Modified Intent-to-treat Population Research Articles

Improving Neck and Jawline Aesthetics With OnabotulinumtoxinA by Minimizing Platysma Muscle Contraction Effects: Efficacy and Safety Results in a Phase 3 Randomized, Placebo-Controlled Study.

Platysma prominence (PP) describes the noticeable appearance of the platysma muscle upon contraction, causing less defined jawline contour and vertical neck bands. To assess safety and efficacy of onabotulinumtoxinA for improvement of PP in adults. Participants with moderate-to-severe (Grade 3 to 4) PP at maximum contraction received onabotulinumtoxinA or placebo on Day 1 and were monitored for 120 days. OnabotulinumtoxinA dosage (26, 31, or 36 U) was customized based on baseline PP severity on each side of the neck. Efficacy analyses were conducted in the intent-to-treat (ITT) population (all randomized participants), and modified ITT population (mITT; psychosocially impacted by PP appearance). Results from ITT and mITT populations were comparable. As assessed by investigators, 76.7% of onabotulinumtoxinA mITT participants achieved ≥1-grade improvement versus 21.2% in the placebo group, and 41.0% versus 2.2% (P < 0.0001) achieved ≥2-grade improvement at Day 14. As assessed by participants, 79.9% of onabotulinumtoxinA mITT participants versus 21.8% in the placebo group and 40.8% versus 3.9% (P < 0.0001) achieved ≥1- or ≥2-grade improvement, respectively, at Day 14. OnabotulinumtoxinA responder rates remained higher than placebo through Day 120, gradually declining over time. OnabotulinumtoxinA participants reported significantly higher satisfaction with treatment effect, lower bother from jawline and vertical neck bands, and lower psychosocial impact from PP than placebo at Day 14 (P < 0.0001). OnabotulinumtoxinA effectively improved self-perceived jawline definition and was well tolerated. OnabotulinumtoxinA was well tolerated and effective in improving moderate-to-severe PP, including neck bands and jawline definition.

Role of MIC levels and 23S rRNA mutation sites to clarithromycin in 14-day clarithromycin bismuth quadruple therapy for Helicobacter pylori eradication: A prospective trial in Beijing

BackgroundRising clarithromycin resistance undermines Helicobacter pylori (H. pylori) treatment efficacy. We aimed to determine clarithromycin's minimum inhibitory concentration (MIC) levels and identify specific mutation sites in the 23S ribosomal subunit (23S rRNA) that predict treatment outcomes in a 14-day regimen of clarithromycin bismuth quadruple therapy (amoxicillin 1g, clarithromycin 500 mg, rabeprazole 10 mg, and colloidal bismuth pectin 200 mg). Materials and methodsWe included adult H. pylori patients who hadn't previously undergone clarithromycin-based treatment, either as initial or rescue therapy. Exclusions were made for penicillin allergy, recent use of related medications, severe illnesses, or inability to cooperate. Patients underwent a 14-day clarithromycin bismuth quadruple therapy. Gastric mucosa specimens were obtained during endoscopy before eradication. MIC against amoxicillin and clarithromycin was determined using the E-test method. The receiver operating characteristic (ROC) curve helped to find the optimal clarithromycin resistance MIC breakpoint. Genetic sequences of H. pylori 23S rRNA were identified through Sanger Sequencing. (ChiCTR2200061476) ResultsOut of 196 patients recruited, 92 met the inclusion criteria for the per-protocol (PP) population. The overall intention-to-treat (ITT) eradication rate was 80.00 % (84/105), while the modified intention-to-treat (MITT) and PP eradication rates were 90.32 % (84/93) and 91.30 % (84/92) respectively. No amoxicillin resistance was observed, but clarithromycin resistance rates were 36.19 % (38/105), 35.48 % (33/93), and 34.78 % (33/92) in the ITT, MITT, and PP populations respectively. Compared with the traditional clarithromycin resistance breakpoint of 0.25 μg/mL, a MIC threshold of 12 μg/mL predicted better eradication. Among 173 mutations on 152 sites in the 23S rRNA gene, only the 2143A > G mutation could predict eradication outcomes (p < 0.000). ConclusionsInterpretation of elevated MIC values is crucial in susceptibility testing, rather than a binary "susceptible" or "resistant" classification. The 2143A > G mutation has limited specificity in predicting eradication outcomes, necessitating further investigation into additional mutation sites associated with clarithromycin resistance.

Efficacy and safety of omadacycline for treating complicated skin and soft tissue infections: a meta-analysis of randomized controlled trials.

In the present study, we aimed to compare the clinical efficacy and safety of omadacycline (OMC) with its comparators for the treatment of complicated skin and soft tissue infections (cSSTIs) in adult patients. Randomized controlled trials (RCTs) evaluating OMC for cSSTIs were searched in databases of PubMed, Embase, Cochrane, Web of Science, and Clinical Trial, up to July 2022. The primary outcomes were clinical efficacy and microbiological response, with secondary outcome was safety. Four RCTs consisting of 1,757 patients were included, with linezolid (LZD) as a comparator drug. For clinical efficacy, OMC was not inferior to LZD in the modified intent-to-treat (MITT) (OR: 1.24, 95% Cl: [0.93, 1.66], P = 0.15) and clinically evaluable (CE) populations (OR: 1.92, 95% Cl: [0.94, 3.92], P = 0.07). For microbiological response, OMC was numerically higher than LZD in the microbiologically evaluable (ME) (OR: 1.74, 95% Cl: [0.81, 3.74], P = 0.16) and microbiological MITT (micro-MITT) populations (OR: 1.27, 95% Cl: [0.92, 1.76], P = 0.14). No significant difference was found in subpopulations of monomicrobial or polymicrobial mixed infection populations. The mortality and adverse event rates were similar between OMC and LZD. OMC was as good as LZD in terms of clinical efficacy and microbiological response, and has similar safety issues in treating cSSTIs. OMC might be a promising option for treating cSSTIs in adult patients.

