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)

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.

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.

Study Overview

• Status: Withdrawn
• Conditions: Covid19; Acute Respiratory Distress Syndrome; ARDS; COVID-19 Acute Respiratory Distress Syndrome; Pulmonary Oedema
• Intervention / Treatment: Drug: Imatinib Mesylate; Drug: Placebo

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• India
  • Mangalore, India, 575002
    • Father Muller Hospital and Medical College
  • Mysuru, India, 570004
    • JSS Hospital
  • Nagpur, India, 440018
    • Indira Gandhi Government Medical College and Hospital
  • Gujarat
    • Vadodara, Gujarat, India, 390001
      • Sir Sayajirao General Hospital (SSG Hospital), Medical College Baroda, Jail Road Indira Avenue)Anandpura
  • Maharashtra
    • Mumbai, Maharashtra, India, 400001
      • St George's Hospital, P D Mello Road, Fort Road, CST Terminal,
    • Nagpur, Maharashtra, India, 440003
      • Government Medical College and Hospital
  • Pune
    • Nagar, Pune, India, 411018
      • PCMC PGI Yashwantrao Chavan Memorial Hospital
  • West Bengal
    • Kolkata, West Bengal, India, 700014
      • NRS Medical College and Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in Oxygen Saturation Index (OSI) at Day 3 and Day 5	Oxygen saturation measured by pulse oximetry	From Baseline to Day 3 and from baseline to Day 5
Mortality rate at Day 29 and Day 60	Mortality at Day 29 and Day 60	Day 29 and Day 60
Change from baseline in WHO 9-point ordinal scale for clinical improvement to Day 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.	The WHO ordinal scale will be recorded Days 1-10 and Day 29
Duration of mechanical ventilation (Days) to Day 29 and Day 60	Number of days requiring to be on mechanical ventilation	To Day 29 and to Day 60
Duration of stay in ICU (Days) to Day 29 and Day 60	Number of days within the ICU	To Day 29 and to Day 60
Time to first successful extubation (Hours) to Day 29	Number of hours to extubation (removal of the endotracheal tube)	To Day 29
Number of days free of mechanical ventilation and survival (VFDsurv) at Day 29 and Day 60	Amongst survivors, the number of days free from mechanical ventilation	At Day 29 and Day 60

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	Safety adverse events and serious adverse event collection	Day 1 to Day 29
Incidence of related Treatment-Emergent Adverse Events- Tolerability	Tolerability	Day 1 to Day 29
Pharmacokinetic- Imatinib plasma concentration	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.	4 samples collected Day 1, and single samples collected Days 3 and 5

Collaborators and Investigators

• Sponsor: Exvastat Ltd.
• Investigators: Study Director: Gary Burgess, MD, Exvastat Ltd.

Study record dates

Study Major Dates

• Study Start (Anticipated): October 14, 2021
• Primary Completion (Anticipated): August 31, 2022
• Study Completion (Anticipated): November 30, 2022

Study Registration Dates

• First Submitted: June 29, 2021
• First Submitted That Met QC Criteria: July 5, 2021
• First Posted (Actual): July 7, 2021

Study Record Updates

• Last Update Posted (Actual): July 28, 2022
• Last Update Submitted That Met QC Criteria: July 26, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Covid-19; ARDS; Acute Respiratory Distress Syndrome; Imatinib; Endothelial Dysfunction; Oxygen Saturation Index; OSI; Pulmonary Oedema; Protein Kinase Inhibitor
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; COVID-19; Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Pulmonary Edema; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Imatinib Mesylate
• Other Study ID Numbers: EX003; 959310 (Other Grant/Funding Number: European Innovation Council Accelerator Grant)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No