scholarly journals Tocilizumab in nonventilated patients hospitalized with Covid-19 pneumonia

2020 ◽  
Author(s):  
Carlos Salama ◽  
Jian Han ◽  
Linda Yau ◽  
William G. Reiss ◽  
Benjamin Kramer ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Alaska Native ◽  
Hazard Ratio ◽  
Serious Adverse Events ◽  
Black African ◽  
Cumulative Proportion ◽  
Safety Population ◽  
Interleukin 6 Receptor ◽  
Intent To Treat ◽  
Treat Population

AbstractBackgroundCoronavirus disease 2019 (Covid-19) pneumonia is often associated with hyperinflammation. Safety and efficacy of the anti–interleukin-6 receptor antibody tocilizumab was evaluated in patients hospitalized with Covid-19 pneumonia.MethodsNonventilated patients hospitalized with Covid-19 pneumonia were randomized (2:1) to tocilizumab (8 mg/kg intravenous) or placebo plus standard care. Sites enrolling high-risk and minority populations were emphasized. The primary endpoint was cumulative proportion of patients requiring mechanical ventilation or who had died by Day 28.ResultsOf 389 randomized patients, 249 patients received tocilizumab and 128 received placebo in the modified intent-to-treat population (Hispanic/Latino, 56.0%; Black/African American, 14.9%; American Indian/Alaska Native, 12.7%; White, 12.7%; other/unknown, 3.7%). The cumulative proportion (95% confidence interval [CI]) of patients requiring mechanical ventilation or who had died by Day 28 was 12.0% (8.52% to 16.86%) and 19.3 % (13.34% to 27.36%) for the tocilizumab and placebo arms, respectively (log-rank P=0.0360; hazard ratio, 0.56 [95% CI, 0.33 to 0.97]). Median time to clinical failure up to Day 28 favored tocilizumab over placebo (hazard ratio 0.55 [95% CI, 0.33 to 0.93]). All-cause mortality by Day 28 was 10.4% with tocilizumab and 8.6% with placebo (weighted difference, 2.0% [95% CI, – 5.2% to 7.8%). In the safety population, serious adverse events occurred in 15.2% of tocilizumab patients (38/250 patients) and 19.7% of placebo patients (25/127).ConclusionsThis trial demonstrated the efficacy and safety of tocilizumab over placebo in reducing the likelihood of progression to requiring mechanical ventilation or death in nonventilated patients hospitalized with Covid-19 pneumonia.Trial registrationClinicalTrials.gov NCT04372186

Major impact of personalized dosimetry using 90Y loaded glass microspheres SIRT in HCC: Final overall survival analysis of a multicenter randomized phase II study (DOSISPHERE-01).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 516-516 ◽  
Author(s):  
Etienne Garin ◽  
Lambros Tzelikas ◽  
Boris Guiu ◽  
Julia Chalaye ◽  
Julien Edeline ◽  
...  
Keyword(s):  
Overall Survival ◽  
Index Lesion ◽  
Phase 2 Trial ◽  
Randomized Phase Ii ◽  
Safety Population ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Intent To Treat ◽  
Treat Population ◽  
Clinical Trial Information

