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A Randomized Study to Investigate the Effect of Intravenous Imatinib on the Amount of Oxygen in the Lungs and Blood of Adults With COVID-19 Needing Mechanical Ventilation and Supportive Care. (IMPRESS COVID)

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ClinicalTrials.gov Identifier: NCT04953052
Recruitment Status : Recruiting
First Posted : July 7, 2021
Last Update Posted : November 9, 2021
Sponsor:
Information provided by (Responsible Party):
Exvastat Ltd.

Brief Summary:

The COVID-19 pandemic has led to an increase in the number of patients admitted to intensive care units (ICU) with acute respiratory distress syndrome (ARDS). ARDS is a severe, life-threatening medical condition characterised by inflammation and fluid in the lungs. There is no proven therapy to reduce fluid leak, also known as pulmonary oedema, in ARDS. However, recent studies have discovered that imatinib prevents fluid leak in the lungs in inflammatory conditions, while leaving the immune response intact.

Adding imatinib into the standard care package may, therefore, decrease mortality and reduce the duration of mechanical ventilation compared with standard care alone, in critically-ill patients with COVID-19.

To help determine the impact of imatinib in these patients we present a randomised, double-blind, multi-centre, 2-arm, parallel-group, placebo-controlled clinical study of intravenous imatinib in 84 mechanically-ventilated, adult subjects with COVID-19-related ARDS.

Study participants (patients who have consented into the study) will receive the study drug (imatinib or placebo) twice daily for a period of 10 days. The effect of the intervention will be tested by measuring the change from baseline in the Oxygen Saturation Index (OSI) at day 10. OSI is a non-invasive means of measuring oxygenation and is an independent predictor of mortality in patients with ARDS, serving thus as a relevant endpoint from which to assess the efficacy of imatinib.

Other measurements will include regular blood tests as part of safety assessments.

Time on ventilation and morbidity and mortality will be recorded as secondary outcome measures.

Blood tests will also allow the investigation of the pharmacokinetic properties of imatinib, as well as biomarkers of inflammation.


Condition or disease Intervention/treatment Phase
Acute Respiratory Distress Syndrome COVID-19 Acute Respiratory Distress Syndrome Covid19 ARDS Pulmonary Oedema Drug: Imatinib Mesylate Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 84 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind, Multicentre 2-arm, Parallel-group, Placebo-controlled Study to Investigate the Efficacy and Safety of Intravenous Imatinib Mesylate in Reducing the Severity of Hypoxemic Respiratory Failure in Patients With Critical COVID-19 Receiving Standard of Care.
Estimated Study Start Date : November 2021
Estimated Primary Completion Date : February 2022
Estimated Study Completion Date : April 2022


Arm Intervention/treatment
Experimental: Intravenous Imatinib Mesylate
Intravenous Imatinib Mesylate solution- 200mg as an 8mg/ml solution, administered twice daily (400mg total daily dose). Each dose administered in a 25ml solution over a two-hour infusion period.
Drug: Imatinib Mesylate
An isotonic sterile solution of imatinib.
Other Name: Impentri

Placebo Comparator: Intravenous Placebo
Intravenous Placebo matched solution- administered 25ml solution, twice daily over a two-hour infusion period
Drug: Placebo
An isotonic sterile solution




Primary Outcome Measures :
  1. Change from baseline in Oxygen Saturation Index (OSI) at Day 10 [ Time Frame: From Baseline to Day 10 ]
    Oxygen saturation is a calculation derived from [mean airway pressure × FiO2 × 100] / SpO2.


Secondary Outcome Measures :
  1. Change from Baseline in Oxygen Saturation Index (OSI) at Day 3 and Day 5 [ Time Frame: From Baseline to Day 3 and from baseline to Day 5 ]
    Oxygen saturation measured by pulse oximetry

  2. Mortality rate at Day 29 and Day 60 [ Time Frame: Day 29 and Day 60 ]
    Mortality at Day 29 and Day 60

  3. Change from baseline in WHO 9-point ordinal scale for clinical improvement to Day 10 and Day 29 [ Time Frame: The WHO ordinal scale will be recorded Days 1-10 and Day 29 ]

    The WHO Ordinal Scale for Clinical Improvement (0 to 8, where a higher value indicates worse outcome).