Molnupiravir for intra-household prevention of COVID-19: The MOVe-AHEAD randomized, placebo-controlled trial

To evaluatethe efficacy and safety of molnupiravir for intra-household post-exposure prophylaxis (PEP) of COVID-19. MOVe-AHEAD was a randomized, controlled, double-blind, phase 3 trial comparing molnupiravir (800mg twice daily for 5 days) with placebo. Eligible participants were adult, unvaccinated, asymptomatic household contacts of patients with laboratory-confirmed COVID-19. The primary efficacy endpoint was the incidence of COVID-19 through day 14 in modified intention-to-treat (MITT) participants (those who received ≥1 dose of study intervention) without detectable SARS-CoV-2 at baseline, termed the MITT-VN population. Superiority of molnupiravir was prespecified as a stratified one-sided p-value of <0.0249 for the treatment difference in this endpoint. The MITT population comprised 763 participants randomized to molnupiravir and 764 to placebo; 83.6% had anti-SARS-CoV-2 antibodies at baseline. In the MITT-VN population, COVID-19 rates through day 14 were 6.5% with molnupiravir and 8.5% with placebo (one-sided p-value: 0.0848). In the molnupiravir arm, 25/35 of confirmed COVID-19 events (71.4%) occurred after completion of treatment (versus 17/49 [34.7%] for placebo). Adverse event rates were low and similar between molnupiravir and placebo. Molnupiravir was well-tolerated but did not meet the prespecified superiority criterion, possibly influenced in part by the high pre-existing immunity in the trial population.

Antivirals for adult patients hospitalised with SARS-CoV-2 infection: a randomised, phase II/III, multicentre, placebo-controlled, adaptive study, with multiple arms and stages. COALITION COVID-19 BRAZIL IX – REVOLUTIOn trial

Repurposed drugs for treatment of new onset disease may be an effective therapeutic shortcut. We aimed to evaluate the efficacy of repurposed antivirals compared to placebo in lowering SARS-CoV2 viral load of COVID-19 patients. REVOLUTIOn is a randomised, parallel, blinded, multistage, superiority and placebo controlled randomised trial conducted in 35 centres in Brazil. We include patients aged 18 years or older admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, symptoms onset 9 days or less and SpO2 94% or lower at room air were eligible. All participants were randomly allocated to receive either atazanavir, daclatasvir or sofosbuvir/daclatasvir or placebo for 10 days. The primary outcome was the decay rate (slope) of the SARS-CoV-2 viral load logarithm assessed in the modified intention to-treat population. This trial was registered with ClinicalTrials.gov, number NCT04468087. Between February 09, 2021, and August 04, 2021, 255 participants were enrolled and randomly assigned to atazanavir (n=64), daclatasvir (n=66), sofosbuvir/daclatasvir (n=67) or placebo (n=58). Compared to placebo group, the change from baseline to day 10 in log viral load was not significantly different for any of the treatment groups (0.05 [95% CI,-0.03 to 0.12],-0.02 [95% CI,-0.09 to 0.06], and-0.03 [95% CI,-0.11 to 0.04] for atazanavir, daclatasvir and sofosbuvir/daclatasvir groups respectively). There was no significant difference in the occurrence of serious adverse events between treatment groups. No significant reduction in viral load was observed from the use of atazanavir, daclatasvir or sofosbuvir/daclatasvir compared to placebo in hospitalised COVID-19 patients who need oxygen support with symptoms onset 9 days or less. Ministério da Ciência, Tecnologia e Inovação (MCTI) - Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ); Cia Latino-Americana de Medicamentos (Clamed); Cia Industrial H. Carlos Schneider (Ciser); Hospital Research Foundation Incorporation, Australia, HCor São Paulo; Blanver Farmoquímica; Instituto de Tecnologia em Fármacos (Farmanguinhos) da Fundação Oswaldo Cruz (Fiocruz); Coordenação Geral de Planejamento Estratégico (Cogeplan)/Fiocruz; and Fundação de apoio a Fiocruz (Fiotec, VPGDI-054-FIO-20-2-13).

Efficacy and Safety of Plazomicin in the Treatment of Enterobacterales Infections: A Meta-analysis of Randomized Controlled Trials

BackgroundIn the present study, we aimed to compare the efficacy and safety of plazomicin with comparators for the treatment of Enterobacterales infections.MethodsRandomized controlled trials (RCTs) assessing plazomicin for Enterobacterales infections were searched on the PubMed, Embase, and Cochrane Library databases. Meta-analyses were used to evaluate the efficacy and safety in RCTs.ResultsA total of 3 RCTs consisting of 761 patients were included in the present analysis. The study population included complex urinary tract infections (cUTIs), bloodstream infections (BSIs), and hospital-acquired pneumonia (HAP). Plazomicin had a clinical remission rate in the modified intention-to-treat (MITT) population that was similar to that of comparators (odds ratio [OR], 1.02; 95% CI, 0.60–1.73; I2 = 45%) in the pooled analysis of the 3 studies. The overall microbiologic eradication rate in the microbiological MITT (mMITT) population was similar to that of the comparators group (OR, 1.46; 95% CI, 0.72–2.95; I2 = 0%). However, the microbiologic recurrence rate of plazomicin for Enterobacterales was lower than that in the comparators group (OR, 0.38; 95% CI, 0.17–0.86; P = .02; I2 = 0%). No significant differences were found between plazomicin and comparators for the risk of any adverse events (OR, 0.78; 95% CI, 0.55–1.11; I2 = 0%).ConclusionsPlazomicin is as good as comparators in terms of efficacy and tolerance in the treatment of Enterobacterales infections. Therefore, plazomicin is a suitable choice for antibiotic treatment in adult patients with cUTIs, BSIs, or HAP.