516 Background: 90Y loaded microsphere SIRT (radioembolization) is a treatment option in advanced HCC. However, no personalized dosimetric endpoints are currently used. The goal of this study was to compare the efficacy of 90Y loaded glass microsphere SIRT in HCC using a standard versus a personalized dosimetric approach. Methods: DOSISPHERE-01 was a multicenter, randomized phase 2 trial in unresectable HCC patients with at least one tumor ≥7cm. Treatment arm was randomly assigned (1:1) to standard dosimetry arm (SDA), with a goal to deliver 120±20Gy to the treated volume or to personalized dosimetry arm (PDA) with a goal to deliver at least 205Gy to the index lesion. The primary endpoint was the response rate (RR) of the index lesion according to EASL criteria. Secondary endpoints included dose response evaluation, safety and overall survival (OS). Results: Sixty HCC patients were randomized (PDA 31, SDA 29, intent to treat population-ITTP-), and 56 treated (28 in each arm). RR was significantly increased in the PDA versus the SDA, in the ITTP, respectively 64.5% versus 31% (p=0.0095) as in the safety population -SP- (treatment effectively received, personalized 35, standard 21), respectively 74.3% versus 14.3% (p<0.0001). Median OS was significantly increased in the PDA versus the SDA, in the ITTP, respectively 26.7m (CI 95%:11.7-NR) versus 10.6m (CI 95%:6-16.8), p=0.0096, HR=0.421 (95%CI:0.215-0.826), p=0.0119, as in the SP, respectively 26.7m (CI 95%:11.7- NR) versus 9.5m (CI 95%:4.8-14.9), p=0.0015, HR=0.342 (95%CI:0.171-0.683), p=0.0023. Median OS was 26.7m (CI 95%:13.5-NR) versus 6.0m (CI 95%:3.8-14.9) for the patients who received a tumor dose ≥205 Gy or <205 Gy respectively, p=0.0106, HR=0.336 (95%CI:0.154-0.735), p=0.0063. Treatment-related clinically relevant hepatic ≥grade 3 AEs were observed in 5.7% and 14.2% of the patients of the PDA and SDA arms, respectively, (p=ns). Conclusions: MAA SPECT/CT based personalized dosimetry is safe and dramatically increased RR and OS of HCC patients. These results question the interpretation of all phase 3 trials of SIRT designed without personalized dosimetry in HCC. Clinical trial information: 2015-A00894-45.

487 Effect of Lower-Sodium Oxybate on Sleep Inertia in Idiopathic Hypersomnia in a Double-Blind, Randomized Withdrawal Study

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A192-A192
Author(s):  
Richard Bogan ◽  
Yves Dauvilliers ◽  
Michael Thorpy ◽  
Patricia Chandler ◽  
Abby Chen ◽  
...  
Keyword(s):  
Motor Coordination ◽  
Sodium Oxybate ◽  
Open Label ◽  
Double Blind ◽  
Sleep Inertia ◽  
Safety Population ◽  
Idiopathic Hypersomnia ◽  
Waking Up ◽  
Intent To Treat ◽  
Treat Population

Abstract Introduction Idiopathic hypersomnia (IH) is a rare central hypersomnolence disorder characterized by excessive daytime sleepiness. A common feature is sleep inertia, which is prolonged difficulty waking up accompanied by confusion, disorientation, poor motor coordination, and repeated returns to sleep. Sleep inertia is burdensome to patients, resulting in missed work or school, and patients may be dependent on others to wake them. No treatment is currently approved for IH. The efficacy and safety of lower-sodium oxybate (LXB; Xywav™), a novel oxybate treatment with 92% less sodium than sodium oxybate (Xyrem®), was evaluated in a phase 3 study (NCT03533114) in adults with IH. We focus here on the drug effect on sleep inertia. Methods Eligible participants aged 18–75 years with IH began LXB treatment with an open-label treatment titration and optimization period (OLTTOP; 10–14 weeks), followed by a 2-week, open-label, stable-dose period (SDP). Participants were randomized to placebo or to continue LXB treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). The primary efficacy endpoint was change in Epworth Sleepiness Scale score. The visual analog scale for sleep inertia (VAS-SI) was included as an exploratory endpoint. The VAS-SI, administered daily during the last 2 weeks of screening before baseline, SDP, and DBRWP, is a self-reported retrospective measure of difficulty awakening each morning using a 100-mm line with anchors 0 (very easy) and 100 (very difficult). Results The safety population included 154 participants (mean±SD age, 40±14 years; 68% female); modified intent-to-treat population, n=115. VAS-SI scores gradually decreased from week 2 of screening (mean±SD, 56.6±25.1) to week 2 of SDP (29.0±20.8). During week 2 of DBRWP, VAS-SI scores worsened in participants randomized to placebo (n=59) compared with maintenance of improvement in participants continuing LXB treatment (n=56); LS mean difference (95% CI) in change from SDP, −22.2 (−29.7, −14.8); P&lt;0.0001 (nominal). Common adverse events included nausea (21.4%), headache (16.2%), anxiety (14.9%), dizziness (11.7%), insomnia (11.7%), and vomiting (10.4%). Conclusion Sleep inertia improved with LXB treatment and significant differences were seen between placebo and LXB after DBRWP. The overall safety profile in participants with IH is consistent with that of LXB in narcolepsy. Support (if any) Jazz Pharmaceuticals, Inc

scholarly journals AB0814 SUSTAINED IMPROVEMENTS IN PHYSICAL FUNCTION, QUALITY OF LIFE, AND WORK PRODUCTIVITY WITH IXEKIZUMAB IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS AND PREVIOUS INADEQUATE RESPONSE TO TUMOUR NECROSIS FACTOR-INHIBITORS: 3-YEAR RESULTS FROM SPIRIT-P2 TRIAL

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1709-1710
Author(s):  
A. M. Orbai ◽  
J. Gratacos-Masmitja ◽  
E. Dokoupilova ◽  
B. Combe ◽  
A. Constantin ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Physical Function ◽  
Work Productivity ◽  
Inadequate Response ◽  
Research Support ◽  
Activity Impairment ◽  
Sf 36 ◽  
Intent To Treat ◽  
Treat Population

Background:Ixekizumab (IXE), a high-affinity monoclonal antibody that selectively targets IL-17A, has shown improvements compared to placebo (PBO) not only in disease activity but also in various patient-reported outcomes (PROs) assessing physical function, quality of life (QoL), and work productivity in PsA patients treated for 24 weeks and sustained up to 52 weeks.1, 2Objectives:To report the effects of treatment with IXE on these PROs after up to 3 years of treatment.Methods:In SPIRIT-P2 (NCT02349295), a Phase 3 trial, 363 adult patients with active PsA and prior inadequate response or intolerance to 1 or 2 TNF inhibitors (TNFis) were randomized 1:1:1 to IXE 80 mg every 4 weeks (IXEQ4W; N=122) or every 2 weeks (IXEQ2W; N=123), or PBO (N=118) in the double-blind treatment period (Weeks 0-24). Both IXE regimens had a starting dose of 160 mg. Results are reported from a subset of the intent-to-treat population who were randomized to IXE at baseline (Week 0). The following PROs were assessed during Weeks 0-156: HAQ-DI (minimally clinically important difference [MCID] an improvement ≥0.35), medical outcomes survey Short Form-36 (SF-36) Physical and Mental Component Summary (PCS and MCS), European Quality of Life 5 Dimensions Visual Analog Scale (EQ-5D VAS), and Work Productivity and Activity Impairment Questionnaire-Specific Health Problem (WPAI-SHP; absenteeism, presenteeism, work productivity, and activity impairment). Missing values were imputed by observed analysis and modified baseline observation carried forward (mBOCF) for continuous data or by modified non-responder imputation (mNRI) for categorical data.Results:Mean baseline scores for SF-36 (PCS and MCS), EQ-5D VAS, and WPAI-SHP (Figure 1) and HAQ-DI (mean [SD]: IXEQ4W=1.2 [0.6]; IXEQ2W=1.2 [0.6]), indicated impaired physical function and QoL. The percentage of patients of who completed 156 weeks of the study in IXEQ4W and IXEQ2W arms were 57.4% (n=70) and 44.7% (n=55), respectively. Patients receiving IXE treatment up to 3 years reported sustained improvements in SF-36 (PCS and MCS), EQ-5D VAS, and WPAI-SHP (presenteeism, work productivity, and activity impairment) (Figure 1). Observed HAQ-DI mean change from baseline in IXEQ4W: -0.46 (0.62) and IXEQ2W: -0.48 (0.55). The percentage of IXE treated patients achieving MCID for HAQ-DI (improvement ≥0.35) was sustained at 3 years (Figure 2).Figure 1.Summary of Patient-Reported Outcomes presented as change from baseline at Week 156 (Observed and mBOCF): Intent-to-Treat Population (Patients Randomized to IXE at Baseline)Figure 2.Patients achieving HAQ-DI MCID Response up to Week 156 (Observed) and at Week 156 (mNRI) among patients with HAQ-DI≥0.35 at baseline: Intent-to-Treat Population (Patients Randomized to IXE at Baseline)Conclusion:Improvements in PROs, measuring physical and mental function, quality of life, and work productivity are maintained up to 3 years with IXE treatment in patients with active PsA who have had an inadequate response or intolerance to 1 or 2 TNFis.References:[1]Nash P, et al. Lancet. 2017;389(10086):2317-2327.[2]Genovese MC, et al. Rheumatology (Oxford). 2018;57(11):2001-2011.Disclosure of Interests:Ana-Maria Orbai Grant/research support from: Abbvie, Eli Lilly and Company, Celgene, Novartis, Janssen, Horizon, Consultant of: Eli Lilly; Janssen; Novartis; Pfizer; UCB. Ana-Maria Orbai was a private consultant or advisor for Sun Pharmaceutical Industries, Inc, not in her capacity as a Johns Hopkins faculty member and was not compensated for this service., Jordi Gratacos-Masmitja Grant/research support from: a grant from Pfizzer to study implementation of multidisciplinary units to manage PSA in SPAIN, Consultant of: Pfizzer, MSD, ABBVIE, Janssen, Amgen, BMS, Novartis, Lilly, Speakers bureau: Pfizzer, MSD, ABBVIE, Janssen, Amgen, BMS, Novartis, Lilly, Eva Dokoupilova Grant/research support from: Eli Lilly and Abbvie, Bernard Combe Grant/research support from: Novartis, Pfizer, Roche-Chugai, Consultant of: AbbVie; Gilead Sciences, Inc.; Janssen; Eli Lilly and Company; Pfizer; Roche-Chugai; Sanofi, Speakers bureau: Bristol-Myers Squibb; Gilead Sciences, Inc.; Eli Lilly and Company; Merck Sharp & Dohme; Pfizer; Roche-Chugai; UCB, Arnaud Constantin Grant/research support from: Study was sponsored by Sanofi Genzyme, Consultant of: Consulting fees from Abbvie, BMS, Celgene, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, UCB, Amanda M. Gellett Shareholder of: Eli Lilly and company, Employee of: Eli Lilly and company, Aubrey Trevelin Sprabery Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Julie Birt Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Vladimir Geneus Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Peter Nash Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB

scholarly journals Awake Prone Position in Hypoxemic Patients with Coronavirus Disease 19 (COVI-PRONE): A Study protocol and Statistical Analysis Plan for Randomized Clinical Trial

2021 ◽  
Author(s):  
Zainab Al Duhailib ◽  
Yaseen Arabi ◽  
Sarah Culgin ◽  
Jason Weatherald ◽  
Ken Kuljit S. Parhar ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Prone Position ◽  
Controlled Trial ◽  
Invasive Mechanical Ventilation ◽  
Target Population ◽  
Altered Mental Status ◽  
Hemodynamic Instability ◽  
Hospital Length Of Stay ◽  
Prone Positioning ◽  
Serious Adverse Events

Background Coronavirus disease 2019 (COVID-19), may progress to respiratory failure requiring invasive mechanical ventilation. Due to ventilator shortage and healthcare systems strain, affordable interventions such as awake prone positioning has been used to improve oxygenation, however, the effect of this intervention on patient-important outcomes is uncertain. The COVI-PRONE trial aims to determine if awake prone positioning in hypoxemic COVID-19 patients reduces the need for invasive mechanical ventilation. Study design A pragmatic, multicenter, international, parallel-group, and stratified randomized controlled trial, aiming to enrol 400 hospitalized adults with COVID-19. Participants The target population is hospitalized adults with confirmed or suspected COVID-19, hypoxemia that requires ≥40% oxygen or ≥ 5 L/min by nasal cannula, and abnormal chest x-ray. We will exclude patients with any of the following: immediate need for intubation; altered mental status; contraindication to prone positioning; hemodynamic instability; body mass index > 40 kg/m2; third trimester pregnancy; do not intubate status; previous enrolment or intubation within the same hospital admission; and prone positioning for more than one day prior to randomization. Study intervention and control Following informed a priori or deferred consent, eligible patients will be centrally randomized to either the intervention arm (prone positioning) or standard of care (no prone positioning). Patients randomized to the prone position will be required to either self-prone or assist-prone for a total of eight to ten hours per day until they meet pre-specified stopping criteria. Study outcomes The primary outcome is invasive mechanical ventilation at 30-days of randomization. Other outcomes include mortality at 60 days, invasive and non-invasive mechanical ventilation free days at 30 days, hospital length of stay at 60 days, days alive and outside of the hospital at 60 days, complications of proning, and serious adverse events.

scholarly journals The Efficacy and Safety of Eravacycline in the Treatment of Complicated Intra-Abdominal Infections: A Systemic Review and Meta-Analysis of Randomized Controlled Trials

