Neutralizing COVID-19 Convalescent Plasma in Adults Hospitalized with COVID-19: A Blinded Randomized Placebo-Controlled Trial
BACKGROUND Convalescent plasma has been one of the most common treatments for COVID-19, but most clinical trial data to date have not supported its efficacy. RESEARCH QUESTION Is rigorously selected COVID-19 convalescent plasma with neutralizing anti-SARS-CoV-2 antibodies an efficacious treatment for adults hospitalized with COVID-19? STUDY DESIGN AND METHODS This was a multicenter, blinded, placebo-controlled randomized clinical trial among adults hospitalized with SARS-CoV-2 infection and acute respiratory symptoms for <14 days. Enrolled patients were randomly assigned to receive one unit of COVID-19 convalescent plasma (n=487) or placebo (n=473). The primary outcome was clinical status (illness severity) 14 days after study infusion measured with a seven-category ordinal scale ranging from discharged from the hospital with resumption of normal activities (lowest score) to death (highest score). The primary outcome was analyzed with a multivariable ordinal regression model, with an adjusted odds ratio (aOR) <1.0 indicating more favorable outcomes with convalescent plasma than placebo. In secondary analyses, trial participants were stratified by the presence of endogenous anti-SARS-CoV-2 antibodies ("serostatus") at randomization. The trial included 13 secondary efficacy outcomes, including 28-day mortality. RESULTS Among 974 randomized patients, 960 were included in the primary analysis. Clinical status on the ordinal outcome scale at 14 days did not differ between the convalescent plasma and placebo groups in the overall population (aOR: 1.04; 1/7 support interval (SI): 0.82-1.33), in patients without endogenous antibodies (aOR: 1.15; 1/7 SI: 0.74-1.80), or in patients with endogenous antibodies (aOR: 0.96; 1/7 SI: 0.72-1.30). None of the 13 secondary efficacy outcomes were different between groups. At 28 days, 89/482 (18.5%) patients in the convalescent plasma group and 80/465 (17.2%) patients in the placebo group had died (aOR: 1.04, 1/7 SI: 0.69-1.58). INTERPRETATION Among adults hospitalized with COVID-19, including those seronegative for anti-SARS-CoV-2 antibodies, treatment with convalescent plasma did not improve clinical outcomes.
Balanced Crystalloids Versus Saline in Sepsis: A Secondary Analysis of the SMART Trial
American journal of respiratory and critical care medicine. 2019
RATIONALE Administration of intravenous crystalloid solutions is a fundamental therapy for sepsis, but the effect of crystalloid composition on patient outcomes remains unknown. OBJECTIVES To compare the effect of balanced crystalloids versus saline on 30-day in-hospital mortality among critically ill adults with sepsis. METHODS Secondary analysis of patients from the Isotonic Solutions and Major Adverse Renal Events Trial (SMART) admitted to the medical intensive care unit with an ICD-10-CM code for sepsis, using multivariable regression to control for potential confounders. MEASUREMENTS AND MAIN RESULTS Of 15,802 patients enrolled in SMART, 1,641 patients were admitted to the medical intensive care unit with a diagnosis of sepsis. A total of 217 patients (26.3%) in the balanced crystalloids group experienced 30-day in-hospital morality, compared with 255 patients (31.2%) in the saline group (adjusted odds ratio, 0.74; 95% confidence interval, 0.59 - 0.93; P = 0.01). Patients in the balanced group experienced a lower incidence of major adverse kidney events within 30 days (35.4% vs 40.1%; aOR 0.78; 95% CI 0.63 - 0.97) and a greater number of vasopressor-free days (20 +/- 12 vs 19 +/- 13; aOR 1.25; 95% CI 1.02 - 1.54) and renal replacement therapy-free days (20 +/- 12 vs 19 +/- 13; aOR 1.35 [1.08 - 1.69]), compared to the saline group. CONCLUSIONS Among patients with sepsis in a large randomized trial, use of balanced crystalloids was associated with a lower 30-day in-hospital mortality compared to use of saline. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT02444988.
Effect of an early resuscitation protocol on in-hospital mortality among adults with sepsis and hypotension: a randomized clinical trial
Importance: The effect of an early resuscitation protocol on sepsis outcomes in developing countries remains unknown. Objective: To determine whether an early resuscitation protocol with administration of intravenous fluids, vasopressors, and blood transfusion decreases mortality among Zambian adults with sepsis and hypotension compared with usual care. Design, Setting, and Participants: Randomized clinical trial of 212 adults with sepsis (suspected infection plus ≥2 systemic inflammatory response syndrome criteria) and hypotension (systolic blood pressure ≤90 mm Hg or mean arterial pressure ≤65 mm Hg) presenting to the emergency department at a 1500-bed referral hospital in Zambia between October 22, 2012, and November 11, 2013. Data collection concluded December 9, 2013. Interventions: Patients were randomized 1:1 to either (1) an early resuscitation protocol for sepsis (n = 107) that included intravenous fluid bolus administration with monitoring of jugular venous pressure, respiratory rate, and arterial oxygen saturation and treatment with vasopressors targeting mean arterial pressure (≥65 mm Hg) and blood transfusion (for patients with a hemoglobin level <7 g/dL) or (2) usual care (n = 105) in which treating clinicians determined hemodynamic management. Main Outcomes and Measures: The primary outcome was in-hospital mortality and the secondary outcomes included the volume of intravenous fluid received and receipt of vasopressors. Results: Among 212 patients randomized to receive either the sepsis protocol or usual care, 3 were ineligible and the remaining 209 completed the study and were included in the analysis (mean [SD] age, 36.7 [12.4] years; 117 men [56.0%]; 187 [89.5%] positive for the human immunodeficiency virus). The primary outcome of in-hospital mortality occurred in 51 of 106 patients (48.1%) in the sepsis protocol group compared with 34 of 103 patients (33.0%) in the usual care group (between-group difference, 15.1% [95% CI, 2.0%-28.3%]; relative risk, 1.46 [95% CI, 1.04-2.05]; P = .03). In the 6 hours after presentation to the emergency department, patients in the sepsis protocol group received a median of 3.5 L (interquartile range, 2.7-4.0 L) of intravenous fluid compared with 2.0 L (interquartile range, 1.0-2.5 L) in the usual care group (mean difference, 1.2 L [95% CI, 1.0-1.5 L]; P < .001). Fifteen patients (14.2%) in the sepsis protocol group and 2 patients (1.9%) in the usual care group received vasopressors (between-group difference, 12.3% [95% CI, 5.1%-19.4%]; P < .001). Conclusions and Relevance: Among adults with sepsis and hypotension, most of whom were positive for HIV, in a resource-limited setting, a protocol for early resuscitation with administration of intravenous fluids and vasopressors increased in-hospital mortality compared with usual care. Further studies are needed to understand the effects of administration of intravenous fluid boluses and vasopressors in patients with sepsis across different low- and middle-income clinical settings and patient populations. Trial Registration: clinicaltrials.gov Identifier: NCT01663701.
Recombinant activated factor VII safety in trauma patients: results from the CONTROL trial
The Journal of Trauma. 2011;71((1):):12-9.
