Hydroxychloroquine Versus Placebo in COVID-19 Patients at Risk for Severe Disease

Coronavirus Clinical Trial

— HYCOVID  

Official title:

Hydroxychloroquine Versus Placebo in Patients Presenting COVID-19 Infection and at Risk of Secondary Complication: a Prospective, Multicentre, Randomised, Double-blind Study

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04325893
• Other study ID #: 49RC20_0071
• Status: Terminated
• Phase: Phase 3
• Start date: April 1, 2020
• Est. completion date: June 18, 2020

Study information

• Verified date: April 2020
• Source: University Hospital, Angers
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A new human coronavirus responsible for pneumonia, SARS-CoV-2, emerged in China in December 2019 and has spread rapidly. COVID-19, the disease caused by this virus, has a very polymorphous clinical presentation, which ranges from upper respiratory tract infections to acute respiratory distress syndrome. It may appear serious straightaway or may evolve in two stages, with a worsening 7 to 10 days after the first clinical signs, potentially linked to a cytokine storm and accompanied by a high risk of thrombosis. The global mortality rate of COVID-19 is between 3% and 4%, with severe forms being more frequent among older patients. Management is symptomatic as no antiviral treatment has demonstrated any clinical benefit in this condition. Hydroxychloroquine is a derivative of chloroquine commonly used in some autoimmune diseases, such as systemic lupus erythematosus. It is active in vitro in cellular models of infection by many viruses such as HIV, hepatitis C or SARS-CoV. However, its interest in viral infections in humans has not been demonstrated.

Very recently, a preliminary uncontrolled study evaluated the effect of hydroxychloroquine on viral shedding in subjects with COVID-19. Among 20 patients treated with hydroxychloroquine at a dose of 600 mg per day, the percentage of patients with detectable SARS-CoV-2 RNA in the nasopharynx decreased from 100% at inclusion (start of treatment) to 43% six days later. In comparison, 15 of 16 untreated patients had a positive RT-PCR six days after inclusion. Furthermore, hydroxychloroquine has immunomodulating and anti-inflammatory properties, which could theoretically prevent or limit secondary worsening.

The research hypothesis is that treatment with hydroxychloroquine improves prognosis and reduces the risk of death or use for invasive ventilation in patients with COVID-19.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 259
• Est. completion date: June 18, 2020
• Est. primary completion date: June 18, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age = 18 years old

• Symptomatic infection with COVID-19 confirmed by positive RT-PCR SARS-CoV-2 or, failing that, by thorax CT-scan suggesting viral pneumopathy of peripheral predominance in a clinically significant context.

• Diagnosis in the previous two calendar days or, for an asymptomatic patient at the time of virological diagnosis, onset of symptoms in the previous two calendar days.

• Patient having at least one of the following risk factors for developing complications:

• Age =75 years old

• Age between 60 and 74 years old and presence of at least one comorbidity among the following: obesity (body mass index = 30 kg/m²), arterial hypertension requiring treatment, diabetes mellitus requiring treatment

• Need for supplemental oxygen to reach a peripheral capillary oxygen saturation of more than 94% (SpO2 > 94%), or a ratio of partial oxygen pressure to the fraction of inspired oxygen less than or equal to 300 mmHg (PaO2/FiO2 = 300 mmHg).

• Patient affiliated to a social security scheme.

• Written and signed consent of the patient or a relative or emergency inclusion procedure.

Exclusion criteria

• Last RT-PCR negative for SARS-CoV-2

• Peripheral capillary oxygen saturation less than or equal to 94% (SpO2 = 94%) despite oxygen therapy greater than or equal to 3 L/min (> 3 L/min)

• Organ failure requiring admission to a critical or intensive care unit.

• Comorbidity that is life threatening in the short-term (life expectancy < 3 months)

• Any reason that makes patient follow-up throughout the study impossible

• Current treatment with hydroxychloroquine

• Absolute contraindication to treatment with hydroxychloroquine (known hypersensitivity, retinopathy, concomitant treatment with risk of ventricular disorders, particularly torsades de pointe, known deficit of glucose-6-phosphate dehydrogenase, porphyria)

• Hypokalaemia < 3.5 mmol/L

• Corrected QT prolongation (QTc = 440 ms in men and 460 ms in women).