2019 ◽  
Vol 8 (6) ◽  
pp. 866 ◽  
Author(s):  
Shao-Huan Lan ◽  
Shen-Peng Chang ◽  
Chih-Cheng Lai ◽  
Li-Chin Lu ◽  
Chien-Ming Chao
Keyword(s):  
Adverse Event ◽  
Clinical Cure ◽  
Clinical Cure Rate ◽  
Clinical Failure ◽  
Efficacy And Safety ◽  
Cure Rate ◽  
Randomized Controlled ◽  
Evaluable Population ◽  
Intent To Treat ◽  
Treat Population

This study aims to assess the clinical efficacy and safety of eravacycline for treating complicated intra-abdominal infection (cIAI) in adult patients. The PubMed, Web of Science, EBSCO, Cochrane databases, Ovid Medline, Embase, and ClinicalTrials.gov were searched up to May 2019. Only randomized controlled trials (RCTs) that evaluated eravacycline and other comparators for the treatment of cIAI were included. The primary outcome was the clinical cure rate at the test-of-cure visit based on modified intent-to-treat population, microbiological intent-to-treat population, clinically evaluable population, and microbiological evaluable population, and the secondary outcomes were clinical failure rate and the risk of adverse event. Three RCTs were included. Overall, eravacycline had a clinical cure rate (88.7%, 559/630) at test-of-cure in modified intent-to-treat population similar to comparators (90.1%, 492/546) in the treatment of cIAIs (risk ratio (RR), 0.99; 95% confidence interval (CI), 0.95–1.03; I2 = 0%, Figure 3). In the microbiological intent-to-treat, clinically evaluable, and microbiological evaluable populations, no difference was found between eravacycline and comparators in terms of clinical cure rate at test-of-cure (microbiological intent-to-treat population, RR, 0.99; 95% CI, 0.95–1.04; I2 = 0%, clinically evaluable population, RR, 1.00; 95% CI, 0.97–1.03; I2 = 0%, microbiological evaluable population, RR, 0.98; 95% CI, 0.95–1.02; I2 = 0%). In addition, eravacycline had clinical failure rate similar to comparators at test-of-cure in modified intent-to-treat population (RR, 1.01; 95% CI, 0.61–0.69; I2 = 0%), microbiological intent-to-treat population (RR, 1.34; 95% CI, 0.77–2.31; I2 = 16%), clinically evaluable population (RR, 1.03; 95% CI, 0.61–1.76; I2 = 0%), and microbiological evaluable population (RR, 1.32; 95% CI, 0.75–2.32; I2 = 10%). Although eravacycline was associated with higher risk of treatment-emergent adverse event than comparators (RR, 1.34; 95% CI, 1.13–1.58; I2 = 0%), no significant differences were found between eravacycline and comparators for the risk of serious adverse event (RR, 1.04; 95% CI, 0.65–1.65; I2 = 0%), discontinuation of study drug because of adverse event (RR, 0.68; 95% CI, 0.23–1.99; I2 = 13%), and all-cause mortality (RR, 1.09; 95% CI, 0.41–2.9; I2 = 28%). In conclusion, the clinical efficacy of eravacycline is as high as that of the comparator drugs in the treatment of cIAIs and this antibiotic is as well tolerated as the comparators.

scholarly journals Efficacy and Safety of Daprodustat Compared with Darbepoetin Alfa in Japanese Hemodialysis Patients with Anemia

2020 ◽  
Vol 15 (8) ◽  
pp. 1155-1165 ◽  
Author(s):  
Tadao Akizawa ◽  
Masaomi Nangaku ◽  
Taeko Yonekawa ◽  
Nobuhiko Okuda ◽  
Shinya Kawamatsu ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Darbepoetin Alfa ◽  
Binding Capacity ◽  
Geometric Mean ◽  
Japanese Patients ◽  
Target Range ◽  
Link Type ◽  
Group Frequency ◽  
Intent To Treat ◽  
Treat Population

