Clinical trial NCT04598594: Evaluation of the Efficacy of Nicotine Patches in SARS-CoV2 (COVID-19) Infection in Intensive Care Unit Patients
Official title: Evaluation of the Efficacy of Nicotine Patches in SARS-CoV2 (COVID-19) Infection in Intensive Care Unit Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Covid19
SARS-Associated Coronavirus as Cause of Disease Classified Elsewhere
Keywords: Covid19
SARS-CoV2
Mechanical ventilation
ICU
Nicotine
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2020-10-22
Enrollment: 220
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: There is currently no known treatment for COVID19. Active smokers are infrequent among patients with COVID-19 which has led our team to hypothesize that nicotine is responsible for this protective effect via the nicotinic acetylcholine receptor (nAChR). In fact, nAChR possess the ability to modulate ACE2 expression, the cellular doorway for SARS-CoV2. nAChR modulation by the virus would be responsible for the numerous clinical signs observed in COVID-19, including the cytokine storm manifested in intensive care hyperinflammatory patients.

Based on epidemiological data and experimental data from scientific literature, our team hypothesize that nicotine could inhibit the penetration and propagation of SARS-CoV2. Our team also claim that nicotine could attenuate the hyperinflammatory response and cytokine storm leading to acute respiratory failure and a probable multi-organ failure associated with COVID19.


Eligibility criteria: Inclusion Criteria:

1. Patient ≥ 18 years
2. Documented diagnosis of COVID 19 (according to the tests referenced on the list published on the website : https://covid-19.sante.gouv.fr.tests)
3. Hospitalized in intensive care unit, intubated and mechanically ventilated for less than 48 hours
4. Non-smoker and non-vaping or abstinent patient for at least 12 months
5. Obtain written informed consent from a relative / relative / support person. In the absence of a close/relative/trusted person, the patient may be included according to the emergency procedure by the investigating doctor.
6. Affiliated to a social security scheme or beneficiary of such a scheme (AME excluded)

Exclusion Criteria:

1. Chronic respiratory failure defined by PaCO2\> 60 mmHg in ambulatory patients (respiratory parameters at baseline).
2. Mechanical ventilation at home (non-invasive mechanical ventilation or via a tracheostomy) with the exception of CPAP / BIPAP used only for sleep apnea syndromes
3. Predictable mechanical ventilation duration \<48 hours
4. Moribund patient or death expected on the day of randomization, or with a SAPS II score\> 90
5. Cerebral deficiency with dilated areactive pupils or irreversible neurological pathology.
6. Other concomitant severe pathology with an estimated life expectancy of less than 1 year
7. Treatment with nicotine replacement therapy or varenicline or bupropion ongoing
8. Contraindication for nicotine patches:

   * Pregnant or breastfeeding women
   * Allergy to nicotine or to one of the excipients of the transdermal patch
   * Generalized skin pathologies
   * Cerebrovascular accident or acute coronary syndrome for less than 3 months
   * Pheochromocytoma
   * Unstable or worsening angor
   * Severe cardiac arrhythmia (Defined by wearing an automatic implantable defibrillator)
   * Known severe heart failure (Defined, for this study, by systolic LV dysfunction with an LV ejection fraction (LVEF) of less than 30%)
   * Severe renal failure (Defined by KDIGO stage 3)
   * Severe hepatic impairment (Defined by a factor V \<30%)
   * Arteriopathy obliterating of the lower limbs stage III and IV
   * Uncontrolled hyperthyroidism
   * Gastroduodenal esophagitis or ulcer undergoing treatment or active
9. Patient under guardianship or curatorship
10. Patient deprived of liberty by judicial or administrative decision
11. Patient included in another interventional trial evaluating a health product