BACKGROUND Safety data on recombinant activated factor VII (rFVIIa, NovoSeven; Novo Nordisk A/S, BagsvÃ¦rd, Denmark) in actively hemorrhaging trauma patients are limited. We present detailed safety data from a large multicenter, randomized, placebo-controlled phase III study (the CONTROL trial). METHODS Data from 560 patients were analyzed. Subjects were monitored for adverse events (AEs) after rFVIIa or placebo administration. Incidences, timing, and presence of risk factors were reported by site investigators, supported by external study monitors and overseen by an independent Data Monitoring Committee. RESULTS There were no differences in overall mortality, organ system failure, or AEs, serious AEs, or medical events of special interest. Arterial and venous thromboembolic (TE) events and their risk factors were similar in both groups. The greatest risk factor for TE events was a chest injury requiring mechanical ventilation >3 days (86%). There were four site investigator-reported myocardial infarctions in the rFVIIa group of which only one met diagnostic criteria preestablished by the Data Monitoring Committee. There were no reported myocardial infarctions in the placebo group. Troponins were increased in 30% of all patients. The rate of acute respiratory distress syndrome was lower in the rFVIIa (3.0%) than in the placebo (7.2%) group (p = 0.022). CONCLUSIONS This represents the largest placebo-controlled dataset of rFVIIa use in trauma patients to date. In this prospective study of critically bleeding trauma patients, rFVIIa use was associated with an imbalance of investigator-reported Acute myocardial infarction/non-ST segment elevation myocardial infarction (AMI/NSTEMI), but was not associated with an increased risk for other AEs, including TE complications.
Results of the CONTROL trial: efficacy and safety of recombinant activated Factor VII in the management of refractory traumatic hemorrhage
The Journal of Trauma. 2010;69((3):):489-500.
BACKGROUND Traumatic coagulopathy contributes to early death by exsanguination and late death in multiple organ failure. Recombinant Factor VIIa (rFVIIa, NovoSeven) is a procoagulant that might limit bleeding and improve trauma outcomes. METHODS We performed a phase 3 randomized clinical trial evaluating efficacy and safety of rFVIIa as an adjunct to direct hemostasis in major trauma. We studied 573 patients (481 blunt and 92 penetrating) who bled 4 to 8 red blood cell (RBC) units within 12 hours of injury and were still bleeding despite strict damage control resuscitation and operative management. Patients were assigned to rFVIIa (200 μg/kg initially; 100 μg/kg at 1 hour and 3 hours) or placebo. Intensive care unit management was standardized using evidence-based trauma bundleswith formal oversight of compliance. Primary outcome was 30-day mortality. Predefined secondary outcomes included blood products used. Safety was assessed through 90 days. Study powering was based on prior randomized controlled trials and large trauma center databases. RESULTS Enrollment was terminated at 573 of 1502 planned patients because of unexpected low mortality prompted by futility analysis (10. 8% vs. 27. 5% planned/predicted) and difficulties consenting and enrolling sicker patients. Mortality was 11. 0% (rFVIIa) versus 10. 7% (placebo) (p = 0. 93, blunt) and 18. 2% (rFVIIa) versus 13. 2% (placebo) (p = 0. 40, penetrating). Blunt trauma rFVIIa patients received (mean +/- SD) 7. 8 +/- 10. 6 RBC units and 19. 0 +/- 27. 1 total allogeneic units through 48 hours, and placebo patients received 9. 1 +/- 11. 3 RBC units (p = 0. 04) and 23. 5 +/- 28. 0 total allogeneic units (p = 0. 04). Thrombotic adverse events were similar across study cohorts. CONCLUSIONS rFVIIa reduced blood product use but did not affect mortality compared with placebo. Modern evidence-based trauma lowers mortality, paradoxically making outcomes studies increasingly difficult.
Efficacy and safety of recombinant activated factor vii in the management of hemorrhagic shock due to trauma
ISTH Congress. 2009;: Abstract No. OC-TH-069.
A randomized, controlled trial of furosemide with or without albumin in hypoproteinemic patients with acute lung injury
Critical Care Medicine. 2005;33((8):):1681-7.
