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Inflammatory Signal Inhibitors for COVID-19 (MATIS) (MATIS)

Primary Purpose

Coronavirus, Covid19, Pneumonia

Status
Recruiting
Phase
Phase 1
Locations
United Kingdom
Study Type
Interventional
Intervention
Ruxolitinib
Fostamatinib
Standard of care
Sponsored by
Imperial College London
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Coronavirus focused on measuring coronavirus, covid19, pneumonia, ruxolitinib, fostamatinib

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Imperial College Healthcare NHS TrustRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Active Comparator

Arm Label

Standard of care

Fostamatinib

Ruxolitinib

Arm Description

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

Full Information

First Posted
October 5, 2020
Last Updated
June 27, 2022
Sponsor
Imperial College London
Collaborators
Imperial College Healthcare NHS Trust, Rigel Pharmaceuticals, Novartis
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1. Study Identification

Unique Protocol Identification Number
NCT04581954
Brief Title
Inflammatory Signal Inhibitors for COVID-19 (MATIS)
Acronym
MATIS
Official Title
Randomised Multi-arm Trial of Ruxolitinib (RUX) and Fostamatinib (FOS) for COVID-19 Pneumonia
Study Type
Interventional

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Recruiting
Study Start Date
October 2, 2020 (Actual)
Primary Completion Date
June 30, 2022 (Anticipated)
Study Completion Date
June 30, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Imperial College London
Collaborators
Imperial College Healthcare NHS Trust, Rigel Pharmaceuticals, Novartis

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Coronavirus, Covid19, Pneumonia
Keywords
coronavirus, covid19, pneumonia, ruxolitinib, fostamatinib

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
456 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Standard of care
Arm Type
Active Comparator
Arm Title
Fostamatinib
Arm Type
Active Comparator
Arm Title
Ruxolitinib
Arm Type
Active Comparator
Intervention Type
Drug
Intervention Name(s)
Ruxolitinib
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Fostamatinib
Intervention Description
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).
Intervention Type
Other
Intervention Name(s)
Standard of care
Intervention Description
Standard of care treatment as per site-level policies and guidelines.
Primary Outcome Measure Information:
Title
All-cause mortality
Time Frame
Day 14
Title
Number and proportion of patients requiring invasive ventilation
Time Frame
Day 14
Title
Number and proportion of patients requiring non-invasive ventilation (CPAP and high flow nasal oxygen)
Time Frame
Day 14
Title
Number and proportion of patients with O2 saturation < 90% on >/=60% inspired oxygen
Time Frame
Day 14
Secondary Outcome Measure Information:
Title
All-cause mortality
Time Frame
Day 28
Title
Number and proportion of patients requiring invasive ventilation or extracorporeal membrane oxygenation (ECMO)
Time Frame
Day 14, 28
Title
Number and proportion of patients requiring non-invasive ventilation including continuous positive airway pressure (CPAP) or high flow nasal oxygen
Time Frame
Day 14, 28
Title
Number and proportion of patients requiring renal replacement therapy
Time Frame
Day 14, 28
Title
Number and proportion of patients experiencing venous thromboembolism events
Time Frame
Day 14, 28
Title
Length of stay
Time Frame
Day 14, 28
Title
Number and proportion of serious adverse events and discontinuations
Time Frame
Day 14, 28
Title
Absolute change in pneumonia severity on the modified WHO COVID-19 Ordinal Scale
Description
Scale range from 0 (uninfected) to 9 (dead)
Time Frame
Day 14, 28
Title
Inflammatory markers: CRP, LDH, ferritin, D-dimer
Time Frame
Day 14, Day 28

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Nichola Cooper
Phone
+44 (0)20 3313 1175
Email
n.cooper@imperial.ac.uk
First Name & Middle Initial & Last Name or Official Title & Degree
Clio Pillay
Phone
+44 (0)7778552277
Email
clio.pillay@nhs.net
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nichola Cooper
Organizational Affiliation
Imperial College London
Official's Role
Principal Investigator
Facility Information:
Facility Name
Imperial College Healthcare NHS Trust
City
London
ZIP/Postal Code
W12 0HS
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Zayneb Alsaadi
Phone
02033134113
Email
imperial.covidtrials@nhs.net
First Name & Middle Initial & Last Name & Degree
Sophie Ryder
Phone
02033134113
Email
imperial.covidtrials@nhs.net
First Name & Middle Initial & Last Name & Degree
Nichola Cooper
First Name & Middle Initial & Last Name & Degree
Nikhil Vergis
First Name & Middle Initial & Last Name & Degree
Richard Turner

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
To be determined
Citations:
PubMed Identifier
33845867
Citation
Vergis N, Phillips R, Cornelius V, Katsarou A, Youngstein T, Cook L, Willicombe M, Pilay C, Shturova T, Almonte M, Charania A, Turner R, Kon OM, Cooke G, Thursz M, Cherlin S, Wason J, Milojkovic D, Innes AJ, Cooper N. Multi-arm Trial of Inflammatory Signal Inhibitors (MATIS) for hospitalised patients with mild or moderate COVID-19 pneumonia: a structured summary of a study protocol for a randomised controlled trial. Trials. 2021 Apr 12;22(1):270. doi: 10.1186/s13063-021-05190-z.
Results Reference
derived

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Inflammatory Signal Inhibitors for COVID-19 (MATIS)

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