Repurposing of Chlorpromazine in Covid-19 Treatment
Trial Snapshot
- Phase
- Phase 3
- Status
- Withdrawn
- Sponsor
- Locations
- 1
- Primary Endpoint
- Time To Response (TTR)
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- 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.
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Arms & Interventions
CHLORPROMAZINE (CPZ)
Standard of Care (SOC) plus CHLORPROMAZINE (CPZ)
Intervention: CHLORPROMAZINE (CPZ) (Drug)
CHLORPROMAZINE (CPZ)
Standard of Care (SOC) plus CHLORPROMAZINE (CPZ)
Intervention: Standard of Care (SOC) (Combination Product)
standard of care (SOC)
In the absence of a reference treatment in COVID-19, the "standard of care" (SOC) is the comparator arm
Intervention: Standard of Care (SOC) (Combination Product)
Outcomes
Primary Outcomes
Time To Response (TTR)
Time Frame: 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 Outcomes
- Define the optimal dose of CPZ and its tolerance: CPZ dose administered(28 days)
- Number of days without oxygen therapy(28 days after randomization)
- Parenchymal involvement (chest CT)(day 7)
- Objective Response Rate (ORR)(28 days from randomization)
- All-cause mortality(28 days after randomization)
- Biochemical response: C-reactive protein (CRP)(day: 3,5,7,14,21,28)
- Define the optimal dose of CPZ and its tolerance: rates of non-serious side effects(28 days)
- Define the optimal dose of CPZ and its tolerance: ECG abnormalities(day: 3,5,7,14,21,28)
- Define the optimal dose of CPZ and its tolerance: plasma CPK assessment(day: 3,5,7,14,21,28)
- Duration in days of oxygen prescription, 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(day 7 from randomization)
- Biochemical response: viral load of SARS-CoV-2 on a nasopharyngeal sample(day 7 from randomization)
- Biochemical response: serum viral load of SARS-CoV-2(day: 3,5,7,14,21,28)
- Define the optimal dose of CPZ and its tolerance: rates of serious adverse events(28 days)
- Define the optimal dose of CPZ and its tolerance:plasma CPZ assessment(day: 3,5,7,14,21,28)
- Duration in days required for hospital discharge(28 days after randomization)
- Duration in days required for National Early Warning Score ≤ 2 maintained 24 hours(28 days after randomization)
- Incidence of oxygen use, NIV or high flow oxygen therapy(28 days after randomization)
- Biochemical response: blood test for lymphocytes (lymphopenia)(day: 3,5,7,14,21,28)
- Define the optimal dose of CPZ and its tolerance: biological anomalies(day: 3,5,7,14,21,28)
- Define the optimal dose of CPZ and its tolerance: anxiety assessment on Global Anxiety - Visual Analog Scale (GA-VAS)(28 days)
- Define the optimal dose of CPZ and its tolerance: Rates of drug discontinuation(28 days)