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

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

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.

Study Overview

• Status: Recruiting
• Conditions: 2019 Novel Coronavirus
• Intervention / Treatment: Drug: HCQ01; Other: standard of care (SOC) for COVID-19

• Study Type: Interventional
• Enrollment (Anticipated): 110
• Phase: Phase 2

Contacts and Locations

Study Locations

• Jordan
  • Amman, Jordan, 00962
    • Recruiting
    • Prince Hamza Hospital/ Amman Field Hospital
    • Contact: Khaldoun Khader, MD
    • Contact: Mohammed Shakeeb, MSc; Phone Number: 0781633832; Email: mshakeeb95@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Pregnant (positive β-human chorionic gonadotropin test, β-HCG) or lactating female at screening.
2. 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.
3. Patients admitted in ICU.
4. 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.
5. History of Glucose-6-phosphate dehydrogenase deficiency.
6. Pre-treatment corrected QT interval (QTc) ≥450 milliseconds.

Exclusion Criteria:

1. Pregnant (positive β-human chorionic gonadotropin test, β-HCG) or lactating female at screening.
2. 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.
3. Patients admitted in ICU.
4. 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.
5. History of Glucose-6-phosphate dehydrogenase deficiency.
6. Pre-treatment corrected QT interval (QTc) ≥450 milliseconds.
7. Acute or chronic kidney disease (stage-4 or -5 renal impairment; eGFR<30 mL/min/1.73 m2 or hemodialysis).
8. Liver Child-Pugh grade C.
9. Patients with Hypokalemia (<3.5mmol/L), Hypocalcemia (<2.2mmol/L), Hypomagnesemia (<0.66mmol/L). Will be included after correction.
10. Need for mechanical ventilation.
11. History of hypersensitivity to hydroxychloroquine.
12. History of Chronic Hepatitis B or hepatitis C infections.
13. History of Human Immunodeficiency Virus (HIV) infection.

14. 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.
15. 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.
16. 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.
17. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: First Arm (Hydroxychloroquine sulfate, 5 days); 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; HCQ01 is a sterile, clear and colorless, ready-to-use aqueous nebulizer solution. Hydroxychloroquine sulfate administered via nebulization
Active Comparator: Second Arm (Continued Standard of Care (SOC) Therapy); Participants will receive continued standard of care therapy for COVID-19	Other: standard of care (SOC) for COVID-19; Standard of care (SOC) for COVID-19

What is the study measuring?

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
All-cause mortality		Day 28
Proportion of participants who improve by at least one level lower on the 11-point WHO-OSCI		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

Collaborators and Investigators

• Sponsor: Ministry of Health Jordan
• Collaborators: King Hussein Cancer Center; ACDIMA Biocenter; Amman Pharmaceutical Industries; Sana Pharmaceutical Industry
• Investigators: Principal Investigator: Feras Hawari, MD, The Jordanian Ministry of Health

Study record dates

Study Major Dates

• Study Start (Anticipated): March 20, 2022
• Primary Completion (Anticipated): July 20, 2022
• Study Completion (Anticipated): July 20, 2022

Study Registration Dates

• First Submitted: November 6, 2021
• First Submitted That Met QC Criteria: November 6, 2021
• First Posted (Actual): November 9, 2021

Study Record Updates

• Last Update Posted (Actual): March 7, 2022
• Last Update Submitted That Met QC Criteria: March 2, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: COVID-19; Inhaled/nebulized Hydroxychloroquine
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: 1093-2021

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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