Nicotine patches in patients on mechanical ventilation for severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial

Guylaine Labro, Florence Tubach, Lisa Belin, Jean-Louis Dubost, David Osman, Grégoire Muller, Jean-Pierre Quenot, Daniel Da Silva, Jonathan Zarka, Matthieu Turpin, Julien Mayaux, Christian Lamer, Denis Doyen, Guillaume Chevrel, Gaétan Plantefeve, Sophie Demeret, Gaël Piton, Cyril Manzon, Evelina Ochin, Raphael Gaillard, Bertrand Dautzenberg, Mathieu Baldacini, Said Lebbah, Makoto Miyara, Marc Pineton de Chambrun, Zahir Amoura, Alain Combes, NICOVID-REA Trial Group, Jessica Palmyre, Linda Gimeno, Assitan Kone, Cedric Vialette, Ouramdane Slimi, Juliette Chommeloux, Lucie Lefevre, Matthieu Schmidt, Guillaume Hekimian, Charles-Edouard Luyt, Laure Stiel, Anne-Florence Dureau, Kuteifan Khaldoun, Hanna Eid, Matthieu Baldacini, Cecile Zyberfajn, Julien Manson, Nathanael Charrier, Angelique Balabanian, Damien Contou, Olivier Pajot, Megan Fraisse, Paul Desaint, Florence Sarfati, Muriel Fartoukh, Guillaume Voirot, Alexandre Elabbabi, Michel Djibre, Cyrielle Desnos, Pierre Garcon, Ly van Vong, Andrea Issad, Bertrand Pillot, Delphine Reither, Patrick Rouge, Pascale Foliot, Lynda Bendjamar, Valentin Pointurier, Hadrien Winiszewski, Gilles Capellier, Jean-Christophe Navellou, Romain Tapponnier, Emilie Panicucci, Lucas Morand, Jean Dellamonica, Clement Saccheri, Nicolas Weiss, Clemence Marois, Loic Le Guennec, Benjamin Rohaut, Luis Ensenat, Cecilia Billiou, Maria Aroca, Marie Baron, Alexandre Demoule, Alexandra Beurton, Come Bureau, Maxens Decavele, Martin Dres, Frederique Bayle, Quoc Viet Le, Lionel Liron, Jean-Baptiste Putegnat, Francois Salord, Pascal Andreu, Hakim Slimani, Baptiste Roudeau, Marie Labruyere, Marine Jacquier, Nadia Anguel, Soufia Ayed, Edgard Durand, Laurent Guerin, Christopher Lai, Jerome Aboab, Sophie Alviset, Laurent Laine, Mathilde Azzi, Tazime Issoufaly, Laurent Tric, Lyes Knani, Chahrazad Bey Boumezrag, Nicolas Viault, Francois Barbier, Thierry Boulain, Toufik Kamel, Mai-Anh Nay, Sophie Tollec, An Hung Nguyen, Guylaine Labro, Florence Tubach, Lisa Belin, Jean-Louis Dubost, David Osman, Grégoire Muller, Jean-Pierre Quenot, Daniel Da Silva, Jonathan Zarka, Matthieu Turpin, Julien Mayaux, Christian Lamer, Denis Doyen, Guillaume Chevrel, Gaétan Plantefeve, Sophie Demeret, Gaël Piton, Cyril Manzon, Evelina Ochin, Raphael Gaillard, Bertrand Dautzenberg, Mathieu Baldacini, Said Lebbah, Makoto Miyara, Marc Pineton de Chambrun, Zahir Amoura, Alain Combes, NICOVID-REA Trial Group, Jessica Palmyre, Linda Gimeno, Assitan Kone, Cedric Vialette, Ouramdane Slimi, Juliette Chommeloux, Lucie Lefevre, Matthieu Schmidt, Guillaume Hekimian, Charles-Edouard Luyt, Laure Stiel, Anne-Florence Dureau, Kuteifan Khaldoun, Hanna Eid, Matthieu Baldacini, Cecile Zyberfajn, Julien Manson, Nathanael Charrier, Angelique Balabanian, Damien Contou, Olivier Pajot, Megan Fraisse, Paul Desaint, Florence Sarfati, Muriel Fartoukh, Guillaume Voirot, Alexandre Elabbabi, Michel Djibre, Cyrielle Desnos, Pierre Garcon, Ly van Vong, Andrea Issad, Bertrand Pillot, Delphine Reither, Patrick Rouge, Pascale Foliot, Lynda Bendjamar, Valentin Pointurier, Hadrien Winiszewski, Gilles Capellier, Jean-Christophe Navellou, Romain Tapponnier, Emilie Panicucci, Lucas Morand, Jean Dellamonica, Clement Saccheri, Nicolas Weiss, Clemence Marois, Loic Le Guennec, Benjamin Rohaut, Luis Ensenat, Cecilia Billiou, Maria Aroca, Marie Baron, Alexandre Demoule, Alexandra Beurton, Come Bureau, Maxens Decavele, Martin Dres, Frederique Bayle, Quoc Viet Le, Lionel Liron, Jean-Baptiste Putegnat, Francois Salord, Pascal Andreu, Hakim Slimani, Baptiste Roudeau, Marie Labruyere, Marine Jacquier, Nadia Anguel, Soufia Ayed, Edgard Durand, Laurent Guerin, Christopher Lai, Jerome Aboab, Sophie Alviset, Laurent Laine, Mathilde Azzi, Tazime Issoufaly, Laurent Tric, Lyes Knani, Chahrazad Bey Boumezrag, Nicolas Viault, Francois Barbier, Thierry Boulain, Toufik Kamel, Mai-Anh Nay, Sophie Tollec, An Hung Nguyen

