IMPRESS COVID: 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.

Sponsor

Exvastat Ltd. (Industry)

Overall Status

Withdrawn

CT.gov ID

NCT04953052

Collaborator

(none)

Enrollment

Locations

Arms

13.5

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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

Study Design

Study Type:

Interventional

Actual Enrollment :

0 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.

Anticipated Study Start Date :

Oct 14, 2021

Anticipated Primary Completion Date :

Aug 31, 2022

Anticipated Study Completion Date :

Nov 30, 2022

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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]
Oxygen saturation measured by pulse oximetry
Mortality rate at Day 29 and Day 60 [Day 29 and Day 60]
Mortality at 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]
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.
Duration of mechanical ventilation (Days) to Day 29 and Day 60 [To Day 29 and to Day 60]
Number of days requiring to be on mechanical ventilation
Duration of stay in ICU (Days) to Day 29 and Day 60 [To Day 29 and to Day 60]
Number of days within the ICU
Time to first successful extubation (Hours) to Day 29 [To Day 29]
Number of hours to extubation (removal of the endotracheal tube)
Number of days free of mechanical ventilation and survival (VFDsurv) at Day 29 and Day 60 [At Day 29 and Day 60]
Amongst survivors, the number of days free from mechanical ventilation

Other Outcome Measures

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]
Safety adverse events and serious adverse event collection
Incidence of related Treatment-Emergent Adverse Events- Tolerability [Day 1 to Day 29]
Tolerability
Pharmacokinetic- Imatinib plasma concentration [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Exclusion Criteria:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sir Sayajirao General Hospital (SSG Hospital), Medical College Baroda, Jail Road Indira Avenue)Anandpura	Vadodara	Gujarat	India	390001
2	St George's Hospital, P D Mello Road, Fort Road, CST Terminal,	Mumbai	Maharashtra	India	400001
3	Government Medical College and Hospital	Nagpur	Maharashtra	India	440003
4	PCMC PGI Yashwantrao Chavan Memorial Hospital	Nagar	Pune	India	411018
5	NRS Medical College and Hospital	Kolkata	West Bengal	India	700014
6	Father Muller Hospital and Medical College	Mangalore		India	575002
7	JSS Hospital	Mysuru		India	570004
8	Indira Gandhi Government Medical College and Hospital	Nagpur		India	440018