Primary outcomes:
measure: Mortality
timeFrame: Day 28
Secondary outcomes:
measure: Mortality
timeFrame: Day 60
measure: Time before successful extubation
timeFrame: Day 60
measure: Number of days living without invasive mechanical ventilation
timeFrame: Day 28
measure: Composite score incorporating death and the number of days living without mechanical ventilation
timeFrame: Day 60
measure: Mean evolution of blood gases
timeFrame: Day 1 to Day 14
measure: Mean evolution of Tidal Volume (ventilator parameters)
timeFrame: Day 1 to Day 14
measure: Mean evolution of respiratory rate (ventilator parameters)
timeFrame: Day 1 to Day 14
measure: Mean evolution of Positive Expiratory Pressure (ventilator parameters)
timeFrame: Day 1 to Day 14
measure: Mean evolution of plateau pressure (ventilator parameters)
timeFrame: Day 1 to Day 14
measure: Mean evolution of fraction of inspired oxygen (ventilator parameters)
timeFrame: Day 1 to Day 14
measure: Evolution of the Sequential Organ Failure Assessment (SOFA) score and its components by organ
timeFrame: Day 1 to Day 28
measure: Number of days alive without organ failure
timeFrame: Day 28, day 60
measure: Duration of hospitalization in intensive care unit
timeFrame: From day 1 up to 3 months
measure: Duration of hospitalization in hospital
timeFrame: From day 1 up to 3 months
measure: Number of days alive and out of the ICU and hospital
timeFrame: Day 28, day 60
measure: Evolution of viral load
timeFrame: Day 7, Day 14 or day of ICU discharge if before day 14
measure: Proportion of active smoker or active vapers or taking nicotine substitutes documented by examination
timeFrame: 2 weeks after treatment decrease, 8 weeks after treatment decrease
measure: Proportion of active smoker or active vapers or taking nicotine substitutes documented by urinary cotinine
timeFrame: 2 weeks after treatment decrease, 8 weeks after treatment decrease
measure: Mean score of Desire to smoke defined by French Tobacco Craving scale
timeFrame: 2 weeks after treatment decrease, 8 weeks after treatment decrease
measure: Mean score of Withdrawal symptoms scale
timeFrame: 2 weeks after treatment decrease, 8 weeks after treatment decrease
measure: Mean score of Hospital anxiety and depression scale
timeFrame: 2 weeks after treatment decrease, 8 weeks after treatment decrease
measure: Post traumatic stress disorder scale
timeFrame: 2 weeks after treatment decrease, 8 weeks after treatment decrease
measure: Mean score of Insomnia severity scale
timeFrame: 2 weeks after treatment decrease
measure: Cotinin rate in blood
timeFrame: 8 weeks after treatment decrease
Other outcomes:
Locations:
city: Argenteuil
country: France
facility: Centre Hospitalier Victor Dupouy - Service de Réanimation polyvalente et USC
city: Besançon
country: France
facility: CHRU de Besançon - Service de Médecine Intensive Réanimation
city: Corbeil-Essonnes
country: France
facility: Centre Hospitalier Sud Francilien - Service de réanimation
city: Dijon
country: France
facility: CHU Dijon - Hôpital François Miterrand Service de Médecine Intensive Réanimation
city: Eaubonne
country: France
facility: Hôpital Simone VEIL - Service d'Anesthésie-Réanimation
city: Jossigny
country: France
facility: Grand Hôpital de l'Est Francilien - Site Jossigny - Réanimation
city: Le Kremlin-Bicêtre
country: France
facility: Hôpital Bicêtre - Service de Médecine Intensive Réanimation
city: Meaux
country: France
facility: Grand Hôpital de l'Est Francilien Site Meaux - Service de Réanimation Médico-Chirurgicale
city: Mulhouse
country: France
facility: Groupement Hospitalier de la Région de Mulhouse Sud Alsace - Hop Emile MULLER
city: Nice
country: France
facility: CHU Nice - Hôpital L'Archet 1 - Service de Médecine Intensive Réanimation
city: Orléans
country: France
facility: CHR Orléans Service de Médecine Intensive Réanimation
city: Paris
country: France
facility: Hôpital Pitié Salpêtrière - ICU
city: Paris
country: France
facility: Hôpital Pitié Salpêtrière - Intensive care unit
city: Paris
country: France
facility: Institut Mutualiste Montsouris Service de Réanimation Polyvalente
city: Paris
country: France
facility: Hôpital Tenon - Service de Médecine Intensive Réanimation
city: Pontoise
country: France
facility: Centre Hospitalier René Dubos - Service de Réanimation Médico-Chirurgicale
city: Saint-Denis
country: France
facility: Hôpital DELAFONTAINE Service de Médecine Intensive Réanimation
city: Villeurbanne
country: France
facility: Médipôle Hôpital Privé - MHP Service de Médecine Intensive Réanimation
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Alain COMBES, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Labro G, Tubach F, Belin L, Dubost JL, Osman D, Muller G, Quenot JP, Da Silva D, Zarka J, Turpin M, Mayaux J, Lamer C, Doyen D, Chevrel G, Plantefeve G, Demeret S, Piton G, Manzon C, Ochin E, Gaillard R, Dautzenberg B, Baldacini M, Lebbah S, Miyara M, Pineton de Chambrun M, Amoura Z, Combes A; NICOVID-REA Trial Group. Nicotine patches in patients on mechanical ventilation for severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial. Intensive Care Med. 2022 Jul;48(7):876-887. doi: 10.1007/s00134-022-06721-1. Epub 2022 Jun 9.