by site of infection and randomized 1:1 to receive 1.5 g C/T (1 g ceftolozane and 0.5 g tazobactam) + 0.5 g MTZ administered intravenously (IV) every 8 hours (q8h) or 1 g MEM + pbo administered IV q8h for 4-14 days. The primary endpoint was clinical cure at test of cure (TOC) in the clinically evaluable (CE) population. Secondary endpoints included rates of clinical cure, per-participant microbiologic response, per-pathogen microbiologic response, and adverse events (AE). Non-inferiority for clinical cure at TOC in the CE population was confirmed if the lower bound of the 2-sided 95% CI for the between-treatment difference in the clinical cure rate was larger than −12.5%. Results A total of 134 participants were randomized to each treatment group. Demographics and baseline characteristics were generally well balanced between treatment groups (Table 1). The median (range) age in the ITT population was 50 (18-75) years and 61% were men. The most frequent sites of infection were the appendix (C/T + MTZ, 50.0%; MEM + pbo, 49.3%) and gallbladder (C/T + MTZ, 27.6%; MEM + pbo, 29.1%). Overall, the most frequently isolated pathogens were Escherichia coli (61.4%) and Klebsiella pneumoniae (17.3%); few anaerobes were isolated (Table 1). C/T + MTZ was non-inferior to MEM + pbo for clinical cure in the CE population (C/T + MTZ, 95.2%; MEM + pbo, 93.1%; difference, 2.1% [95% CI, −4.7% to 8.8%]). Results for key secondary endpoints were comparable between treatment groups (Table 2). Rates of AEs were generally similar between treatment groups (Table 3). Conclusion C/T + MTZ was non-inferior to MEM + pbo in the treatment of adult Chinese participants with cIAI and demonstrated a favorable safety profile. Disclosures Xiaofei Chen, n/a, MSD, China (Employee) Xiaoling Du, n/a, MSD, China (Employee) Ye Wang, n/a, MSD, China (Employee) Hui Wang, n/a, MSD, China (Employee) Fang Sun, n/a, MSD, China (Employee) Matthew G. Johnson, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Mekki Bensaci, PhD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Jennifer A. Huntington, PharmD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Christopher Bruno, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee)

1098. A Phase 1 Safety and Tolerability of Single Ascending Doses of a Novel Engineered Cationic Peptide, PLG0206, in Healthy Subjects

Background PLG0206 is a novel engineered cationic antimicrobial peptide being evaluated for treatment of prosthetic joint infections (PJI). This abstract presents the results from the first in human study to evaluate the safety, tolerability and pharmacokinetic (PK) profile of PLG0206 when administered as an intravenous (IV) infusion. Methods 6 cohorts of 8 participants were planned to receive escalating single 1-hour IV infusions of PLG0206 at 0.05, 0.125, 0.25, 0.5, 1, 2 and 3 mg/kg dose or placebo. Participants were randomized to receive either PLG0206 (6 per cohort) or placebo (2 per cohort). At each dose level, there were 2 sentinel participants (1 active, 1 placebo) who were dosed at least 48 hours in advance of the other participants in their group. Serial pharmacokinetic samples were taken prior to infusion and up to 48 post infusion. Safety and tolerability was assessed throughout the study. There was at least a 7-day period after dosing at each of the dose levels before dose escalation. Results PLG0206 was safe and well tolerated when administered to healthy volunteers at doses ranging from 0.05 and 1 mg/kg. Therapeutic exposures were achieved at 1 mg/kg. The 2 and 3 mg/kg cohorts were not studied. The incidence of treatment emergent adverse events related to study drug administration was low and most events mild (Grade 1) in severity and was similar between the PLG0206 treatment and placebo groups. There were no SAEs, life-threatening events or deaths throughout the study. IV PLG0206 exhibited linear PK over the dose range of 0.05 to 1.0 mg/kg. The median terminal half-life (t½) ranged from 7.37 to 19.97 hours. AUC0-∞ increased with increasing PLG0206 dose ranging between 1581.41 and 21141.52 ng.hr/mL. Cmax ranged between 256 and 2653 ng/mL. The mean apparent volume of distribution (Vz) increased was between 25.49 and 94.2 L, mean clearance (CL) were similar across all and ranged from 2.42 to 4.18 L/hour. Conclusion Following single IV infusion to healthy volunteers, PLG0206 was safe and well tolerated at doses ranging from 0.05 to 1 mg/kg. IV PLG0206 exhibits linear PK over the dose range. These findings support the ongoing development of IV PLG0206 and will inform dosing regimens in future studies to investigate its utility as an antimicrobial agent. Disclosures David Huang, MD, PhD, Peptilogics (Employee) Despina Dobbins, BS, Peptilogics (Employee) Parviz Ghahramani, PhD, PharmD, MSc, MBA, Peptilogics (Consultant) Jonathan Steckbeck, PhD, Peptilogics (Employee)