OBJECTIVE Hypoproteinemia is a common condition in critically ill patients, associated with the development of acute lung injury and acute respiratory distress syndrome and subsequent worse clinical outcomes. Albumin with furosemide benefits lung physiology in hypoproteinemic patients with acute lung injury/acute respiratory distress syndrome, but the independent pharmacologic effects of these drugs are unknown. DESIGN Randomized, double-blinded, placebo-controlled multicentered trial. SETTING Eleven medical, surgical, and trauma intensive care units including 190 beds within two university hospital systems. PATIENTS Forty mechanically ventilated patients with acute lung injury/acute respiratory distress syndrome, whose serum total protein concentrations were <6. 0 g/dL were included. Patients were excluded for hemodynamic instability or significant renal or hepatic failure. INTERVENTIONS Subjects were equally randomly allocated to receive furosemide with albumin or furosemide with placebo for 72 hrs, titrated to fluid loss and normalization of serum total protein concentration. MEASUREMENTS AND MAIN RESULTS The primary outcome was change in oxygenation from baseline to day 1, with secondary physiologic and clinical outcomes. There were no differences in baseline characteristics of the subjects in relation to group assignment. Albumin-treated patients had greater increases in oxygenation (mean change in Pao2/Fio2: +43 vs. -24 mm Hg at 24 hrs and +49 vs. -13 mm Hg at day 3), serum total protein (1. 5 vs. 0. 5 g/dL at day 3), and net fluid loss (-5480 vs. -1490 mL at day 3) throughout the study period (all p < . 05). Fluid bolus administration to control patients reduced net negative fluid balance; control patients more frequently developed hypotension and had fewer shock-free days, which translated to differences in organ failure at study end. CONCLUSIONS The addition of albumin to furosemide therapy in hypoproteinemic patients with acute lung injury/acute respiratory distress syndrome significantly improves oxygenation, with greater net negative fluid balance and better maintenance of hemodynamic stability. Additional randomized clinical trials are necessary to examine mechanisms and determine the effect on important clinical outcomes, such as the duration of mechanical ventilation.
The effect of drotrecogin alfa (activated) on long-term survival after severe sepsis
Critical Care Medicine. 2004;32((11):):2199-206.
Objective: To determine long-term survival for subjects with severe sepsis enrolled in the previous multiple-center trial (PROWESS) of drotrecogin alfa (activated) (DrotAA) vs. placebo. Design: Retrospective, cross-sectional, blinded follow-up of subjects enrolled in a previous randomized, controlled trial. Setting: One hundred sixty-four tertiary care institutions in 11 countries. Participants: The 1,690 subjects with severe sepsis enrolled and treated with study drug in PROWESS, of whom 1,220 were alive at 28 days (the end of the original PROWESS follow-up). Interventions: DrotAA (n = 850), 24 mug/kg/hr for 96 hrs, or placebo (n = 840). Measurements and Main Results: Long-term survival data were collected. We had follow-up information on 100% of subjects at 28 days, 98% at hospital discharge, 94% at 3 months, and 93% at 1 yr. The longest follow-up was 3. 6 yrs. Hospital survival was higher with DrotAA vs. placebo (70. 3% vs. 65. 1%, p =. 03). There was no statistically significant difference in duration of survival time or in landmark survival rates in subjects who received DrotAA compared with those who received placebo (median duration of survival = 1113 days vs. 846 days for DrotAA vs. placebo, p =. 10; landmark survival rates for DrotAA vs. placebo, 66. 1% vs. 62. 4% at 3 months [p =. 11], 62. 2% vs. 60. 3% at 6 months [p =. 44], 58. 9% vs. 57. 2% at 1 yr [p =. 49], and 52. 6% vs. 49. 3% at 21/2 yrs [p =. 21]). There was a significant interaction (p =. 0008) between treatment assignment and baseline Acute Physiology and Chronic Health Evaluation (APACHE) II scores, suggesting qualitative differences in treatment effect with severity of illness. Subjects with APACHE II >=25 had better survival time with DrotAA (median duration of survival: 450 vs. 71 days, p =. 0005). Survival rates were also higher at landmark time points (DrotAA vs. placebo, 58. 9% vs. 48. 4% at 3 months [p =. 003], 55. 2% vs. 45. 3% at 6 months [p =. 005], 52. 1% vs. 41. 3% at 1 yr [p =. 002], and 45. 6% vs. 33. 8% at 21/2 yrs [p =. 001]). In the APACHE II <25 group there was no significant difference in survival time or survival rates at landmark time points except at 1 yr (DrotAA vs. placebo, 65. 5% vs. 72. 0% at 1 yr, p =. 04). Conclusions: The acute survival benefit observed in subjects with severe sepsis who received DrotAA persists to hospital discharge. The survival benefit loses statistical significance thereafter. Post hoc analysis suggests the effect of DrotAA varies by APACHE II score with improved long-term survival in subjects with APACHE II scores >=25 but no benefit in those with lower scores. Copyright © 2011 Elsevier B. V. , Amsterdam. All Rights Reserved.