AZTEC—azithromycin therapy for prevention of chronic lung disease of prematurity: a statistical analysis plan for clinical outcomes

BackgroundThe AZTEC trial is a multi-centre, randomised, placebo-controlled trial of azithromycin to improve survival without development of chronic lung disease of prematurity (CLD) in preterm infants. The statistical analysis plan for the clinical outcomes of the AZTEC trial is described.Methods and designA double-blind, randomised, placebo-controlled trial of a 10-day course of intravenous azithromycin (20 mg/kg for 3 days; 10 mg/kg for 7 days) administered to preterm infants born at < 30 weeks’ gestational age across UK tertiary neonatal units. Following parental consent, infants are randomly allocated to azithromycin or placebo, with allocated treatment starting within 72 h of birth. The primary outcome is survival without moderate/severe CLD at 36 weeks’ postmenstrual age (PMA). Serial respiratory fluid and stool samples are being collected up to 21 days of life. The target sample size is 796 infants, which is based on detecting a 12% absolute difference in survival without moderate/severe CLD at 36 weeks’ PMA (90% power, two-sided alpha of 0.05) and includes 10% loss to follow-up.ResultsBaseline demographic and clinical characteristics will be summarised by treatment arm and in total. Categorical data will be summarised by numbers and percentages. Continuous data will be summarised by mean, standard deviation, if data are normal, or median, interquartile range, if data are skewed. Tests of statistical significance will not be undertaken for baseline characteristics. The primary analysis, on the intention to treat (ITT) population, will be analysed using multilevel logistic regression, within a multiple imputation framework. Adjusted odds ratios, 95% confidence intervals, and p-values will be presented. For all other analyses, the analysis population will be based on the complete case population, which is a modified ITT population. All analyses will be adjusted for gestational age and treatment arm and account for any clustering by centre and/or multiple births as a random effect.ConclusionWe describe the statistical analysis plan for the AZTEC trial, including the analysis principles, definitions of the key clinical outcomes, methods for primary analysis, pre-specified subgroup analysis, sensitivity analysis, and secondary analysis. The plan has been finalised prior to the completion of recruitment.Trial registrationISRCTN registry ISRCTN11650227. Registered on 31 July 2018.

Prospective, randomized, controlled, noninferiority clinical trial to evaluate the safety and efficacy of absorbable macroporous polysaccharide composites as adjunct to hemostasis during open surgery.

To address intraoperative bleeding in cardiac surgery, reducing blood transfusion requirements, is mandatory to achieve effective hemostasis. Hemostatic agents may limit localized persistent bleeding. The introduction of carboxymethyl-chitosan component into the hemostatic agent and the application of the radiation crosslinking technique maintain its capacity for achieving intraoperative hemostasis, thus increasing the clinical utility. A prospective, noninferiority and randomized controlled clinical trial to compare the safety and efficacy of absorbable macroporous polysaccharide composites (AMPC, treatment group) with compound microporous polysaccharide hemostatic powder (CMPHP, control group) (2:1 ratio) as adjuncts to hemostasis in open surgery. The main indication was used for hemostasis in various traumatic hemorrhage areas, including cardiothoracic, vascular, and general surgery. The primary endpoint was success rate of hemostasis within 300 s (at a 10% noninferiority margin). The secondary endpoint was hemostasis time. Both endpoints were assessed in the modified intention-to-treat (MITT) population. Safety parameters were assessed. This study is fully compliant with theCONSORT statement. Randomized patients in AMPC and CMPHP groups were 168 and 84, respectively. In MITT population, the success rates of hemostasis within 300 s were 98.8% (163 of 165) in AMPC and 94.0% (78 of 83) in CMPHP (treatment difference 4.8% [95% CI -0.57% to 10.20%]). AMPC was thus noninferior to CMPHP. Hemostasis time (median [interquartile range]) with AMPC (87 [52.5, 180] s) was better than CMPHP (110 [54.5, 181] s). Changes in laboratory parameters over time and shifts to abnormal values were typical of surgeries and similar between two groups. No noticeable adverse effects associated with AMPC or CMPHP were observed. AMPC is well tolerated as topical hemostatic agent, noninferior to commercial CMPHP, and exhibits excellent safety. This study provides a novel hemostatic agent which appears to offer significant clinical advantage in various hemorrhage areas.

1154. Safety and Efficacy of Ceftolozane/Tazobactam Plus Metronidazole Versus Meropenem in Pediatric Participants With Complicated Intra-abdominal Infection: A Phase 2, Randomized Clinical Trial

BackgroundCeftolozane/tazobactam (C/T), a cephalosporin–β-lactamase inhibitor combination, is approved for treatment of complicated urinary tract infections, complicated intra-abdominal infections (cIAI), and nosocomial pneumonia in adults. Safety and efficacy of C/T in pediatric participants with cIAI was assessed.MethodsThis phase 2 study (NCT03217136) compared C/T + metronidazole (MTZ) with meropenem (MEM) for treatment of cIAI. Age- and weight-adjusted dosing is summarized in Table 1. The primary objective was to evaluate the safety and tolerability of C/T + MTZ compared with MEM. A key secondary endpoint was clinical cure at end of treatment (EOT) and test of cure (TOC).Table 1. Summary of Dosing and Pharmacokinetic Sampling Schedule by Age Cohort ResultsA total of 94 participants were randomized 3:1; 91 were treated with C/T + MTZ (n=70) or MEM (n=21) comprising the modified intent-to-treat (MITT) population. The clinically evaluable population included 78 participants at EOT (C/T + MTZ, n=59; MEM, n=19) and 77 participants at TOC (C/T + MTZ, n=58; MEM, n=19). The most common diagnosis and pathogen in the MITT population were complicated appendicitis (C/T + MTZ, 91.4%; MEM, 100%) and Escherichia coli (C/T + MTZ, 67.1%; MEM, 61.9%). The mean (SD) intravenous therapy/overall treatment duration was 6.4 (2.8)/9.3 (3.6) days and 5.8 (1.8)/9.0 (3.2) days for C/T + MTZ and MEM, respectively. In total, ≥1 adverse events (AE) occurred in 80.0% and 61.9% of participants receiving C/T + MTZ and MEM, respectively (Table 2), of which 18.6% and 14.3% were considered drug related. Serious AE occurred in 11.4% (8/70) and 0% (0/21) of participants receiving C/T + MTZ and MEM, respectively; none were considered drug related. No drug-related study drug discontinuations occurred. In the MITT population, rates of clinical cure for C/T + MTZ and MEM at EOT were 80.0% and 95.2%, and at TOC were 80.0% and 100%, respectively (Figure 1); 6 of the 14 failures for C/T + MTZ were indeterminate responses scored as endpoint failures per protocol. In the clinically evaluable (CE) population, rates of clinical cure for C/T + MTZ and MEM were 89.8% and 100% at EOT, and 89.7% and 100% at TOC, respectively (Figure 1). ConclusionC/T + MTZ was well tolerated in pediatric participants with cIAI, and rates of clinical success were high with C/T treatment. C/T is a promising new treatment option for children with cIAI.Disclosures Carl-Christian A. Jackson, MD, Merck & Co. Inc. (Shareholder) Julia Lonchar, MSc, Merck Sharp & Dohme Corp. (Employee, Shareholder) Feng-Hsiu Su, MPH, MBA, Merck Sharp & Dohme Corp. (Employee, Shareholder) Jennifer A. Huntington, PharmD, 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) Myra W. Popejoy, PharmD, Merck Sharp & Dohme Corp. (Employee) Matthew G. Johnson, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Carisa S. De Anda, PharmD, Merck Sharp & Dohme Corp. (Employee, Shareholder) Elizabeth G. Rhee, MD, Merck Sharp & Dohme Corp (Employee, Shareholder) Christopher Bruno, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee)

