reCoVery: Repurposing of Chlorpromazine in Covid-19 Treatment

Sponsor

Centre Hospitalier St Anne (Other)

Overall Status

Unknown status

CT.gov ID

NCT04366739

Collaborator

Hôpital Cochin (Other)

Enrollment

Location

Arms

5.1

Anticipated Duration (Months)

7.9

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
COVID-19	Drug: CHLORPROMAZINE (CPZ) Combination Product: Standard of Care (SOC)	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

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).Allocation: Randomized Intervention Model: Parallel AssignmentIntervention 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 (Outcomes Assessor)

Masking Description:

The evaluator of the primary endpoint and secondary endpoints relating to the clinical efficacy of CPZ and the evaluator of the biological and radiological effects of the CPZ will be maintained blindly throughout their duration of inclusion. This evaluator will collect clinical data, biological data, and imaging data without knowing the drug treatments delivered to patients. The radiologists responsible for calculating the parenchymal damage score on the thoracic CT scan will be blind to the patient delivered drugs. The biologists responsible for carrying out the analyzes on the biobank will be blind to the patient delivered drugs. The biostatistician responsible for statistical study analysis will be kept blind to the drugs delivered to the subjects.

Primary Purpose:

Treatment

Official Title:

Repurposing of Chlorpromazine in Covid-19 Treatment

Anticipated Study Start Date :

Apr 29, 2020

Anticipated Primary Completion Date :

Aug 30, 2020

Anticipated Study Completion Date :

Sep 30, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CHLORPROMAZINE (CPZ) Standard of Care (SOC) plus CHLORPROMAZINE (CPZ)	Drug: CHLORPROMAZINE (CPZ) 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 Combination Product: Standard of Care (SOC) In the absence of a reference treatment in COVID-19, the "standard of care" (SOC) is the comparison arm
Active Comparator: standard of care (SOC) 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) In the absence of a reference treatment in COVID-19, the "standard of care" (SOC) is the comparison arm

Arm

Intervention/Treatment

Experimental: CHLORPROMAZINE (CPZ)

Standard of Care (SOC) plus CHLORPROMAZINE (CPZ)

Drug: CHLORPROMAZINE (CPZ)

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

Combination Product: Standard of Care (SOC)

In the absence of a reference treatment in COVID-19, the "standard of care" (SOC) is the comparison arm

Active Comparator: standard of care (SOC)

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)

In the absence of a reference treatment in COVID-19, the "standard of care" (SOC) is the comparison arm

Outcome Measures

Primary Outcome Measures

Time To Response (TTR) [28 days]
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.

Secondary Outcome Measures

Objective Response Rate (ORR) [28 days from randomization]
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).
All-cause mortality [28 days after randomization]
All-cause mortality rates at Day 28th after randomization
Duration in days required for hospital discharge [28 days after randomization]
This will be a continuous outcome defined by the amount of time in days between randomization and the hospital discharge
Duration in days required for National Early Warning Score ≤ 2 maintained 24 hours [28 days after randomization]
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.
Number of days without oxygen therapy [28 days after randomization]
This will be a continuous outcome defined by the amount of time in days without oxygen therapy
Incidence of oxygen use, NIV or high flow oxygen therapy [28 days after randomization]
Number of clinical conditions that need a prescription for Oxygen therapy, NIV or high flow oxygen therapy
Duration in days of oxygen prescription, NIV or high flow oxygen therapy [28 days after randomization]
This will be a continuous outcome defined by the amount of time in days with oxygen therapy, NIV, or high flow oxygen therapy.
Biochemical response: rate of patients positive for SARS-CoV-2 PCR on a nasopharyngeal sample [day 7 from randomization]
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
Biochemical response: viral load of SARS-CoV-2 on a nasopharyngeal sample [day 7 from randomization]
This will be a quantitative variable. Biobank sample at day 7
Biochemical response: serum viral load of SARS-CoV-2 [day: 3,5,7,14,21,28]
This will be a quantitative variable. Biobank blood sample at D3, D5, D7 then, if hospitalization continues blood sample at D14, D21, and D28
Biochemical response: C-reactive protein (CRP) [day: 3,5,7,14,21,28]
This will be a quantitative variable. Biobank blood sample at D3, D5, D7 then, if hospitalization continues blood sample at D14, D21, and D28
Biochemical response: blood test for lymphocytes (lymphopenia) [day: 3,5,7,14,21,28]
This will be a quantitative variable. Biobank blood sample at D3, D5, D7 then, if hospitalization continues blood sample at D14, D21, and D28
Parenchymal involvement (chest CT) [day 7]
Extension score of parenchymal involvement in thoracic computed tomography (CT) (D7)
Define the optimal dose of CPZ and its tolerance: rates of serious adverse events [28 days]
Rates of serious adverse events
Define the optimal dose of CPZ and its tolerance: rates of non-serious side effects [28 days]
Rates of non-serious side effects
Define the optimal dose of CPZ and its tolerance: anxiety assessment on Global Anxiety - Visual Analog Scale (GA-VAS) [28 days]
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.
Define the optimal dose of CPZ and its tolerance: Rates of drug discontinuation [28 days]
Rates of drug discontinuation in all causes under study
Define the optimal dose of CPZ and its tolerance: biological anomalies [day: 3,5,7,14,21,28]
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
Define the optimal dose of CPZ and its tolerance: ECG abnormalities [day: 3,5,7,14,21,28]
Rate of patients with ECG abnormalities at D3, D5, D7 then, if hospitalization continues blood sample at D14, D21, and D28
Define the optimal dose of CPZ and its tolerance: plasma CPK assessment [day: 3,5,7,14,21,28]
plasma CPK assessment at D3, D5, D7 then, if hospitalization continues blood sample at D14, D21, and D28
Define the optimal dose of CPZ and its tolerance:plasma CPZ assessment [day: 3,5,7,14,21,28]
Plasma CPZ assessment at D3, D5, D7 then, if hospitalization continues blood sample at D14, D21, and D28
Define the optimal dose of CPZ and its tolerance: CPZ dose administered [28 days]
CPZ dosages administered

Other Outcome Measures

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) [day: 1, 3,5,7,14,21,28]
Biobank by blood samples of 20 ml per patient (on D1, D3, D5, D7, then, if continued hospitalization at D14, D21, D28) allowing, in addition to viral markers:Cytokine and lymphocyte profile assays in flow cytometry: IL-2, IL-6, IL-7, IL-10, GCSF, IP10, MCP1, M1P1A and TNF-alfa, FACs CD3, CD4, CD8, CD38

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Centre Hospitalier Sainte-Anne	Paris		France	75014

Sponsors and Collaborators

Centre Hospitalier St Anne
Hôpital Cochin

Investigators

Principal Investigator: Marion Plaze, MD, PHD, Service Hospitalo-Universitaire - GHU PARIS Psychiatrie & Neurosciences

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:

Centre Hospitalier St Anne

ClinicalTrials.gov Identifier:

NCT04366739

Other Study ID Numbers:

D20-P016

First Posted:

Apr 29, 2020

Last Update Posted:

Apr 29, 2020

Last Verified:

Apr 1, 2020

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Centre Hospitalier St Anne

COVID-19

Chlorpromazine

Additional relevant MeSH terms:

COVID-19

Chlorpromazine

Study Results

No Results Posted as of Apr 29, 2020