Back to resultsEvaluation of the Efficacy of Nicotine Patches in SARS-CoV2 (COVID-19) Infection in Intensive Care Unit Patients (NICOVID-REA)
Primary Purpose
Covid19, SARS-Associated Coronavirus as Cause of Disease Classified Elsewhere
Status
Completed
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
Patch, Nicotine
Patch, Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Covid19 focused on measuring Covid19, SARS-CoV2, Mechanical ventilation, ICU, Nicotine
Eligibility Criteria
Inclusion Criteria:
- Patient ≥ 18 years
- Documented diagnosis of COVID 19 (according to the tests referenced on the list published on the website : https://covid-19.sante.gouv.fr.tests)
- Hospitalized in intensive care unit, intubated and mechanically ventilated for less than 48 hours
- Non-smoker and non-vaping or abstinent patient for at least 12 months
- 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.
- Affiliated to a social security scheme or beneficiary of such a scheme (AME excluded)
Exclusion Criteria:
- Chronic respiratory failure defined by PaCO2> 60 mmHg in ambulatory patients (respiratory parameters at baseline).
- Mechanical ventilation at home (non-invasive mechanical ventilation or via a tracheostomy) with the exception of CPAP / BIPAP used only for sleep apnea syndromes
- Predictable mechanical ventilation duration <48 hours
- Moribund patient or death expected on the day of randomization, or with a SAPS II score> 90
- Cerebral deficiency with dilated areactive pupils or irreversible neurological pathology.
- Other concomitant severe pathology with an estimated life expectancy of less than 1 year
- Treatment with nicotine replacement therapy or varenicline or bupropion ongoing
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
- Patient under guardianship or curatorship
- Patient deprived of liberty by judicial or administrative decision
- Patient included in another interventional trial evaluating a health product
Sites / Locations
- Centre Hospitalier Victor Dupouy - Service de Réanimation polyvalente et USC
- CHRU de Besançon - Service de Médecine Intensive Réanimation
- Centre Hospitalier Sud Francilien - Service de réanimation
- CHU Dijon - Hôpital François Miterrand Service de Médecine Intensive Réanimation
- Hôpital Simone VEIL - Service d'Anesthésie-Réanimation
- Grand Hôpital de l'Est Francilien - Site Jossigny - Réanimation
- Hôpital Bicêtre - Service de Médecine Intensive Réanimation
- Grand Hôpital de l'Est Francilien Site Meaux - Service de Réanimation Médico-Chirurgicale
- Groupement Hospitalier de la Région de Mulhouse Sud Alsace - Hop Emile MULLER
- CHU Nice - Hôpital L'Archet 1 - Service de Médecine Intensive Réanimation
- CHR Orléans Service de Médecine Intensive Réanimation
- Hôpital Pitié Salpêtrière - ICU
- Hôpital Pitié Salpêtrière - Intensive care unit
- Institut Mutualiste Montsouris Service de Réanimation Polyvalente
- Hôpital Tenon - Service de Médecine Intensive Réanimation
- Centre Hospitalier René Dubos - Service de Réanimation Médico-Chirurgicale
- Hôpital DELAFONTAINE Service de Médecine Intensive Réanimation
- Médipôle Hôpital Privé - MHP Service de Médecine Intensive Réanimation
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Nicotine patch
Placebo patch
Arm Description
Outcomes
Primary Outcome Measures
Mortality
Secondary Outcome Measures
Mortality
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).