Statins for Graves' orbitopathy (STAGO): a phase 2, open-label, adaptive, single centre, randomised clinical trial

A protective action of statins on development of Graves' orbitopathy suggests that statins might be used for treatment of the disease. We aimed to assess the efficacy of the addition of a statin, atorvastatin, to intravenous glucocorticoids (ivGCs) on Graves' orbitopathy outcomes in patients with hypercholesterolaemia. We did a randomised, open-label, phase 2, adaptive, clinical trial at a single, tertiary, referral hospital in Pisa, Italy. Patients with moderate-to-severe, active Graves' orbitopathy, with a low-density lipoprotein cholesterol concentration between 2·97 and 4·88 mmol/L were eligible for inclusion. Patients were randomly assigned (1:1) in 11 blocks of eight, using a computer-based system, to the ST group or the NST group. The ST group received ivGCs (methylprednisolone 500 mg once a week for 6 weeks followed by 250 mg once a week for an additional six weeks) for 12 weeks and oral atorvastatin (20 mg once a day) for 24 weeks. The NST group only received the ivGC regimen. Patients were unmasked to group allocation; however, the ophthalmological investigator was masked to randomisation. The primary endpoint was the Graves' orbitopathy outcome (composite evaluation of exophthalmos, clinical activity score, eyelid aperture, and diplopia) at 24 weeks in the modified intention-to-treat (ITT) population (patients who attended the week 12 visit). Patients were considered responders when at least two of the following criteria were fulfilled in the most affected eye, without worsening in any of the same measures in both eyes: (1) reduction in exophthalmos of 2 mm or more, with no increase by 2 mm or more in the other eye; (2) reduction of clinical activity score by two or more points; (3) reduction in eyelid aperture by 2 mm or more, with no increase by 2 mm or more in the other eye; and (4) disappearance or improvement (change from constant to inconstant, intermittent, or absent, or from inconstant to intermittent or absent) of diplopia, and (5) improvement in visual acuity by 0·2 decimals or more. The trial is registered with EUDRACT, 2018-001317-33, and ClinicalTrials.gov, NCT03110848. Between June 1, 2020, and Nov 30, 2020, 119 patients were screened for inclusion, of whom 88 (74%) patients were enrolled and randomly assigned to one of the two treatment groups (44 [50%] to the ST group and 44 [50%] to the NST group). Eight (9%) patients did not attend the 12 week visit; 80 (91%) patients (18 [23%] men and 62 [78%] women) were included in the modified ITT population (41 [51%] in the ST group and 39 [49%] in the NST group]. The proportion of Graves' orbitopathy composite evaluation responders at 24 weeks was higher in the ST group (21 [51%] of 41 patients) than the NST group (11 [28%] of 39 patients; attributable risk 0·23 [95% CI 0·02-0·44]; p=0·042). 26 adverse events occurred in 21 (24%) of 88 patients in the safety population. One (2%) of 44 patients in each group required treatment discontinuation, with no serious adverse events and no difference between groups. Addition of oral atorvastatin to an ivGC regimen improved Graves' orbitopathy outcomes in patients with moderate-to-severe, active eye disease who were hypercholesterolaemic. Future phase 3 studies, which could potentially recruit patients regardless of low-density lipoprotein cholesterol concentration, are required to confirm this association. Associazione Allievi Endocrinologia Pisana.

High Sustained Virologic Response Rates of Glecaprevir/Pibrentasvir in Patients With Dosing Interruption or Suboptimal Adherence.

INTRODUCTION:Pangenotypic, all-oral direct-acting antivirals, such as glecaprevir/pibrentasvir (G/P), are recommended for treatment of hepatitis C virus (HCV) infection. Concerns exist about the impact on efficacy in patients with suboptimal adherence, particularly with shorter treatment durations. These post hoc analyses evaluated adherence (based on pill count) in patients prescribed 8- or 12-week G/P, the impact of nonadherence on sustained virologic response at post-treatment week 12 (SVR12), factors associated with nonadherence, and efficacy in patients interrupting G/P treatment.METHODS:Data were pooled from 10 phase 3 clinical trials of treatment-naive patients with HCV genotype 1–6 without cirrhosis/with compensated cirrhosis (treatment adherence analysis) and 13 phase 3 clinical trials of all patients with HCV (interruption analysis).RESULTS:Among 2,149 patients included, overall mean adherence was 99.4%. Over the treatment duration, adherence decreased (weeks 0–4: 100%; weeks 5–8: 98.3%; and weeks 9–12: 97.1%) and the percentage of patients with ≥80% or ≥90% adherence declined. SVR12 rate in the intention-to-treat (ITT) population was 97.7% (modified ITT SVR12 99.3%) and remained high in nonadherent patients in the modified ITT population (<90%: 94.4%–100%; <80%: 83.3%–100%). Psychiatric disorders were associated with <80% adherence, and shorter treatment duration was associated with ≥80% adherence. Among 2,902 patients in the interruption analysis, 33 (1.1%) had a G/P treatment interruption of ≥1 day, with an SVR12 rate of 93.9% (31/33). No virologic failures occurred.DISCUSSION:These findings support the impact of treatment duration on adherence rates and further reinforce the concept of “treatment forgiveness” with direct-acting antivirals.

