Clinical trial NCT04461353: A Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Orally Inhaled Aerosolized Hydroxychloroquine Sulfate in Healthy Adult Volunteers
Official title: A Phase 1 Randomized 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Severe Acute Respiratory Syndrome Coronavirus 2
Keywords: coronavirus
COVID-19
Hydroxychloroquine Sulfate
Hydroxychloroquine
Lead sponsor: Pulmoquine Therapeutics, Inc
Sponsor class: INDUSTRY
Collaborators: name: Rockefeller University
First posted: 2020-07-08
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.

A sentinel dose strategy will be employed and the decision to escalate to the next dose level, or deescalate or stop the study, will be based on review and analysis of all available blinded safety and tolerability data by the Safety Review Committee (SRC), which will make a recommendation to the Sponsor and the Sponsor will inform the PI of the recommendation.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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).

Primary outcomes:
measure: Incidences of treatment-emergent adverse events (TEAEs) as assessed by TGSHAAV (September 2007) or CTCAE version 5.0
timeFrame: after treatment (Day 1) through to Day 30
measure: Change from baseline in clinical laboratory test results for CBC with differential
timeFrame: Screening and Day 8
measure: Incidence of abnormal laboratory test results for CBC with differential at Screening
timeFrame: Screening
measure: Incidence of abnormal laboratory test results for CBC with differential - Day 8
timeFrame: Day 8
measure: Changes from baseline for blood glucose
timeFrame: Screening and Day 1
measure: Incidence of abnormal laboratory test results for chemistry -Screening
timeFrame: Screening
measure: Incidence of abnormal laboratory tests results for chemistry - Day 8
timeFrame: Day 8
measure: Incidence of abnormal laboratory tests results for urinalysis - Screening
timeFrame: Screening
measure: Incidence of abnormal laboratory tests results for urinalysis- Day 8
timeFrame: Day 8
measure: Changes in vital signs from baseline (pre-dose) - respiratory rate
timeFrame: Screening, Day 1, Day 2 and Day 8
measure: Changes in vital signs from baseline (pre-dose)- temperature
timeFrame: Screening, Day 1, Day 2 and Day 8
measure: Changes in vital signs from baseline (pre-dose) - seated blood pressure
timeFrame: Screening, Day 1, Day 2 and Day 8
measure: Changes in vital signs from baseline (pre-dose) - pulse
timeFrame: Screening, Day 1, Day 2 and Day 8
measure: Changes in vital signs from baseline (pre-dose) - O2 saturation
timeFrame: Screening, Day 1, Day 2 and Day 8
measure: Incidence of abnormal and physical examinations findings during Screening- general appearance
timeFrame: Screening
measure: Incidence of abnormal and physical examinations findings on Day 1 - general appearance
timeFrame: Day 1
measure: Incidence of abnormal and physical examinations findings on Day 2- general appearance
timeFrame: Day 2
measure: Incidence of abnormal and physical examinations findings on Day 8- general appearance
timeFrame: Day 8
measure: Incidence of abnormal and physical examinations findings during Screening- neurological
timeFrame: Screening
measure: Incidence of abnormal and physical examinations findings on Day 1- neurological
timeFrame: Day 1
measure: Incidence of abnormal and physical examinations findings on Day 2- neurological
timeFrame: Day 2
measure: Incidence of abnormal and physical examinations findings on Day 8- neurological
timeFrame: Day 8
measure: Incidence of abnormal and physical examinations findings during Screening - heart/cardiovascular
timeFrame: Screening
measure: Incidence of abnormal and physical examinations findings on Day 1 - heart/cardiovascular
timeFrame: Day 1 (pre-dose, within 3 hours of dose)
measure: Incidence of abnormal and physical examinations findings on Day 2 - heart/cardiovascular
timeFrame: Day 2
measure: Incidence of abnormal and physical examinations findings on Day 8 - heart/cardiovascular
timeFrame: Day 8
measure: Incidence of abnormal and physical examinations findings during Screening - lungs
timeFrame: Screening
measure: Incidence of abnormal and physical examinations findings on Day 1 - lungs
timeFrame: Day 1
measure: Incidence of abnormal and physical examinations findings on Day 2 - lungs
timeFrame: Day 2
measure: Incidence of abnormal and physical examinations findings on Day 8 - lungs
timeFrame: Day 8
measure: Incidence of abnormal and physical examinations findings during Screening- abdomen
timeFrame: Screening
measure: Incidence of abnormal and physical examinations findings on Day 1 - abdomen
timeFrame: Day 1
measure: Incidence of abnormal and physical examinations findings on Day 2- abdomen
timeFrame: Day 2
measure: Incidence of abnormal and physical examinations findings on Day 8- abdomen
timeFrame: Day 8
measure: Incidence of abnormal and physical examinations findings during screening- endocrine
timeFrame: Screening
measure: Incidence of abnormal and physical examinations findings on Day 1 - endocrine
timeFrame: Day 1
measure: Incidence of abnormal and physical examinations findings on Day 2- endocrine
timeFrame: Day 2
measure: Incidence of abnormal and physical examinations findings on Day 8- endocrine
timeFrame: Day 8
measure: Incidence of abnormal and physical examinations findings during Screening- extremities
timeFrame: Screening
measure: Incidence of abnormal and physical examinations findings on Day 1- extremities
timeFrame: Day 1
measure: Incidence of abnormal and physical examinations findings on Day 2- extremities
timeFrame: Day 2
measure: Incidence of abnormal and physical examinations findings on Day 8- extremities
timeFrame: Day 8
measure: Incidence of abnormal and physical examinations findings during Screening- lymphatic
timeFrame: Screening
measure: Incidence of abnormal and physical examinations findings on Day 1- lymphatic
timeFrame: Day 1
measure: Incidence of abnormal and physical examinations findings on Day 2 - lymphatic
timeFrame: Day 2
measure: Incidence of abnormal and physical examinations findings on Day 8- lymphatic
timeFrame: Day 8
measure: Incidence of abnormal and physical examinations findings during screening - skin
timeFrame: Screening
measure: Incidence of abnormal and physical examinations findings on Day 1 - skin
timeFrame: Day 1
measure: Incidence of abnormal and physical examinations findings on Day 2 - skin
timeFrame: Day 2
measure: Incidence of abnormal and physical examinations findings on Day 8 - skin
timeFrame: Day 8
measure: Changes from baseline for pulmonary function tests (PFTs) - FEV1
timeFrame: Screening, Day 1 at pre-dose (within 25 minutes of dose) and at +15 minutes, +1, +3 and +6 hours after study treatment, and on Day 2 and Day 8.
measure: Changes from baseline for pulmonary function tests (PFTs) - FVC
timeFrame: Screening, Day 1 at pre-dose (within 25 minutes of dose) and at +15 minutes, +1, +3 and +6 hours after study treatment, and on Day 2 and Day 8.
measure: Changes from baseline for pulmonary function tests (PFTs) - FEV1/FVC
timeFrame: creening, Day 1 at pre-dose (within 25 minutes of dose) and at +15 minutes, +1, +3 and +6 hours after study treatment, and on Day 2 and Day 8.
measure: Changes from baseline for ECG readings - QT interval
timeFrame: Screening and on Day 1 pre-dose (within 3 hours of dose) and approximately +2 and +6 hours, and on Days 2 and 8.
measure: Changes from baseline for ECG readings - QTcB Interval
timeFrame: Screening and on Day 1 pre-dose (within 3 hours of dose) and approximately +2 and +6 hours, and on Days 2 and 8.
measure: Changes from baseline for ECG readings - QRS duration
timeFrame: Screening and on Day 1 pre-dose (within 3 hours of dose) and approximately +2 and +6 hours, and on Days 2 and 8.
measure: Changes from baseline for ECG readings - PR interval
timeFrame: Screening and on Day 1 pre-dose (within 3 hours of dose) and approximately +2 and +6 hours, and on Days 2 and 8.
measure: Changes from baseline for ECG readings - heart rate
timeFrame: Screening and on Day 1 pre-dose (within 3 hours of dose) and approximately +2 and +6 hours, and on Days 2 and 8.
measure: Incidence of abnormal ECG - Screening
timeFrame: Screening
measure: Incidence of abnormal ECG- Day 1
timeFrame: Day 1 pre-dose (within 3 hours of dose) and +2 and +6 hours
measure: Incidence of abnormal ECG - Day 2
timeFrame: Days 2
measure: Incidence of abnormal ECG - Day 8
timeFrame: Days 8.
Secondary outcomes:
measure: HCQ concentration in whole blood versus time profiles
timeFrame: Day 1 pre-dose (time 0) and +2, +3, +5, and +15 minutes after dose, and also +1, +2, +4 and +6 hours post-dose completion. Day 2 (+24±4 hours post dose) and Day 8.
Other outcomes:
Locations:
city: New York
country: United States
facility: The Rockefeller University
state: New York
Study officials:
affiliation: Rockefeller University
name: Ohad S Bentur, MD, MHA
role: PRINCIPAL_INVESTIGATOR
References: