Hydroxychloroquine or Diltiazem-Niclosamide for the Treatment of COVID-19

Study Overview
=================
Brief Summary
-----------------
No optimal antiviral intervention has been yet validated to treat COVID-19 disease. Comorbidities, such as older age, obesity, diabetes, history of cardiovascular diseases are associated with poor prognosis. This study aims to evaluate the efficacy of two experimental antiviral treatments, compared to standard of care (SOC), to prevent clinical worsening, hospitalization or death at day 14 in adults with documented SARS-CoV-2 infection, asymptomatic or with symptoms lasting less than 8 days, and associated comorbidities without any severity criteria of the disease at inclusion. Participants will be randomized to receive SOC alone or SOC + hydroxychloroquine 200 mg three times a day during 10 days or SOC + association of niclosamide 2 g at J1 then 500 mg two times a day with diltiazem 60 mg three times a day during 10 days. Efficacy and tolerance of each treatments will be compared across the three treatment groups during the 28 days of follow-up.

Official Title
-----------------
Efficacy of HYdroxychloroquine and DILtiazem-nIClosamide Combination for the Treatment of Non-severe Forms of SARS-CoV2 Infection in Patients With Co-morbidities: Multicenter, Randomized, Open-labeled Controlled Trial

Conditions
-----------------
Sars-CoV2

Intervention / Treatment
-----------------
* Other: Standard of care (SOC)
* Drug: Hydroxychloroquine
* Drug: Association of diltiazem and niclosamide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Positive SARS-CoV-2 test on nasopharyngeal swab Onset of symptoms <8 days prior to randomization NEWS score<4 AND no item ≥2 At least one comorbidity among: age ≥ 70 years old, history of cardiac disease, diabetes, obesity, chronic kidney disease, chronic respiratory failure, immunosuppression, neoplasia, liver failure (stage ≥ Child-Pugh B) Fully able to understand the challenges of the trial Signed informed consent Covered by Health Insurance Exclusion Criteria: For all patients: Inability to decide to participate Pregnancy or breath feeding Hypersensitivity to any of the test drugs stage 4 or 5 chronic kidney disease (DFG <30 mL/min/1.73 m²) For hydroxychloroquine arm: Long QT syndrome or QTc space >500 ms Treatment with piperazine, halofantrine, dasatinib, nilotinib, citalopram, escitalopram, hydroxyzine, domperidone Hepatic porphyria, retinopathy, known glucose-6-phosphate dehydrogenase deficiency, Heart rate <50/min hypokaliemia < 3.5 mmol/L For diltiazem arm: Heart rate<40/min Sinus bradycardia, second- or third-degree atrioventricular block Left heart insufficiency with pulmonary stasis Treatment with dantrolene, pimozide, dihydroergotamine, ergotamine, nifedipine, ivabradine, esmolol, bêta-blockers (bisoprolol, carvedilol, metoprolol, nebivolol), fingolimod

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: standard of care (SOC)<br> | Other: Standard of care (SOC)<br>* SOC procedures including self-monitoring and medical follow-up of clinical signs and if necessary any other symptomatic treatment (paracetamol, antibiotics, steroids, oxygen…) during the whole study duration<br>|
| Experimental: SOC + Hydroxychloroquine<br> | Other: Standard of care (SOC)<br>* SOC procedures including self-monitoring and medical follow-up of clinical signs and if necessary any other symptomatic treatment (paracetamol, antibiotics, steroids, oxygen…) during the whole study duration<br>Drug: Hydroxychloroquine<br>* 200 mg x 3 per day during 10 days in addition to SOC<br>|
| Experimental: SOC + Diltiazem-Niclosamide<br> | Other: Standard of care (SOC)<br>* SOC procedures including self-monitoring and medical follow-up of clinical signs and if necessary any other symptomatic treatment (paracetamol, antibiotics, steroids, oxygen…) during the whole study duration<br>Drug: Association of diltiazem and niclosamide<br>* niclosamide 500 mg x 4 at J1 then 500 mg x 2 per day + diltiazem 60 mg x 3 per day during 10 days in addition to SOC<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| death | Composite criteria | At day 14 | 
| clinical worsening (composite criteria) | clinical worsening defined by at least one of the NEWS score item > 2 (temperature >39,1°C or<35°C, cardiac rate >111 or ≤40 bpm, respiratory rate > 21 or ≤8 cycles par minute, SaO2 ≤ 93% room air (if its measure is available),need of oxygen | At day 14 | 
| Assisted-ventilation and/or hospitalization (composite criteria) |  | At day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| National Early Warning Score (NEWS) | clinical state as reflected by NEWS scoring, the clinical state of the patient regarding respiratory state as defined by the NEWS scoring system | at day 3, day 8, day 14 day 28 | 
| cumulative incidence of hospitalizations |  | at day 14 | 
| cumulative incidence of the use of oxygen therapy, non-invasive ventilation or invasive ventilation ( composite criteria) |  | at day 14 | 
| Mortality | Number of patients death | at day 14 and at day 28 | 
| cumulative incidence of viral shedding on SARS-CoV-2 rt-PCR on nasopharyngeal swab; |  | at day 3, day 8 | 
| adverse drug reactions |  | during study, up to 28 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Covid-19, Hydroxychloroquine, Dilitazem, Niclosamide