ABSTRACT
Introduction: Severe COVID-19 pneumonia is characterised by respiratory and multi-organ failure in the context of marked systemic inflammation. This hyperinflammatory syndrome is reflected by the elevation of several inflammatory molecules, such as C-reactive protein (CRP), ferritin, IL-6, troponin, and D-dimer. In a subset of patients, early intervention with signal inhibitors may treat the Covid-19 hyperinflammatory syndrome before the development of acute lung injury and organ failure. We present a summary of a study protocol for a randomised controlled, multi-arm trial with two novel inflammatory signal inhibitors;Ruxolitinib (RUX) and Fostamatinib (FOS) for the treatment of Covid-19 pneumonia. RUX is an oral Janus Associated Kinase (JAK1/JAK2) inhibitor approved for the treatment of splenomegaly, myelofibrosis and polycythaemia vera. Inhibition of STAT3 downregulates IL-6 and IL-23, which are important for the inflammatory effects of Th17 cells. Further, JAK2 inhibition has been shown to reduce levels of TNFa and CRP, as well as reducing viral cellular entry and assembly. FOS is an oral spleen tyrosine kinase (SYK) inhibitor approved for the treatment of chronic immune thrombocytopenia. Studies of severe acute respiratory distress syndrome (ARDS) suggest that the pathogenesis relies on a series of SYK events leading to cytokine and chemokine release. FOS acts by inhibiting SYK activity, blocking the production and release of cytokines induced via C-lectin receptors and Fc receptor activation, ameliorating the cytokine storm which precedes ARDS. Primary Objective: The primary objective of MATIS is to determine the efficacy of RUX or FOS compared to standard of care (SOC) to reduce the proportion of hospitalised patients progressing from mild or moderate to severe COVID-19 pneumonia at 14 days from baseline. Secondary objectives at 7, 14 and 28 days: - Determine the efficacy of RUX or FOS to reduce mortality - Determine the efficacy of RUX or FOS to reduce the need for invasive ventilation or ECMO - Determine the efficacy of RUX or FOS to reduce the need for non-invasive ventilation - Determine the efficacy of RUX or FOS to reduce the proportion of patients suffering significant oxygen desaturation - Determine the efficacy of RUX or FOS to reduce the need for renal replacement therapy - Determine the efficacy of RUX and FOS to reduce the incidence of venous thromboembolism COVID-19 pneumonia - Determine the efficacy of RUX and FOS to reduce the severity of COVID-19 pneumonia [graded by a modified WHO Ordinal Scale] - Determine the efficacy of RUX or FOS to reduce the level of inflammatory biomarkers - Determine the efficacy of RUX or FOS to reduce the duration of hospital admission - Evaluate the safety of RUX and FOS for COVID-19 pneumonia Study Design: This is a multi-arm, two-stage, open-label, randomised (1:1:1) controlled trial. Participants will be recruited during hospitalisation for COVID-19 in multiple centres in the UK. Eligible participants (table 1) are randomised to one of the three interventions (RUX, FOS, SOC) by a central web-based randomisation service. This uses randomisation sequences with random block sizes, stratified by age (<65 and ≥65 years) and site. The treatment duration is 14 days from baseline. Patients receiving RUX will be administered 10mg BD for Day 1-7 and 5mg BD for Day 8-14. FOS will be administered as 150mg BD day 1-7 and 100mg BD day 8-14. Participants receive follow up assessments on days 7, 14 and 28 after the first dose. Outcomes: Primary endpoints will be assessed with a pairwise comparison (FOS vs SOC and RUX vs SOC) of the proportion of participants diagnosed with severe COVID-19 pneumonia within 14 days. Severe COVID-19 pneumonia is defined by a modified WHO COVID-19 Ordinal Score 5, comprising the following indicators of disease severity: - Death - Requirement for invasive ventilation - Requirement for non-invasive ventilation including CPAP or high flow oxygen - O2 saturation < 90% on 60% inspired oxygen Samples size: In stage 1 of this multi-arm study, 171 parti ipants will be randomised (57 per arm). Following an interim analysis, if either intervention shows a signal of efficacy, stage 2 will recruit a further 95 participants per arm (Fig 1). Trial Status: Recruitment is ongoing and commenced 2nd October 2020. Currently 127 patients are recruited and stage 1 is projected to be completed by 1st September 2021. The full protocol can be accessed via the trial's website. [Formula presented] Disclosures: Milojkovic: Novartis: Honoraria, Speakers Bureau;Incyte: Honoraria, Speakers Bureau;Bristol-Myers Squibb: Honoraria, Speakers Bureau;Pfizer: Honoraria, Speakers Bureau. Cooper: Principia and Sanofi: Consultancy;Sanofi and Principia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations expenses. OffLabel Disclosure: Fostamatanib - is a tyrosine kinase inhibitor with activity against spleen tyrosine kinase (SYK). In the context of treating COVID-19, Fostamatanib acts by inhibiting SYK activist, blocking the production and release of cytokines induced via C-lectin receptors and Fc receptor activation, ameliorating the cytokine storm which precedes ARDS. Studies of severe acute respiratory syndrome induced by coronavirus, suggest that pathogenesis relies on a series of SYK events. SYK medicates ctuokine and chemokine release, induced by the activation of C-lectin receptors and immunoglobulin Fc receptors, resulting in neutrophil and monocyte lung ingress, sequential activation of neutrophil extracellular traps and activation of lung epithelium and multiple myeloid cell. This is followed by inflammation and tissue destruction that contribute to ARDS. Ruxolitinib - A JAK1/JAK2 inhibitor. JAK and STAT molecules are proteins that trance extracellular stimulation into intracellular signalling, leading to expression of host inflammatory cytokines and a variety of immune cells. In the context of MATIS, we use low dose ruxolitinib to treat COVID-19 by targeting key signalling pathways implicated in the hyper-inflammatory response of patients with COVID-19 infection. The mechanisms of Ruxolitinib to act in COVID-19 is through inhibition of STAT3 activation, down regulating IL-6 and IL-23, signalling important for the inflammatory effects of Th17 cells. Furthermore it leads to reductions of TNFa and CRP.
ABSTRACT
Background : Management of ITP became increasingly challenging during the COVID-19 pandemic. Immunosuppressive treatments increase susceptibility of patients to COVID-19. Therapies increasing the thrombotic risk are suboptimal due to coagulopathy observed with COVID-19. The need to minimize office visits to limit potential viral exposure renders intravenous administration or injections less suitable. Consequently, ITP management requires careful patientcentric consideration during the pandemic. Fostamatinib is a potent oral SYK inhibitor that abrogates SYKmediated destruction of platelets and may abrogate SYK-mediated thromboinflammation. Aims : To evaluate fostamatinib as an ITP treatment during the COVID-19 era. Methods : Review of safety, immunotoxicology, and mechanism of action and administration for fostamatinib. Results : Preclinical studies demonstrated intact innate and humoral responses to immune challenges in fostamatinib (R406) treated rodents. 1 In ITP clinical trials, the incidence of adverse events (including infections) was somewhat higher with fostamatinib vs placebo (83% vs 75%), which is consistent with the 2.4-fold increase in exposure to fostamatinib vs. placebo (29 vs. 12 patient-exposure years, respectively). No patients had opportunistic infections. The rate of thromboembolic events with fostamatinib (0.7% over 5 years) was low compared with similar studies with other ITP treatments (2.6-8.9% over 2-8 years). Office visits can be minimized due to oral administration of fostamatinib and simplified titration: fostamatinib is initiated at 100mg BID and increased to 150mg BID after 4 weeks if needed. Thrombocytosis was uncommon (1.4% over 5 years). Conclusions : Fostamatinib is an immunomodulatory treatment for ITP that may lower the risk of thrombosis. The need for office visits may be reduced due to oral administration, simplified titration, and infrequency of thrombocytosis. Fostamatinib is an appropriate option for the treatment of ITP in the COVID-19 era.
ABSTRACT
Background: Management of immune thrombocytopenia (ITP) has become increasingly challenging during the COVID-19 pandemic. Immunosuppressive treatments used to treat ITP can increase the susceptibility of patients to develop COVID-19. Additionally, therapies which increase the risk of thrombosis may not be optimal due to the hypercoagulable state also observed in patients with COVID-19 infection. The need to minimize office visits, to limit potential exposure to the virus, renders therapies requiring intravenous administration or injections as well as treatments requiring frequent titration less suitable. Consequently, ITP management requires careful patient-centric consideration during the pandemic. Aims: To evaluate fostamatinib as an ITP treatment during the COVID- 19 era Methods: Review of the safety data from the phase 3 studies for fostamatinib in ITP as well as titration and mode of administration. Results: Patients (n=146) in the trials had a median age of 53 years (range 20-88), a median of 5 prior ITP treatments, and 229 years of fostamatinib exposure. An increase in platelet count ≥50,000/μL was observed in 54% of patients on fostamatinib treatment. These patients maintained their response to treatment for 86% of treatment days. In the placebo-controlled phase, there was a 2.4-fold difference in duration of exposure to fostamatinib vs. placebo (29 vs. 12 patient-exposure years, respectively). Consequently, the incidence of infections with fostamatinib was somewhat higher than with placebo (27% vs. 21%). The incidence of overall adverse events was similarly higher with fostamatinib vs placebo (83% vs 75%). No patients had opportunistic infections. Office visits can be minimized due to oral administration of fostamatinib and simplified titration. Fostamatinib dosing is initiated at 100mg BID in patients and increased to 150mg BID after 4 weeks if needed. Titration visits are also minimized due to the low incidence of thrombocytosis (1.4% over 5 years). ITP patients have an increased risk of thrombotic events, which may be due to SYK-dependent platelet activation in patients with ITP.2 In the randomized fostamatinib studies, 87% of patients had at least one risk factor for thrombosis, and 58% had multiple risk factors. Over the 62-month study, one (0.7%) thrombotic event was reported: a patient with pre-existing atherosclerosis had a mild transient ischemic attack, which resolved spontaneously. This rate is lower than seen in long-term ITP clinical trials (2-8 years duration), which ranged from 2.6% to 8.9%. Summary/Conclusion: Fostamatinib is an immunomodulatory treatment that elevates platelet counts and may lower the risk of thrombosis in ITP. There is also a reduced need for office visits due to oral administration, simplified titration, and infrequency of thrombocytosis. Fostamatinib is an appropriate therapeutic option for the treatment of ITP in the COVID-19 era.