Influence of enrollment sequence effect on observed outcomes in the ADDRESS and PROWESS studies of drotrecogin alfa (activated) in patients with severe sepsis

INTRODUCTION: We performed a study to determine whether an enrollment sequence effect noted in the PROWESS (recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis) trial exists in the ADDRESS (Administration of Drotrecogin Alfa [Activated] [DrotAA] in Early Stage Severe Sepsis) trial. METHODS: We evaluated prospectively defined subgroups from two large phase 3 clinical trials: ADDRESS, which included 516 sites in 34 countries, and PROWESS, which included 164 sites in 11 countries. ADDRESS consisted of patients with severe sepsis at low risk of death not indicated for treatment with DrotAA. PROWESS consisted of patients with severe sepsis with one or more organ dysfunctions. DrotAA (24 microg/kg per hour) or placebo was infused for 96 hours. RESULTS: In ADDRESS and PROWESS, there was a statistically significant interaction between the DrotAA treatment effect and the sequence in which patients were enrolled. In both trials, higher mortality was associated with DrotAA use in the subgroup of patients enrolled first at study sites. Compared with placebo, PROWESS mortality was lower with DrotAA treatment for the second and subsequent patients enrolled, whereas in ADDRESS, mortality remained higher for the second patient enrolled but thereafter was lower for DrotAA-treated patients. Comparison of patients enrolled first with subsequent patients enrolled indicated that the characteristics of patients changed. Subsequently enrolled patients were treated earlier, were less likely to suffer nonserious bleeds (ADDRESS), and experienced fewer protocol violations (PROWESS). CONCLUSIONS: Analyses suggest that an enrollment sequence effect was present in the ADDRESS and PROWESS trials. Analysis of this effect on outcomes suggests that it is most apparent in patients at lower risk of death. In PROWESS, this effect appeared to be associated with a reduction of the DrotAA treatment effect for the first patients enrolled at each site. In ADDRESS, this effect may have contributed to early termination of the study. The finding of an enrollment sequence effect in two separate trials suggests that trial designs, site selection and training, data collection and monitoring, and statistical analysis plans may need to be adjusted for these potentially confounding events. TRIAL REGISTRATION: ADDRESS trial registration number: NCT00568737. PROWESS was completed before trial registration was required

Association of interleukin 7 immunotherapy with lymphocyte counts among patients with severe coronavirus disease 2019 (COVID-19)

This case series examines whether interleukin 7 (IL-7) is associated with restored host protective immunity in patients with severe coronavirus disease 2019 (COVID-19) and immunosuppression

A phase II study of human allogeneic liver-derived progenitor cell therapy for acute-on-chronic liver failure and acute decompensation

Malaltia hepàtica alcohòlica; Cèl·lules mare; Medicina regenerativa del fetgeEnfermedad hepática alcohólica; Células madre; Medicina regenerativa del higadoAlcoholic liver disease; Stem cell; Liver regenerative medicineBackground & Aims Human allogeneic liver-derived progenitor cells (HALPC, HepaStem®; Promethera Biosciences, Mont-Saint-Guibert, Belgium) are an advanced therapy medicinal product that could potentially alleviate systemic inflammation and ameliorate liver function in patients with acute-on-chronic liver failure (ACLF) or acute decompensation of cirrhosis (AD). Methods This open-label phase II study was conducted in 9 centres in Belgium, Spain, and Bulgaria between 2016 and 2019. The primary objective was to assess the safety of HALPC therapy up to Day 28 and the secondary objectives were to assess its safety and preliminary efficacy up to Month 3. Results The 24 treated patients (mean age: 51 years) were mostly male with an alcoholic cirrhosis. On pre-infusion Day 1, 15 patients had ACLF and 9 patients had AD. Two of the 3 initial patients treated with high HALPC doses (∼5×106 cells/kg body weight [BW]) had severe adverse bleeding events attributed to treatment. In 21 patients subsequently treated with lower HALPC doses (0.6 or 1.2×106 cells/kg BW, 1 or 2 times 7 days apart), no serious adverse events were related to treatment, and the other adverse events were in line with those expected in patients with ACLF and AD. Overall, markers of systemic inflammation and altered liver function decreased gradually for the surviving patients. The Day-28 and Month-3 survival rates were 83% (20/24) and 71% (17/24), and at Month 3, no patient had ACLF. Conclusions The treatment of patients with ACLF or AD with up to 2 doses of 1.2×106 HALPC/kg BW appeared safe. The results of this study support the initiation of a proof-of-concept study in a larger cohort of patients with ACLF to further confirm the safety and evaluate the efficacy of HALPC therapy

