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Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial.
Aman, Jurjan; Duijvelaar, Erik; Botros, Liza; Kianzad, Azar; Schippers, Job R; Smeele, Patrick J; Azhang, Sara; Bartelink, Imke H; Bayoumy, Ahmed A; Bet, Pierre M; Boersma, Wim; Bonta, Peter I; Boomars, Karin A T; Bos, Lieuwe D J; van Bragt, Job J M H; Braunstahl, Gert-Jan; Celant, Lucas R; Eger, Katrien A B; Geelhoed, J J Miranda; van Glabbeek, Yurika L E; Grotjohan, Hans P; Hagens, Laura A; Happe, Chris M; Hazes, Boaz D; Heunks, Leo M A; van den Heuvel, Michel; Hoefsloot, Wouter; Hoek, Rianne J A; Hoekstra, Romke; Hofstee, Herman M A; Juffermans, Nicole P; Kemper, E Marleen; Kos, Renate; Kunst, Peter W A; Lammers, Ariana; van der Lee, Ivo; van der Lee, E Laurien; Maitland-van der Zee, Anke-Hilse; Mau Asam, Pearl F M; Mieras, Adinda; Muller, Mirte; Neefjes, Elisabeth C W; Nossent, Esther J; Oswald, Laurien M A; Overbeek, Maria J; Pamplona, Carolina C; Paternotte, Nienke; Pronk, Niels; de Raaf, Michiel A; van Raaij, Bas F M.
  • Aman J; Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VUMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
  • Duijvelaar E; Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VUMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
  • Botros L; Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VUMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
  • Kianzad A; Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VUMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
  • Schippers JR; Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VUMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
  • Smeele PJ; Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VUMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
  • Azhang S; Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VUMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands; Department of Pulmonology, Haaglanden Medisch Centrum, The Hague, Netherlands.
  • Bartelink IH; Department of Pharmacy, Amsterdam UMC, VUMC, Amsterdam, Netherlands.
  • Bayoumy AA; Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VUMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands; Department of Pulmonology, Chest Unit, Suez Canal University, Suez, Egypt.
  • Bet PM; Department of Pharmacy, Amsterdam UMC, VUMC, Amsterdam, Netherlands.
  • Boersma W; Department of Pulmonology, Noordwest Ziekenhuisgroep, Alkmaar, Netherlands.
  • Bonta PI; Department of Respiratory Medicine, Amsterdam UMC, AMC, University of Amsterdam, Amsterdam, Netherlands.
  • Boomars KAT; Department of Pulmonology, Erasmus Medisch Centrum, Rotterdam, Netherlands.
  • Bos LDJ; Department of Respiratory Medicine, Amsterdam UMC, AMC, University of Amsterdam, Amsterdam, Netherlands; Department of Intensive Care, Amsterdam UMC, AMC, Amsterdam, Netherlands.
  • van Bragt JJMH; Department of Respiratory Medicine, Amsterdam UMC, AMC, University of Amsterdam, Amsterdam, Netherlands.
  • Braunstahl GJ; Department of Pulmonology, Sint Franciscus Ziekenhuis, Rotterdam, Netherlands.
  • Celant LR; Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VUMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
  • Eger KAB; Department of Respiratory Medicine, Amsterdam UMC, AMC, University of Amsterdam, Amsterdam, Netherlands.
  • Geelhoed JJM; Department of Pulmonology Leiden University Medical Center, Leiden, Netherlands.
  • van Glabbeek YLE; Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VUMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
  • Grotjohan HP; Department of Pulmonology, Isala Ziekenhuizen, Zwolle, Netherlands.
  • Hagens LA; Department of Intensive Care, Amsterdam UMC, AMC, Amsterdam, Netherlands.
  • Happe CM; Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VUMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
  • Hazes BD; Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VUMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
  • Heunks LMA; Department of Intensive Care, Amsterdam UMC, VUMC, Amsterdam, Netherlands.
  • van den Heuvel M; Department of Pulmonology, Radboud UMC, Nijmegen, Netherlands.
  • Hoefsloot W; Department of Pulmonology, Radboud UMC, Nijmegen, Netherlands.
  • Hoek RJA; Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VUMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
  • Hoekstra R; Department of Pulmonology, Antonius Ziekenhuis, Sneek, Netherlands.
  • Hofstee HMA; Department of Internal Medicine, Haaglanden Medisch Centrum, The Hague, Netherlands.
  • Juffermans NP; Department of Intensive Care, Amsterdam UMC, AMC, Amsterdam, Netherlands; Department of Intensive Care, Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands.
  • Kemper EM; Hospital Pharmacy, Amsterdam UMC, AMC, Amsterdam, Netherlands.
  • Kos R; Department of Respiratory Medicine, Amsterdam UMC, AMC, University of Amsterdam, Amsterdam, Netherlands.
  • Kunst PWA; Department of Pulmonology, Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands.
  • Lammers A; Department of Respiratory Medicine, Amsterdam UMC, AMC, University of Amsterdam, Amsterdam, Netherlands.
  • van der Lee I; Department of Pulmonology, Spaarne Gasthuis, Haarlem, Netherlands.
  • van der Lee EL; Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VUMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
  • Maitland-van der Zee AH; Department of Respiratory Medicine, Amsterdam UMC, AMC, University of Amsterdam, Amsterdam, Netherlands.
  • Mau Asam PFM; Department of Respiratory Medicine, Amsterdam UMC, AMC, University of Amsterdam, Amsterdam, Netherlands.
  • Mieras A; Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VUMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
  • Muller M; Department of Pulmonology, Catharina Ziekenhuis, Eindhoven, Netherlands.
  • Neefjes ECW; Department of Pulmonology, Catharina Ziekenhuis, Eindhoven, Netherlands.
  • Nossent EJ; Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VUMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
  • Oswald LMA; Department of Pulmonology, Sint Franciscus Ziekenhuis, Rotterdam, Netherlands.
  • Overbeek MJ; Department of Pulmonology, Haaglanden Medisch Centrum, The Hague, Netherlands.
  • Pamplona CC; Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VUMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
  • Paternotte N; Department of Pulmonology, Noordwest Ziekenhuisgroep, Alkmaar, Netherlands.
  • Pronk N; Department of Pulmonology, Gelre Ziekenhuis, Apeldoorn, Netherlands.
  • de Raaf MA; Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VUMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
  • van Raaij BFM; Department of Pulmonology Leiden University Medical Center, Leiden, Netherlands.
Lancet Respir Med ; 9(9): 957-968, 2021 09.
Article in English | MEDLINE | ID: covidwho-1275790
ABSTRACT

