Hydroxychloroquine or Diltiazem-Niclosamide for the Treatment of COVID-19 (HYdILIC)

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

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 Overview

• Status: Withdrawn
• Conditions: Sars-CoV2
• Intervention / Treatment: Other: Standard of care (SOC); Drug: Hydroxychloroquine; Drug: Association of diltiazem and niclosamide

• Study Type: Interventional
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: standard of care (SOC)	Other: Standard of care (SOC); 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
Experimental: SOC + Hydroxychloroquine	Other: Standard of care (SOC); 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; Drug: Hydroxychloroquine; 200 mg x 3 per day during 10 days in addition to SOC
Experimental: SOC + Diltiazem-Niclosamide	Other: Standard of care (SOC); 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; Drug: Association of diltiazem and niclosamide; 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

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

Collaborators and Investigators

• Sponsor: University Hospital, Lille
• Collaborators: I-site University Lille North Europe
• Investigators: Principal Investigator: Karine Faure, MD,PhD, University Hospital, Lille

Study record dates

Study Major Dates

• Study Start (Anticipated): May 1, 2020
• Primary Completion (Anticipated): May 1, 2023
• Study Completion (Anticipated): May 1, 2023

Study Registration Dates

• First Submitted: April 30, 2020
• First Submitted That Met QC Criteria: April 30, 2020
• First Posted (Actual): May 1, 2020

Study Record Updates

• Last Update Posted (Actual): March 11, 2021
• Last Update Submitted That Met QC Criteria: March 8, 2021
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Covid-19; Hydroxychloroquine; Dilitazem; Niclosamide
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Antiprotozoal Agents; Antiparasitic Agents; Calcium Channel Blockers; Antimalarials; Antinematodal Agents; Anthelmintics; Antiplatyhelmintic Agents; Anticestodal Agents; Hydroxychloroquine; Diltiazem; Niclosamide
• Other Study ID Numbers: 2020_40; 2020-002188-72 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No