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.
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
Drug: Ruxolitinib
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.
Drug: Fostamatinib
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).
Other: Standard of care
Standard of care treatment as per site-level policies and guidelines.
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
Imperial College Healthcare NHS Trust
London, United Kingdom
Investigator: Zayneb Alsaadi
Contact: 02033134113
imperial.covidtrials@nhs.net
Nichola Cooper
+44 (0)20 3313 1175
n.cooper@imperial.ac.uk
Clio Pillay
+44 (0)7778552277
clio.pillay@nhs.net
Nichola Cooper, Principal Investigator
Imperial College London