BACKGROUND:

The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak.

METHODS:

This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged ≥18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (11) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1-9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020-001236-10).

FINDINGS:

Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56-73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0·95 [95% CI 0·76-1·20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0·51 [0·27-0·95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0·52 (95% CI 0·26-1·05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1·07 (0·63-1·80; p=0·81). The median duration of invasive mechanical ventilation was 7 days (IQR 3-13) in the imatinib group compared with 12 days (6-20) in the placebo group (p=0·0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events.

INTERPRETATION:

The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings.

FUNDING:

Amsterdam Medical Center Foundation, Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ZonMW, and the European Union Innovative Medicines Initiative 2.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Respiration, Artificial / Respiratory Insufficiency / Protein Kinase Inhibitors / Imatinib Mesylate / COVID-19 Type of study: Controlled clinical trial / Diagnostic study / Randomized controlled trials Topics: Long Covid / Vaccines Limits: Aged / Female / Humans / Male / Middle aged Country/Region as subject: Europa Language: English Journal: Lancet Respir Med Year: 2021 Document Type: Article Affiliation country: S2213-2600(21)00237-X

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Respiration, Artificial / Respiratory Insufficiency / Protein Kinase Inhibitors / Imatinib Mesylate / COVID-19 Type of study: Controlled clinical trial / Diagnostic study / Randomized controlled trials Topics: Long Covid / Vaccines Limits: Aged / Female / Humans / Male / Middle aged Country/Region as subject: Europa Language: English Journal: Lancet Respir Med Year: 2021 Document Type: Article Affiliation country: S2213-2600(21)00237-X