Background and objectivesDaprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates genes related to iron metabolism. The efficacy (noninferiority) and safety of daprodustat compared with standard therapy (darbepoetin alfa) was evaluated.Design, setting, participants, & measurements This was a randomized, phase 3, double-blind, active-control study in Japanese patients receiving hemodialysis with anemia of CKD. Participants’ treatment was switched from current erythropoiesis-stimulating agents (ESAs) to daprodustat 4 mg once daily or darbepoetin alfa 10–60 μg once weekly (on the basis of the prestudy ESA dose). Dose was adjusted every 4 weeks for daprodustat or every 2 weeks for darbepoetin alfa, according to a protocol-specified algorithm. The primary end point was mean hemoglobin during weeks 40–52 in the intent-to-treat population.ResultsOf 332 participants screened, 271 participants were randomized (safety evaluation: 271 participants; efficacy evaluation: 267 intent-to-treat population). The mean hemoglobin during weeks 40–52 were maintained within the target range in both groups (10.9 g/dl [95% confidence interval (95% CI), 10.8 to 11.0] for daprodustat, and 10.8 g/dl [95% CI, 10.7 to 11.0] for darbepoetin alfa). Daprodustat was noninferior to darbepoetin alfa, as the lower bound of the confidence interval for the treatment difference (0.1 g/dl; 95% CI, −0.1 to 0.2 g/dl) was greater than the noninferiority criterion of −1.0 g/dl. For most participants, hemoglobin was maintained within the target range (10.0–12.0 g/dl) during weeks 40–52 (88% daprodustat; 90% darbepoetin alfa). Geometric mean hepcidin levels decreased more at week 52 with daprodustat (−37%; 95% CI, −49 to −23) than with darbepoetin alfa (−20%; 95% CI, −36 to −1), and an increase in total iron-binding capacity was observed in the daprodustat group. Frequency of adverse events were generally similar between daprodustat and darbepoetin alfa.ConclusionsOral daprodustat was noninferior to darbepoetin alfa as measured by mean hemoglobin over weeks 40–52 in Japanese patients receiving hemodialysis switched from ESAs.Clinical Trial registry name and registration number201754, Clinicaltrials.gov, NCT02969655.

scholarly journals Rezafungin versus Caspofungin in a Phase 2, Randomized, Double-Blind Study for the Treatment of Candidemia and Invasive Candidiasis- The STRIVE Trial

2020 ◽  
Author(s):  
George R Thompson ◽  
Alex Soriano ◽  
Athanasios Skoutelis ◽  
Jose A Vazquez ◽  
Patrick M Honore ◽  
...  
Keyword(s):  
Invasive Candidiasis ◽  
Double Blind Study ◽  
Phase 2 ◽  
Double Blind ◽  
Once Daily ◽  
Secondary Endpoints ◽  
Intent To Treat ◽  
Cure Rates ◽  
Treat Population

Abstract Background Rezafungin (RZF) is a novel echinocandin exhibiting distinctive pharmacokinetics/pharmacodynamics. STRIVE was a phase 2, double-blind, randomized trial designed to compare the safety and efficacy of RZF once weekly (QWk) to caspofungin (CAS) once daily for treatment of candidemia and/or invasive candidiasis (IC). Methods Adults with systemic signs and mycological confirmation of candidemia and/or IC were randomized to RZF 400 mg QWk (400 mg), RZF 400 mg on week 1 then 200 mg QWk (400/200 mg), or CAS 70 mg as a loading dose followed by 50 mg daily for ≤ 4 weeks. Efficacy assessments included overall cure (resolution of signs of candidemia/IC + mycological eradication) at day 14 (primary endpoint), investigator-assessed clinical response at day 14, and 30-day all-cause mortality (ACM) (secondary endpoints), and time to negative blood culture. Safety was evaluated by adverse events and ACM through follow-up. Results Of 207 patients enrolled, 183 were in the microbiological intent-to-treat population (~21% IC). Overall cure rates were 60.5% (46/76) for RZF 400 mg, 76.1% (35/46) for RZF 400/200 mg, and 67.2% (41/61) for CAS; investigator-assessed clinical cure rates were 69.7% (53/76), 80.4% (37/46), and 70.5% (43/61), respectively. 30-day ACM was 15.8% for RZF 400 mg, 4.4% for RZF 400/200 mg, and 13.1% for CAS. Candidemia was cleared in 19.5 and 22.8 hours in RZF and CAS patients, respectively. No concerning safety trends were observed; ACM through follow-up was 15.2% (21/138) for RZF and 18.8% (13/69) for CAS. Conclusions RZF was safe and efficacious in the treatment of candidemia and/or IC.

scholarly journals RESTORE-IMI 1: A Multicenter, Randomized, Double-blind Trial Comparing Efficacy and Safety of Imipenem/Relebactam vs Colistin Plus Imipenem in Patients With Imipenem-nonsusceptible Bacterial Infections

2019 ◽  
Vol 70 (9) ◽  
pp. 1799-1808 ◽  
Author(s):  
Johann Motsch ◽  
Cláudia Murta de Oliveira ◽  
Viktor Stus ◽  
Iftihar Köksal ◽  
Olexiy Lyulko ◽  
...  
Keyword(s):  
Clinical Response ◽  
Bacterial Infections ◽  
Infection Type ◽  
Complicated Urinary Tract Infection ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Overall Response ◽  
Dose Study ◽  
Intent To Treat ◽  
Hospital Acquired

Abstract Background The β-lactamase inhibitor relebactam can restore imipenem activity against imipenem-nonsusceptible gram-negative pathogens. We evaluated imipenem/relebactam for treating imipenem-nonsusceptible infections. Methods Randomized, controlled, double-blind, phase 3 trial. Hospitalized patients with hospital-acquired/ventilator-associated pneumonia, complicated intraabdominal infection, or complicated urinary tract infection caused by imipenem-nonsusceptible (but colistin- and imipenem/relebactam-susceptible) pathogens were randomized 2:1 to 5–21 days imipenem/relebactam or colistin+imipenem. Primary endpoint: favorable overall response (defined by relevant endpoints for each infection type) in the modified microbiologic intent-to-treat (mMITT) population (qualifying baseline pathogen and ≥1 dose study treatment). Secondary endpoints: clinical response, all-cause mortality, and treatment-emergent nephrotoxicity. Safety analyses included patients with ≥1 dose study treatment. Results Thirty-one patients received imipenem/relebactam and 16 colistin+imipenem. Among mITT patients (n = 21 imipenem/relebactam, n = 10 colistin+imipenem), 29% had Acute Physiology and Chronic Health Evaluation II scores &gt;15, 23% had creatinine clearance &lt;60 mL/min, and 35% were aged ≥65 years. Qualifying baseline pathogens: Pseudomonas aeruginosa (77%), Klebsiella spp. (16%), other Enterobacteriaceae (6%). Favorable overall response was observed in 71% imipenem/relebactam and 70% colistin+imipenem patients (90% confidence interval [CI] for difference, –27.5, 21.4), day 28 favorable clinical response in 71% and 40% (90% CI, 1.3, 51.5), and 28-day mortality in 10% and 30% (90% CI, –46.4, 6.7), respectively. Serious adverse events (AEs) occurred in 10% of imipenem/relebactam and 31% of colistin+imipenem patients, drug-related AEs in 16% and 31% (no drug-related deaths), and treatment-emergent nephrotoxicity in 10% and 56% (P = .002), respectively. Conclusions Imipenem/relebactam is an efficacious and well-tolerated treatment option for carbapenem-nonsusceptible infections. Clinical Trials Registration NCT02452047.

Analyzing the impact of duration of ventilation, hospitalization, and ventilation episodes on the risk of pneumonia

2019 ◽  
Vol 40 (3) ◽  
pp. 301-306 ◽  
Author(s):  
Martin Wolkewitz ◽  
Mercedes Palomar-Martinez ◽  
Francisco Alvarez-Lerma ◽  
Pedro Olaechea-Astigarraga ◽  
Martin Schumacher
Keyword(s):  
Mechanical Ventilation ◽  
Intensive Care ◽  
Cumulative Risk ◽  
Hazard Ratio ◽  
Competing Risk ◽  
First Episode ◽  
Intubation Time ◽  
Unbiased Risk ◽  
The Impact ◽  
Duration Of Ventilation