Number of days living without invasive mechanical ventilation
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
Mean evolution of blood gases
measured each day from day 1 to day 14
Mean evolution of Tidal Volume (ventilator parameters)
measured each day from day 1 to day 14
Mean evolution of respiratory rate (ventilator parameters)
measured each day from day 1 to day 14
Mean evolution of Positive Expiratory Pressure (ventilator parameters)
measured each day from day 1 to day 14
Mean evolution of plateau pressure (ventilator parameters)
measured each day from day 1 to day 14
Mean evolution of fraction of inspired oxygen (ventilator parameters)
measured each day from 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
Number of days alive without organ failure
Duration of hospitalization in intensive care unit
Duration of hospitalization in hospital
Number of days alive and out of the ICU and hospital
Evolution of viral load
samples taken on D7 and D14 or the day of discharge from intensive care unit if before D14
Proportion of active smoker or active vapers or taking nicotine substitutes documented by examination
Proportion of active smoker or active vapers or taking nicotine substitutes documented by urinary cotinine
Mean score of Desire to smoke defined by French Tobacco Craving scale
Mean score of Withdrawal symptoms scale
Mean score of Hospital anxiety and depression scale
Post traumatic stress disorder scale
Mean score of Insomnia severity scale
Cotinin rate in blood
Full Information
NCT ID
NCT04598594
First Posted
October 15, 2020
Last Updated
June 21, 2021
Sponsor
Assistance Publique - Hôpitaux de Paris
1. Study Identification
Unique Protocol Identification Number
NCT04598594
Brief Title
Evaluation of the Efficacy of Nicotine Patches in SARS-CoV2 (COVID-19) Infection in Intensive Care Unit Patients
Acronym
NICOVID-REA
Official Title
Evaluation of the Efficacy of Nicotine Patches in SARS-CoV2 (COVID-19) Infection in Intensive Care Unit Patients
Study Type
Interventional
2. Study Status
Record Verification Date
June 2021
Overall Recruitment Status
Completed
Study Start Date
November 6, 2020 (Actual)
Primary Completion Date
April 29, 2021 (Actual)
Study Completion Date
June 20, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Covid19, SARS-Associated Coronavirus as Cause of Disease Classified Elsewhere
Keywords
Covid19, SARS-CoV2, Mechanical ventilation, ICU, Nicotine
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
220 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Nicotine patch
Arm Type
Experimental
Arm Title
Placebo patch
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Patch, Nicotine
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Patch, Placebo
Intervention Description
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
Primary Outcome Measure Information:
Title
Mortality
Time Frame
Day 28
Secondary Outcome Measure Information:
Title
Mortality
Time Frame
Day 60
Title
Time before successful extubation
Description
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).
Time Frame
Day 60
Title
Number of days living without invasive mechanical ventilation
Time Frame
Day 28
Title
Composite score incorporating death and the number of days living without mechanical ventilation
Description
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
Time Frame
Day 60
Title
Mean evolution of blood gases
Description
measured each day from day 1 to day 14
Time Frame
Day 1 to Day 14
Title
Mean evolution of Tidal Volume (ventilator parameters)
Description
measured each day from day 1 to day 14
Time Frame
Day 1 to Day 14
Title
Mean evolution of respiratory rate (ventilator parameters)
Description
measured each day from day 1 to day 14
Time Frame
Day 1 to Day 14
Title
Mean evolution of Positive Expiratory Pressure (ventilator parameters)
Description
measured each day from day 1 to day 14
Time Frame
Day 1 to Day 14
Title
Mean evolution of plateau pressure (ventilator parameters)
Description
measured each day from day 1 to day 14
Time Frame
Day 1 to Day 14
Title
Mean evolution of fraction of inspired oxygen (ventilator parameters)
Description
measured each day from day 1 to day 14
Time Frame
Day 1 to Day 14
Title
Evolution of the Sequential Organ Failure Assessment (SOFA) score and its components by organ
Description
A higher score indicate a worse outcome
Time Frame
Day 1 to Day 28
Title
Number of days alive without organ failure
Time Frame
Day 28, day 60
Title
Duration of hospitalization in intensive care unit
Time Frame
From day 1 up to 3 months
Title
Duration of hospitalization in hospital
Time Frame
From day 1 up to 3 months
Title
Number of days alive and out of the ICU and hospital
Time Frame
Day 28, day 60
Title
Evolution of viral load
Description
samples taken on D7 and D14 or the day of discharge from intensive care unit if before D14
Time Frame
Day 7, Day 14 or day of ICU discharge if before day 14
Title
Proportion of active smoker or active vapers or taking nicotine substitutes documented by examination
Time Frame
2 weeks after treatment decrease, 8 weeks after treatment decrease
Title
Proportion of active smoker or active vapers or taking nicotine substitutes documented by urinary cotinine
Time Frame
2 weeks after treatment decrease, 8 weeks after treatment decrease
Title
Mean score of Desire to smoke defined by French Tobacco Craving scale
Time Frame
2 weeks after treatment decrease, 8 weeks after treatment decrease
Title
Mean score of Withdrawal symptoms scale
Time Frame
2 weeks after treatment decrease, 8 weeks after treatment decrease
Title
Mean score of Hospital anxiety and depression scale
Time Frame
2 weeks after treatment decrease, 8 weeks after treatment decrease
Title
Post traumatic stress disorder scale
Time Frame
2 weeks after treatment decrease, 8 weeks after treatment decrease
Title
Mean score of Insomnia severity scale
Time Frame
2 weeks after treatment decrease
Title
Cotinin rate in blood
Time Frame
8 weeks after treatment decrease
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patient ≥ 18 years
Documented diagnosis of COVID 19 (according to the tests referenced on the list published on the website : https://covid-19.sante.gouv.fr.tests)
Hospitalized in intensive care unit, intubated and mechanically ventilated for less than 48 hours
Non-smoker and non-vaping or abstinent patient for at least 12 months
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.