• Child-Pugh's class C liver cirrhosis

• Chronic kidney failure with estimated GFR = 30 ml/min, or = 40 ml/min in patients with concomitant treatment with azithromycin

• Women who are pregnant, breastfeeding, or parturient

Related Conditions & MeSH terms

• Coronavirus
• Coronavirus Infections

Intervention

Drug:
• Hydroxychloroquine
First dose of 400 mg will be taken immediately after inclusion at day 0, the second dose of 400 mg will be taken on the same evening and at least 4 hours after the first dose. The treatment will then be continued for the following eight days at a rate of 200 mg in the morning and evening.
• Placebo
TFirst dose of 400 mg will be taken immediately after inclusion at day 0, the second dose of 400 mg will be taken on the same evening and at least 4 hours after the first dose. The treatment will then be continued for the following eight days at a rate of 200 mg in the morning and evening.

Locations

Country	Name	City	State
France	CH Agen	Agen
France	CHU Amiens	Amiens
France	CHU Angers	Angers
France	CH Auxerre	Auxerre
France	APHP Avicenne	Bobigny
France	CHU Brest	Brest
France	CHU Caen	Caen
France	CH Chalon Sur Saône	Chalon Sur Saône
France	CH Cherbroug	Cherbourg
France	CH Cholet	Cholet
France	CH Colmar	Colmar
France	CH Compiègne	Compiègne
France	APHP Henri Mondor	Créteil
France	CH Intercommunal Créteil	Créteil
France	CHU Dijon	Dijon
France	APHP Joffre Dupuytren	Draveil
France	CHD Vendée	La Roche-sur-Yon
France	CH Laval	Laval
France	CH Le Mans	Le Mans
France	CH Emile Roux	Le Puy-en-Velay
France	APHP Emile ROUX	Limeil-Brevannes
France	CHU Limoges	Limoges
France	CH Lorient	Lorient
France	Hôpital Européen - Marseille	Marseille
France	Hôpital Saint-Joseph	Marseille
France	CH Melun	Melun
France	CHU Nantes	Nantes
France	Hôpital Privé du Confluent	Nantes
France	CH Niort	Niort
France	CHR Orléans	Orléans
France	APHP Saint-Antoine	Paris
France	GH Croix Saint Simon	Paris
France	La Pitié-Salpétrière	Paris
France	CHU Poitiers	Poitiers
France	CH Pointoise	Pontoise
France	CH Quimper	Quimper
France	CH Saint-Brieuc	Saint-Brieuc
France	CHU Saint-Etienne	Saint-Étienne
France	CH Saint-Nazaire	Saint-Nazaire
France	CHU Toulouse	Toulouse
France	CH Tourcoing	Tourcoing
France	CHU Tours	Tours
France	CH Valenciennes	Valenciennes
France	Clinique Tessier Valenciennes	Valenciennes
France	CH Vannes	Vannes
France	CH Versailles	Versailles
Monaco	CH Princesse Grace	Monaco

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Angers

Countries where clinical trial is conducted

France,  Monaco, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of death from any cause, or the need for intubation and mechanical ventilation during the 14 days following inclusion and start of treatment.		Day 14
Secondary	Number of death from any cause, or the need for intubation and mechanical ventilation during the 28 days following inclusion and start of treatment.		Day 28
Secondary	Clinical evolution on the WHO Ordinal Scale for Clinical Improvement for COVID-19 between day 0 and day 14	WHO Ordinal Scale for Clinical Improvement ranges from 0 to 8, higher score meaning poorer outcome	Day 14
Secondary	Clinical evolution on the WHO Ordinal Scale for Clinical Improvement for COVID-19 between day 0 and day 28.	WHO Ordinal Scale for Clinical Improvement ranges from 0 to 8, higher score meaning poorer outcome	Day 28
Secondary	Number of all-cause mortality at day 14		Day 14
Secondary	Number of all-cause mortality at day 28		Day 28
Secondary	Rate of positive SARS-CoV-2 RT-PCR on nasopharyngeal samples at day 5		Day 5
Secondary	Rate of positive SARS-CoV-2 RT-PCR on nasopharyngeal samples at day 10		Day 10
Secondary	The rate of venous thromboembolic events at day 28, documented and confirmed by an adjudication committee.		Day 28
Secondary	Number of all-cause mortality at day 28 in patients aged 75 and older		day 28
Secondary	Clinical evolution on the WHO OSCI scale for COVID-19 between day 0 and day 28 for patients aged 75 or older		day 28
Secondary	Rate of severe adverse events at day 28		day 28
Secondary	Number of all-cause mortality at day 14 in patients aged 75 and older		day 14