Clinical trial NCT04325893: Hydroxychloroquine Versus Placebo in COVID-19 Patients at Risk for Severe Disease
Official title: Hydroxychloroquine Versus Placebo in Patients Presenting COVID-19 Infection and at Risk of Secondary Complication: a Prospective, Multicentre, Randomised, Double-blind Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Coronavirus
Lead sponsor: University Hospital, Angers
Sponsor class: OTHER_GOV
First posted: 2020-03-30
Enrollment: 259
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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

Primary outcomes:
measure: Number of death from any cause, or the need for intubation and mechanical ventilation during the 14 days following inclusion and start of treatment.
timeFrame: Day 14
Secondary outcomes:
measure: Number of death from any cause, or the need for intubation and mechanical ventilation during the 28 days following inclusion and start of treatment.
timeFrame: Day 28
measure: Clinical evolution on the WHO Ordinal Scale for Clinical Improvement for COVID-19 between day 0 and day 14
timeFrame: Day 14
measure: Clinical evolution on the WHO Ordinal Scale for Clinical Improvement for COVID-19 between day 0 and day 28.
timeFrame: Day 28
measure: Number of all-cause mortality at day 14
timeFrame: Day 14
measure: Number of all-cause mortality at day 28
timeFrame: Day 28
measure: Rate of positive SARS-CoV-2 RT-PCR on nasopharyngeal samples at day 5
timeFrame: Day 5
measure: Rate of positive SARS-CoV-2 RT-PCR on nasopharyngeal samples at day 10
timeFrame: Day 10
measure: The rate of venous thromboembolic events at day 28, documented and confirmed by an adjudication committee.
timeFrame: Day 28
measure: Number of all-cause mortality at day 28 in patients aged 75 and older
timeFrame: day 28
measure: Clinical evolution on the WHO OSCI scale for COVID-19 between day 0 and day 28 for patients aged 75 or older
timeFrame: day 28
measure: Rate of severe adverse events at day 28
timeFrame: day 28
measure: Number of all-cause mortality at day 14 in patients aged 75 and older
timeFrame: day 14
Other outcomes:
Locations:
city: Agen
country: France
facility: CH Agen
city: Amiens
country: France
facility: CHU Amiens
city: Angers
country: France
facility: CHU Angers
city: Auxerre
country: France
facility: CH Auxerre
city: Bobigny
country: France
facility: APHP Avicenne
city: Brest
country: France
facility: CHU Brest
city: Caen
country: France
facility: CHU Caen
city: Chalon Sur Saône
country: France
facility: CH Chalon Sur Saône
city: Cherbourg
country: France
facility: CH Cherbroug
city: Cholet
country: France
facility: CH Cholet
city: Colmar
country: France
facility: CH Colmar
city: Compiègne
country: France
facility: CH Compiègne
city: Créteil
country: France
facility: APHP Henri Mondor
city: Créteil
country: France
facility: CH Intercommunal Créteil
city: Dijon
country: France
facility: CHU Dijon
city: Draveil
country: France
facility: APHP Joffre Dupuytren
city: La Roche-sur-Yon
country: France
facility: CHD Vendée
city: Laval
country: France
facility: CH Laval
city: Le Mans
country: France
facility: CH Le Mans
city: Le Puy-en-Velay
country: France
facility: CH Emile Roux
city: Limeil-Brevannes
country: France
facility: APHP Emile ROUX
city: Limoges
country: France
facility: CHU Limoges
city: Lorient
country: France
facility: CH Lorient
city: Marseille
country: France
facility: Hôpital Européen - Marseille
city: Marseille
country: France
facility: Hôpital Saint-Joseph
city: Melun
country: France
facility: CH Melun
city: Nantes
country: France
facility: CHU Nantes
city: Nantes
country: France
facility: Hôpital Privé du Confluent
city: Niort
country: France
facility: CH Niort
city: Orléans
country: France
facility: CHR Orléans
city: Paris
country: France
facility: APHP Saint-Antoine
city: Paris
country: France
facility: GH Croix Saint Simon
city: Paris
country: France
facility: La Pitié-Salpétrière
city: Poitiers
country: France
facility: CHU Poitiers
city: Pontoise
country: France
facility: CH Pointoise
city: Quimper
country: France
facility: CH Quimper
city: Saint-Brieuc
country: France
facility: CH Saint-Brieuc
city: Saint-Nazaire
country: France
facility: CH Saint-Nazaire
city: Saint-Étienne
country: France
facility: CHU Saint-Etienne
city: Toulouse
country: France
facility: CHU Toulouse
city: Tourcoing
country: France
facility: CH Tourcoing
city: Tours
country: France
facility: CHU Tours
city: Valenciennes
country: France
facility: CH Valenciennes
city: Valenciennes
country: France
facility: Clinique Tessier Valenciennes
city: Vannes
country: France
facility: CH Vannes
city: Versailles
country: France
facility: CH Versailles
city: Monaco
country: Monaco
facility: CH Princesse Grace
Study officials:
References:
citation: Dubee V, Roy PM, Vielle B, Parot-Schinkel E, Blanchet O, Darsonval A, Lefeuvre C, Abbara C, Boucher S, Devaud E, Robineau O, Rispal P, Guimard T, d'Anglejean E, Diamantis S, Custaud MA, Pellier I, Mercat A; HYCOVID study group; HYCOVID investigators; Angers University Hospital; Cholet Hospital; Laval Hospital; Le Mans Hospital; Tours University Hospital; Quimper Hospital; La Roche sur Yon Hospital; Tourcoing Hospital; Orleans Hospital; Nantes University Hospital; Niort Hospital; Lorient Hospital; Brest University Hospital; Cherbourg Hospital; Saint-Brieuc Hospital; Creteil - APHP University Hospital; Saint-Antoine - APHP University Hospital; Saint-Etienne University Hospital; Toulouse University Hospital; Melun Hospital; Dijon University Hospital; Princesse Grace - Monaco Hospital; Versailles Hospital; Colmar Hospital; Agen-Nerac Hospital; Caen University Hospital; Saint-Nazaire Hospital; Nantes - Confluent Hospital; Limoges University Hospital; Poitiers University Hospital; Amiens University Hospital; Bobigny - APHP University Hospital; Cergy-Pontoise Hospital; Valencienne Hospital; Valencienne - Clinique Tessier Hospital; Henri-Mondor - APHP University Hospital; Chalon-sur-Saone Hospital; Marseille European Hospital; Auxerre Hospital; Diaconnesses Croix-Saint-Simon Hospital; Marseille - Saint Joseph Hospital; HYCOVID management team: Steering committee (authors); HYCOVID management team: Independant data safety and monitoring board; HYCOVID management team: Independent adjudication of clinical events committee; Study management: Coordination; Study management: Data management. Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: a placebo-controlled double blind trial. Clin Microbiol Infect. 2021 Aug;27(8):1124-1130. doi: 10.1016/j.cmi.2021.03.005. Epub 2021 Apr 1.