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

Study Overview
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Brief Summary
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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.

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

Conditions
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Covid19, SARS-Associated Coronavirus as Cause of Disease Classified Elsewhere

Intervention / Treatment
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* Drug: Patch, Nicotine
* Drug: Patch, Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nicotine patch<br> | Drug: Patch, Nicotine<br>* 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<br>|
| Placebo Comparator: Placebo patch<br> | Drug: Patch, Placebo<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ICU, Covid19, SARS-CoV2, Mechanical ventilation, Nicotine