Clinical trial NCT04953052: 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.
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.
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
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
Lead sponsor: Exvastat Ltd.
Sponsor class: INDUSTRY
First posted: 2021-07-07
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Change from baseline in Oxygen Saturation Index (OSI) at Day 10
timeFrame: From Baseline to Day 10
Secondary outcomes:
measure: Change from Baseline in Oxygen Saturation Index (OSI) at Day 3 and Day 5
timeFrame: From Baseline to Day 3 and from baseline to Day 5
measure: Mortality rate at Day 29 and Day 60
timeFrame: Day 29 and Day 60
measure: Change from baseline in WHO 9-point ordinal scale for clinical improvement to Day 10 and Day 29
timeFrame: The WHO ordinal scale will be recorded Days 1-10 and Day 29
measure: Duration of mechanical ventilation (Days) to Day 29 and Day 60
timeFrame: To Day 29 and to Day 60
measure: Duration of stay in ICU (Days) to Day 29 and Day 60
timeFrame: To Day 29 and to Day 60
measure: Time to first successful extubation (Hours) to Day 29
timeFrame: To Day 29
measure: Number of days free of mechanical ventilation and survival (VFDsurv) at Day 29 and Day 60
timeFrame: At Day 29 and Day 60
Other outcomes:
measure: 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)
timeFrame: Day 1 to Day 29
measure: Incidence of related Treatment-Emergent Adverse Events- Tolerability
timeFrame: Day 1 to Day 29
measure: Pharmacokinetic- Imatinib plasma concentration
timeFrame: 4 samples collected Day 1, and single samples collected Days 3 and 5
Locations:
city: Vadodara
country: India
facility: Sir Sayajirao General Hospital (SSG Hospital), Medical College Baroda, Jail Road Indira Avenue)Anandpura
state: Gujarat
city: Mumbai
country: India
facility: St George's Hospital, P D Mello Road, Fort Road, CST Terminal,
state: Maharashtra
city: Nagpur
country: India
facility: Government Medical College and Hospital
state: Maharashtra
city: Nagar
country: India
facility: PCMC PGI Yashwantrao Chavan Memorial Hospital
state: Pune
city: Kolkata
country: India
facility: NRS Medical College and Hospital
state: West Bengal
city: Mangalore
country: India
facility: Father Muller Hospital and Medical College
city: Mysuru
country: India
facility: JSS Hospital
city: Nagpur
country: India
facility: Indira Gandhi Government Medical College and Hospital
Study officials:
affiliation: Exvastat Ltd.
name: Gary Burgess, MD
role: STUDY_DIRECTOR
References: