To test whether treatment with oral imatinib reduce disease burden and consumption of medical resources.
ID
Source
Brief title
Condition
- Respiratory tract infections
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main study parameter is the time to liberation from ventilation and
supplemental oxygen and alive during a 28 day period after randomization
Secondary outcome
- Secondary efficacy parameters
o 28-day mortality
o Need for ICU admission
o Length of ICU admission
o Need for invasive ventilation
o Days on ventilator
o Need for ECMO
o Need for non-invasive ventilation
o Length of non-invasive ventilation
o SpO2 at Day 1,2,3,4,5,7,9
o Fi O2 at Day 1,2,3,4,5,7,9
o SpO2/FiO2 at Day 1,2,3,4,5,7,9
o Length of oxygen suppletion
- Safety parameters
o Blood cell count Day 0,1,2,3,5,7,9
o Kidney function Day 0,1,2,3,5,7,9
o Liver enzymes Day 0,1,2,3,5,7,9
o NTproBNP at Day 0,1,2,3,5,7,9
o SAEs / AE
o ECG at Day 1,3,5,9
- Pharmacokinetics
o Study drug plasma levels at 4h, 8h, Day 1,3,5,7,9
o Albumin, AGP1 at Day 0,1,2,3,5,7,9
- Immune responses (subgroups of 50 patients per study arm)
o Host response plasma biomarkers on day 0, 5 and 9, and on the first
day of any additional interventions (invasive ventilation, CT scanning,
bronchoscopy).
o Neutrophil RNA sequencing, metabolomics and lipidomics on day 0 and 5
o Phenotypic and functional analysis of whole blood, peripheral blood
mononuclear cells and polymorphonuclear leukocytes on day 0 and 5, and on the
first day of additional interventions (invasive ventilation, CT scanning,
bronchoscopy).
- Fibrotic responses (subgroups of 50 patients per study arm)
o Fibrotic plasma biomarkers on day 0, 5 and 9, and on the first day of
any additional interventions (invasive ventilation, CT scanning, bronchoscopy)
Background summary
Covid19 is characterized by hypoxemic respiratory failure, caused by extensive
vascular leak and pulmonary edema early in the course of disease. Although
there is no proven therapy to reduce viral replication in Covid19, recent
studies from our department have discovered that the tyrosine kinase inhibitor
imatinib reinforces the endothelial barrier and prevents vascular leak in
inflammatory conditions, while leaving the immune response intact. We
hypothesize that reversing vascular leak is an effective approach to reduce
disease burden and consumption of medical resources.
Study objective
To test whether treatment with oral imatinib reduce disease burden and
consumption of medical resources.
Study design
Study design: A randomized, double-blind, placebo controlled, clinical trial.
Intervention
Intervention: The intervention group will receive a starting dose of 800mg oral
imatinib once daily, followed by 400mg once daily during 9 days. The control
group will receive a similar dosing schedule with a placebo.
Study burden and risks
Common side effects of imatinib include flushing, cough, flatulence,
gastro-esophageal reflux, and gastritis. Relevant uncommon side effects include
palpitations, cardiac failure, pleural effusion, acute renal failure, melena,
chest pain and pancytopenia (although the pancytopenia was observed in patients
in CML was shown to result from apoptosis of leukemic cells, and that
repopulation with non-affected leucocytes was undisturbed under imatinib
treatment). In general side effects are mild, and usually occur after chronic
use. As the imatinib treatment in this study is relatively short (days)
compared to the chronic use in CML (months-years), we anticipate that the side
effects observed in CML studies are less frequent in the study proposed here.
An extensive discussion of relevant side effect and imatinib toxicity is
provided in the investigators brochure. Altogether, the potential benefit of
preventing mechanical ventilation and reducing health care consumption
outweighs the mild side effects observed in imatinib use.
de Boelelaan 1117
Amsterdam 1007 MB
NL
de Boelelaan 1117
Amsterdam 1007 MB
NL
Listed location countries
Age
Inclusion criteria
- Age >18 years
- Hospital admission with proven SARS2-Covid19 infection
- Hypoxemic respiratory failure (SpaO2 <94% or, PaO2 <9kPa)
- Ability to give informed consent.
Exclusion criteria
- Pre-existing chronic pulmonary disease
- Former diagnosis of Interstitial pulmonary disease
- Former diagnosis of COPD 4 or FEV1<30%pred
- Previous DLCO <45%
- Total lung capacity (TLC) < 60% of predicted
- Lung cancer with non-surgical treatment in last year
- Chronic home oxygen treatment
- Pre-existing heart failure with a known left ventricular ejection fraction
<40%
- Active treatment of hematological or non-hematological cancer with targeted,
immuno- or chemotherapy or targeted radiotherpay in the last year
- Inability to provide informed consent
- Any subject who had received any investigational medication within 1 month
prior to the start of this study or who is scheduled to receive another
investigational drug during the course of this study
- Active liver disease, porphyria or elevations of serums transaminases >5 x
ULN (upper limit of normal) or bilirubin > 1.5 x ULN
- History or suspicion of inability to cooperate adequately.
- White blood count < 4.0^109/l
- Hemoglobin < 6.0 mmol/l
- Thrombocytes < 100^109/l
- Pregnant femae subjects (pregnancy test will be performed in all women of
childbearing age prior to inclusion)
- Breastfeeding female subjects
- Use of strong Cyp3A4 inductors, including the following drugs: Carbamazepine,
efavirenz, enzalutamide, fenobarbital, fenytoine, hypericum, mitotaan,
nevirapine, primidon, rifabutine, rifampicine
- Concomittant use of chloroquine or hydroxychloroquine.
- QTc >500msec at baseline.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | 2020-001236-10 (EUDRACT) |
| EudraCT | EUCTR2020-001236-10-NL |
| CCMO | NL73501.029.20 |