AbstractObjective:To study the impact of duration of mechanical ventilation, hospitalization and multiple ventilation episodes on the development of pneumonia while accounting for extubation as a competing event.Design:A multicenter data base from a Spanish surveillance network was used to conduct a retrospective analysis of prospectively collected intensive care patients followed from admission to discharge.Setting:Spanish intensive care units (ICUs).Patients:Mechanically ventilated adult patients from 158 ICUs with 45,486 admissions, 48,705 ventilation episodes, and 314,196 ventilator days.Methods:Competing-risk models were applied to account for extubation plus 48 hours as a competing event for acquiring ventilator-associated pneumonia (VAP).Results:Time in the ICU before mechanical ventilation was associated with an increased VAP hazard rate and with longer intubation time. This indirect prolongation of intubation increased the cumulative risk to eventually acquire VAP. For instance, comparing 3–4 versus 0 days, the adjusted VAP hazard ratio was 1.40 (95% confidence interval [CI], 1.19–1.64) and the adjusted extubation hazard ratio was 0.64 (95% CI, 0.61–0.68), which leads to an adjusted VAP subdistribution hazard ratio (sHR) of 2.13 (95% CI, 1.83–2.50). Similarly, due to prolonged intubation, multiple ventilation episodes increase the risk for VAP; the adjusted sHR is 1.52 (95% CI, 1.35–1.72) for the second episode compared to the first episode, and the adjusted sHR is 1.54 (95% CI, 1.03–2.30) for the third episode compared to the first episode. The Kaplan-Meier method produced an upward biased estimated cumulative risk for VAP.Conclusions:A competing-risk analysis is necessary to receive unbiased risk estimates and to quantify the indirect effect of intubation time on the cumulative VAP risk. Our findings may guide physicians to improve medical decisions related to the harms and benefits of the duration of ventilation.

scholarly journals Early Outcomes in the ROADSTER 2 Study of Transcarotid Artery Revascularization in Patients With Significant Carotid Artery Disease

Stroke ◽  
2020 ◽  
Vol 51 (9) ◽  
pp. 2620-2629 ◽  
Author(s):  
Vikram S. Kashyap ◽  
Peter A. Schneider ◽  
Mazin Foteh ◽  
Raghu Motaganahalli ◽  
Rasesh Shah ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
High Risk ◽  
Carotid Artery ◽  
Death Rate ◽  
Technical Success ◽  
Protocol Population ◽  
Procedural Success ◽  
Intent To Treat ◽  
Treat Population ◽  
Stroke Death

Background and Purpose: Transcarotid artery revascularization (TCAR) is comprised of carotid artery stent placement with cerebral protection via proximal carotid artery clamping and reversal of cerebral arterial flow. The aim of the present study was to evaluate the safety and efficacy of TCAR performed by a broad group of physicians with variable TCAR experience. Methods: The ROADSTER 2 study is a prospective, open label, single arm, multicenter, postapproval registry for patients undergoing TCAR. Patients considered at high risk for complications from carotid endarterectomy with symptomatic stenosis ≥50% or asymptomatic stenosis ≥80% were included. The primary end point was procedural success, which encompassed technical success plus the absence of stroke, myocardial infarction, or death within the 30-day postoperative period. Secondary end points included technical success and individual/composite rates of stroke, death, and myocardial infarction (MI). All patients underwent independent neurological assessments before the procedure, within 24 hours, and at 30 days after TCAR. An independent clinical events committee adjudicated all major adverse events. Results: Between 2015 and 2019, 692 patients (Intent to Treat Population) were enrolled at 43 sites. Sixty cases had major protocol violations, leaving 632 patients adhering to the Food and Drug Administration-approved protocol (per-protocol population). The majority (81.2%) of operators were TCAR naïve before study initiation. Patients underwent TCAR for neurological symptoms in 26% of cases, and all patients had high-risk factors for carotid endarterectomy (anatomic-related 44%; physiological 32%; both 24%). Technical success occurred in 99.7% of all cases. The primary end point of procedural success rate in the Intent to Treat population was 96.5% (per-protocol 97.9%). The early postoperative outcomes in the Intent to Treat population included stroke in 13 patients (1.9%), death in 3 patients (0.4%), and MI in 6 patients (0.9%). The composite 30-day stroke/death rate was 2.3%, and stroke/death/MI rate was 3.2%. In the per-protocol population, there were strokes in 4 patients (0.6%), death in one patient (0.2%), and MI in 6 patients (0.9%) leading to a composite 30-day stroke/death rate of 0.8% and stroke/death/MI rate of 1.7%. Conclusions: TCAR results in excellent early outcomes with high technical success combined with low rates of postprocedure stroke and death. These results were achieved by a majority of operators new to this technology at the start of the trial. Adherence to the study protocol and peri-procedural antiplatelet therapy optimizes outcomes. Longer-term follow-up data are needed to confirm these early outcomes. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02536378.

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