Three-Day Icatibant on Top of Standard Care in Patients With Coronavirus Disease 2019 Pneumonia: A Randomized, Open-Label, Phase 2, Proof-of-Concept Trial

Malchair, Pierre; Giol, Jordi; Garcia, Vanesa Garcia; Rodríguez, Orlando; Ruibal, José Carlos; Zarauza, Alvaro; Llopis, Ferrán; Matellán, Leire; Bernal, Tania; Solís, Beatriz; Otero, Aurema; Carnaval, Thiago; Jofre, Héctor Ignacio; Jacob, Javier; Solanich, Xavier; Antolí, Arnau; Rocamora, G.; Videla, Sebastián

doi:10.1093/cid/ciac984

Cited by 9 publications

(8 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, only retrospective data from patients requiring continuous positive airway pressure support ( 41 ) and a single phase 3 trial reported a survival benefit when administering an anti-C5a antibody, albeit in mechanically ventilated COVID-19 patients for the latter ( 42 ), whereas another large phase 3 trial in the same population using a C5 inhibitor was futile ( 43 ). Clinical trials targeting the CAS and KKS are scarce, and consist of small sample sizes ( 44 , 45 ). In the only published randomized controlled trial of C1INH in COVID-19, C1INH did not influence clinical improvement and length of stay compared to the SOC arm, in line with our study results ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

Recombinant C1 inhibitor in the prevention of severe COVID-19: a randomized, open-label, multi-center phase IIa trial

Urwyler,

Leimbacher,

Charitos

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

BackgroundConestat alfa (ConA), a recombinant human C1 inhibitor, may prevent thromboinflammation.MethodsWe conducted a randomized, open-label, multi-national clinical trial in which hospitalized adults at risk for progression to severe COVID-19 were assigned in a 2:1 ratio to receive either 3 days of ConA plus standard of care (SOC) or SOC alone. Primary and secondary endpoints were day 7 disease severity on the WHO Ordinal Scale, time to clinical improvement within 14 days, and safety, respectively.ResultsThe trial was prematurely terminated because of futility after randomization of 84 patients, 56 in the ConA and 28 in the control arm. At baseline, higher WHO Ordinal Scale scores were more frequently observed in the ConA than in the control arm. On day 7, no relevant differences in the primary outcome were noted between the two arms (p = 0.11). The median time to defervescence was 3 days, and the median time to clinical improvement was 7 days in both arms (p = 0.22 and 0.56, respectively). Activation of plasma cascades and endothelial cells over time was similar in both groups. The incidence of adverse events (AEs) was higher in the intervention arm (any AE, 30% with ConA vs. 19% with SOC alone; serious AE, 27% vs. 15%; death, 11% vs. 0%). None of these were judged as being related to the study drug.ConclusionThe study results do not support the use of ConA to prevent COVID-19 progression.Clinical trial registrationhttps://clinicaltrials.gov, identifier NCT04414631.

show abstract

Section: Discussionmentioning

confidence: 99%

Recombinant C1 inhibitor in the prevention of severe COVID-19: a randomized, open-label, multi-center phase IIa trial

Urwyler,

Leimbacher,

Charitos

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…Interestingly, increased vascular permeability during experimental hantavirus infection can be prevented with drugs that block BK binding [ 78 ]. Icantibant, in fact, may be a useful therapy in various infections since adding it to standard care improved both COVID-19 pneumonia and mortality in a very recent proof-of-concept study [ 79 ].…”

Section: Role Of Different Factors In the Variationmentioning

confidence: 99%

Puumala Hantavirus Infections Show Extensive Variation in Clinical Outcome

Vaheri

Smura

Vauhkonen

et al. 2023

Viruses

View full text Add to dashboard Cite

The clinical outcome of Puumala hantavirus (PUUV) infection shows extensive variation, ranging from inapparent subclinical infection (70–80%) to severe hemorrhagic fever with renal syndrome (HFRS), with about 0.1% of cases being fatal. Most hospitalized patients experience acute kidney injury (AKI), histologically known as acute hemorrhagic tubulointerstitial nephritis. Why this variation? There is no evidence that there would be more virulent and less virulent variants infecting humans, although this has not been extensively studied. Individuals with the human leukocyte antigen (HLA) alleles B*08 and DRB1*0301 are likely to have a severe form of the PUUV infection, and those with B*27 are likely to have a benign clinical course. Other genetic factors, related to the tumor necrosis factor (TNF) gene and the C4A component of the complement system, may be involved. Various autoimmune phenomena and Epstein-Barr virus infection are associated with PUUV infection, but hantavirus-neutralizing antibodies are not associated with lower disease severity in PUUV HFRS. Wide individual differences occur in ocular and central nervous system (CNS) manifestations and in the long-term consequences of nephropathia epidemica (NE). Numerous biomarkers have been detected, and some are clinically used to assess and predict the severity of PUUV infection. A new addition is the plasma glucose concentration associated with the severity of both capillary leakage, thrombocytopenia, inflammation, and AKI in PUUV infection. Our question, “Why this variation?” remains largely unanswered.

show abstract

“…Of interest, many recent clinical trials are assessing the use of Icatibant in treating other diseases. In a phase 2 clinical trial conducted in Barcelona by Malchair et al, they found that Icatibant improved mortality and pneumonia in patients with COVID-19 when a three-day Icatibant was added to the standard care of COVID-19 [ 51 ]. In another RCT by Gamboa et al, they found that continuous infusion of icatibant during hemodialysis prevented blood pressure decrease in patients complaining of intradialytic hypotension compared to placebo.…”

Section: Reviewmentioning

confidence: 99%

Pseudo-Allergies in the Emergency Department: A Common Misdiagnosis of Hypersensitivity Type 1 Allergic Reaction

Eraky,

Wright,

McDonald

2023

Cureus

View full text Add to dashboard Cite

Type-1 hypersensitivity reaction represents an acute IgE-mediated reaction that can cause life-threatening conditions, such as anaphylactic shock, angioedema, and airway obstruction. Other reactions that can mimic type-1 hypersensitivity reactions include IgE-independent mast cell degranulation, bradykinin-mediated reactions, leukotrienes-mediated reactions, and pseudo-allergies. We use the term pseudo-allergy in this article for histamine-mediated reactions that are mast cell-independent. We did not discuss pseudo-allergic reactions that are not acute or life-threatening, such as celiac disease, Heiner’s syndrome, eosinophilic esophagitis, and food protein-induced enterocolitis in our article because the emergency department is not the primary location to diagnose or treat these reactions. Herein, we present some allergic-like reactions that can be life-threatening, such as scombroid food poisoning (SFP), bradykinin-induced angioedema, IgE-independent angioedema, opioid-induced angioedema, and non-steroidal anti-inflammatory drug (NSAID)-induced hypersensitivity and angioedema. These reactions may have different treatments based on their mechanism of reaction. Histamine-mediated reactions, such as SFP, histamine-mediated angioedema, and mast cell degranulation induced by NSAIDs, and opioids can be treated with antihistamines, epinephrine, and corticosteroids. Bradykinin-induced angioedema, including hereditary angioedema and acquired angioedema, can be treated with fresh frozen plasma. Hereditary angioedema can be treated with many FDA-approved targeted medications, such as plasma-derived C1-INH, plasma kallikrein inhibitor (Ecallantide), and selective bradykinin-2 receptor antagonist (Icatibant). However, these targeted agents are not well-studied enough to be used for acquired angioedema. It is crucial for emergency medicine physicians to be familiar with and predict these reactions to prevent misdiagnosis, be prepared to treat these life-threatening conditions appropriately without delay and eliminate patients’ exposure to any unnecessary investigations or treatments.

show abstract

Three-Day Icatibant on Top of Standard Care in Patients With Coronavirus Disease 2019 Pneumonia: A Randomized, Open-Label, Phase 2, Proof-of-Concept Trial

Cited by 9 publications

References 26 publications

Recombinant C1 inhibitor in the prevention of severe COVID-19: a randomized, open-label, multi-center phase IIa trial

Recombinant C1 inhibitor in the prevention of severe COVID-19: a randomized, open-label, multi-center phase IIa trial

Puumala Hantavirus Infections Show Extensive Variation in Clinical Outcome

Pseudo-Allergies in the Emergency Department: A Common Misdiagnosis of Hypersensitivity Type 1 Allergic Reaction

Contact Info

Product

Resources

About