Intravenous Imatinib in Mechanically Ventilated COVID-19 Patients : A Randomised, Double-blind, Placebo-controlled Study to Investigate the Safety and Efficacy of Intravenous Imatinib Mesylate (Impentri®) in Subjects With Acute Respiratory Distress Syndrome Induced by COVID-19

INTRODUCTION1.1 Background of ARDS due to COVID-19The COVID-19 pandemic has led to an unanticipated increase of the number of patients with ARDS admitted to the ICU, contributing to high morbidity and mortality, as well as an unprecedented consumption of medical resources. COVID-19 is caused by a coronavirus (scientific name: SARS-CoV-2), a non-segmented, positive sense RNA virus. Although most SARS-CoV-2 infections have an asymptomatic or mild course of disease (80%), COVID-19 has a detrimental course in a minority of patients (20%), particularly in older patients or patients with pulmonary or cardiovascular comorbidities. In these cases, COVID-19 infection is characterized by damage to the alveolocapillary wall and extensive pulmonary capillary leak. The alveolar flooding results in impairment of oxygen diffusion and severe hypoxemic respiratory failure. In Chinese registries these cases of COVID-19 disease were classified as either 'severe' in case of low oxygen saturation or 'critical' when invasive mechanical ventilation was needed or multi-organ failure occurred. Radiological imaging demonstrates extensive ground glass opacities, consistent with alveolar oedema.Radiological as well as pathological examination demonstrated that critical COVID-19 infections closely mimic Acute Respiratory Distress Syndrome (ARDS), a condition characterized by damage to the alveolo-capillary membrane by various insults. Mortality in ICU treated 'critical' COVID-19 patients is comparable to mortality in ARDS patients. Of the patients admitted with COVID-19 infection to hospital, 17-35% develop ARDS, requiring ICU admission or even invasive mechanical ventilation (29-91%). According to recent reviews, mortality may mount up to 15-20% (hospitalized patients) to even 40% in ICU patients. For these reasons, the current COVID-19 pandemic has resulted in a huge increase in the incidence of ARDS with a homogenous aetiology i.e., SARS-CoV2 infection.According to the Berlin definition, ARDS is '…an acute diffuse, inflammatory lung injury, leading to increased pulmonary vascular permeability, increased lung weight, and loss of aerated lung tissue…[with] hypoxemia and bilateral radiographic opacities, associated with increased venous admixture, increased physiological dead space and decreased lung compliance'. It is characterised by an acute onset, with bilateral infiltrates on chest imaging due to pulmonary oedema, and with severe hypoxemia despite mechanical ventilation. Pathophysiologically, ARDS results from an overwhelming inflammatory process involving alveolar epithelial and vascular endothelial injury in the lung which can be infective and non-infective in origin. The early phase of ARDS is characterized by alveolar flooding with protein-rich fluid due to increased vascular permeability. Pulmonary oedema then leads to the clinical manifestation of poor lung compliance, severe hypoxaemia, and bilateral infiltrates on chest radiograph. It also leads to alveolar epithelial injury of type I cells, which contributes further to the pulmonary oedema. Despite decades of efforts, there is currently no registered drug to target pulmonary vascular permeability in ARDS.Current treatment of patients with 'critical' COVID-19 consists of supportive measures, including oxygen supplementation, diuretics and (non)-invasive mechanical ventilation. Current guidelines prescribe dexamethasone and remdesivir for patients with hypoxemia. Although remdesivir and dexamethasone target key pathophysiological processes of COVID-19 like viral replication and inflammatory damage, respectively, there is currently no proven benefit of pharmacological intervention to reverse pulmonary vascular leak and oedema.1.2 Rationale for intervention Earlier studies demonstrate that the anti-leukemic drug imatinib effectively and consistently protects against pulmonary vascular leak and alveolar oedema during inflammatory stimuli. In 2008, a patient with acute respiratory failure due to widespread pulmonary oedema was treated with imatinib mesylate for another indication than the acute respiratory failure itself. However, initiation of the imatinib treatment (200mg/day) was followed by a surprisingly fast reversal of respiratory failure. The reversal of respiratory failure was paralleled by decrease in pulmonary oedema on radiological imaging, resulting in the hypothesis that imatinib directly protects the pulmonary endothelial barrier. This unexpected effect of imatinib was published in 2008. The hypothesis was tested in an extensive preclinical study, evaluating the effect of imatinib on endothelial barrier function in several conditions. These studies demonstrated that imatinib protects the endothelial barrier under inflammatory conditions, both in in vitro models using several types of endothelial cells and various inflammatory mediators, and in vivo, using various animal models for vascular leak. The protective effects of imatinib were confirmed by several studies by independent research groups.After the publication of the first case report and the preclinical evidence for a protective effect of imatinib on the endothelial barrier, imatinib (300mg/day) was associated with clinical improvement of acute respiratory failure in 1 patient in an independent hospital. In addition, imatinib has been used in a compassionate use setting in 2 additional patients in the investigators' hospital - in both cases initiation of imatinib therapy (200-400mg/day) was followed by reversal of vascular leak and/or respiratory failure. Although these cases should be interpreted with caution, they consistently suggest a beneficial effect of imatinib on pulmonary vascular leak and/or respiratory failure. To date, one case report using oral imatinib to successfully treat COVID-19 pneumonia has been published. The protective effects of imatinib at the endothelial level 2-10μM were found at concentrations that are comparable to plasma levels found in patients treated with imatinib for CML (2-5μM), indicating that regular dosing schemes of imatinib are sufficient to induce its protective effect on the endothelial barrier. Indeed, preliminary data from the COUNTER-COVID study, which evaluates the effect of oral imatinib mesylate in hospitalized patients with COVID-19, demonstrate that dosing of 400mg/day orally is sufficient to reach target levels described above.Based on the observations that the optimal protective effect of imatinib on the endothelial barrier ranges between 2-10μM, together with previous pharmacokinetic studies after intravenous imatinib, the investigators propose a dosing scheme of 200mg b.i.d. This dosing scheme was shown to provide plasma levels that correspond to the 2-10μM range found in prior in vitro studies. The current study will evaluate the effect of intravenous imatinib on pulmonary oedema as measured by EVLWi. Several arguments drive the use of intravenous imatinib in the current study: 1) since most ICU patients are intubated, oral administration is suboptimal. 2) Intestinal uptake in mechanically ventilated ICU patients is often impaired due to intestinal oedema. 3) by intravenous administration, imatinib directly reaches the target organ, i.e., the endothelium, requiring lower dosing and fewer side-effects. A detailed analysis on dosing and route of administration is provided in the Investigators Brochure.Concerning safety, imatinib was shown to have mild or no effects on the immune response. Although developed to target leukemic cells, imatinib hardly affects healthy leucocytes and a normal lymphocytic response was observed in lymphocytes from patients treated with imatinib. Of particular relevance for the current protocol, it was shown that treatment with imatinib does not affect the control of primary viral infections. The investigators demonstrated in a healthy volunteer model of lung injury that imatinib did not affect the immune response to LPS inhalation in healthy human subjects. Finally, the first interim analysis of the COUNTER-COVID study, which tests oral imatinib in COVID-19 patients admitted to hospital with hypoxemia, did not reveal safety concerns after inclusion of the first 140 patients.Altogether, substantial evidence indicates that imatinib is an ideal candidate for treatment of the pulmonary complications of SARS-CoV2 like ARDS, since it protects against vascular leak and alveolar oedema thereby reducing hypoxemic respiratory failure. The current study seeks to directly measure the effect of intravenous imatinib on pulmonary vascular leak in COVID-19 ARDS. COVID-19 offers a homogenous cause of ARDS, however, the available evidence indicates that ARDS due to other causes will respond similarly to imatinib. Therefore, the identification of a compound that reverses pulmonary vascular leak may benefit well beyond COVID-19 ARDS and provide a first treatment for other forms of ARDS as well.OBJECTIVESPrimary:Efficacy: To evaluate the effect of intravenous imatinib comp....

Medienart:	Klinische Studie

Erscheinungsjahr:	2023
Erschienen:	2023

Enthalten in:	ClinicalTrials.gov - (2023) vom: 23. Jan. Zur Gesamtaufnahme - year:2023

Sprache:	Englisch

Links:	Volltext [kostenfrei]

Themen:	610 Acute Lung Injury COVID-19 Phase: Phase 2 Pulmonary Edema Recruitment Status: Terminated Respiratory Distress Syndrome Respiratory Distress Syndrome, Newborn Study Type: Interventional Syndrome

Anmerkungen:	Source: Link to the current ClinicalTrials.gov record., First posted: March 11, 2021, Last downloaded: ClinicalTrials.gov processed this data on February 01, 2023, Last updated: February 01, 2023

Study ID:

NCT04794088 INVENT COVID

Veröffentlichungen zur Studie:

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PPN (Katalog-ID):	CTG003703517