A Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Orally Inhaled Aerosolized Hydroxychloroquine Sulfate in Healthy Adult Volunteers

Pulmoquine Therapeutics, Inc12 enrolled

Overview

This study is 'A Randomized Phase 1 Double Blind Placebo Controlled, Single-Dose, Dose-Escalation Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Orally Inhaled Aerosolized Hydroxychloroquine Sulfate in Healthy Adult Volunteers.' The primary objectives are as follows: * To assess the safety and tolerability of AHCQ administered as a single dose by oral inhalation in healthy individuals at escalating doses until either the maximum tolerated dose (MTD) is identified or 1 mL of a 50 mg/mL solution is administered. * To determine the recommended Phase 2a dose (RP2D). Secondary objectives: • To characterize pharmacokinetics (PK) of single dose AHCQ in healthy individuals.

Study Design: This is a randomized, double-blind placebo-controlled Phase 1 single-dose dose-escalation study to assess the safety, tolerability and PK of oral inhalation of AHCQ in healthy participants. Escalating single doses of AHCQ will be studied in healthy participants. The study drug will be administered by inhalation through the mouth, and participants will be encouraged to exhale through the nose. The study drug, AHCQ, will be administered starting at an initial dose of 20 mg (Cohort A1, 1 mL of 20 mg/mL AHCQ solution) with a proposed subsequent doses of 50 mg (Cohort A2, 1 mL of 50 mg/mL AHCQ). Number of Participants (Planned): Two dose levels are planned to be evaluated. Each cohort will comprise 8 participants (6 active, 2 placebo). Therefore, 16 participants will initially be planned to be enrolled in the study. Additional participants may be enrolled if one or more enrolled participants do not complete the study.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Eligibility

Sex: ALLMin age: 18 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: 1. Willing and able to give written informed consent. 2. Males or females aged ≥18 years old. 3. Good general health as determined by no acute illness and no clinically significant abnormal findings on medical history, vital signs, laboratory tests, or physical examination at screening that, in the opinion of the PI, would interfere with study drug administration, jeopardize the safety of the study participant, or impact the validity of the study results; participants with stable chronic illness are allowed at the discretion of the PI. 4. An interpretable 12-lead ECG with a corrected QT (QTc) interval ≤450 ms, according to Bazett's formula, without evidence of clinically significant abnormal findings. 5. Normal FEV1/FVC ratio, defined as any value above 0.7 or above the lower 5th percentile of normal AND FEV1 \>80% of predicted or above the lower 5th percentile of normal. 6. Pulse oximetry 02 saturation ≥95% in room air. 7. Negative test result for COVID-19 within 7 days of Day 1 AND concurrent with local hospital policy: * A nasopharyngeal swab tested with the ID NOW COVID-19 assay (Abbot). OR * A negative RNA-based test result of an oropharyngeal or nasopharyngeal swab or saliva sample performed according to CLIA/CLEP. 8. Females of child-bearing potential must be non-pregnant, non-lactating, have a negative urine pregnancy test at screening, and agree to use an acceptable form of birth control for 200 days after the last administration of the study drug. Females are considered of non-childbearing potential if they are postmenopausal (last menstrual period at least 1 year before screening) or have been surgically sterilized (documented hysterectomy, tubal ligation, or bilateral oophorectomy) for at least 6 months at screening. 9. Willing to comply with protocol-defined procedures and complete all study visits. 10. Willing to use the Inhalation System and exhale through the nose. 11. Adequate venous access in the left or right arm to allow collection of required blood samples. 12. Participant understands and communicates in English. 13. Serum Potassium level ≥3.5 mEq/L, Serum Magnesium level ≥1.5 mg/dL, and Serum Calcium ≥8.5 mg/dL. Exclusion Criteria: 1. Any self-reported symptoms of influenza-like or COVID-19-like illness in the 14 days preceding the study visit: Fever \>101.4 °F, sore throat, nasal congestion, post-nasal discharge, shortness of breath, gastrointestinal distress, wheezing, cough, headache, or fatigue. 2. Any history of diagnosed chronic lung disease, including but not limited to asthma or chronic obstructive lung disease. 3. Symptoms of seasonal allergies or use of any drugs for seasonal allergies or any inhaled (oral/nasal) drugs in the 2 weeks prior to Day 1. Mild seasonal allergy symptoms that have not altered sleep or activity patterns nor required use of over-the-counter (OTC) or prescription medications are allowed. 4. Any close contact exposure in the past 28 days to a person who was diagnosed as having COVID-19, with or without laboratory confirmation, during that close contact exposure or in the ensuing 14 days OR a similar encounter with a person who was determined to have suspected COVID-19, defined by that person being ordered to enter isolation for that indication by a medical authority. Close contact is defined as being within approximately 6 feet of a COVID-19 case for a prolonged (\>10 minutes) period of time and can occur while caring for, living with, visiting, or sharing a healthcare waiting area or room with a COVID-19 patient OR having direct contact with infectious secretions of a COVID-19 patient (e.g., being coughed on), if such contact occurred while not wearing the recommended personal protective equipment for that type of contact \[e.g., gowns, gloves, N95 respirator (or equivalent), eye protection\]. 5. Any participant with a history of SARS-CoV-2 infection that was confirmed by testing or diagnosed without testing within 4 weeks preceding Day 1. If infection occurred more than 4 weeks prior, candidates may be enrolled if they meet the rest of the eligibility criteria. 6. Any participant with a history severe respiratory illness that required hospitalization in the 60 days preceding Day 1 OR any participant with a history severe respiratory illness that required hospitalization in the preceding 120 days without full recovery. 7. Participation in another clinical study that involved treatment with an investigational product or device within 30 days of screening or during the study. 8. Participants with a known history of human immunodeficiency virus (HIV) infection. 9. Known, active hepatitis A, B, or C infection. 10. History of bronchospasm in response to use of an inhalation device. 11. Use of any prescription medication (except oral contraceptives) during the 30 days prior to study dosing that may affect drug absorption, metabolism and excretion, prolong the QTc interval, affect drug efficacy, or increase the risk of adverse reactions, unless approved by the Principal Investigator. 12. Use of any OTC product, herbal product, diet aid, hormone supplement, etc., within 7 days prior to dosing unless approved by the Principal Investigator. 13. Unwilling or unable to provide written informed consent. 14. Any known hypersensitivity to quinolines (e.g., hydroxychloroquine, chloroquine, primaquine, quinine) or known history of glucose-6-phosphate dehydrogenase (G6PD) deficiency or any contraindication to oral hydroxychloroquine. 15. Known retinopathy, fundus disease, or macular disease. 16. Diagnosis of long QT Syndrome. 17. Smoking of tobacco or non-tobacco substances, or vaping, within the last 6 months. 18. Severe obesity (body mass index \[BMI\] ≥35 kg/m2).

