Repurposing of Chlorpromazine in Covid-19 Treatment

Study Overview
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Brief Summary
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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
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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.

Official Title
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Repurposing of Chlorpromazine in Covid-19 Treatment

Conditions
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COVID-19

Intervention / Treatment
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* Drug: CHLORPROMAZINE (CPZ)
* Combination Product: Standard of Care (SOC)


Participation Criteria
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Eligibility Criteria
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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

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
Interventional 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).
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CHLORPROMAZINE (CPZ)<br>Standard of Care (SOC) plus CHLORPROMAZINE (CPZ) | Drug: CHLORPROMAZINE (CPZ)<br>* Drug List 1, AMM obtained in 1952, AMM 3400930571187 1952/90, RCP revised 22/08/2019 Administration: oral route, if the clinical condition requires it, intravenous administration. Initial dosage: 75 mg per day orally (or 37.5 mg per day orally in subjects 75 years of age or older). Then: titration up to the maximum tolerated dose, with a minimum of 12.5 mg and a maximum of 300 mg per day by the oral administration (or 600 mg per day by the oral in certain exceptional cases which also correspond to the CPM CPM marketing authorization indications); or from 6.25 to 150 mg per day intravenously. Duration of treatment: until healing criteria are obtained (≥ 8 days from the onset of COVID-19 symptoms AND ≥ 48 hours of apyrexia and absence of dyspnea) or 21 days maximum<br>Combination Product: Standard of Care (SOC)<br>* In the absence of a reference treatment in COVID-19, the standard of care (SOC) is the comparison arm<br>|
| Active Comparator: standard of care (SOC)<br>In the absence of a reference treatment in COVID-19, the standard of care (SOC) is the comparator arm | Combination Product: Standard of Care (SOC)<br>* In the absence of a reference treatment in COVID-19, the standard of care (SOC) is the comparison arm<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time To Response (TTR) | The primary endpoint is the time to response (TTR) in days, from randomization to 28th day. By response to treatment is meant the reduction of at least one severity level on the World Health Organization Ordinal Scale for Clinical Improvement (WHO-OSCI) The WHO-OSCI is an ordinal scale of 9 severity levels (from 0 to 8) for COVID-19. This scale was established by the WHO, which recommends its use for any therapeutic study on COVID-19. This will be a continuous outcome defined by the amount of time between randomization to the first response. This will be treated as a time-to-event with possible censoring. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Response rate regarding the World Health Organization Ordinal Scale for Clinical Improvement (WHO-OSCI). This will be a binary outcome defined by clinical conditions improvement assessment from randomization to 28th Day, by the response to treatment is meant the reduction of at least one severity level on the World Health Organization Ordinal Scale for Clinical Improvement (WHO-OSCI). | 28 days from randomization | 
| All-cause mortality | All-cause mortality rates at Day 28th after randomization | 28 days after randomization | 
| Duration in days required for hospital discharge | This will be a continuous outcome defined by the amount of time in days between randomization and the hospital discharge | 28 days after randomization | 
| Duration in days required for National Early Warning Score ≤ 2 maintained 24 hours | This will be a continuous outcome defined by the amount of time in days between randomization and National Early Warning Score ≤ 2 maintained for almost 24 hours The National Early Warning Score (NEWS) is a score used in the ICU to evaluate the overall severity of the clinical condition of a patient. | 28 days after randomization | 
| Number of days without oxygen therapy | This will be a continuous outcome defined by the amount of time in days without oxygen therapy | 28 days after randomization | 
| Incidence of oxygen use, NIV or high flow oxygen therapy | Number of clinical conditions that need a prescription for Oxygen therapy, NIV or high flow oxygen therapy | 28 days after randomization | 
| Duration in days of oxygen prescription, NIV or high flow oxygen therapy | This will be a continuous outcome defined by the amount of time in days with oxygen therapy, NIV, or high flow oxygen therapy. | 28 days after randomization | 
| Biochemical response: rate of patients positive for SARS-CoV-2 PCR on a nasopharyngeal sample | Rate of patients positive for SARS-CoV-2 PCR on a nasopharyngeal sample (biobank sample) (day 7) This will be a binary outcome defined by positive or negative results at SARS-CoV-2 PCR on a nasopharyngeal sample | day 7 from randomization | 
| Biochemical response: viral load of SARS-CoV-2 on a nasopharyngeal sample | This will be a quantitative variable. Biobank sample at day 7 | day 7 from randomization | 
| Biochemical response: serum viral load of SARS-CoV-2 | This will be a quantitative variable. Biobank blood sample at D3, D5, D7 then, if hospitalization continues blood sample at D14, D21, and D28 | day: 3,5,7,14,21,28 | 
| Biochemical response: C-reactive protein (CRP) | This will be a quantitative variable. Biobank blood sample at D3, D5, D7 then, if hospitalization continues blood sample at D14, D21, and D28 | day: 3,5,7,14,21,28 | 
| Biochemical response: blood test for lymphocytes (lymphopenia) | This will be a quantitative variable. Biobank blood sample at D3, D5, D7 then, if hospitalization continues blood sample at D14, D21, and D28 | day: 3,5,7,14,21,28 | 
| Parenchymal involvement (chest CT) | Extension score of parenchymal involvement in thoracic computed tomography (CT) (D7) | day 7 | 
| Define the optimal dose of CPZ and its tolerance: rates of serious adverse events | Rates of serious adverse events | 28 days | 
| Define the optimal dose of CPZ and its tolerance: rates of non-serious side effects | Rates of non-serious side effects | 28 days | 
| Define the optimal dose of CPZ and its tolerance: anxiety assessment on Global Anxiety - Visual Analog Scale (GA-VAS) | Global Anxiety - Visual Analog Scale (GA-VAS) is a scale for the assessment of anxiety. The 100 mm GA-VAS varies from minimum (not at all anxious) to maximum (Extremely anxious). This will be a quantitative variable, the distance from the left edge of the line to the mark placed by the patient is measured to the nearest millimeter and used in analyses as the patient's GA-VAS score. | 28 days | 
| Define the optimal dose of CPZ and its tolerance: Rates of drug discontinuation | Rates of drug discontinuation in all causes under study | 28 days | 
| Define the optimal dose of CPZ and its tolerance: biological anomalies | NFS, TP TCA, blood ionogram and hepatic check-up, glycemia. This will be a quantitative variable. Biobank blood sample at D3, D5, D7 then, if hospitalization continues blood sample at D14, D21, and D28 | day: 3,5,7,14,21,28 | 
| Define the optimal dose of CPZ and its tolerance: ECG abnormalities | Rate of patients with ECG abnormalities at D3, D5, D7 then, if hospitalization continues blood sample at D14, D21, and D28 | day: 3,5,7,14,21,28 | 
| Define the optimal dose of CPZ and its tolerance: plasma CPK assessment | plasma CPK assessment at D3, D5, D7 then, if hospitalization continues blood sample at D14, D21, and D28 | day: 3,5,7,14,21,28 | 
| Define the optimal dose of CPZ and its tolerance:plasma CPZ assessment | Plasma CPZ assessment at D3, D5, D7 then, if hospitalization continues blood sample at D14, D21, and D28 | day: 3,5,7,14,21,28 | 
| Define the optimal dose of CPZ and its tolerance: CPZ dose administered | CPZ dosages administered | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, Chlorpromazine