    It measures illness severity over time using the following categories: Uninfected, Ambulatory (no limitation of activities), Ambulatory (limitation of activities), Hospitalized (no O2 therapy), Hospitalized (O2 by nasal prongs or mask), Hospitalized (O2 by NIV or HFNO), Hospitalized (intubation and invasive mechanical ventilation), Hospitalized (ventilation and additional organ support [vasopressors, CVVH, ECMO]), Death.


  4. Duration of mechanical ventilation (Days) to Day 29 and Day 60 [ Time Frame: To Day 29 and to Day 60 ]
    Number of days requiring to be on mechanical ventilation

  5. Duration of stay in ICU (Days) to Day 29 and Day 60 [ Time Frame: To Day 29 and to Day 60 ]
    Number of days within the ICU

  6. Time to first successful extubation (Hours) to Day 29 [ Time Frame: To Day 29 ]
    Number of hours to extubation (removal of the endotracheal tube)

  7. Number of days free of mechanical ventilation and survival (VFDsurv) at Day 29 and Day 60 [ Time Frame: At Day 29 and Day 60 ]
    Amongst survivors, the number of days free from mechanical ventilation


Other Outcome Measures:
  1. Safety- Type, frequency, severity, and relationship to study treatment of any AEs, SAEs or AEs leading to discontinuation of study treatment from Day 1 to Day 29 (final follow up visit) [ Time Frame: Day 1 to Day 29 ]
    Safety adverse events and serious adverse event collection

  2. Incidence of related Treatment-Emergent Adverse Events- Tolerability [ Time Frame: Day 1 to Day 29 ]
    Tolerability

  3. Pharmacokinetic- Imatinib plasma concentration [ Time Frame: 4 samples collected Day 1, and single samples collected Days 3 and 5 ]
    Imatinib plasma concentration- Multivariate hierarchical analysis will be performed on various factors (age, sex, weight, height,appha-1-acid glycoprotein, haemoglobin, ALAT, CRP, eGFR, albumin, smoking, and concomitant drugs) to explore sources of variability in patient outcome. Significant predictors will be used as covariates to improve the performance of the PK model.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female patients aged ≥18 years
  2. Women of childbearing potential must have a negative serum pregnancy test to confirm eligibility
  3. Provision of signed written informed consent from the patient or patient's legally acceptable representative
  4. SARS-CoV-2 infection confirmed by RT-PCR laboratory test (which may include results from a test that was performed prior to hospital admission if, in the opinion of the Investigator, it is relevant to ongoing COVID-19)
  5. Meet Berlin definition for moderate - severe ARDS

    1. Bilateral opacities - not fully explained by effusions, lobar/lung collapse, or nodules
    2. Respiratory failure not fully explained by cardiac failure or fluid overload.
    3. PaO2/FIO2 ≤200 mmHg with PEEP ≥5 cmH2O
  6. Patient requires intubation or is currently intubated and has been for ≤48 hours

Exclusion Criteria:

  1. Persistent septic shock (>24 hours) with a Mean Arterial Pressure (MAP) ≤65 mm Hg and serum lactate level >4 mmol/L (36 mg/dL) despite adequate volume resuscitation and vasopressor use (norepinephrine >0.2 μg/kg/min) for >6 hours
  2. Major trauma in the past 5 days
  3. Presence of any active malignancy (other than non-melanoma skin cancer) that required treatment within the last year
  4. Pre-existing severe cardiopulmonary disease including, but not limited to, interstitial lung disease; severe COPD (GOLD Stage IV or FEV1<30% predicted); heart failure (estimated left ventricular ejection fraction < 40%); or a chronic lung condition requiring home oxygen treatment
  5. An underlying clinical condition that, in the opinion of the Investigator, would make it very unlikely for the patient to be successfully weaned from ventilation due to severe underlying diseases (e.g., severe malnutrition, severe neurological disease)
  6. Patients considered inappropriate for critical care (e.g., being considered for palliative care)
  7. Currently receiving extracorporeal membrane oxygenation (ECMO)
  8. Severe chronic liver disease with Child-Pugh score >12 (Appendix 1)
  9. White blood count <2.5 x 109/L; Hemoglobin <4.0 mmol/L (6.5g/dL); Platelets <50 x 109/L
  10. ALT or AST >10x upper limit of normal (ULN) or bilirubin >3x ULN
  11. Women who are pregnant or breast-feeding
  12. Use of drugs with strong CYP3A4 induction potential, such as carbamazepine, efavirenz, enzalutamide, phenobarbital, phenytoin, hypericum, mitotane, nevirapine, primidone, rifabutin and rifampicin
  13. Inability of the ICU staff to initiate administration of study treatment within 48 hours of intubation
  14. Enrolled in a concomitant clinical trial of an investigational medicinal product
  15. In the opinion of the investigator, progression to death is highly probable, irrespective of the provision of treatments

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04953052


Contacts
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Contact: Sarah J Fritchley, PhD 07944371590 clinicaltrials@Exvastat.com

Locations
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India
Sir Sayajirao General Hospital (SSG Hospital), Medical College Baroda, Jail Road Indira Avenue)Anandpura Not yet recruiting
Vadodara, Gujarat, India, 390001
Contact: Dr Keyur M Brahme, MD    9727729105    drkeyur@gmail.com   
St George's Hospital, P D Mello Road, Fort Road, CST Terminal, Recruiting
Mumbai, Maharashtra, India, 400001
Contact: Vinayak Sawardekar, MD    9820747703    Vinayaks1812@gmail.com   
Principal Investigator: Vinayak Sawardekar, MD         
Sub-Investigator: Akash Khobragade, MD         
Government Medical College and Hospital Recruiting
Nagpur, Maharashtra, India, 440003
Contact: Atul Rajkondawar, MD         
Principal Investigator: Atul Rajkondawar, MD         
PCMC PGI Yashwantrao Chavan Memorial Hospital Not yet recruiting
Nagar, Pune, India, 411018
Principal Investigator: Pravin Nagulal Soni, MD         
Sub-Investigator: Seema Soni, MD         
NRS Medical College and Hospital Not yet recruiting
Kolkata, West Bengal, India, 700014
Principal Investigator: Deb Jaydip, MD         
Sub-Investigator: Janyanta Chakraborty, MD         
Father Muller Hospital and Medical College Recruiting
Mangalore, India, 575002
Principal Investigator: Venkatesh, MD         
Sub-Investigator: Arachana Bhat, MD         
JSS Hospital Recruiting
Mysuru, India, 570004
Principal Investigator: Akshay, MD         
Sub-Investigator: Kalabharathi, MD         
Indira Gandhi Government Medical College and Hospital Not yet recruiting
Nagpur, India, 440018
Principal Investigator: Vaishali Shelgaonkar, MD         
Sub-Investigator: Radha Munje, MD         
Sponsors and Collaborators
Exvastat Ltd.
Investigators
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Study Director: Gary Burgess, MD Exvastat Ltd.
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Responsible Party: Exvastat Ltd.
ClinicalTrials.gov Identifier: NCT04953052    
Other Study ID Numbers: EX003
959310 ( Other Grant/Funding Number: European Innovation Council Accelerator Grant )
First Posted: July 7, 2021    Key Record Dates
Last Update Posted: November 9, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Exvastat Ltd.:
Acute Respiratory Distress Syndrome
ARDS
Covid-19
Imatinib
Oxygen Saturation Index
OSI
Endothelial Dysfunction
Pulmonary Oedema
Protein Kinase Inhibitor
Additional relevant MeSH terms:
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COVID-19
Imatinib Mesylate
Respiratory Distress Syndrome
Respiratory Distress Syndrome, Newborn
Acute Lung Injury
Pulmonary Edema
Syndrome
Disease
Pathologic Processes
Respiratory Tract Infections
Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Lung Injury
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action