Clinical trial NCT04366739: Repurposing of Chlorpromazine in Covid-19 Treatment
Official title: Repurposing of Chlorpromazine in Covid-19 Treatment
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE3
Conditions: COVID-19
Keywords: COVID-19
Chlorpromazine
Lead sponsor: Centre Hospitalier St Anne
Sponsor class: OTHER
Collaborators: name: Hôpital Cochin
First posted: 2020-04-29
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Allocation: Randomized Intervention Model: Parallel Assignment

Intervention Model Description:

reCoVery is a multi-center, randomized, single-blind, standard care-controlled (1:1) pilot clinical study to explore the efficacy and safety of chlorpromazine (CPZ) in the treatment of adult subjects with COVID-19-moderate type (WHO-OSCI 3-5).
Primary purpose: TREATMENT

Brief summary: This study evaluates the effects of the addition of chlorpromazine to the standard therapeutic protocol in COVID-19 patients hospitalized for respiratory symptom management (score 3-5 WHO Ordinal Scale for Clinical Improvement).

Detailed description: This study evaluates the effects of the addition of chlorpromazine to the standard therapeutic protocol in COVID 19 patients hospitalized for respiratory symptom management (score 3-5 WHO Ordinal Scale for Clinical Improvement).

The investigators have observed in GHU-Paris psychiatry Hospital units (140 beds), significantly lower prevalence of symptomatic and severe forms of COVID-19 in patients (3%) than in the health workers operating in the same facilities (19% of nurses and 18% of physicians). COVID-psychiatry units report similar feedback in France, Spain, and Italy. One hypothesis could be that psychotropic drugs have a protective action on COVID-19 and protect patients from symptomatic and virulent forms of COVID-19.

This hypothesis is consistent with research studies that have shown that several psychotropic drugs inhibit in vitro viral replication of the coronaviruses MERS-CoV and SARS-CoV-1. The SARS-CoV-2 has many characteristics in common with the coronavirus family and has phylogenetic similarities to the SARS-CoV-1 engaged in the 2002-2003 outbreak. It is, therefore, possible that one or more psychotropic drugs having demonstrated efficacy against MERS-CoV and SARS-CoV-1 also have anti-SARS-CoV-2 antiviral activity.

The current global epidemic of COVID-19, with a high number of deaths in many countries, makes it urgent to search drugs potentially useful to reduce the severity and lethality of the infection. Drug repositioning represents a possible alternative to the news medicines discovery. This strategy makes it possible to eliminate many stages of development; it makes it possible to deploy a therapy whose side effects are known and which physicians already well know how to handle.

To confirm the hypothesis of the antiviral action of chlorpromazine on SARS-CoV-2, a preclinical in vitro experiment began in April 2020 at the level III high-security biological laboratory at the Pasteur Institute (in collaboration with the GHU PARIS Psychiatry \& Neurosciences). The first results are encouraging and show a marked antiviral effect of chlorpromazine on SARS-CoV-2. Technical replicas are underway to validate these preliminary results.

By integrating all these evidence, the investigators hypothesize that chlorpromazine could decrease the unfavorable evolution of COVID-19 infection when administered at the onset of respiratory signs.

Eligibility criteria: Inclusion Criteria:

* Biological and/or radiological diagnosis of COVID-19 infection
* WHO-OSCI at 3, 4 or 5 at the time of inclusion
* Benefiting from a social security scheme
* Voluntarily participating in the clinical study; fully understanding and being fully informed of the study and having signed the Informed Consent Form (ICF); willingness and capability to complete all the study procedures

Exclusion Criteria:

