The Potential Use of Nebulized Hydroxychloroquine for the Treatment of COVID-19

Study Overview
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Brief Summary
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This is a pilot, randomized, single-center, parallel group, open-label controlled study to evaluate the feasibility, safety, efficacy, and pharmacokinetics of nebulized HCQ01 plus Standard of Care (SOC) versus SOC alone in hospitalized COVID-19 patients. The Jordanian Ministry of Health (MOH) is the study sponsor, and the study will be conducted at MOH COVID-19 hospitals. Approximately 110 patients, ≥18 years of age with a confirmed SARS-CoV-2 infection, will be enrolled and randomized 1:1 to the treatment and control arms where they will receive ten doses of Hydroxychloroquine solution via nebulizer in addition to SOC or the control arm where treatment will follow the MOH SOC.

Official Title
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A Pilot, Randomized, Open-label Trial to Determine the Feasibility, Safety, Efficacy, and Pharmacokinetics of Nebulized HCQ01for the Treatment of Patients With COVID-19

Conditions
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2019 Novel Coronavirus

Intervention / Treatment
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* Drug: HCQ01
* Other: standard of care (SOC) for COVID-19


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pregnant (positive β-human chorionic gonadotropin test, β-HCG) or lactating female at screening. Patients with a history of retinopathy, sickle cell disease or trait, psoriasis, porphyria, history of splenectomy, mental illness or uncontrolled seizures disorder, known active tuberculosis or history of incompletely treated tuberculosis, patients on chronic immunosuppression for other medical conditions such as rheumatological disorders, inflammatory bowel disease, or in patients with organ transplants. Patients admitted in ICU. Taking medications which may lead to interactions with hydroxychloroquine, including penicillamine, telbivudine, botulinum toxin, fluconazole, digoxin, propafenone , cimetidine, statins, warfarin, and cyclosporine within 2 weeks of dosing start, and during the duration of the study. History of Glucose-6-phosphate dehydrogenase deficiency. Pre-treatment corrected QT interval (QTc) ≥450 milliseconds. Exclusion Criteria: Pregnant (positive β-human chorionic gonadotropin test, β-HCG) or lactating female at screening. Patients with a history of retinopathy, sickle cell disease or trait, psoriasis, porphyria, history of splenectomy, mental illness or uncontrolled seizures disorder, known active tuberculosis or history of incompletely treated tuberculosis, patients on chronic immunosuppression for other medical conditions such as rheumatological disorders, inflammatory bowel disease, or in patients with organ transplants. Patients admitted in ICU. Taking medications which may lead to interactions with hydroxychloroquine, including penicillamine, telbivudine, botulinum toxin, fluconazole, digoxin, propafenone , cimetidine, statins, warfarin, and cyclosporine within 2 weeks of dosing start, and during the duration of the study. History of Glucose-6-phosphate dehydrogenase deficiency. Pre-treatment corrected QT interval (QTc) ≥450 milliseconds. Acute or chronic kidney disease (stage-4 or -5 renal impairment; eGFR<30 mL/min/1.73 m2 or hemodialysis). Liver Child-Pugh grade C. Patients with Hypokalemia (<3.5mmol/L), Hypocalcemia (<2.2mmol/L), Hypomagnesemia (<0.66mmol/L). Will be included after correction. Need for mechanical ventilation. History of hypersensitivity to hydroxychloroquine. History of Chronic Hepatitis B or hepatitis C infections. History of Human Immunodeficiency Virus (HIV) infection. Concurrent serious illness including, but not limited to, any of the following: Clinically significant cardiovascular disease (e.g., uncontrolled hypertension, myocardial infarction, or unstable angina). New York Heart Association class II-IV congestive heart failure. Serious cardiac arrhythmia requiring medication. -Peripheral vascular disease ≥ grade 2 within the past year. - Psychiatric illness/social situation that would limit compliance with study requirements. -COPD, Lung cancer, and moderate to severe asthma. Any other significant finding based on the judgment of the PI would increase the risk of having an adverse outcome from participating in this study. Any other concomitant treatment based on the judgment of the PI would increase the risk of having an adverse outcome from participating in this study. Is currently participating in or has participated in an interventional clinical trial with an investigational compound or device within 80 days of signing the informed consent/assent for this current trial.

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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Accepts Healthy Volunteers

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: First Arm (Hydroxychloroquine sulfate, 5 days)<br>Participants will receive continued standard of care therapy (SOC) for COVID-19 together with 2 ml HCQ01 (12.5 mg/ml) twice a day for 5 consecutive days. | Drug: HCQ01<br>* HCQ01 is a sterile, clear and colorless, ready-to-use aqueous nebulizer solution. Hydroxychloroquine sulfate administered via nebulization<br>|
| Active Comparator: Second Arm (Continued Standard of Care (SOC) Therapy)<br>Participants will receive continued standard of care therapy for COVID-19 | Other: standard of care (SOC) for COVID-19<br>* Standard of care (SOC) for COVID-19<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| WHO Ordinal Scale for for Clinical Improvement | Change in condition measured using the Ordinal Scale for Clinical Improvement. Patients are scored on a scale of 0-10 with 0 being uninfected and 10 being dead | [ Day -1 (screening) to Days 3,6, and 14 ] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants who improve by at least one level lower on the 11-point WHO-OSCI |  | Day 28 | 
| All-cause mortality |  | Day 28 | 
| HCQ concentration in plasma versus time profiles |  | Day 1 pre-dose (within 1-hour prior dosing) and +2, +5, +10, +15, +20, +25, and +30 minutes after dose, and also +1, +2, +3, +4 and +6 hours post-dose completion | 
| Change from Baseline Oxygenation as determined by the SpO2/FiO2 ratio |  | Days 3 & 6 | 
| Rate of Transfer to the Intensive Care Unit |  | Up to day 28 | 
| Time to Hospital Discharge or NEWS2 (National Early Warning Score 2) of ≤ 2 |  | Up to day 28 | 
| Treatment-related adverse events of HCQ |  | Up to day 28 | 
| Cardiac Arrhythmia - Polymorphic Ventricular Tachycardia [Time Frame | Cardiologist Diagnostic Documentation | Up to day 6 | 
| Cardiac Arrhythmia - Ventricular Tachycardia | Cardiologist Diagnostic Documentation | Up to day 6 | 
| Cardiac Arrhythmia - Lengthening QTc | Cardiologist Diagnostic Documentation | Up to day 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, Inhaled/nebulized Hydroxychloroquine