The airways and lungs are the primary sites of SARS-CoV-2 entry, replication, and damage, so there is reason to administer drugs to these regions. Oral hydroxychloroquine (oHCQ) has produced mixed results in COVID-19, despite reported antiviral activity in vitro (EC 50 50.72-119 mM). We tested the hypothesis that aerosolized HCQ sulfate (aHCQ) tolerably, safely, and rapidly achieves high respiratory tissue concentrations, while minimizing systemic toxicity. METHODS: aHCQ was administered via Aerogen nebulizer (oral inhalation, nasal exhalation) to healthy volunteers in a Phase 1 study to assess tolerability, safety, and pharmacokinetics. RESULTS: 10 volunteers (age 55613 years, 60% female) were randomized to Placebo (n52), or aHCQ (20 mg, n52; 50 mg, n56); all completed the inhalation. 6/8 receiving aHCQ had adverse events (all mild; 75% transient dysgeusia, 25% dizziness). FEV 1 and FVC were essentially unchanged from baseline after 15-360 minutes and 1 and 7 days. QT segments were minimally changed from baseline (maximum change 34 msec) after 1-6 hours, and 1 and 7 days; all were < _455 msec. Pharmacokinetics of 50 mg: Area Under the Blood Curve 0-24 hours post-inhalation was 3776127 ng*hr/mL, <15% of that reported for oHCQ 200 mg; Pharmacokinetic modelling predicts initial epithelial lining fluid concentrations in excess of reported EC 50 s, and peak respiratory tissue concentrations of 0.5 mM, decreasing to 0.01 mM at 24 hours as HCQ slowly releases into blood. CONCLUSIONS: aHCQ was safe, well-tolerated, and appears to be sequestered in respiratory tissues. Administering aHCQ at a fraction of oral dosing may rapidly achieve respiratory tract concentrations sufficient to inhibit SARS-CoV-2.

Based on early reports of the efficacy of hydroxychloroquine sulfate (HCQS) to inhibit SARS-CoV-2 viral replication in vitro, and since severe pulmonary involvement is the major cause of COVID-19 mortality, we assessed the safety and efficacy of aerosolized HCQS (aHCQS) therapy in animals and humans. In a Phase 1 study of aHCQS in healthy volunteers, doses up to 50 mg were well tolerated and estimated epithelial lining fluid concentrations immediately after inhalation (>2,000 uM) exceeded the in vitro concentrations needed for suppression of viral replication (>=119 uM). A study in rats comparing HCQS solution administered orally (13.3 mg/kg) and by intratracheal installation (IT 0.18 mg/kg, <5% of oral dose) demonstrated that at 2 minutes, IT administration was associated with 5X higher mean hydroxychloroquine (HCQ) concentrations in the lung (IT: 49.5 +/- 6.5 ug HCQ/g tissue, oral: 9.9 +/- 3.4; p<0.01). A subsequent study of IT and intranasal HCQS in the Syrian hamster model of SARS-CoV-2 infection, however, failed to show clinical benefit. We conclude that aHCQS alone is unlikely to be effective for COVID-19, but based on our aHCQS pharmacokinetics and current viral entry data, adding oral HCQS to aHCQS, along with a transmembrane protease inhibitor, may improve efficacy.

OBJECTIVES/GOALS: We have developed a comprehensive Translational Research Navigation Program to guide investigators all the way from protocol development through study closure. As the program evolved, we initially developed organizational tools and then restructured them into a series of checklists to ensure that critical elements were not excluded or duplicated. METHODS/STUDY POPULATION: A series of checklists to assure that all research elements, including regulatory, scientific, and institutional, are addressed from protocol inception through study closure were developed by clinical research coordinators/navigators. The checklists are periodically updated and modified to reflect changing local and national regulations and policies. The first tool became the “Protocol Development Checklist” and then additional tools were developed and modified into a suite of navigation checklists that include “Protocol Implementation Checklist,” “Protocol Conduct Checklist,” and “Protocol Completion Checklist.” RESULTS/ANTICIPATED RESULTS: The checklists have been incorporated into the Translational Research Navigation Program and have enhanced the organization and quality of protocols throughout their lifespan. For example, implementation of the Protocol Development Checklist resulted in a reduction in time to IRB approval (currently 10 days), and implementation of the Protocol Implementation Checklist has impacted the time from IRB approval to study start-up. The Protocol Conduct Checklist has aided investigators in being better prepared and more organized for study conduct activities and the Protocol Closure Checklist has assured timely protocol closure and regulatory compliance, including reporting to ClinicalTrials.gov. DISCUSSION/SIGNIFICANCE OF IMPACT: Protocol checklists are powerful tools to enhance thoroughness, organization, and quality of the clinical research process. The Rockefeller University protocol checklists are available to the CTSA and Scientific Communities. CONFLICT OF INTEREST DESCRIPTION: NA.