Posaconazole for prevention of invasive pulmonary aspergillosis in critically ill influenza patients (POSA-FLU): a randomised, open-label, proof-of-concept trial.

PurposeInfluenza-associated pulmonary aspergillosis (IAPA) is a frequent complication in critically ill influenza patients, associated with significant mortality. We investigated whether antifungal prophylaxis reduces the incidence of IAPA.MethodsWe compared 7 days of intravenous posaconazole (POS) prophylaxis with no prophylaxis (standard-of-care only, SOC) in a randomised, open-label, proof-of-concept trial in patients admitted to an intensive care unit (ICU) with respiratory failure due to influenza (ClinicalTrials.gov, NCT03378479). Adult patients with PCR-confirmed influenza were block randomised (1:1) within 10 days of symptoms onset and 48 h of ICU admission. The primary endpoint was the incidence of IAPA during ICU stay in patients who did not have IAPA within 48 h of ICU admission (modified intention-to-treat (MITT) population).ResultsEighty-eight critically ill influenza patients were randomly allocated to POS or SOC. IAPA occurred in 21 cases (24%), the majority of which (71%, 15/21) were diagnosed within 48 h of ICU admission, excluding them from the MITT population. The incidence of IAPA was not significantly reduced in the POS arm (5.4%, 2/37) compared with SOC (11.1%, 4/36; between-group difference 5.7%; 95% CI − 10.8 to 21.7; p = 0.32). ICU mortality of early IAPA was high (53%), despite rapid antifungal treatment.ConclusionThe higher than expected incidence of early IAPA precludes any definite conclusion on POS prophylaxis. High mortality of early IAPA, despite timely antifungal therapy, indicates that alternative management strategies are required. After 48 h, still 11% of patients developed IAPA. As these could benefit from prophylaxis, differentiated strategies are likely needed to manage IAPA in the ICU.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00134-021-06431-0.

Palliative radiotherapy after oesophageal cancer stenting (ROCS): a multicentre, open-label, phase 3 randomised controlled trial

SummaryBackgroundPatients with advanced oesophageal cancer have a median survival of 3–6 months, and most require intervention for dysphagia. Self-expanding metal stent (SEMS) insertion is the most typical form of palliation in these patients, but dysphagia deterioration and re-intervention are common. This study examined the efficacy of adjuvant external beam radiotherapy (EBRT) compared with usual care alone in preventing dysphagia deterioration and reducing service use after SEMS insertion.MethodsThis was a multicentre, open-label, phase 3 randomised controlled trial based at cancer centres and acute care hospitals in England, Scotland, and Wales. Patients (aged ≥16 years) with incurable oesophageal carcinoma receiving stent insertion for primary management of dysphagia were randomly assigned (1:1) to receive usual care alone or EBRT (20 Gy in five fractions or 30 Gy in ten fractions) plus usual care after stent insertion. Usual care was implemented according to need as identified by the local multidisciplinary team (MDT). Randomisation was via the method of minimisation stratified by treating centre, stage at diagnosis (I–III vs IV), histology (squamous or non-squamous), and MDT intent to give chemotherapy (yes vs no). The primary outcome was difference in proportions of participants with dysphagia deterioration (>11 point decrease on patient-reported European Organisation for Research and Treatment of Cancer quality of life questionnaire-oesophagogastric module [QLQ-OG25], or a dysphagia-related event consistent with such a deterioration) or death by 12 weeks in a modified intention-to-treat (ITT) population, which excluded patients who did not have a stent inserted and those without a baseline QLQ-OG25 assessment. Secondary outcomes included survival, quality of life (QoL), morbidities (including time to first bleeding event or hospital admission for bleeding event and first dysphagia-related stent complications or re-intervention), and cost-effectiveness. Safety analysis was undertaken in the modified ITT population. The study is registered with the International Standard Randomised Controlled Trial registry, ISRCTN12376468, and ClinicalTrials.gov, NCT01915693, and is completed.Findings220 patients were randomly assigned between Dec 16, 2013, and Aug 24, 2018, from 23 UK centres. The modified ITT population (n=199) comprised 102 patients in the usual care group and 97 patients in the EBRT group. Radiotherapy did not reduce dysphagia deterioration, which was reported in 36 (49%) of 74 patients receiving usual care versus 34 (45%) of 75 receiving EBRT (adjusted odds ratio 0·82 [95% CI 0·40–1·68], p=0·59) in those with complete data for the primary endpoint. No significant difference was observed in overall survival: median overall survival was 19·7 weeks (95% CI 14·4–27·7) with usual care and 18·9 weeks (14·7–25·6) with EBRT (adjusted hazard ratio 1·06 [95% CI 0·78–1·45], p=0·70; n=199). Median time to first bleeding event or hospital admission for a bleeding event was 49·0 weeks (95% CI 33·3–not reached) with usual care versus 65·9 weeks (52·7–not reached) with EBRT (adjusted subhazard ratio 0·52 [95% CI 0·28–0·97], p=0·038; n=199). No time versus treatment interaction was observed for prespecified QoL outcomes. We found no evidence of differences between trial group in time to first stent complication or re-intervention event. The most common (grade 3–4) adverse event was fatigue, reported in 19 (19%) of 102 patients receiving usual care alone and 22 (23%) of 97 receiving EBRT. On cost-utility analysis, EBRT was more expensive and less efficacious than usual care.InterpretationPatients with advanced oesophageal cancer having SEMS insertion for the primary management of their dysphagia did not gain additional benefit from concurrent palliative radiotherapy and it should not be routinely offered. For a minority of patients clinically considered to be at high risk of tumour bleeding, concurrent palliative radiotherapy might reduce bleeding risk and the need for associated interventions.FundingNational Institute for Health Research Health Technology Assessment Programme.