Affiliated to a social security scheme or beneficiary of such a scheme (AME excluded)
Exclusion Criteria:
Chronic respiratory failure defined by PaCO2> 60 mmHg in ambulatory patients (respiratory parameters at baseline).
Mechanical ventilation at home (non-invasive mechanical ventilation or via a tracheostomy) with the exception of CPAP / BIPAP used only for sleep apnea syndromes
Predictable mechanical ventilation duration <48 hours
Moribund patient or death expected on the day of randomization, or with a SAPS II score> 90
Cerebral deficiency with dilated areactive pupils or irreversible neurological pathology.
Other concomitant severe pathology with an estimated life expectancy of less than 1 year
Treatment with nicotine replacement therapy or varenicline or bupropion ongoing
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
Patient under guardianship or curatorship
Patient deprived of liberty by judicial or administrative decision
Patient included in another interventional trial evaluating a health product
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alain COMBES, MD
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris
Official's Role
Principal Investigator
Facility Information:
Facility Name
Centre Hospitalier Victor Dupouy - Service de Réanimation polyvalente et USC
City
Argenteuil
ZIP/Postal Code
95100
Country
France
Facility Name
CHRU de Besançon - Service de Médecine Intensive Réanimation
City
Besançon
ZIP/Postal Code
25030
Country
France
Facility Name
Centre Hospitalier Sud Francilien - Service de réanimation
City
Corbeil-Essonnes
ZIP/Postal Code
91100
Country
France
Facility Name
CHU Dijon - Hôpital François Miterrand Service de Médecine Intensive Réanimation
City
Dijon
ZIP/Postal Code
22033
Country
France
Facility Name
Hôpital Simone VEIL - Service d'Anesthésie-Réanimation
City
Eaubonne
ZIP/Postal Code
95000
Country
France
Facility Name
Grand Hôpital de l'Est Francilien - Site Jossigny - Réanimation
City
Jossigny
ZIP/Postal Code
77600
Country
France
Facility Name
Hôpital Bicêtre - Service de Médecine Intensive Réanimation
City
Le Kremlin-Bicêtre
ZIP/Postal Code
94270
Country
France
Facility Name
Grand Hôpital de l'Est Francilien Site Meaux - Service de Réanimation Médico-Chirurgicale
City
Meaux
ZIP/Postal Code
77104
Country
France
Facility Name
Groupement Hospitalier de la Région de Mulhouse Sud Alsace - Hop Emile MULLER
City
Mulhouse
ZIP/Postal Code
68100
Country
France
Facility Name
CHU Nice - Hôpital L'Archet 1 - Service de Médecine Intensive Réanimation
City
Nice
ZIP/Postal Code
06000
Country
France
Facility Name
CHR Orléans Service de Médecine Intensive Réanimation
City
Orléans
ZIP/Postal Code
45067
Country
France
Facility Name
Hôpital Pitié Salpêtrière - ICU
City
Paris
ZIP/Postal Code
75013
Country
France
Facility Name
Hôpital Pitié Salpêtrière - Intensive care unit
City
Paris
ZIP/Postal Code
75013
Country
France
Facility Name
Institut Mutualiste Montsouris Service de Réanimation Polyvalente
City
Paris
ZIP/Postal Code
75014
Country
France
Facility Name
Hôpital Tenon - Service de Médecine Intensive Réanimation
City
Paris
ZIP/Postal Code
75020
Country
France
Facility Name
Centre Hospitalier René Dubos - Service de Réanimation Médico-Chirurgicale
City
Pontoise
ZIP/Postal Code
95303
Country
France
Facility Name
Hôpital DELAFONTAINE Service de Médecine Intensive Réanimation
City
Saint-Denis
ZIP/Postal Code
93200
Country
France
Facility Name
Médipôle Hôpital Privé - MHP Service de Médecine Intensive Réanimation
City
Villeurbanne
ZIP/Postal Code
69100
Country
France
12. IPD Sharing Statement
Citations:
PubMed Identifier
35676335
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.
Results Reference
derived
Learn more about this trial
Evaluation of the Efficacy of Nicotine Patches in SARS-CoV2 (COVID-19) Infection in Intensive Care Unit Patients
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