Evaluation of the Efficacy of Nicotine Patches in SARS-CoV2 (COVID-19) Infection in Intensive Care Unit Patients (NICOVID-REA)

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.

Study Overview

• Status: Completed
• Conditions: Covid19; SARS-Associated Coronavirus as Cause of Disease Classified Elsewhere
• Intervention / Treatment: Drug: Patch, Nicotine; Drug: Patch, Placebo

• Study Type: Interventional
• Enrollment (Actual): 220
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Argenteuil, France, 95100
    • Centre Hospitalier Victor Dupouy - Service de Réanimation polyvalente et USC
  • Besançon, France, 25030
    • CHRU de Besançon - Service de Médecine Intensive Réanimation
  • Corbeil-Essonnes, France, 91100
    • Centre Hospitalier Sud Francilien - Service de réanimation
  • Dijon, France, 22033
    • CHU Dijon - Hôpital François Miterrand Service de Médecine Intensive Réanimation
  • Eaubonne, France, 95000
    • Hôpital Simone VEIL - Service d'Anesthésie-Réanimation
  • Jossigny, France, 77600
    • Grand Hôpital de l'Est Francilien - Site Jossigny - Réanimation
  • Le Kremlin-Bicêtre, France, 94270
    • Hôpital Bicêtre - Service de Médecine Intensive Réanimation
  • Meaux, France, 77104
    • Grand Hôpital de l'Est Francilien Site Meaux - Service de Réanimation Médico-Chirurgicale
  • Mulhouse, France, 68100
    • Groupement Hospitalier de la Région de Mulhouse Sud Alsace - Hop Emile MULLER
  • Nice, France, 06000
    • CHU Nice - Hôpital L'Archet 1 - Service de Médecine Intensive Réanimation
  • Orléans, France, 45067
    • CHR Orléans Service de Médecine Intensive Réanimation
  • Paris, France, 75013
    • Hôpital Pitié Salpêtrière - ICU
  • Paris, France, 75013
    • Hôpital Pitié Salpêtrière - Intensive care unit
  • Paris, France, 75014
    • Institut Mutualiste Montsouris Service de Réanimation Polyvalente
  • Paris, France, 75020
    • Hôpital Tenon - Service de Médecine Intensive Réanimation
  • Pontoise, France, 95303
    • Centre Hospitalier René Dubos - Service de Réanimation Médico-Chirurgicale
  • Saint-Denis, France, 93200
    • Hôpital DELAFONTAINE Service de Médecine Intensive Réanimation
  • Villeurbanne, France, 69100
    • Médipôle Hôpital Privé - MHP Service de Médecine Intensive Réanimation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo patch	Drug: Patch, Placebo; Two patches of 7 mg/day Treatment at 14 mg/day during mechanical ventilation since after first successful extubation then, dose decreasing: Week 1: 10,5 mg/day Week 2 : 7 mg/day Week 3 : 3,5 mg/day
Experimental: Nicotine patch	Drug: Patch, Nicotine; Two patches of 7 mg/day Treatment at 14 mg/day during mechanical ventilation since after first successful extubation then, dose decreasing: Week 1: 10,5 mg/day Week 2 : 7 mg/day Week 3 : 3,5 mg/day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Mortality	Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality		Day 60
Time before successful extubation	Without reintubation or death in the following 48 hours for tracheotomized patients: alive and not ventilated for 48 hours (with death and LATA in competitive risks).	Day 60
Number of days living without invasive mechanical ventilation		Day 28
Composite score incorporating death and the number of days living without mechanical ventilation	This is a ranked composite score that incorporates death and days free from mechanical ventilation through day 28, calculated in such a manner that death constitutes a worse outcome than fewer days off the ventilator.16 Time free from mechanical ventilation was calculated as the number of days between successful liberation from the ventilator and study day 60. Each patient was compared with every other patient in the study and assigned a score (tie: 0, win: +1, loss: -1) for each pairwise comparison based on whom fared better	Day 60
Mean evolution of blood gases	measured each day from day 1 to day 14	Day 1 to Day 14
Mean evolution of Tidal Volume (ventilator parameters)	measured each day from day 1 to day 14	Day 1 to Day 14
Mean evolution of respiratory rate (ventilator parameters)	measured each day from day 1 to day 14	Day 1 to Day 14
Mean evolution of Positive Expiratory Pressure (ventilator parameters)	measured each day from day 1 to day 14	Day 1 to Day 14
Mean evolution of plateau pressure (ventilator parameters)	measured each day from day 1 to day 14	Day 1 to Day 14
Mean evolution of fraction of inspired oxygen (ventilator parameters)	measured each day from day 1 to day 14	Day 1 to Day 14
Evolution of the Sequential Organ Failure Assessment (SOFA) score and its components by organ	A higher score indicate a worse outcome	Day 1 to Day 28
Number of days alive without organ failure		Day 28, day 60
Duration of hospitalization in intensive care unit		From day 1 up to 3 months
Duration of hospitalization in hospital		From day 1 up to 3 months
Number of days alive and out of the ICU and hospital		Day 28, day 60
Evolution of viral load	samples taken on D7 and D14 or the day of discharge from intensive care unit if before D14	Day 7, Day 14 or day of ICU discharge if before day 14
Proportion of active smoker or active vapers or taking nicotine substitutes documented by examination		2 weeks after treatment decrease, 8 weeks after treatment decrease
Proportion of active smoker or active vapers or taking nicotine substitutes documented by urinary cotinine		2 weeks after treatment decrease, 8 weeks after treatment decrease
Mean score of Desire to smoke defined by French Tobacco Craving scale		2 weeks after treatment decrease, 8 weeks after treatment decrease
Mean score of Withdrawal symptoms scale		2 weeks after treatment decrease, 8 weeks after treatment decrease
Mean score of Hospital anxiety and depression scale		2 weeks after treatment decrease, 8 weeks after treatment decrease
Post traumatic stress disorder scale		2 weeks after treatment decrease, 8 weeks after treatment decrease
Mean score of Insomnia severity scale		2 weeks after treatment decrease
Cotinin rate in blood		8 weeks after treatment decrease

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Alain COMBES, MD, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 6, 2020
• Primary Completion (Actual): April 29, 2021
• Study Completion (Actual): June 20, 2021

Study Registration Dates

• First Submitted: October 15, 2020
• First Submitted That Met QC Criteria: October 21, 2020
• First Posted (Actual): October 22, 2020

Study Record Updates

• Last Update Posted (Actual): June 22, 2021
• Last Update Submitted That Met QC Criteria: June 21, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Covid19; ICU; SARS-CoV2; Nicotine; Mechanical ventilation
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Severe Acute Respiratory Syndrome; COVID-19; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Agents; Ganglionic Stimulants; Nicotinic Agonists; Cholinergic Agonists; Nicotine
• Other Study ID Numbers: APHP200537; 2020-003723-42 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No