1230. Clinical and Microbiologic Outcomes by Causative Pathogen in Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia (HABP/VABP) Treated with Imipenem/Cilastatin (IMI)/Relebactam (REL) Versus Piperacillin/Tazobactam (PIP/TAZ)

BackgroundIMI/REL is a combination of IMI and the novel class A and class C β-lactamase inhibitor REL. Here we present per-pathogen outcomes from a recent phase 3 clinical trial (RESTORE-IMI 2), in which IMI/REL was shown to be non-inferior to piperacillin/tazobactam (PIP/TAZ) for empiric therapy of HABP/VABP, in both primary and key secondary endpoints.MethodsRandomized, controlled, double-blind, multinational, phase 3, non-inferiority trial in adults with HABP/VABP. Lower respiratory tract specimens were obtained ≤48 hours prior to screening. Participants (pts) were randomized 1:1 to IMI/REL 500 mg/250 mg or PIP/TAZ 4 g/500 mg, given intravenously every 6 h for 7-14 d. Pts also received empiric linezolid until baseline cultures confirmed absence of MRSA. This analysis evaluated outcomes by causative LRT pathogen in modified intent to treat (MITT) pts (randomized pts with ≥1 dose of study drug, excluding pts with only gram-positive cocci present on baseline Gram stain) who had ≥1 baseline LRT pathogen susceptible (according to CLSI criteria) to both study drugs. Outcomes assessed were microbiologic response at end of therapy (EOT), clinical response at early follow-up (EFU; 7-14 d after EOT), and Day 28 all-cause mortality (ACM).ResultsOf 531 MITT pts, 51.4% (130 IMI/REL, 143 PIP/TAZ) had ≥1 baseline LRT pathogen susceptible to both study drugs. The most common causative pathogens in this analysis population were Klebsiella spp (30.4% of patients), Pseudomonas aeruginosa (22.3%), Escherichia coli (22.0%), and Haemophilus influenzae (9.2%), consistent with other recent trials in HABP/VABP and with surveillance data. Outcomes by pathogen were generally comparable between IMI/REL and PIP/TAZ (Table). In a separate subgroup analysis of the microbiologic MITT population, in pts with ≥1 ESBL-positive LRT pathogen (45 IMI/REL, 35 PIP/TAZ), microbiologic response at EOT was 82.2% (IMI/REL) vs 68.6%% (PIP/TAZ), clinical response at EFU was 64.4% vs 60.0%, and Day 28 ACM was 20.0% and 22.9%, respectively. In the IMI/REL arm, 8 pts had ≥1 confirmed KPC-positive baseline LRT pathogen; KPC status was not assessed in the PIP/TAZ arm.ConclusionIMI/REL is an efficacious treatment option for HABP/VABP, regardless of causative pathogen.Table. Primary and secondary efficacy outcomes in patients who were in the MITT population and had at least 1 baseline LRT pathogen susceptible to both study drugs DisclosuresMaria C. Losada, BA, Merck & Co., Inc. (Employee, Shareholder) Jiejun Du, PhD, Merck & Co., Inc. (Employee, Shareholder) Michelle L. Brown, BS, Merck & Co., Inc. (Employee, Shareholder) Katherine Young, MS, Merck & Co., Inc. (Employee, Shareholder)Merck & Co., Inc. (Employee, Shareholder) Robert Tipping, MS, Merck & Co., Inc. (Employee, Shareholder) C. Andrew DeRyke, PharmD, Merck & Co., Inc. (Employee, Shareholder) Joan R. Butterton, MD, Merck & Co., Inc. (Employee, Shareholder) Amanda Paschke, MD MSCE, Merck & Co., Inc. (Employee, Shareholder) Luke F. Chen, MBBS MPH MBA FRACP FSHEA FIDSA, Merck & Co., Inc. (Employee, Shareholder)Merck & Co., Inc. (Employee, Shareholder)

Safety and efficacy of omadacycline for treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections in patients with mild-to-moderate renal impairment

Many antibiotics require dosage adjustments in patients with renal impairment. In Phase III studies, omadacycline was non-inferior to moxifloxacin and linezolid in adults with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI), respectively. This analysis evaluated efficacy and safety measures from three omadacycline studies by patient renal function. Patients were stratified as having normal renal function (creatinine clearance >89 mL/min), mild renal impairment (creatinine clearance 60-89 mL/min) or moderate renal impairment (creatinine clearance <60 mL/min); creatine clearance ≤30 mL/min (severe renal impairment) was an exclusion criterion. Efficacy endpoints were clinical success at the early clinical response (ECR) and post-treatment evaluation (PTE) time-points. Safety was evaluated as treatment-emergent adverse events (TEAEs) and laboratory measures. This subgroup analysis included 773 patients with CABP and 1339 patients with ABSSSI in intent-to-treat (ITT) and modified ITT populations, respectively. Clinical success rates were high at ECR and PTE across the studies (CABP 75-90%; ABSSSI 74-95%), and broadly similar between treatments, irrespective of renal function. Rates of TEAEs in patients with ABSSSI ranged from 33% to 52%, and were similar across renal function groups. In patients with CABP, higher rates were observed in patients with moderate renal impairment (56-61%) compared with patients with normal renal function or mild renal impairment (35-49%). The most common TEAEs were nausea and vomiting. Clinical success was similar across renal function groups, indicating no notable difference in the efficacy of omadacycline in patients with mild or moderate renal impairment. Omadacycline and comparators displayed similar safety profiles. CLINICALTRIALS. OPTIC (NCT02531438); OASIS-1 (NCT02378480); OASIS-2 (NCT02877927).

Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial

Nosocomial pneumonia due to multidrug-resistant Gram-negative pathogens poses an increasing challenge. We compared the efficacy and safety of cefiderocol versus high-dose, extended-infusion meropenem for adults with nosocomial pneumonia. We did a randomised, double-blind, parallel-group, phase 3, non-inferiority trial in 76 centres in 17 countries in Asia, Europe, and the USA (APEKS-NP). We enrolled adults aged 18 years and older with hospital-acquired, ventilator-associated, or health-care-associated Gram-negative pneumonia, and randomly assigned them (1:1 by interactive response technology) to 3-h intravenous infusions of either cefiderocol 2 g or meropenem 2 g every 8 h for 7-14 days. All patients also received open-label intravenous linezolid (600 mg every 12 h) for at least 5 days. An unmasked pharmacist prepared the assigned treatments; investigators and patients were masked to treatment assignment. Only the unmasked pharmacist was aware of the study drug assignment for the infusion bags, which were administered in generic infusion bags labelled with patient and study site identification numbers. Participants were stratified at randomisation by infection type and Acute Physiology and Chronic Health Evaluation II (APACHE II) score (≤15 and ≥16). The primary endpoint was all-cause mortality at day 14 in the modified intention-to-treat (ITT) population (ie, all patients receiving at least one dose of study drug, excluding patients with Gram-positive monomicrobial infections). The analysis was done for all patients with known vital status. Non-inferiority was concluded if the upper bound of the 95% CI for the treatment difference between cefiderocol and meropenem groups was less than 12·5%. Safety was investigated to the end of the study in the safety population, which included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03032380, and EudraCT, 2016-003020-23. Between Oct 23, 2017, and April 14, 2019, we randomly assigned 148 participants to cefiderocol and 152 to meropenem. Of 292 patients in the modified ITT population, 251 (86%) had a qualifying baseline Gram-negative pathogen, including Klebsiella pneumoniae (92 [32%]), Pseudomonas aeruginosa (48 [16%]), Acinetobacter baumannii (47 [16%]), and Escherichia coli (41 [14%]). 142 (49%) patients had an APACHE II score of 16 or more, 175 (60%) were mechanically ventilated, and 199 (68%) were in intensive care units at the time of randomisation. All-cause mortality at day 14 was 12·4% with cefiderocol (18 patients of 145) and 11·6% with meropenem (17 patients of 146; adjusted treatment difference 0·8%, 95% CI -6·6 to 8·2; p=0·002 for non-inferiority hypothesis). Treatment-emergent adverse events were reported in 130 (88%) of 148 participants in the cefiderocol group and 129 (86%) of 150 in the meropenem group. The most common treatment-emergent adverse event was urinary tract infection in the cefiderocol group (23 patients [16%] of 148) and hypokalaemia in the meropenem group (23 patients [15%] of 150). Two participants (1%) of 148 in the cefiderocol group and two (1%) of 150 in the meropenem group discontinued the study because of drug-related adverse events. Cefiderocol was non-inferior to high-dose, extended-infusion meropenem in terms of all-cause mortality on day 14 in patients with Gram-negative nosocomial pneumonia, with similar tolerability. The results suggest that cefiderocol is a potential option for the treatment of patients with nosocomial pneumonia, including those caused by multidrug-resistant Gram-negative bacteria. Shionogi.

Eight Weeks of Treatment With Glecaprevir/Pibrentasvir Is Safe and Efficacious in an Integrated Analysis of Treatment-Naïve Patients With Hepatitis C Virus Infection

The direct-acting antiviral combination glecaprevir/pibrentasvir has been approved by the Food and Drug Administration for 8 weeks of treatment in treatment-naïve patients with hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis. We performed an integrated analysis of data from trials to evaluate the overall efficacy and safety of 8 weeks of glecaprevir/pibrentasvir in treatment-naïve patients without cirrhosis or with compensated cirrhosis. We pooled data from 8 phase 2 or phase 3 trials of treatment-naïve patients with HCV genotype 1 to 6 infections, without cirrhosis or with compensated cirrhosis, who received 8 weeks of glecaprevir/pibrentasvir. Of 1248 patients, 343 (27%) had cirrhosis. Most patients were white (80%) and had HCV genotype 1 infection (47%) or genotype 3 infection (22%); the median age was 54 years. Overall rates of sustained virologic response at post-treatment week 12 were 97.6% (1218 of 1248) in the intention to treat (ITT) and 99.3% (1218 of 1226) in the modified ITT populations. When we excluded patients with genotype 3 infections with compensated cirrhosis (consistent with the European label), rates of sustained virologic response at post-treatment week 12 were 97.6% in the ITT and 99.4% in the modified ITT populations. Eight virologic failures (7 in patients without cirrhosis and 1 in a patient with cirrhosis) occurred in the ITT population. Virologic failure was not associated with markers of advanced liver disease or populations of interest (current alcohol use, opioid substitution therapy, history of injection-drug use, and severe renal impairment). Treatment-emergent adverse events (AEs) occurred in 58% of patients. The most frequent AEs (>10%) were headache (12%) and fatigue (12%). Serious AEs and AEs that led to glecaprevir/pibrentasvir discontinuation were reported in 2% and less than 1% of patients, respectively. In a pooled analysis of data from 8 trials, we found that 8 weeks of treatment with glecaprevir/pibrentasvir is efficacious and well tolerated in treatment-naïve patients with HCV genotype 1 to 6 infections, with or without cirrhosis.

Baseline Characteristics and Outcomes Among Patients with Complicated Skin and Soft Tissue Infections Admitted to the Intensive Care Unit: Analysis of the Phase 3 COVERS Randomized Trial of Ceftaroline Fosamil Versus Vancomycin Plus Aztreonam.