Proenkephalin A 119-159 (Penkid) Is an Early Biomarker of Septic Acute Kidney Injury: The Kidney in Sepsis and Septic Shock (Kid-SSS) Study

Introduction: Sepsis is the leading cause of acute kidney injury (AKI) in critically ill patients. The Kidney in Sepsis and Septic Shock (Kid-SSS) study evaluated the value of proenkephalin A 119-159 (penkid)—a sensitive biomarker of glomerular function, drawn within 24 hours upon intensive care unit (ICU) admission and analyzed using a chemiluminescence immunoassay—for kidney events in sepsis and septic shock. Methods: The Kid-SSS study was a substudy of Adrenomedullin and Outcome in Severe Sepsis and Septic Shock (AdrenOSS) (NCT02393781), a prospective, observational, multinational study including 583 patients admitted to the intensive care unit with sepsis or septic shock and a validation cohort of 525 patients from the French and euRopean Outcome reGistry in Intensive Care Units (FROG-ICU) study. The primary endpoint was major adverse kidney events (MAKEs) at day 7, composite of death, renal replacement therapy, and persistent renal dysfunction. The secondary endpoints included AKI, transient AKI, worsening renal function (WRF), and 28-day mortality. Results: Median age was 66 years (interquartile range 55–75), and 28-day mortality was 22% (95% confidence interval [CI] 19%−25%). Of the patients, 293 (50.3%) were in shock upon ICU admission. Penkid was significantly elevated in patients with MAKEs, persistent AKI, and WRF (median = 65 [IQR = 45–106] vs. 179 [114–242]; 53 [39–70] vs. 133 [79–196] pmol/l; and 70 [47–121] vs. 174 [93–242] pmol/l, all P < 0.0001), also after adjustment for confounding factors (adjusted odds ratio = 3.3 [95% CI = 1.8–6.0], 3.9 [95% CI = 2.1–7.2], and 3.4 [95% CI = 1.9–6.2], all P < 0.0001). Penkid increase preceded elevation of serum creatinine with WRF and was low in renal recovery. Conclusion: Admission penkid concentration was associated with MAKEs, AKI, and WRF in a timely manner in septic patients

Assessment of panobacumab as adjunctive immunotherapy for the treatment of nosocomial Pseudomonas aeruginosa pneumonia.

The fully human anti-lipopolysaccharide (LPS) immunoglobulin M (IgM) monoclonal antibody panobacumab was developed as an adjunctive immunotherapy for the treatment of O11 serotype Pseudomonas aeruginosa infections. We evaluated the potential clinical efficacy of panobacumab in the treatment of nosocomial pneumonia. We performed a post-hoc analysis of a multicenter phase IIa trial (NCT00851435) designed to prospectively evaluate the safety and pharmacokinetics of panobacumab. Patients treated with panobacumab (n = 17), including 13 patients receiving the full treatment (three doses of 1.2 mg/kg), were compared to 14 patients who did not receive the antibody. Overall, the 17 patients receiving panobacumab were more ill. They were an average of 72 years old [interquartile range (IQR): 64-79] versus an average of 50 years old (IQR: 30-73) (p = 0.024) and had Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of 17 (IQR: 16-22) versus 15 (IQR: 10-19) (p = 0.043). Adjunctive immunotherapy resulted in an improved clinical outcome in the group receiving the full three-course panobacumab treatment, with a resolution rate of 85 % (11/13) versus 64 % (9/14) (p = 0.048). The Kaplan-Meier survival curve showed a statistically significantly shorter time to clinical resolution in this group of patients (8.0 [IQR: 7.0-11.5] versus 18.5 [IQR: 8-30] days in those who did not receive the antibody; p = 0.004). Panobacumab adjunctive immunotherapy may improve clinical outcome in a shorter time if patients receive the full treatment (three doses). These preliminary results suggest that passive immunotherapy targeting LPS may be a complementary strategy for the treatment of nosocomial O11 P. aeruginosa pneumonia