A study protocol for the cardiac effects of a single dose of either oxytocin 2.5 IU or carbetocin 100 µg after caesarean delivery: a prospective randomized controlled multi-centre trial in Norway

Background: Both oxytocin and carbetocin are used to prevent uterine atony and post-partum haemorrhage after caesarean delivery in many countries, including Norway. Oxytocin causes dose-dependent ST-depression, troponin release, prolongation of QT-time and arrythmia, but little is known about myocardial effects of carbetocin. We have previously demonstrated comparable vasodilatory effects of oxytocin and carbetocin and are now undertaking a Phase 4 trial to investigate whether carbetocin causes similar changes to myocardial markers compared with oxytocin. Methods: Our randomized controlled trial will be conducted at three obstetrics units at Oslo University Hospital and Akershus University Hospital, Norway. Planned enrolment will be of 240 healthy, singleton pregnant women aged 18 to 50 years undergoing planned caesarean delivery. Based on pilot study data, each participant will receive a one-minute intravenous injection of either oxytocin 2.5 IU or carbetocin 100 µg during caesarean delivery. The prespecified primary outcome is the change from baseline in high-sensitive troponin I plasma concentrations at 6–10 hours after study drug administration. Secondary outcomes include uterine tone grade at 2.5 and five minutes after study drug administration, adverse events for up to 48 hours after study drug administration, estimated blood loss within eight hours of delivery, need for rescue treatment and direct/indirect costs. Enrolment and primary analysis are expected to be completed by the end of 2021. Discussion: Women undergoing caesarean delivery should be assessed for cardiovascular risk particularly as women with an obstetric history of pregnancy induced hypertension, gestational diabetes mellitus, preterm birth, placental abruption, and stillbirth are at increased risk of future cardiovascular disease. Any additional ischaemic myocardial risk from uterotonic agents will need to be balanced with the benefit of reducing the risk of postpartum haemorrhage. Any potential cardiotoxicity difference between oxytocin and carbetocin will help inform treatment decisions for pregnant women. Registration: Clinicaltrials.gov NCT03899961 (02/04/2019).

Efficacy and Safety of Fospropofol Disodium for Injection in General Anesthesia Induction for Adult Patients: A Phase 3 Trial

Background: Fospropofol disodium for injection (FospropofolFD) is a prodrug that is metabolized into propofol to produce a general anesthesia effect when administered intravenously.Objective: This study aimed to assess the efficacy and safety of FospropofolFD in comparison with propofol medium/long-chain fat emulsion injections (propofol-MCT/LCT) for general anesthesia induction in adult patients undergoing elective surgeries.Setting: Nine academic medical centers in China.Method: This multicenter, randomized, double-blind, double-simulated, controlled, and non-inferiority trial evaluated 540 eligible adult patients randomly assigned (2:1) to the intervention (20 mg/kg FospropofolFD) or control (2 mg/kg propofol-MCT/LCT) groups.Main Outcome Measure: The primary efficacy endpoint was the success rate, defined as a Modified Observer’s Assessment of Alertness/Sedation Scale score of 1 within 5 min after study drug administration. The safety endpoints consisted of adverse events (AEs) related to consciousness, cognitive function, hemodynamic status, liver and kidney function, and blood tests.Results: A total of 347 (96.3%) and 175 (97.2%) patients in the intervention and control groups, respectively, completed the study. The success rate for the primary outcome was 97.7% for both study drugs. The most frequent AEs in the intervention group were abnormal feeling (62.0%), blood pressure reduction (13.5%), and injection site pain (13.3%). No AEs related to consciousness and mental and cognitive functions or serious adverse events were reported.Conclusion: FospropofolFD (20 mg/kg) is not inferior to propofol-MCT/LCT (2 mg/kg) in general anesthesia induction for American Society of Anesthesiologists (ASA) physical status I-II adult patients undergoing elective surgeries. It is safe and effective for clinical use under anesthesiologist monitoring.Impact on Practice Statement: FospropofolFD can produce a general anesthesia effect and reduce the incidence of pain at the site of injection.