* Treatment with chlorpromazine (CPZ) the month preceding the inclusion visit
* Contraindication to the CPZ:
* Hypersensitivity to the active substance or any of the excipients
* Risk of glaucoma by closing the angle.
* Risk of urinary retention linked to urethroprostatic disorders.
* History of agranulocytosis
* Association with dopaminergic outside Parkinson's (cabergoline, quinagolide), citalopram, escitalopram, domperidone, hydroxyzine, and piperaquine
* Wheat allergy
* Risk of QT prolongation and occurrence of severe ventricular rhythm disorders: the existence of bradycardia, hypokalaemia, long congenital or acquired QT
* History of ischemic stroke
* Treatment with chloroquine or hydroxychloroquine during the inclusion visit or the previous month
* Need for mechanical ventilation linked to COVID-19, during the inclusion visit or the last month
* In the opinion of the clinical team, imminent progression to death within the next 24 hours regardless of treatment
* Psychiatric care under duress
* Protected adults, persons under the protection of justice
* Pregnant or lactating woman

Primary outcomes:
measure: Time To Response (TTR)
timeFrame: 28 days
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: 28 days from randomization
measure: All-cause mortality
timeFrame: 28 days after randomization
measure: Duration in days required for hospital discharge
timeFrame: 28 days after randomization
measure: Duration in days required for National Early Warning Score ≤ 2 maintained 24 hours
timeFrame: 28 days after randomization
measure: Number of days without oxygen therapy
timeFrame: 28 days after randomization
measure: Incidence of oxygen use, NIV or high flow oxygen therapy
timeFrame: 28 days after randomization
measure: Duration in days of oxygen prescription, NIV or high flow oxygen therapy
timeFrame: 28 days after randomization
measure: Biochemical response: rate of patients positive for SARS-CoV-2 PCR on a nasopharyngeal sample
timeFrame: day 7 from randomization
measure: Biochemical response: viral load of SARS-CoV-2 on a nasopharyngeal sample
timeFrame: day 7 from randomization
measure: Biochemical response: serum viral load of SARS-CoV-2
timeFrame: day: 3,5,7,14,21,28
measure: Biochemical response: C-reactive protein (CRP)
timeFrame: day: 3,5,7,14,21,28
measure: Biochemical response: blood test for lymphocytes (lymphopenia)
timeFrame: day: 3,5,7,14,21,28
measure: Parenchymal involvement (chest CT)
timeFrame: day 7
measure: Define the optimal dose of CPZ and its tolerance: rates of serious adverse events
timeFrame: 28 days
measure: Define the optimal dose of CPZ and its tolerance: rates of non-serious side effects
timeFrame: 28 days
measure: Define the optimal dose of CPZ and its tolerance: anxiety assessment on Global Anxiety - Visual Analog Scale (GA-VAS)
timeFrame: 28 days
measure: Define the optimal dose of CPZ and its tolerance: Rates of drug discontinuation
timeFrame: 28 days
measure: Define the optimal dose of CPZ and its tolerance: biological anomalies
timeFrame: day: 3,5,7,14,21,28
measure: Define the optimal dose of CPZ and its tolerance: ECG abnormalities
timeFrame: day: 3,5,7,14,21,28
measure: Define the optimal dose of CPZ and its tolerance: plasma CPK assessment
timeFrame: day: 3,5,7,14,21,28
measure: Define the optimal dose of CPZ and its tolerance:plasma CPZ assessment
timeFrame: day: 3,5,7,14,21,28
measure: Define the optimal dose of CPZ and its tolerance: CPZ dose administered
timeFrame: 28 days
Other outcomes:
measure: Evaluate the biological parameters to treatment response (biobank constitution for carrying out cytokine assays, lymphocyte profiles in flow cytometry and additional explorations according to the evolution of knowledge on COVID-19)
timeFrame: day: 1, 3,5,7,14,21,28
Locations:
city: Paris
country: France
facility: Centre Hospitalier Sainte-Anne
Study officials:
affiliation: Service Hospitalo-Universitaire - GHU PARIS Psychiatrie & Neurosciences
name: Marion Plaze, MD, PHD
role: PRINCIPAL_INVESTIGATOR
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