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

Covid19 Clinical Trial

— NICOVID-REA  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04598594
• Other study ID #: APHP200537
• Secondary ID: 2020-003723-42
• Status: Completed
• Phase: Phase 3
• Start date: November 6, 2020
• Est. completion date: June 20, 2021

Study information

• Verified date: June 2021
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 220
• Est. completion date: June 20, 2021
• Est. primary completion date: April 29, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Covid19
• SARS-Associated Coronavirus as Cause of Disease Classified Elsewhere
• Severe Acute Respiratory Syndrome

Intervention

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
• 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

Locations

Country	Name	City	State
France	Centre Hospitalier Victor Dupouy - Service de Réanimation polyvalente et USC	Argenteuil
France	CHRU de Besançon - Service de Médecine Intensive Réanimation	Besançon
France	Centre Hospitalier Sud Francilien - Service de réanimation	Corbeil-Essonnes
France	CHU Dijon - Hôpital François Miterrand Service de Médecine Intensive Réanimation	Dijon
France	Hôpital Simone VEIL - Service d'Anesthésie-Réanimation	Eaubonne
France	Grand Hôpital de l'Est Francilien - Site Jossigny - Réanimation	Jossigny
France	Hôpital Bicêtre - Service de Médecine Intensive Réanimation	Le Kremlin-Bicêtre
France	Grand Hôpital de l'Est Francilien Site Meaux - Service de Réanimation Médico-Chirurgicale	Meaux
France	Groupement Hospitalier de la Région de Mulhouse Sud Alsace - Hop Emile MULLER	Mulhouse
France	CHU Nice - Hôpital L'Archet 1 - Service de Médecine Intensive Réanimation	Nice
France	CHR Orléans Service de Médecine Intensive Réanimation	Orléans
France	Hôpital Pitié Salpêtrière - ICU	Paris
France	Hôpital Pitié Salpêtrière - Intensive care unit	Paris
France	Hôpital Tenon - Service de Médecine Intensive Réanimation	Paris
France	Institut Mutualiste Montsouris Service de Réanimation Polyvalente	Paris
France	Centre Hospitalier René Dubos - Service de Réanimation Médico-Chirurgicale	Pontoise
France	Hôpital DELAFONTAINE Service de Médecine Intensive Réanimation	Saint-Denis
France	Médipôle Hôpital Privé - MHP Service de Médecine Intensive Réanimation	Villeurbanne

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mortality		Day 28
Secondary	Mortality		Day 60
Secondary	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
Secondary	Number of days living without invasive mechanical ventilation		Day 28
Secondary	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
Secondary	Mean evolution of blood gases	measured each day from day 1 to day 14	Day 1 to Day 14
Secondary	Mean evolution of Tidal Volume (ventilator parameters)	measured each day from day 1 to day 14	Day 1 to Day 14
Secondary	Mean evolution of respiratory rate (ventilator parameters)	measured each day from day 1 to day 14	Day 1 to Day 14
Secondary	Mean evolution of Positive Expiratory Pressure (ventilator parameters)	measured each day from day 1 to day 14	Day 1 to Day 14
Secondary	Mean evolution of plateau pressure (ventilator parameters)	measured each day from day 1 to day 14	Day 1 to Day 14
Secondary	Mean evolution of fraction of inspired oxygen (ventilator parameters)	measured each day from day 1 to day 14	Day 1 to Day 14
Secondary	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
Secondary	Number of days alive without organ failure		Day 28, day 60
Secondary	Duration of hospitalization in intensive care unit		From day 1 up to 3 months
Secondary	Duration of hospitalization in hospital		From day 1 up to 3 months
Secondary	Number of days alive and out of the ICU and hospital		Day 28, day 60
Secondary	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
Secondary	Proportion of active smoker or active vapers or taking nicotine substitutes documented by examination		2 weeks after treatment decrease, 8 weeks after treatment decrease
Secondary	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
Secondary	Mean score of Desire to smoke defined by French Tobacco Craving scale		2 weeks after treatment decrease, 8 weeks after treatment decrease
Secondary	Mean score of Withdrawal symptoms scale		2 weeks after treatment decrease, 8 weeks after treatment decrease
Secondary	Mean score of Hospital anxiety and depression scale		2 weeks after treatment decrease, 8 weeks after treatment decrease
Secondary	Post traumatic stress disorder scale		2 weeks after treatment decrease, 8 weeks after treatment decrease
Secondary	Mean score of Insomnia severity scale		2 weeks after treatment decrease
Secondary	Cotinin rate in blood		8 weeks after treatment decrease