Study Evaluating Diltiazem in Combination With Standard Treatment in the Management of Patients Hospitalized With COVID-19 Pneumonia

Study Overview
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Brief Summary
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SARS-CoV-2 infection is responsible for hypoxemic pneumonia, which is sometimes serious and associated with excess mortality. To date, with the exception of dexamethasone, which has shown clinical efficacy by reducing the mortality of infected patients, no other therapeutic strategy has demonstrated a curative clinical benefit, particularly in the initial stages facilitating viral eviction. . Based on the mechanism of action and the available data, diltiazem, administered in the first days post-infection, could facilitate viral eradication in these patients through the stimulation of the innate immune response of cells of the infected respiratory epithelium, actor in the fight against SARS-CoV-2. In this context, the investigators propose the DICOV trial, to demonstrate the ability of diltiazem to reduce the viral load more rapidly, in patients hospitalized for COVID-19 hypoxemic pneumonia.

Official Title
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Multicenter, Double-blind, Randomized, Placebo-controlled Study Evaluating Diltiazem in Combination With Standard Treatment in the Management of Patients Hospitalized With COVID-19 Pneumonia - A Phase IIB, Proof of Concept Study

Conditions
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COVID-19

Intervention / Treatment
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* Drug: DILTIAZEM TEVA 60 mg or placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged 18 or over SARS-CoV-2 infection proven by RT-PCR on a nasopharyngeal sample within 72 hours prior to inclusion in the study Onset of symptoms of viral infection ≤ 7 days Hospitalization required due to hypoxemia (air saturation < 94% at rest) Presence of radiological pneumopathy (chest X-ray or non-enhanced thoracic CT) Patient affiliated to a social security scheme. Patient capable of giving free, informed and written consent. Patient with a history of SARS-CoV-2 infection may participate in the study, but this infection must not have occurred within the 3 months prior to his current hospitalization. Patient who has been vaccinated against SARS-CoV-2 can participate in the study (regardless of the number of doses) Patient not eligible for specific anti-COVID treatment authorized in France (MA or early access) and not part of the standard of care at the time of the study Female patient of childbearing age using effective contraception during study participation, the same applies to partners of childbearing age of male patients. Male patients must use condoms. Exclusion Criteria: Need for hospitalization in intensive care unit at inclusion Patient with cognitive impairment, at the discretion of the investigator Pregnant woman (positive urine pregnancy test on inclusion) or breastfeeding Participation in another interventional study or being in the exclusion period from a previous study Patient on diltiazem therapy Contraindication to diltiazem Hypersensitivity to diltiazem or to any of the excipients Unaided sinus dysfunction Unaided 2nd and 3rd degree atrioventricular blocks Left ventricular failure with pulmonary stasis (cardiogenic edema) Severe bradycardia (≤ 40 beats per minute) In combination with: dantrolene infusion, pimozide, dihydroergotamine, ergotamine, nifedipine, ivabradine, beta blockers, antiarrhythmics, esmolol, fingolimod. Patient with renal, hepatic or cardiac insufficiency (at the discretion of the investigator) Hypersensitivity to mannitol Use of anti-COVID medications other than those offered in routine testing and care. Presence of hemodynamic instability, systolic blood pressure < 100 mmHg, presence of multi-visceral failure Prior respiratory pathology requiring oxygen therapy at the long-term and/or non-invasive ventilation Immunocompromised patients (organ transplant, allograft, under chemotherapy, under Rituximab or a history of Rituximab), for any other situation seek the advice of the coordinating investigator Patient under guardianship, curatorship or safeguard of justice

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Standard Of Care (SOC) + diltiazem<br>Patients will receive the standard of care at the time of their inclusion in the trial and will also receive diltiazem (60mg 3 times a day) for 7 days. | Drug: DILTIAZEM TEVA 60 mg or placebo<br>* DILTIAZEM TEVA 60 mg 3 times a day during 7 days + standard of care Or placebo 3 times a day during 7 days + standard of care.<br>|
| Placebo Comparator: SOC + placebo<br>Patients will receive the standard of care at the time of their inclusion in the trial and will also receive a diltiazem placebo (3 times a day) for 7 days | Drug: DILTIAZEM TEVA 60 mg or placebo<br>* DILTIAZEM TEVA 60 mg 3 times a day during 7 days + standard of care Or placebo 3 times a day during 7 days + standard of care.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SARS-CoV-2 viral load decrease between D1 and D7 | Dosage of the standardized SARS-CoV-2 viral load on nasopharyngeal samples on day 1 and day 7 after treatment initiation. | At day 1 and day 7 post treatment initiation. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to clinical improvement | Time to clinical improvement (in days), defined as the time from randomization to an improvement of at least 2 points on a 7-point ordinal scale | Within 28 days post-randomization | 
| Overall survival | Percentage of patients who died between D1 and D28 of the start of treatment | at day 28 | 
| SARS-CoV-2 viral load kinetics | Kinetics of viral load decrease by dosage of the normalized SARS-CoV-2 viral load on nasopharyngeal samples | Day 1, day 7, day 15, day 21 and day 28 | 
| proportion of patients who are potential transfer candidates in intensive care | Percentage of patients candidates for transfer to intensive care at Day 15 of the start of treatment | At Day 15 | 
| Tolerance of the study treatment | Occurrence of adverse events, severe adverse events and premature discontinuation of study treatment | Within 28 days after treatment initiation | 
| Duration of oxygen therapy | Number of days the patient was put on oxygen therapy | Within 28 days after treatment initiation | 
| Proportion of patients requiring assisted or non-invasive ventilation | Percentage of patients requiring assisted or non-invasive ventilation | Within 28 days after treatment initiation | 
| Duration of assisted or non-invasive ventilation | Number of days the patient was put on assisted or non-invasive ventilation | Within 28 days after treatment initiation | 
| Duration of hospitalization in intensive care unit | Number of days spent in intensive care | At day 28. | 
| Duration of hospitalization in intensive care unit | Number of days spent in intensive care. For patients still in intensive care on D28 this information will be collected on D90 | At day 90 | 
| Hospital length of stay | Number of days spent in hospital | At day 28. | 
| Hospital length of stay | Number of days spent in hospital. For patients still in intensive care on D28 this information will be collected on D90 | At day 90 | 
| Flow rate of oxygen used | Maximum oxygen rate used | Within 28 days after treatment initiation | 
| Extension of viral pneumonitis | Difference in extension of viral pneumonitis on comparative analysis scans performed at D1 and D28 | Day 1, day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pneumonia, Viral, Diltiazem