P358 An observational, prospective cohort study to evaluate the long term safety and effectiveness of intravenous CT-P13 (biosimilar of infliximab) in patients with Crohn’s Disease or Ulcerative Colitis

Background CT-P13 is the world’s first approved biosimilar infliximab for all indications of the reference infliximab. The purpose of this study was to assess long term safety and effectiveness of CT-P13 intravenous (IV) in patients with Crohn’s Disease (CD) and Ulcerative Colitis (UC). We now present the result of safety and effectiveness of CT-P13 in patient with CD, UC for up to 5 years from this longitudinal, observational, prospective cohort Phase IV study. Methods The study was conducted from 17 April 2014 to 28 February 2020 in 22 and 21 study centres, in Korea and European Union, respectively. Patients were administered 5 mg/kg of CT-P13 by IV at weeks 0, 2 and 6 and every 8 weeks thereafter. The primary objective was to evaluate adverse events of special interest (AESI) including HBV reactivation, congestive heart failure, opportunistic infections, serious infection including sepsis, tuberculosis, serum sickness (delayed hypersensitivity reactions), hematologic reactions, systemic lupus erythematosus/lupus like syndrome, demyelinating disorders, lymphoma, hepatobiliary events, hepatosplenic T cell lymphoma (HSTCL), intestinal or perianal abscess (in CD), serious infusion reactions during a re-induction regimen following disease flare, sarcoidosis/sarcoid-like reactions, paediatric malignancy, leukaemia, malignancy, colon carcinoma, dysplasia (in UC), skin cancer, pregnancy exposure and bowel stenosis, stricture and obstruction (in CD). Results A total of 470 patients with inflammatory bowel disease (IBD) were analysed. Overall 352 (74.9%) patients have been continuously treated for more than 1 year and the mean duration of drug exposure was 26.3 months. The safety profile of CT-P13 and switching from the reference infliximab to CT-P13 was well-tolerated. A total of 329 (70.0%) patients experienced at least one treatment-emergent adverse event (TEAE). Adverse events of special interest of CT-P13 were analysed by safety analysis set (Table 1). Immunogenicity testing was optional and 72 (15.3%) patients had at least one ADA positive after first infusion of study drug. The incidence of TEAEs in ADA positive subset (83.3%) were slightly higher compared to the incidence of TEAEs in ADA negative subset (76.6%). The effectiveness results of clinical remission for each indication was generally well maintained after the study drug administration (Table 2). Conclusion The results show that CT-P13 was well-tolerated and efficacious in IBD patients. There was no new safety and effectiveness findings in patients who have been exposed to CT-P13 or patients who have switched treatment from the reference infliximab to CT-P13.

Use of the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) in X-Linked Myotubular Myopathy: Content Validity and Psychometric Performance

X-linked myotubular myopathy (XLMTM) is a life-threatening, congenital myopathy characterized by extreme hypotonia, weakness, delayed motor milestones, and respiratory failure, often resulting in pediatric mortality. This study evaluated the content validity and psychometric performance of the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders as a measure of neuromuscular functioning in children with X-linked myotubular myopathy. This study was conducted in two phases. Phase I assessed the content validity of the measure for use in an XLMTM pediatric population through: literature review, clinical expert interviews, caregiver interviews, and a modified-Delphi panel among clinicians. Phase II assessed psychometric performance based on the INCEPTUS observational clinical study and the ASPIRO interventional gene therapy study, including tests of reliability (internal consistency, test-retest, and interrater), validity (construct and criterion), and responsiveness based on observational and interventional clinical trial data analyses. Data established construct validity and reliability of the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders among XLMTM patients before administration of resamirigene bilparvovec, and sensitivity to study drug administration as evidenced by the significant post-administration response in ASPIRO. Findings support the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders as an appropriate neuromuscular functioning assessment in a pediatric X-linked myotubular myopathy patient population.

