Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial.
Aman J., Duijvelaar E., Botros L., Kianzad A., Schippers JR., Smeele PJ., Azhang S., Bartelink IH., Bayoumy AA., Bet PM., Boersma W., Bonta PI., Boomars KAT., Bos LDJ., van Bragt JJMH., Braunstahl G-J., Celant LR., Eger KAB., Geelhoed JJM., van Glabbeek YLE., Grotjohan HP., Hagens LA., Happe CM., Hazes BD., Heunks LMA., van den Heuvel M., Hoefsloot W., Hoek RJA., Hoekstra R., Hofstee HMA., Juffermans NP., Kemper EM., Kos R., Kunst PWA., Lammers A., van der Lee I., van der Lee EL., Maitland-van der Zee A-H., Mau Asam PFM., Mieras A., Muller M., Neefjes ECW., Nossent EJ., Oswald LMA., Overbeek MJ., Pamplona CC., Paternotte N., Pronk N., de Raaf MA., van Raaij BFM., Reijrink M., Schultz MJ., Serpa Neto A., Slob EMA., Smeenk FWJM., Smit MR., Smits AJ., Stalenhoef JE., Tuinman PR., Vanhove ALEM., Wessels JN., van Wezenbeek JCC., Vonk Noordegraaf A., de Man FS., Bogaard HJ.
BackgroundThe 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.MethodsThis 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 (1:1) 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).FindingsBetween 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.InterpretationThe 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.FundingAmsterdam Medical Center Foundation, Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ZonMW, and the European Union Innovative Medicines Initiative 2.