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

Phase 3WithdrawnNCT04372082

University Hospital, Lille

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Conditions

Sars-CoV2

Interventions

Standard of care (SOC)OTHER

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

HydroxychloroquineDRUG

200 mg x 3 per day during 10 days in addition to SOC

Association of diltiazem and niclosamideDRUG

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

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

death

Composite criteria

Time frame: 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

Time frame: At day 14

Assisted-ventilation and/or hospitalization (composite criteria)

Time frame: At day 14

Secondary Outcomes

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

Time frame: at day 3, day 8, day 14 day 28

cumulative incidence of hospitalizations

Time frame: at day 14

cumulative incidence of the use of oxygen therapy, non-invasive ventilation or invasive ventilation ( composite criteria)

Time frame: at day 14

Mortality

Number of patients death

Time frame: at day 14 and at day 28

cumulative incidence of viral shedding on SARS-CoV-2 rt-PCR on nasopharyngeal swab;

Time frame: at day 3, day 8

adverse drug reactions

Time frame: during study, up to 28 days

Data from ClinicalTrials.gov

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