Intravenous immunoglobulins in patients with COVID-19-associated moderate-to-severe acute respiratory distress syndrome (ICAR): multicentre, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a major complication of COVID-19 and is associated with high mortality and morbidity. We aimed to assess whether intravenous immunoglobulins (IVIG) could improve outcomes by reducing inflammation-mediated lung injury. METHODS: In this multicentre, double-blind, placebo-controlled trial, done at 43 centres in France, we randomly assigned patients (1:1) receiving invasive mechanical ventilation for up to 72 h with PCR confirmed COVID-19 and associated moderate-to-severe ARDS to receive either IVIG (2 g/kg over 4 days) or placebo. Random assignment was done with a web-based system and was stratified according to the participating centre and the duration of invasive mechanical ventilation before inclusion in the trial (<12 h, 12-24 h, and >24-72 h), and treatment was administered within the first 96 h of invasive mechanical ventilation. To minimise the risk of adverse events, the IVIG administration was divided into four perfusions of 0·5 g/kg each administered over at least 8 hours. Patients in the placebo group received an equivalent volume of sodium chloride 0·9% (10 mL/kg) over the same period. The primary outcome was the number of ventilation-free days by day 28, assessed according to the intention-to-treat principle. This trial was registered on ClinicalTrials.gov, NCT04350580. FINDINGS: Between April 3, and October 20, 2020, 146 patients (43 [29%] women) were eligible for inclusion and randomly assigned: 69 (47%) patients to the IVIG group and 77 (53%) to the placebo group. The intention-to-treat analysis showed no statistical difference in the median number of ventilation-free days at day 28 between the IVIG group (0·0 [IQR 0·0-8·0]) and the placebo group (0·0 [0·0-6·0]; difference estimate 0·0 [0·0-0·0]; p=0·21). Serious adverse events were more frequent in the IVIG group (78 events in 22 [32%] patients) than in the placebo group (47 events in 15 [20%] patients; p=0·089). INTERPRETATION: In patients with COVID-19 who received invasive mechanical ventilation for moderate-to-severe ARDS, IVIG did not improve clinical outcomes at day 28 and tended to be associated with an increased frequency of serious adverse events, although not significant. The effect of IVIGs on earlier disease stages of COVID-19 should be assessed in future trials. FUNDING: Programme Hospitalier de Recherche Clinique.

Effect of early treatment with polyvalent immunoglobulin on acute respiratory distress syndrome associated with SARS-CoV-2 infections (ICAR trial): study protocol for a randomized controlled trial.

BACKGROUND: As of mid-June 2020, 7,500,000 people were infected with SARS-CoV-2 worldwide and 420,000 people died, mainly from coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome (ARDS). COVID-19-related ARDS is subject to a mortality rate of 50% and prolonged period of mechanical ventilation, with no specific pharmacological treatment currently available (Infection au nouveau Coronavirus (SARS-CoV-2), COVID-19, France et Monde. https://www.santepubliquefrance.fr/dossiers/coronavirus-covid-19 ). Because of its immunomodulatory action, we propose to evaluate the efficacy and safety of intravenous immunoglobulin (IVIG) administration in patients developing COVID-19-related ARDS. METHODS: The trial is a phase III double-blind, randomized, multicenter, parallel group, concurrent, controlled study in hospitalized participants with COVID-19 requiring mechanical ventilation using a sequential design. Participants in the treatment group will receive infusions of polyvalent immunoglobulin for 4 consecutive days, and the placebo group will receive an equivalent volume of sodium chloride 0.9% for the same duration. The primary outcome is the number of ventilator-free days up to the 28th day. Secondary objectives are to evaluate the effect of IVIG on (1) organ failure according to the Sequential Organ Failure Assessment (SOFA) score at 14 and 28 days, (2) lung injury score at 14 and 28 days, (3) the occurrence of grade 3 or 4 adverse events of IVIG, (4) length of intensive care unit (ICU) stay, (5) length of hospital stay, (6) functional outcomes at day 90 defined by the activities of daily living and instrumental activities of the daily living scales, and (7) 90-day survival. One hundred thirty-eight subjects will be randomized in a 1:1 ratio to IVIG or placebo groups (69 in each group), considering 90% power, alpha level 0.05 (two sides), and 0.67 effect size level. DISCUSSION: The ICAR trial investigates the effect of IVIG in COVID-19-related ARDS. We expect an increase in the survival rate and a reduction in the duration of mechanical ventilation, which is associated with significant morbidity. TRIAL REGISTRATION: EudraCT 2020-001570-30. ClinicalTrials.gov NCT04350580 . Registered on 17 April 2020.

One-year mirror-image study of the impact of olanzapine long-acting injection on healthcare resource utilization and costs in severe schizophrenia.

Olanzapine long-acting injections (OLAIs) are often prescribed to patients with severe schizophrenia who are typically excluded from randomized clinical trials. To date, no mirror-image study has examined the impact of OLAIs on healthcare resource utilizations in these patients. We conducted a retrospective, one-year mirror-image study of OLAIs on 40 patients with severe schizophrenic disorder. Illness severity was defined by failure to respond to two sequential antipsychotics. Outcomes included: (i) healthcare resource utilizations via hospitalization admissions, bed days, outpatient visits, and inpatient service costs computations (ii) clinical efficacy through changes in the Brief Psychiatric Rating Scale (BPRS) and in the Clinical Global Impression-Schizophrenia Scale (CGI-SCH), and (iii) adverse effects. After one year, OLAIs were associated with significant decreases of 65.7%, 86.2% and 86.2% in hospitalization admissions, bed days, and inpatient service costs respectively. A significant mean change of -0.47 and -0.63 was determined the BPRS and the CGI-SCH scores, respectively. There were no significant differences in the number of outpatient visits and adverse effects, except for post-injection sedation/delirium syndrome whose incidence was 0.30% per injection. This mirror-image study provides the first evidence that prescribing OLAIs reduces in a cost-effective manner average bed days and hospital admissions in patients with severe schizophrenia.

Clozapine and long-acting injectable antipsychotic combination: A retrospective one-year mirror-image study.

To evaluate efficacy and tolerability of the combination of clozapine with an antipsychotic long-acting injectable (LAI) in multi-episode patients with schizophrenia or schizoaffective disorder. Efficacy and tolerability were assessed in seventeen patients admitted to a hospital in Paris between January 2010 and June 2015, using a one-year mirror-image design. Number and length of hospitalizations significantly decreased after introducing the combination (2.1 vs 0.8, p=0.004 and 155.4days vs 26.6days, p<0.001 respectively). No major adverse events occurred in terms of increased weight, agranulocytosis, hyperglycemia and/or dyslipidemia. This combination can be beneficial and safe in multi-episode patients.