key: cord-0781524-giusf2rw
authors: King, Andrew; Vail, Andy; O'Leary, Claire; Hannan, Cathal; Brough, David; Patel, Hiren; Galea, James; Ogungbenro, Kayode; Wright, Megan; Pathmanaban, Omar; Hulme, Sharon; Allan, Stuart
title: Anakinra in COVID-19: important considerations for clinical trials
date: 2020-05-21
journal: Lancet Rheumatol
DOI: 10.1016/s2665-9913(20)30160-0
sha: 4218c8d3a97c7c88653a308a055eb89b7642eba6
doc_id: 781524
cord_uid: giusf2rw

nan

The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 320 000 deaths as of May 19, 2020. COVID-19 deaths are primarily caused by acute respiratory distress syndrome (ARDS) and by a cytokine storm syndrome-ie, a state of hyperinflammation leading to multiorgan failure. 1 A recent Lancet letter 2 suggested that screening patients with COVID-19 for hyperinflammation and treating them with immunosuppressive drugs could improve mortality. Cytokine storm complicating macrophage activation syndrome associated with rheumatic disease shares considerable biochemical overlap with the hyperinflammation observed in patients with COVID-19. 1, 3 At the time of writing, there are ten ongoing clinical trials in COVID-19 with the drug anakinra (table). Anakinra inhibits the proinflammatory cytokines interleukin (IL)-1α and IL-1β and has been used with some success to treat macrophage activation syndrome caused by various inflammatory conditions, 4, 5 and in several small studies in patients with COVID-19. 6, 7 Here we support the rationale for targeting hyperinflammation in COVID-19 with anakinra and comment on different aspects of its use, patient selection, dosing, and outcome measures.

Anakinra is an immunosuppressive drug that carries the theoretical risk of harm in the wrong patient group by potentially targeting beneficial inflammation; however, positive effects might also be missed if the correct patient group is not ascertained. It is important, therefore, to target treatment to individuals considered to have hyperinflammation. Diagnostic criteria in this patient group are poorly developed and there is no consensus, as seen from the inclusion criteria listed for the ongoing anakinra trials (table) . Although serum ferritin and IL-6 concentrations are highly specific to hyperinflammation and have been shown to be associated with a need for ventilation in patients with COVID-19, 8 they are not routinely measured in the clinical setting, a short coming that is highly relevant given the requirement to identify as many patients as possible that might benefit. We suggest a pragmatic approach to patient selection based on identifying patients with progressive disease and evidence of increasing inflammation. Therefore, we pro pose using worsening lymphopenia, a marker of disease progression and severity in COVID-19, and increas ing C-reactive protein as evidence of worsening inflammation. The dose and route of administration of anakinra is especially relevant given its short plasma half-life, with both intravenous and subcutaneous routes being considered. 6, 7 While a short half-life is beneficial in limiting the drug's duration of action in case of adverse events, it also leads to large peak-trough fluctuations with an intravenous formulation. Variation in dosing needs to be minimised to ensure constant and adequate bioavailability, and to avoid a detrimental rebound increase of inflammation. Pharmacokinetic studies in vari ous disease states have shown that subcutaneous anakinra might ensure adequate and consistent plasma concentrations, with bioavailability ranging from 80-95%. 9 to the development of peripheral oedema and poor skin perfusion. Repeated subcutaneous injections might also lead to patient discomfort. However, these downsides should be weighed against the considerable benefits of subcutaneous administration in the context of this pandemic, which include easy administration by any health-care professional, increased cost-effectiveness with no need for infusion pumps or equivalent, and reduced fluid load. Reduced fluid load is important as current guidelines for management of severe ARDS recommend a nega tive fluid balance of 0·5-1·0 L per day, 11 and the most commonly adopted mode of intravenous anakinra results in infusion of a minimum of 400 mL of fluid. Another important consideration is the choice of how to record the success (or otherwise) of the intervention. It is rare for single trials to provide definitive answers, so a core set of outcomes that are reported by all trials of a given intervention are important to allow systematic reviewers to combine results in similar patient populations. 12 Of the ten identified trials (table), six trials consider patients with a severe condition. These trials are dominated by the REMAP-CAP trial (NCT02735707), which has an open-ended recruitment and a target of 7100 patients. The other five trials have a total of fewer than 400 participants receiving anakinra, with no outcome common to all. Some trials focus on effectiveness (clinical) and others on efficacy (biomarker) endpoints. The other four trials include patients with less severe disease but who are hospitalised, with total recruitment around 250 participants. These trials have a similar mix of effectiveness and efficacy endpoints, with mortality being the most commonly reported outcome. Only five trials explicitly mention ferritin as an outcome, which is regarded as an important parameter for assessing hyperinflammation, and these trials will report data in different ways that will preclude pooling. Even without the clinical heterogeneity inherent in the range of eligibility criteria and dosing regimens under study (table), power for meaningful meta-analysis will be low.

Anakinra is a highly plausible drug candidate in COVID-19, but we encourage trialists to consider patient selection, dosing, and outcome measures, and, impor tantly, to ensure collection of core outcome measures for current and future trials.

The trinity of COVID-19: immunity, inflammation and intervention

COVID-19: consider cytokine storm syndromes and immunosuppression

The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease

Continuous intravenous anakinra infusion to calm the cytokine storm in macrophage activation syndrome

Anakinra treatment in macrophage activation syndrome: a single center experience and systemic review of literature

Targeting the inflammatory cascade with anakinra in moderate to severe COVID-19 pneumonia: case series

Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Pharmacokinetics of anakinra in subjects with different levels of renal function

Pharmacokinetics of anakinra in subjects of heavier vs. lighter body weights

Treatment for severe acute respiratory distress syndrome from COVID-19

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