Abstract

Purpose: Epidemiologic studies have documented lower rates of active smokers compared to former or non-smokers in symptomatic patients affected by coronavirus disease 2019 (COVID-19). We assessed the efficacy and safety of nicotine administered by a transdermal patch in critically ill patients with COVID-19 pneumonia.

Methods: In this multicentre, double-blind, placebo-controlled trial conducted in 18 intensive care units in France, we randomly assigned adult patients (non-smokers, non-vapers or who had quit smoking/vaping for at least 12 months) with proven COVID-19 pneumonia receiving invasive mechanical ventilation for up to 72 h to receive transdermal patches containing either nicotine at a daily dose of 14 mg or placebo until 48 h following successful weaning from mechanical ventilation or for a maximum of 30 days, followed by 3-week dose tapering by 3.5 mg per week. Randomization was stratified by centre, non- or former smoker status and Sequential Organ Function Assessment score (< or ≥ 7). The primary outcome was day-28 mortality. Main prespecified secondary outcomes included 60-day mortality, time to successful extubation, days alive and free from mechanical ventilation, renal replacement therapy, vasopressor support or organ failure at day 28.

Results: Between November 6th 2020, and April 2nd 2021, 220 patients were randomized from 18 active recruiting centers. After excluding 2 patients who withdrew consent, 218 patients (152 [70%] men) were included in the analysis: 106 patients to the nicotine group and 112 to the placebo group. Day-28 mortality did not differ between the two groups (30 [28%] of 106 patients in the nicotine group vs 31 [28%] of 112 patients in the placebo group; odds ratio 1.03 [95% confidence interval, CI 0.57-1.87]; p = 0.46). The median number of day-28 ventilator-free days was 0 (IQR 0-14) in the nicotine group and 0 (0-13) in the placebo group (with a difference estimate between the medians of 0 [95% CI -3-7]). Adverse events likely related to nicotine were rare (3%) and similar between the two groups.

Conclusion: In patients having developed severe COVID-19 pneumonia requiring invasive mechanical ventilation, transdermal nicotine did not significantly reduce day-28 mortality. There is no indication to use nicotine in this situation.

Trial registration: ClinicalTrials.gov NCT04598594.

Keywords: Acute respiratory failure; Artificial; COVID-19; Intensive care units; Nicotine; Nicotinic receptor; Randomized trial; Ventilation.

Conflict of interest statement

RG has received compensation as a member of the scientific advisory board of Janssen, Lundbeck, Roche, SOBI, Takeda. He has served as consultant and/or speaker for Astra Zeneca, Boehringer-Ingelheim, Pierre Fabre, Lilly, Lundbeck, LVMH, MAPREG, Novartis, Otsuka, Pileje, SANOFI, Servier and received compensation, and he has received research support from Servier. Co-founder and stock shareholder: Regstem. AC reported receiving grants and personal fees from Maquet, Xenios and Baxter outside the submitted work. No other disclosures were reported.

© 2022. Springer-Verlag GmbH Germany, part of Springer Nature.

Figures

Fig. 1
Fig. 1
Enrolment, randomization, and follow-up of the study participants
Fig. 2
Fig. 2
Kaplan–Meier survival estimates in the intention-to-treat population during the first 28 study days
Fig. 3
Fig. 3
Subgroup analysis

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