Repurposing of Chlorpromazine in Covid-19 Treatment

COVID-19 Clinical Trial

— reCoVery  

Official title:

Repurposing of Chlorpromazine in Covid-19 Treatment

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04366739
• Other study ID #: D20-P016
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: April 29, 2020
• Est. completion date: September 30, 2020

Study information

• Verified date: April 2020
• Source: Centre Hospitalier St Anne
• Contact: Marion Plaze, MD, PHD
• Phone: 0145658646
• Email: m.plaze[@]ghu-paris.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 40
• Est. completion date: September 30, 2020
• Est. primary completion date: August 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• COVID-19

Intervention

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

Locations

Country	Name	City	State
France	Centre Hospitalier Sainte-Anne	Paris

Sponsors (2)

Lead Sponsor	Collaborator
Centre Hospitalier St Anne	Hôpital Cochin

Country where clinical trial is conducted

France, 

References & Publications (16)

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Daniel JA, Chau N, Abdel-Hamid MK, Hu L, von Kleist L, Whiting A, Krishnan S, Maamary P, Joseph SR, Simpson F, Haucke V, McCluskey A, Robinson PJ. Phenothiazine-derived antipsychotic drugs inhibit dynamin and clathrin-mediated endocytosis. Traffic. 2015 Jun;16(6):635-54. doi: 10.1111/tra.12272. Epub 2015 Apr 9. — View Citation

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Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: the american headache society evidence assessment of migraine pharmacotherapies. Headache. 2015 Jan;55(1):3-20. doi: 10.1111/head.12499. Review. — View Citation

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Pu Y, Zhang X. Mouse hepatitis virus type 2 enters cells through a clathrin-mediated endocytic pathway independent of Eps15. J Virol. 2008 Aug;82(16):8112-23. doi: 10.1128/JVI.00837-08. Epub 2008 Jun 11. — View Citation

Verity R, Okell LC, Dorigatti I, Winskill P, Whittaker C, Imai N, Cuomo-Dannenburg G, Thompson H, Walker PGT, Fu H, Dighe A, Griffin JT, Baguelin M, Bhatia S, Boonyasiri A, Cori A, Cucunubá Z, FitzJohn R, Gaythorpe K, Green W, Hamlet A, Hinsley W, Laydon D, Nedjati-Gilani G, Riley S, van Elsland S, Volz E, Wang H, Wang Y, Xi X, Donnelly CA, Ghani AC, Ferguson NM. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis. 2020 Mar 30. pii: S1473-3099(20)30243-7. doi: 10.1016/S1473-3099(20)30243-7. [Epub ahead of print] Erratum in: Lancet Infect Dis. 2020 Apr 15;:. — View Citation

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* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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)	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	day: 1, 3,5,7,14,21,28
Primary	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	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
Secondary	All-cause mortality	All-cause mortality rates at Day 28th after randomization	28 days after randomization
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Parenchymal involvement (chest CT)	Extension score of parenchymal involvement in thoracic computed tomography (CT) (D7)	day 7
Secondary	Define the optimal dose of CPZ and its tolerance: rates of serious adverse events	Rates of serious adverse events	28 days
Secondary	Define the optimal dose of CPZ and its tolerance: rates of non-serious side effects	Rates of non-serious side effects	28 days
Secondary	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
Secondary	Define the optimal dose of CPZ and its tolerance: Rates of drug discontinuation	Rates of drug discontinuation in all causes under study	28 days
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Define the optimal dose of CPZ and its tolerance: CPZ dose administered	CPZ dosages administered	28 days