Albumin influences total plasma antioxidant capacity favorably in patients with acute lung injury
Critical Care Medicine. 2004;32((3):):755-9.
OBJECTIVE To ascertain the influence of albumin on antioxidant status in patients with acute lung injury. DESIGN Prospective, randomized, placebo-controlled study. SETTING Intensive care units, teaching hospitals. PATIENTS Twenty patients meeting the American European Consensus criteria for acute lung injury. INTERVENTIONS Ten patients received albumin (25 g of a 25% solution every 8 hrs for a total of nine doses) and ten received placebo (normal saline administered in identical fashion and volume). All received supportive therapy appropriate for patients with acute lung injury. Plasma samples were obtained sequentially from all patients before, 30 mins after, and 4 hrs after albumin/placebo administration. MEASUREMENTS AND MAIN RESULTS Serum albumin and total protein, total antioxidant status, iron-binding antioxidant protection, iron-oxidizing antioxidant protection, lipid hydroperoxides, protein carbonyls, and plasma thiols were measured. Albumin administration increased plasma albumin concentrations (p <. 05 compared with placebo) and decreased concentrations of protein carbonyls (p <. 05 compared with placebo). By contrast, plasma lipid hydroperoxide concentrations were similar in both groups, both in absolute terms and relative to albumin content. For all other variables, no significant differences were apparent. For all patients, there was a positive correlation between albumin and plasma thiol concentrations (r =. 983, p <. 01) and albumin and antioxidant capacity (r =. 885, p =. 01). In the albumin treatment group, there was a strong correlation between thiols and antioxidant capacity (r =. 876, p =. 01). No such correlation was apparent in the placebo group. Plasma iron-binding antioxidant protection was negatively correlated (r = -. 741, p <. 05) with albumin content in the treatment group but not the placebo group. CONCLUSIONS In patients with acute lung injury, albumin administration favorably influences plasma thiol-dependent antioxidant status as well as levels of protein oxidative damage.
Systemic host responses in severe sepsis analyzed by causative microorganism and treatment effects of drotrecogin alfa (activated)
Clinical Infectious Diseases. 2003;37((1):):50-8.
Clinical trials with novel therapeutic agents for severe sepsis have suggested that patients might respond differently depending on causative microorganism. Data from a large, placebo-controlled trial of recombinant human drotrecogin alfa (activated) (DrotAA) were analyzed by type of causative microorganism for treatment-associated differences in mortality, coagulopathy, and inflammatory response. Compared with placebo, mortality rates associated with DrotAA were consistently reduced for each microorganism group (gram-positive bacteria, gram-negative bacteria, mixed bacteria, fungi, other, and unknown microbial etiology), with a stratified relative risk (RR) of 0. 80 (95% confidence interval [CI], 0. 69-0. 94). The greatest reduction in the mortality rate was for Streptococcus pneumoniae infection (RR, 0. 56; 95% CI, 0. 35-0. 88). Levels of coagulation and inflammation biomarkers varied with different pathogens at study entry. Results demonstrate that DrotAA, administered as an adjunct to standard anti-infective therapy, can improve the rate of survival for patients who develop severe sepsis regardless of causative microorganism.