Intravenous Imatinib in Mechanically Ventilated COVID-19 Patients

NCT04794088 | Terminated Phase 2 DMC

• 1 other identifier: INVENT COVID
• Study Type: interventional
• Target: 67
• Locations: 1 country
• Sites: 2

Brief Summary

The SARS-CoV2 pandemic and resulting COVID-19 infection has led to a large increase in the number of patients 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 strengthens the cell barrier and prevents fluid leak in the lungs in inflammatory conditions, while leaving the immune response intact. The investigators hypothesize that imatinib limits pulmonary oedema observed in ARDS due to COVID-19, and may thus help to reverse hypoxemic respiratory failure and to hasten recovery. The hypothesis will be tested by conducting a randomised, double-blind, parallel-group, placebo-controlled multi-centre clinical study of intravenous imatinib in 90 mechanically-ventilated, adult subjects with COVID-19-related ARDS. Study participants will receive the study drug (imatinib or placebo) twice daily for a period of 7 days. The effect of the intervention will be tested by measuring extravascular lung water (i.e. pulmonary oedema) difference between day 1 and day 4, using a PiCCO catheter (= pulse contour cardiac monitoring device). Other measurements will include regular blood tests to investigate the safety and the pharmacokinetic properties of imatinib, as well as biomarkers of inflammation and cellular dysfunction. Furthermore, parameters of ventilation and morbidity and mortality will be recorded as secondary outcome measures.

Conditions

ARDS; Acute Respiratory Distress Syndrome; Covid19; Endothelial Dysfunction; Pulmonary Edema

Keywords

ARDS; Acute Respiratory Distress Syndrome; COVID19; IMATINIB; IMATINIB MESYLATE; ENDOTHELIAL DYSFUNCTION; PULMONARY VASCULAR LEAK; PULMONARY EDEMA

Outcome Measures

Primary Outcomes (1)

• Change in extravascular lung water index

  Change in extravascular lung water index (EVLWi) between day 1 and day 4, measured by PiCCO catheter.

  Measurements conducted on days 1 - 7. Change measured between Day 1 and Day 4

Secondary Outcomes (32)

• Pulmonary vascular permeability

  PVPi measured and recorded on days 1 - 7.

• PaO2/FiO2 ratio as measure of gas-exchange

  Recorded on days 1, 2, 4, 7, 10 and, if available, day 28.

• Oxygenation index as measure of gas-exchange

  Recorded on days 1, 2, 4, 7, 10 and, if available, day 28.

• Driving pressure as an indicator of global lung strain

  Recorded on days 1, 2, 4, 7, 10 and, if available, day 28.

• Compliance as a measure of respiratory mechanics

  Recorded on days 1, 2, 4, 7, 10 and, if available, day 28.

Other Outcomes (9)

• Baseline demographic parameters

  Baseline demographics collected at baseline (day 0).

• Medical history and comorbidities

  Medical history collected at baseline (day 0).

• Heart rate as vital parameter

  Collected on days 1 - 7,10 and, if available, 28.

Study Arms (2)

Intravenous imatinib mesylate (Impentri®)

ACTIVE COMPARATOR

Patients receiving the active investigational medicinal product will be receiving imatinib 200mg b.i.d. (administered as an 8 mg/mL solution for i.v. infusion) for 7 days.

Drug: Imatinib Mesylate intravenous solution

Placebo solution

PLACEBO COMPARATOR

Patients receiving the placebo comparator will be receiving the same amount of intravenous solution, however containing 0.01M acetate buffer with 1.9% glycerol.

Drug: Placebo

Interventions

Imatinib Mesylate intravenous solution DRUG

A 25ml volume of IMP will be administered over 2-hours as an intravenous infusion. This corresponds to a dose of 200mg imatinib (100mg/h).

Also known as: Imatinib, Impetri

Intravenous imatinib mesylate (Impentri®)

Placebo DRUG

A 25ml volume of IMP will be administered over 2-hours as an intravenous infusion. This corresponds to a dose of 25ml placebo (12.5ml/h).

Placebo solution

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years;
• Moderate-severe ARDS, as defined by Berlin definition for ARDS (onset within 1 week of a known clinical insult or new or worsening respiratory symptoms, bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules, respiratory failure not fully explained by cardiac failure or fluid overload and P/F ratio ≤200 mmHg with PEEP ≥5 cmH2O), and intubated for mechanical ventilation.
• PCR positive for SARS-CoV2 within the current disease episode.
• Provision of signed written informed consent from the patient or patient's legally authorised representative;

You may not qualify if:

• Persistent septic shock (\>24h) 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;
• Pre-existing chronic pulmonary disease, including:
• Known diagnosis of Interstitial Lung disease
• Known diagnosis of COPD GOLD Stage IV or FEV1\<30% predicted
• DLCO \<45% (if test results are available)
• Total lung capacity (TLC) \< 60% of predicted (if test results are available);
• Chronic home oxygen treatment;
• Pre-existing heart failure with a known left ventricular ejection fraction \<40%;
• Active treatment of haematological or non-haematological cancer with targeted immuno- or chemotherapy, or thoracic radiotherapy in the last year;
• Currently receiving extracorporeal life support (ECLS);
• Severe chronic liver disease with Child-Pugh score \> 12;
• Subjects in whom a decision to withdraw medical care is made (e.g. palliative setting);
• Inability of the ICU staff to initiate IMP administration within 48 hours of intubation;
• Known to be pregnant or breast-feeding;
• Enrolled in a concomitant clinical trial of an investigational medicinal product;

Sponsors & Collaborators

• Dr. Jurjan Aman: lead
• Simbec-Orion Group: collaborator
• Exvastat Ltd.: collaborator
• KABS laboratories: collaborator

Study Sites (2)

Amsterdam Universitair Medische Centra, location VUmc

Amsterdam, North Holland, 1081 HV, Netherlands

Location

Amsterdam Universitair Medische Centra, location AMC

Amsterdam, North Holland, 1105 AZ, Netherlands

Location

Related Publications (22)

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  PMID: 23099479 BACKGROUND

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  PMID: 32555369 BACKGROUND

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• Kim IK, Rhee CK, Yeo CD, Kang HH, Lee DG, Lee SH, Kim JW. Effect of tyrosine kinase inhibitors, imatinib and nilotinib, in murine lipopolysaccharide-induced acute lung injury during neutropenia recovery. Crit Care. 2013 Jun 20;17(3):R114. doi: 10.1186/cc12786.

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  PMID: 14975929 BACKGROUND

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• Letsiou E, Rizzo AN, Sammani S, Naureckas P, Jacobson JR, Garcia JG, Dudek SM. Differential and opposing effects of imatinib on LPS- and ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol. 2015 Feb 1;308(3):L259-69. doi: 10.1152/ajplung.00323.2014. Epub 2014 Dec 5.

  PMID: 25480336 BACKGROUND

• Morales-Ortega A, Bernal-Bello D, Llarena-Barroso C, Frutos-Perez B, Duarte-Millan MA, Garcia de Viedma-Garcia V, Farfan-Sedano AI, Canalejo-Castrillero E, Ruiz-Giardin JM, Ruiz-Ruiz J, San Martin-Lopez JV. Imatinib for COVID-19: A case report. Clin Immunol. 2020 Sep;218:108518. doi: 10.1016/j.clim.2020.108518. Epub 2020 Jun 27. No abstract available.

  PMID: 32599278 BACKGROUND

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  PMID: 16873671 BACKGROUND

• Overbeek MJ, van Nieuw Amerongen GP, Boonstra A, Smit EF, Vonk-Noordegraaf A. Possible role of imatinib in clinical pulmonary veno-occlusive disease. Eur Respir J. 2008 Jul;32(1):232-5. doi: 10.1183/09031936.00054407.

  PMID: 18591341 BACKGROUND

• Peng B, Dutreix C, Mehring G, Hayes MJ, Ben-Am M, Seiberling M, Pokorny R, Capdeville R, Lloyd P. Absolute bioavailability of imatinib (Glivec) orally versus intravenous infusion. J Clin Pharmacol. 2004 Feb;44(2):158-62. doi: 10.1177/0091270003262101.

  PMID: 14747424 BACKGROUND

• Reeves PM, Bommarius B, Lebeis S, McNulty S, Christensen J, Swimm A, Chahroudi A, Chavan R, Feinberg MB, Veach D, Bornmann W, Sherman M, Kalman D. Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases. Nat Med. 2005 Jul;11(7):731-9. doi: 10.1038/nm1265. Epub 2005 Jun 26.

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• Rhee CK, Lee SH, Yoon HK, Kim SC, Lee SY, Kwon SS, Kim YK, Kim KH, Kim TJ, Kim JW. Effect of nilotinib on bleomycin-induced acute lung injury and pulmonary fibrosis in mice. Respiration. 2011;82(3):273-87. doi: 10.1159/000327719. Epub 2011 Jun 9.

  PMID: 21659722 BACKGROUND

• Rizzo AN, Aman J, van Nieuw Amerongen GP, Dudek SM. Targeting Abl kinases to regulate vascular leak during sepsis and acute respiratory distress syndrome. Arterioscler Thromb Vasc Biol. 2015 May;35(5):1071-9. doi: 10.1161/ATVBAHA.115.305085. Epub 2015 Mar 26.

  PMID: 25814671 BACKGROUND

• Singh N, Kumar L, Meena R, Velpandian T. Drug monitoring of imatinib levels in patients undergoing therapy for chronic myeloid leukaemia: comparing plasma levels of responders and non-responders. Eur J Clin Pharmacol. 2009 Jun;65(6):545-9. doi: 10.1007/s00228-009-0621-z. Epub 2009 Feb 12.

  PMID: 19214491 BACKGROUND

• Stephens RS, Johnston L, Servinsky L, Kim BS, Damarla M. The tyrosine kinase inhibitor imatinib prevents lung injury and death after intravenous LPS in mice. Physiol Rep. 2015 Nov;3(11):e12589. doi: 10.14814/phy2.12589.

  PMID: 26620257 BACKGROUND

• Said MM, Braam AM, Duijvelaar E, Schippers JR, Atmowihardjo L, Twisk J, Bogaard HJ, Swart EL, Aman J, Bartelink IH. Exposure-response analysis of oral and intravenous imatinib in critically ill patients with COVID-19 acute respiratory distress syndrome. Eur J Pharm Sci. 2025 Dec 1;215:107332. doi: 10.1016/j.ejps.2025.107332. Epub 2025 Oct 17.

  PMID: 41109533 DERIVED

• Atmowihardjo LN, Schippers JR, Haaksma ME, Smit MR, Bogaard HJ, Heunks L, Juffermans NP, Schultz MJ, Endeman H, van Velzen P, Tuinman PR, Aman J, Bos LDJ. The diagnostic accuracy of lung ultrasound to determine PiCCO-derived extravascular lung water in invasively ventilated patients with COVID-19 ARDS. Ultrasound J. 2023 Oct 2;15(1):40. doi: 10.1186/s13089-023-00340-7.

  PMID: 37782370 DERIVED

• Atmowihardjo LN, Schippers JR, Duijvelaar E, Bartelink IH, Bet PM, Swart NEL, van Rein N, Purdy K, Cavalla D, McElroy A, Fritchley S, Vonk Noordegraaf A, Endeman H, van Velzen P, Koopmans M, Bogaard HJ, Heunks L, Juffermans N, Schultz MJ, Tuinman PR, Bos LDJ, Aman J. Efficacy and safety of intravenous imatinib in COVID-19 ARDS: a randomized, double-blind, placebo-controlled clinical trial. Crit Care. 2023 Jun 8;27(1):226. doi: 10.1186/s13054-023-04516-4.

  PMID: 37291677 DERIVED

• Duijvelaar E, Vanhove A, Schippers JR, Smeele PJ, de Man FS, Pinto Y, Aman J, Bogaard HJ; CounterCOVID Collaborative Group. Cardiac Safety of Imatinib for the Treatment of COVID-19: A Secondary Analysis of a Randomized, Double-Blind, Placebo-Controlled Trial. J Cardiovasc Pharmacol. 2022 Dec 1;80(6):783-791. doi: 10.1097/FJC.0000000000001344.

  PMID: 35976136 DERIVED

• Atmowihardjo L, Schippers JR, Bartelink IH, Bet PM, van Rein N, Purdy K, Cavalla D, Comberiati V, McElroy A, Snape SD, Bogaard HJ, Heunks L, Juffermans N, Schultz M, Tuinman PR, Bos LDJ, Aman J. The INVENT COVID trial: a structured protocol for a randomized controlled trial investigating the efficacy and safety of intravenous imatinib mesylate (Impentri(R)) in subjects with acute respiratory distress syndrome induced by COVID-19. Trials. 2022 Feb 16;23(1):158. doi: 10.1186/s13063-022-06055-9.

  PMID: 35172891 DERIVED

MeSH Terms

Conditions

Respiratory Distress Syndrome; COVID-19; Pulmonary Edema

Interventions

Imatinib Mesylate

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines

Study Officials

• Jurjan Aman, Dr.

  Amsterdam Universitair Medische Centra, location VUmc

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-blinded trial in which the study participant and legal representative, as well as the treating nurses, physicians and researchers are blinded from viewing randomisation allocation.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Dr. J. Aman, Trial Coordinator

Model Details: Randomised, double-blind, parallel-group, placebo-controlled multi-centre clinical trial

Study Record Dates

• First Submitted: February 26, 2021
• First Posted: March 11, 2021
• Study Start: March 14, 2021
• Primary Completion: March 16, 2022
• Study Completion: April 7, 2022
• Last Updated: January 23, 2023

Record last verified: 2023-01

Locations

NL (2)