Outcomes

Primary Outcomes

Incidences of treatment-emergent adverse events (TEAEs) as assessed by TGSHAAV (September 2007) or CTCAE version 5.0

TEAEs (defined as AEs with onset after study drug administration or existing AEs that worsen in severity after study drug administration)

Time frame: after treatment (Day 1) through to Day 30

Change from baseline in clinical laboratory test results for CBC with differential

Blood sample collected for CBC with differential will be assessed from baseline (at screening)

Time frame: Screening and Day 8

Incidence of abnormal laboratory test results for CBC with differential at Screening

Screening blood sample collected for CBC with differential, counting the number of abnormal clinical tests

Time frame: Screening

Incidence of abnormal laboratory test results for CBC with differential - Day 8

Day 8 blood sample collected for CBC with differential

Time frame: Day 8

Changes from baseline for blood glucose

Blood sample collected for blood glucose and measured with a glucometer

Time frame: Screening and Day 1

Incidence of abnormal laboratory test results for chemistry -Screening

Blood sample collected for chemistry panel (albumin, total protein, ALP, ALT, AST, direct and indirect bilirubin, GGT, BUN, creatinine, glucose, bicarbonate, calcium, chloride, magnesium, phosphate, potassium, sodium, and LDH)

Time frame: Screening

Incidence of abnormal laboratory tests results for chemistry - Day 8

Time frame: Day 8

Incidence of abnormal laboratory tests results for urinalysis - Screening

Collection of urine sample to test pH, specific gravity, protein, glucose, ketones, urobilinogen, bilirubin, leukocyte esterase, squamous cells, epithelial cells, clarity, bacteria, blood

Time frame: Screening

Incidence of abnormal laboratory tests results for urinalysis- Day 8

Collection of urine sample to test pH, specific gravity, protein, glucose, ketones, urobilinogen, bilirubin, leukocyte esterase, squamous cells, epithelial cells, clarity, bacteria, blood

Time frame: Day 8

Changes in vital signs from baseline (pre-dose) - respiratory rate

The Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials (September 2007) (TGSHAAV) will be used as the primary criteria for assessment of clinical abnormalities. Mild (17-20 breaths per minute) to Potentially Life Threatening (intubation)

Time frame: Screening, Day 1, Day 2 and Day 8

Changes in vital signs from baseline (pre-dose)- temperature

Oral temperature

Time frame: Screening, Day 1, Day 2 and Day 8

Changes in vital signs from baseline (pre-dose) - seated blood pressure

Systolic and diastolic blood pressure

Time frame: Screening, Day 1, Day 2 and Day 8

Changes in vital signs from baseline (pre-dose) - pulse

Heart rate measure by radial pulse rate (beats/min)

Time frame: Screening, Day 1, Day 2 and Day 8

Changes in vital signs from baseline (pre-dose) - O2 saturation

O2 saturation (%), measured by pulse oximeter. Graded as per TGSHAAV (September 2007) from Moderate (pulse oximeter \<92%) to Potentially Life Threatening (Life-threatening airway compromise; urgent intervention indicated)

Time frame: Screening, Day 1, Day 2 and Day 8

Incidence of abnormal and physical examinations findings during Screening- general appearance

Physical exam by clinician. A directed physical examination will be conducted

Time frame: Screening

Incidence of abnormal and physical examinations findings on Day 1 - general appearance