Randomized trial evaluating serial protein C levels in severe sepsis patients treated with variable doses of drotrecogin alfa (activated)

Serial alterations in protein C levels appear to correlate with disease severity in patients with severe sepsis, and it may be possible to tailor severe sepsis therapy with the use of this biomarker. The purpose of this study was to evaluate the dose and duration of drotrecogin alfa (activated) treatment using serial measurements of protein C compared to standard therapy in patients with severe sepsis.Clinical Trial, Phase IIComparative StudyJournal ArticleMulticenter StudyRandomized Controlled TrialResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study

Background: Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. Methods: AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. Results: Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8). Conclusions: AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. Trial registration: ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015

Wartenberg’s migrant sensory neuritis: a prospective follow-up study

Migrant sensory neuropathy (Wartenberg’s migrant sensory neuritis) is characterized by sudden numbness in the distribution of one or multiple cutaneous nerves. To study disease course and outcome, we prospectively followed 12 patients who presented to our tertiary referral neuromuscular outpatient clinic between January 2003 and January 2004. Medical history, neurological, laboratory and electrophysiological examinations were obtained from all patients. All patients were reviewed a second time in 2007, and five had a follow-up electrophysiological examination. At the first visit, 50% described an episode of stretching preceding the sensory complaints. All but three described pain in the affected area before or concomitant with sensory loss. At clinical examination a median of six skin areas were affected, and in 75% this could be confirmed by nerve conduction studies in at least one nerve. Forty-two percent had involvement of the trigeminal nerve. After a mean disease duration of 7.5 years, three patients reported a complete disappearance of sensory complaints and five that the pain had disappeared, but numbness remained. Three patients still had both painful and numb sensory deficits. One patient developed a distal symmetric sensory polyneuropathy. In conclusion, Wartenberg’s sensory neuritis is a distinct, exclusively sensory, neuropathy, marked by pain preceding numbness in affected nerves. An episode of stretching preceding pain is not necessary for the diagnosis. Wartenberg’s sensory neuritis often retains its spotty, exclusively sensory characteristics after long term follow-up

Health services changes: is a run-in period necessary before evaluation in randomised clinical trials?

Background Most randomised clinical trials (RCTs) testing a new health service do not allow a run-in period of consolidation before evaluating the new approach. Consequently, health professionals involved may feel insufficiently familiar or confident, or that new processes or systems that are integral to the service are insufficiently embedded in routine care prior to definitive evaluation in a RCT. This study aimed to determine the optimal run-in period for a new physiotherapy-led telephone assessment and treatment service known as PhysioDirect and whether a run-in was needed prior to evaluating outcomes in an RCT. Methods The PhysioDirect trial assessed whether PhysioDirect was as effective as usual care. Prior to the main trial, a run-in of up to 12 weeks was permitted to facilitate physiotherapists to become confident in delivering the new service. Outcomes collected from the run-in and main trial were length of telephone calls within the PhysioDirect service and patients’ physical function (SF-36v2 questionnaire) and Measure Yourself Medical Outcome Profile v2 collected at baseline and six months. Joinpoint regression determined how long it had taken call times to stabilise. Analysis of covariance determined whether patients’ physical function at six months changed from the run-in to the main trial. Results Mean PhysioDirect call times (minutes) were higher in the run-in (31 (SD: 12.6)) than in the main trial (25 (SD: 11.6)). Each physiotherapist needed to answer 42 (95% CI: 20,56) calls for their mean call time to stabilise at 25 minutes per call; this took a minimum of seven weeks. For patients’ physical function, PhysioDirect was equally clinically effective as usual care during both the run-in (0.17 (95% CI: -0.91,1.24)) and main trial (-0.01 (95% CI: -0.80,0.79)). Conclusions A run-in was not needed in a large trial testing PhysioDirect services in terms of patient outcomes. A learning curve was evident in the process measure of telephone call length. This decreased during the run-in and stabilised prior to commencement of the main trial. Future trials should build in a run-in if it is anticipated that learning would have an effect on patient outcome