Inflammatory Signal Inhibitors for COVID-19 (MATIS)

Study Overview
=================
Brief Summary
-----------------
The Multi-arm trial of Inflammatory Signal Inhibitors for COVID-19 (MATIS) study is a two-stage, open-label, randomised controlled trial assessing the efficacy of ruxolitinib (RUX) and fostamatinib (FOS) individually, compared to standard of care in the treatment of COVID-19 pneumonia. The primary outcome is the proportion of hospitalised patients progressing from mild or moderate to severe COVID-19 pneumonia. Patients are treated for 14 days and will receive follow-up assessment at 7, 14 and 28 days after the first study dose. Patients with mild or moderate COVID-19 pneumonia will be recruited. Initially, n=171 (57 per arm) patients will be recruited in Stage 1. Following interim analysis to assess the efficacy and safety of the treatments, approximately n=285 (95 per arm) will be recruited during Stage 2.

Detailed Description
-----------------
COVID-19 pneumonia is characterised by respiratory and multi-organ failure in the context of marked systemic inflammation. It is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV2) infection. The hallmark of severe disease is hypoxia and a radiological pattern of acute lung injury that shares features with Acute Respiratory Distress Syndrome (ARDS). Early features of COVID-19 result from host viral response and typically include symptoms such as fever and dry cough. Later features, typically occurring beyond 7 days, are characterised by marked and progressive systemic inflammation, identified by elevations in a plethora of inflammatory molecules such as C-reactive protein, ferritin and IL6. In a subset of patients, hyperinflammatory responses drive acute lung injury and may result in catastrophic multi-organ failure and death. The aetiology of COVID-19 induced ARDS is incompletely understood but appears to be associated with lung inflammation effected by a monocytic and neutrophilic infiltration, elevated cytokine levels and tissue damage. Elevations in circulating inflammatory molecules are associated with poor prognosis. In particular, the COVID-19 hyperinflammatory response syndrome is associated thrombotic complications which are postulated to drive cardiac dysfunction and microvascular thrombi, suggested by elevations in troponin and D-dimer, respectively. Similar hyperinflammatory responses are also seen in macrophage activation syndromes such as haemophagocytic lymphohistiocytosis, or in the cytokine release syndrome associated with chimeric antigen receptor T cell therapy. Further, preliminary data from China and Italy have shown immediate resolution of symptoms using anti-interleukin-6 agents (anti-IL6) therapy and Janus kinase inhibitors (JAK)/signal transducer and activator of transcription (STAT) inhibitors in patients with severe disease. There may be an early window of opportunity to treat the COVID-19 hyperinflammatory syndrome before acute lung injury leads to organ failure. There are currently no approved treatments for COVID-19 pneumonia. This is a protocol for a randomised controlled, multi-arm trial of early intervention with inflammatory signal inhibitors. Study purpose A number of therapeutic interventions targeting inflammatory signalling might reduce the severity of the inflammatory response phase resulting in amelioration of the lung damage thereby averting respiratory failure and the need for mechanical ventilation. This trial aims to evaluate the efficacy of two inhibitors of key signalling pathways using drugs which are already licensed for use in other clinical indications. Primary objective The primary objective is to determine the efficacy of RUX and FOS to reduce the proportion of hospitalised patients progressing from mild/moderate to severe COVID-19 pneumonia. A modified World Health Organization (WHO) COVID-19 Severity Ordinal Scale (COVID-19 Therapeutic Trial Synopsis published 18th February 2020) will be used to grade clinical deterioration from Hospitalised Mild Disease (<5) to Hospitalised Severe Disease (greater than or equal to 5). The modification includes an additional grade for Hospitalised Severe Disease that allows the capture of clinical deterioration in patients for whom escalation in organ support is not offered. Patients are eligible for recruitment to MATIS at grades 3 or 4. These patients stand to gain the greatest benefit from inflammatory signal inhibitors that may ameliorate the cytokine storm and prevent organ failure. Secondary objectives Determine the efficacy of RUX or FOS to reduce mortality Determine the efficacy of RUX or FOS to reduce the need for invasive ventilation and/or ECMO Determine the efficacy of RUX or FOS to reduce the need for non-invasive ventilation including CPAP or high flow nasal oxygen Determine the efficacy of RUX or FOS to reduce the proportion of patients suffering clinically 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 improve the severity of COVID19 pneumonia on a modified WHO COVID19 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 blood ferritin, CRP, LDH and D-dimer Determine the efficacy of RUX or FOS to reduce the level of serum creatinine. Determine the efficacy of RUX or FOS to reduce duration of hospital admission

Official Title
-----------------
Randomised Multi-arm Trial of Ruxolitinib (RUX) and Fostamatinib (FOS) for COVID-19 Pneumonia

Conditions
-----------------
Coronavirus, Covid19, Pneumonia

Intervention / Treatment
-----------------
* Drug: Ruxolitinib
* Drug: Fostamatinib
* Other: Standard of care


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients age ≥ 18 years at screening Patients with mild or moderate C19 pneumonia, defined as Grade 3 or 4 severity by the WHO COVID-19 Ordinal Scale by Patients meeting criteria: Hospitalization AND SARS-CoV2 infection (clinically suspected* or laboratory-confirmed) AND Radiological change consistent with COVID-19 disease C-reactive protein (CRP) greater than or equal to 30mg/L Informed consent from patient or personal or professional representative No medical history that might, in the opinion of the responsible clinician, put the patient at significant risk if he/she were to participate in the trial Agreement to abstain from sexual intercourse or use contraception that is >99% effective for all participants of childbearing potential for 42 days after the last dose of study drug. For male participants, agreement to abstain from sperm donation for 42 days after the last dose of study drug. Able to read English. Non-English speakers will be able to join the study. If patients are unable to understand verbal or written information in English - hospital translation services will be requested at the participating site for the participant where possible. Exclusion Criteria: Requiring either invasive or non-invasive ventilation including CPAP or high flow nasal oxygen at any point after hospital admission and before baseline not related to a pre-existing condition (e.g. obstructive sleep apnoea) Grade ≥ 5 severity on the modified WHO COVID-19 Ordinal Scale, viz. O2 saturation < 90% on ≥ 60% inspired oxygen at baseline; non-invasive ventilation; or invasive mechanical ventilation at any point since hospital admission. In the opinion of the investigator, progression to death is inevitable within the next 24 hours, irrespective of the provision of therapy Known severe allergic reactions to the investigational agents Child Pugh B or C grade hepatic dysfunction Use of drugs within the preceding 14 days that are known to interact with any study treatment (FOS or RUX), as listed in the Summary of Product Characteristics Pregnant or breast feeding Any medical condition or concomitant medication that in the opinion of the investigator would compromise subjects' safety or compliance with study procedures. Any medical condition which in the opinion of the principal investigator would compromise the scientific integrity of the study Pregnant or breast feeding

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard of care<br> | Other: Standard of care<br>* Standard of care treatment as per site-level policies and guidelines.<br>|
| Active Comparator: Fostamatinib<br> | Drug: Fostamatinib<br>* Fostamatinib is a tyrosine kinase inhibitor with activity against spleen tyrosine kinase (SYK). It has approved for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP).<br>|
| Active Comparator: Ruxolitinib<br> | Drug: Ruxolitinib<br>* Ruxolitinib is a Janus kinase 1 (JAK1)/Janus kinase 2 (JAK2) inhibitor approved for clinical use in the treatment of splenomegaly, myelofibrosis, polycythaemia vera and graft-versus-host disease. It is an oral agent with a rapid mode of action.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality |  | Day 14 | 
| Number and proportion of patients requiring invasive ventilation |  | Day 14 | 
| Number and proportion of patients requiring non-invasive ventilation (CPAP and high flow nasal oxygen) |  | Day 14 | 
| Number and proportion of patients with O2 saturation < 90% on >/=60% inspired oxygen |  | Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality |  | Day 28 | 
| Number and proportion of patients requiring invasive ventilation or extracorporeal membrane oxygenation (ECMO) |  | Day 14, 28 | 
| Number and proportion of patients requiring non-invasive ventilation including continuous positive airway pressure (CPAP) or high flow nasal oxygen |  | Day 14, 28 | 
| Number and proportion of patients requiring renal replacement therapy |  | Day 14, 28 | 
| Number and proportion of patients experiencing venous thromboembolism events |  | Day 14, 28 | 
| Length of stay |  | Day 14, 28 | 
| Number and proportion of serious adverse events and discontinuations |  | Day 14, 28 | 
| Absolute change in pneumonia severity on the modified WHO COVID-19 Ordinal Scale | Scale range from 0 (uninfected) to 9 (dead) | Day 14, 28 | 
| Inflammatory markers: CRP, LDH, ferritin, D-dimer |  | Day 14, Day 28 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
coronavirus, covid19, pneumonia, ruxolitinib, fostamatinib