Rationale and design of the ADAPT-TAVR trial: a randomised comparison of edoxaban and dual antiplatelet therapy for prevention of leaflet thrombosis and cerebral embolisation after transcatheter aortic valve replacement

IntroductionOptimal antithrombotic strategy following transcatheter aortic valve replacement (TAVR) is still unknown. We hypothesised that the direct factor Xa inhibitor edoxaban can potentially prevent subclinical leaflet thrombosis and cerebral embolisation compared with conventional dual antiplatelet therapy (DAPT) in patients undergoing TAVR.Methods and analysisThe ADAPT-TAVR trial is an international, multicentre, randomised, open-label, superiority trial comparing edoxaban-based strategy and DAPT strategy in patients without an indication for oral anticoagulation who underwent successful TAVR. A total of 220 patients are randomised (1:1 ratio), 1–7 days after successful TAVR, to receive either edoxaban (60 mg daily or 30 mg daily if patients had dose-reduction criteria) or DAPT using aspirin (100 mg daily) plus clopidogrel (75 mg daily) for 6 months. The primary endpoint was an incidence of leaflet thrombosis on four-dimensional, volume-rendered cardiac CT imaging at 6 months post-TAVR. The key secondary endpoints were the number of new lesions and new lesion volume on brain diffusion-weighted MRI and the changes in neurological and neurocognitive function assessment between immediate post-TAVR and 6 months of study drug administration. Detailed clinical information on thromboembolic and bleeding events were also assessed.Ethics and disseminationEthic approval has been obtained from the Ethics Committee/Institutional Review Board of Asan Medical Center (approval number: 2017–1317) and this trial is also approved by National Institute of Food and Drug Safety Evaluation of Republic of Korea (approval number: 31511). Results of this study will be disseminated in scientific publication in reputed journals.Trial registration numberNCT03284827.

SAFETY OF AMISELIMOD IN HEALTHY SUBJECTS: RESULTS FROM A PHASE 1 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY

Objective To evaluate the safety profile of amiselimod, a selective sphingosine 1-phosphate receptor modulator which has been shown to regulate lymphocyte trafficking and is in development for the treatment of inflammatory bowel disease. Methods A randomized, double-blind, multiple-dose, placebo-controlled, parallel study with a nested crossover design evaluated the safety and tolerability profile of amiselimod. Healthy adults were randomized in a 2:1:1 ratio during a 28-day treatment period accordingly: a single dose of placebo followed by oral amiselimod (upwardly titrated in doses ranging from 0.4 to 1.6 mg to achieve 0.4 mg and 0.8 mg steady-state exposure; a single dose of oral moxifloxacin 400 mg followed by placebo; or placebo followed by a single dose of moxifloxacin 400 mg. The safety population included all subjects who received at least one dose of treatment. Adverse events (AE) and serious AEs were collected. Treatment-emergent AEs were defined as an AE that was starting or worsening at the time of or after study drug administration. Changes in clinical laboratory parameters (including lymphocyte counts), physical examinations, vital signs, and electrocardiogram parameters (including heart rate, PR, QRS, and QT intervals) were recorded. Subjects were permitted to withdraw if lymphocyte counts were ≤ 0.2 x 109/L. Results The safety population included 190 subjects of which 95 received amiselimod and 95 were in the combined moxifloxacin group. Subjects were 40% female, 83% white, and the mean (standard deviation) age was 39.0 (8.8) years. The discontinuation rate was 8% (n=8) in the amiselimod group and 4% (n=4) in the moxifloxacin group. Three subjects who received amiselimod discontinued because they met the stopping criteria for low lymphocyte counts. One subject experienced an amiselimod-related serious AE of atrial fibrillation on day 26 (after receiving amiselimod 1.6 mg for 3 of the preceding 4 days) that required hospitalization, cardioversion, and led to discontinuation. No deaths were reported. All other AEs were mild to moderate in severity. Decreased white blood counts were the most commonly reported TEAE, followed by headache and constipation (Table). Reductions in white blood counts returned to normal range after study discontinuation without sequelae. Decreased neutrophils, lymphocytes and hemoglobin, and increased creatine kinase, alanine aminotransferase, and aspartate aminotransferase were reported, all of which resolved without sequelae. The mean absolute lymphocyte count for amiselimod exhibited a gradual decrease from predose (1.681 thou/uL) to a nadir of 0.424 thou/uL on day 27 (Figure). Changes to vital signs, physical examinations, and ECG parameters were within normal limits. Conclusions Upwardly titrated doses of amiselimod ranging from 0.4 to 1.6 mg were generally well tolerated in healthy subjects.