AimExploratory analyses evaluated patient characteristics and outcomes among patients with complicated skin and soft tissue infection (cSSTI) in the phase 3 COVERS study who were admitted to an intensive care unit (ICU).MethodsAdults with cSSTI (surface area ≥ 75 cm2) and evidence of systemic inflammation and/or underlying comorbidities were randomized 2:1 to intravenous ceftaroline fosamil (600 mg every 8 h [q8h]) or vancomycin (15 mg/kg every 12 h) plus aztreonam (1 g q8h) for 5–14 days. Clinical response and ICU length of stay (LOS) within first hospitalization were evaluated in the modified intent-to-treat (MITT) and clinically evaluable (CE) populations; a Cox proportional hazards model identified factors associated with increased hospital LOS.ResultsOverall, 42 of 761 randomized patients were admitted to the ICU (ceftaroline fosamil, n = 32; vancomycin plus aztreonam, n = 10) prior to, or at start of, study treatment. Baseline differences between the ICU and non-ICU populations were indicative of more severe disease in ICU patients; within this subset, there were also some notable imbalances between treatment groups. Clinical cure rates at test-of-cure (ceftaroline fosamil vs. vancomycin plus aztreonam) were generally similar in the non-ICU and ICU subsets (MITT population 79% vs. 79% and 69% vs. 90.0%, respectively; CE population 87% vs. 85% and 80% vs. 89%, respectively). Median ICU LOS was 8 vs. 13 days, respectively. ICU admission was a risk factor predicting increased hospital LOS (P < 0.001).ConclusionsClinical outcomes for patients admitted to the ICU were generally similar to non-ICU patients, despite more severe baseline disease, with shorter median treatment duration in the ceftaroline fosamil group. ICU admission was associated with longer hospital LOS. Given the small sample size and unbalanced patient and disease characteristics within the ICU subgroup, differences between treatment groups should be interpreted with caution.Trial registrationClinicalTrials.gov identifier, NCT01499277.Electronic supplementary materialThe online version of this article (10.1007/s40121-020-00297-3) contains supplementary material, which is available to authorized users.

Comparison of ceftriaxone plus macrolide and ampicillin/sulbactam plus macrolide in treatment for patients with community-acquired pneumonia without risk factors for aspiration: an open-label, quasi-randomized, controlled trial

BackgroundCeftriaxone (CTRX) and ampicillin/sulbactam (ABPC/SBT) are recommended by various guidelines as the first-line antibiotics for community-acquired pneumonia (CAP). However, which of these antibiotics is more effective for treating non-aspiration CAP remains unclear.MethodsThis study was a prospective, single-center, open-label, quasi-randomized controlled trial. Patients with adult CAP without risk for aspiration were allocated to either a CTRX or ABPC/SBT group based on the date of hospital admission. Macrolide was added to patients in each group. The primary outcome was the clinical response in the validated per-protocol (VPP) population at end of treatment (EOT). The secondary outcomes were clinical response during treatment and at end of study (EOS) in the VPP population, and mortality rate at day 30 in the modified intention-to-treat (MITT) population.ResultsOf 696 screened patients, 433 patients were excluded and 263 patients were allocated to receive either of the treatments. Males comprised 54% of patients and mean age and PSI were 62.1 ± 19.8 years and 69.3 ± 30.0, respectively, with 124 patients allocated to the CTRX group and 138 patients allocated to the ABPC/SBT group. The clinical effectiveness rate for the VPP population at EOT was 90% in the CTRX and 96% in the ABPC/SBT group (p = 0.072, 95% confidence interval [CI] of risk difference [RD]: − 12.6–0.8%). No significant difference in effectiveness at day 4 was observed between the CTRX and ABPC/SBT groups (p = 0.079, 95%CI of RD: − 12.1–0.4%), but at day 7, ABPC/SBT was significantly more effective than CTRX in the VPP population (p = 0.047, 95%CI of RD: − 13.3–-0.4%). No significant difference in late response at EOS was seen between CTRX and ABPC/SBT groups: cure (89 [86%] and 102 [94%]), relapse (5 [5%] and 1 [1%]) and failure (10 [10%] and 5 [5%]; p = 0.053). Deaths within 30 days in MITT population was higher in CTRX group (4 [3%]) than in ABPC/SBT group (0 [0%]) (p = 0.048, 95%CI of RD: 0.1–6.3%).ConclusionNo significant difference in effectiveness was found between ABPC/SBT and CTRX at EOT. However, ABPC/SBT might be more effective in the early phase of treatment.Trial registrationUMIN-CTR, UMIN000037464. Registered 25 July 2019 – Retrospectively registered, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000042262

Negative Pressure Wound Therapy vs Conventional Wound Treatment in Subcutaneous Abdominal Wound Healing Impairment

Negative pressure wound therapy (NPWT) is an established treatment option, but there is no evidence of benefit for subcutaneous abdominal wound healing impairment (SAWHI). To evaluate the effectiveness and safety of NPWT for SAWHI after surgery in clinical practice. The multicenter, multinational, observer-blinded, randomized clinical SAWHI study enrolled patients between August 2, 2011, and January 31, 2018. The last follow-up date was June 11, 2018. The trial included 34 abdominal surgical departments of hospitals in Germany, Belgium, and the Netherlands, and 539 consecutive, compliant adult patients with SAWHI after surgery without fascia dehiscence were randomly assigned to the treatment arms in a 1:1 ratio stratified by study site and wound size using a centralized web-based tool. A total of 507 study participants (NPWT, 256; CWT, 251) were assessed for the primary end point in the modified intention-to-treat (ITT) population. Negative pressure wound therapy and conventional wound treatment (CWT). The primary outcome was time until wound closure (delayed primary closure or by secondary intention) within 42 days. Safety analysis comprised the adverse events (AEs). Secondary outcomes included wound closure rate, quality of life (SF-36), pain, and patient satisfaction. Of the 507 study participants included in the modified ITT population, 287 were men (56.6%) (NPWT, 155 [60.5%] and CWT, 132 [52.6%]) and 220 were women (43.4%) (NPWT, 101 [39.5%] and CWT 119 [47.4%]). The median (IQR) age of the participants was 66 (18) years in the NPWT arm and 66 (20) years in the CWT arm. Mean time to wound closure was significantly shorter in the NPWT arm (36.1 days) than in the CWT arm (39.1 days) (difference, 3.0 days; 95% CI 1.6-4.4; P < .001). Wound closure rate within 42 days was significantly higher with NPWT (35.9%) than with CWT (21.5%) (difference, 14.4%; 95% CI, 6.6%-22.2%; P < .001). In the therapy-compliant population, excluding study participants with unauthorized treatment changes (NPWT, 22; CWT, 50), the risk for wound-related AEs was higher in the NPWT arm (risk ratio, 1.51; 95% CI, 0.99-2.35). Negative pressure wound therapy is an effective treatment option for SAWHI after surgery; however, it causes more wound-related AEs. ClinicalTrials.gov Identifier: NCT01528033.