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.

NCT04953052 | Withdrawn Phase 2 DMC

• 2 other identifiers: EX003959310
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 8

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.

Conditions

Acute Respiratory Distress Syndrome; COVID-19 Acute Respiratory Distress Syndrome; Covid19; ARDS; Pulmonary Oedema

Keywords

Acute Respiratory Distress Syndrome; ARDS; Covid-19; Imatinib; Oxygen Saturation Index; OSI; Endothelial Dysfunction; Pulmonary Oedema; Protein Kinase Inhibitor

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• Change from Baseline in Oxygen Saturation Index (OSI) at Day 3 and Day 5

  From Baseline to Day 3 and from baseline to Day 5

• Mortality rate 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 will be recorded Days 1-10 and Day 29

• Duration of mechanical ventilation (Days) to Day 29 and Day 60

  To Day 29 and to Day 60

• Duration of stay in ICU (Days) to Day 29 and Day 60

  To Day 29 and to Day 60

Other Outcomes (3)

• 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)

  Day 1 to Day 29

• Incidence of related Treatment-Emergent Adverse Events- Tolerability

  Day 1 to Day 29

• Pharmacokinetic- Imatinib plasma concentration

  4 samples collected Day 1, and single samples collected Days 3 and 5

Study Arms (2)

Intravenous Imatinib Mesylate

EXPERIMENTAL

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

Intravenous Placebo

PLACEBO COMPARATOR

Intravenous Placebo matched solution- administered 25ml solution, twice daily over a two-hour infusion period

Drug: Placebo

Interventions

Imatinib Mesylate DRUG

An isotonic sterile solution of imatinib.

Also known as: Impentri

Intravenous Imatinib Mesylate

Placebo DRUG

An isotonic sterile solution

Intravenous Placebo

Eligibility Criteria

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

You may qualify if:

• Male or female patients aged ≥18 years
• Women of childbearing potential must have a negative serum pregnancy test to confirm eligibility
• Provision of signed written informed consent from the patient or patient's legally acceptable representative
• 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)
• Meet Berlin definition for moderate - severe ARDS
• Bilateral opacities - not fully explained by effusions, lobar/lung collapse, or nodules
• Respiratory failure not fully explained by cardiac failure or fluid overload.
• PaO2/FIO2 ≤200 mmHg with PEEP ≥5 cmH2O
• Patient requires intubation or is currently intubated and has been for ≤48 hours

You may not qualify if:

• 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
• Major trauma in the past 5 days
• Presence of any active malignancy (other than non-melanoma skin cancer) that required treatment within the last year
• 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
• 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)
• Patients considered inappropriate for critical care (e.g., being considered for palliative care)
• Currently receiving extracorporeal membrane oxygenation (ECMO)
• Severe chronic liver disease with Child-Pugh score \>12 (Appendix 1)
• White blood count \<2.5 x 109/L; Hemoglobin \<4.0 mmol/L (6.5g/dL); Platelets \<50 x 109/L
• ALT or AST \>10x upper limit of normal (ULN) or bilirubin \>3x ULN
• Women who are pregnant or breast-feeding
• Use of drugs with strong CYP3A4 induction potential, such as carbamazepine, efavirenz, enzalutamide, phenobarbital, phenytoin, hypericum, mitotane, nevirapine, primidone, rifabutin and rifampicin
• Inability of the ICU staff to initiate administration of study treatment within 48 hours of intubation
• Enrolled in a concomitant clinical trial of an investigational medicinal product
• In the opinion of the investigator, progression to death is highly probable, irrespective of the provision of treatments

Sponsors & Collaborators

• Exvastat Ltd.: lead

Study Sites (8)

Sir Sayajirao General Hospital (SSG Hospital), Medical College Baroda, Jail Road Indira Avenue)Anandpura

Vadodara, Gujarat, 390001, India

Location

St George's Hospital, P D Mello Road, Fort Road, CST Terminal,

Mumbai, Maharashtra, 400001, India

Location

Government Medical College and Hospital

Nagpur, Maharashtra, 440003, India

Location

PCMC PGI Yashwantrao Chavan Memorial Hospital

Nagar, Pune, 411018, India

Location

NRS Medical College and Hospital

Kolkata, West Bengal, 700014, India

Location

Father Muller Hospital and Medical College

Mangalore, 575002, India

Location

JSS Hospital

Mysuru, 570004, India

Location

Indira Gandhi Government Medical College and Hospital

Nagpur, 440018, India

Location

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

• Gary Burgess, MD

  Exvastat Ltd.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 29, 2021
• First Posted: July 7, 2021
• Study Start: October 14, 2021
• Primary Completion: August 31, 2022
• Study Completion: November 30, 2022
• Last Updated: July 28, 2022

Record last verified: 2022-07

Locations

IN (8)