A Study to Assess the Safety, Tolerability and Pharmacokinetics of Inhaled HH-120 Aerosol in Healthy Volunteers

Study Overview
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Brief Summary
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This is a Phase 1, randomized, double-blinded, placebo controlled, dose escalation study of HH-120 in healthy adult volunteers. HH-120 is a novel inhalable biologic being developed for COVID-19 treatment. The study aims to evaluate the safety, tolerability and pharmacokinetic profile of HH-120 administered by aerosol inhalation after single and multiple ascending doses.

Detailed Description
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Approximately 48 participants will be sequentially enrolled into either 1 of 3 SAD cohorts (n=8 per cohort), or 1 of 3 MAD cohorts (n= 8 per cohort). An adaptive dose escalation schedule will be employed for both SAD and MAD parts of the study.

Official Title
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A Double-Blinded, Randomized, and Placebo-Controlled Phase 1 Study to Assess the Safety, Tolerability and Pharmacokinetics Profile of Single and Multiple Ascending Doses of Inhaled HH-120 Aerosol in Healthy Volunteers

Conditions
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COVID-19 Respiratory Infection

Intervention / Treatment
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* Biological: HH-120 Dose 1
* Biological: HH-120 Dose 2
* Biological: HH-120 Dose 3
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male or female volunteers aged 18 to 65 years (both inclusive) Participants must have a body mass index between ≥ 18.0 and ≤ 32 .0 kg/m2 and a bodyweight of at least 45 kg at Screening. Participants must be a non-smoker and must not have used any tobacco products within 90 days prior to Screening. Participants must be in good general health, with no significant medical history, have no clinically significant abnormalities on physical examination at screening and/or before administration of the initial dose of IP. Participants must have clinical laboratory values within normal range. Females must be non-pregnant and non-lactating, and must use an acceptable, highly effective double contraception from Screening until study completion, including the follow-up period. Males must not donate sperm for at least 90 days after the last dose of IP. Participants must have the ability and willingness to attend the necessary visits to the CRU. Exclusion Criteria: Pregnant or lactating at Screening or planning to become pregnant (self or partner) at any time during the study, including the follow-up period. Prior or ongoing medical conditions, medical history, physical findings, or laboratory abnormality that, in the PI's (or delegate's) opinion, could adversely affect the safety of the participant or that might interfere with the conduct of the study. Presence of any underlying physical or psychological medical condition Pre-existing severe obstructive disease of the respiratory system such as chronic obstructive pulmonary disease or asthma , including resolved childhood asthma, which may impact inhalation as judged by the PI, delegate, or Sponsor. History or evidence o f any anatomical airway defect, which in the opinion of the PI, may impact inhalation. Abnormal spirometry findings at Screening that are considered by the PI to be clinically significant, including FEV1 < 80% or FVC < 80%. Blood donation of > 500 mL or significant blood loss within 60 days prior to the first IP administration or plasma donation within 7 days prior to IP administration. Systemic or respiratory infection within 2 weeks before the Screening visit or fever (tympanic temperature > 37.5°C) or symptomatic viral or bacterial infection at time of Screening. Current infection with SARS-CoV-2, infection within the 2 weeks prior to Screening, or a history of SARS-CoV-2 infection plus symptoms of post-COVID syndrome. History of anaphylaxis or other significant allergy in the opinion of the PI or known allergy or hypersensitivity to any of the components of the IP. History of malignancy, except for non-melanoma skin cancer, excised more than 2 years ago and cervical intraepithelial neoplasia that has been successfully cured more than 5 years prior to Screening. A personal history of unexplained blackouts or fainting or known risk factors for Torsade de Pointes (eg, hypokalemia, heart failure). Abnormal 12-lead ECG findings at Screening that are considered by the PI to be clinically significant, including arrhythmias or marked QT interval abnormalities (QTcF < 300 msec or ≥ 450 msec at Screening). Confirmed (eg, 2 consecutive triplicate measurements) average systolic blood pressure (SBP) > 140 or < 90 mmHg, and diastolic blood pressure (DBP) > 90 or < 45 mmHg at Screening. Confirmed (eg, 2 consecutive triplicate measurements) average resting HR > 100 or < 45 beats per minute at Screening. Vaccination with a live vaccine within the 4 weeks prior to Screening or that is planned within 4 weeks of dosing, and any non-live vaccination within the 2 weeks prior to Screening, or that is planned within 2 weeks of dosing or planned during study participation (including vaccines for COVID-19). Positive test for hepatitis C antibody (HCV), hepatitis B surface antigen (HBsAg), or human immunodeficiency virus (HIV) antibody at Screening. Participants with a positive toxicology screening panel (urine test including qualitative identification of barbiturates, tetrahydrocannabinol [THC], amphetamines, benzodiazepines, opiates, cocaine, and cotinine), or alcohol breath test at Screening or Day -1. Participants with a history of substance abuse or dependency or history of recreational intravenous (IV) drug use over the last 6 months (by self-declaration). Use of any IP or medical device within 30 days prior to screening. Use of any prescription drugs for 14 days prior to dosing or over the counter medication, herbal remedies, supplements or vitamins 7 days prior to dosing.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Ascending Dose Cohort A1<br>Subjects will receive a single dose of either dose level 1 of HH-120 or placebo | Biological: HH-120 Dose 1<br>* Dose level 1 of HH-120<br>* Other names: HH-120;Drug: Placebo<br>* Placebo to match<br>|
| Experimental: Single Ascending Dose Cohort A2<br>Subjects will receive a single dose of either dose level 2 of HH-120 or placebo | Biological: HH-120 Dose 2<br>* Dose level 2 of HH-120<br>* Other names: HH-120;Drug: Placebo<br>* Placebo to match<br>|
| Experimental: Single Ascending Dose Cohort A3<br>Subjects will receive a single dose of either dose level 3 of HH-120 or placebo | Biological: HH-120 Dose 3<br>* Dose level 3 of HH-120<br>* Other names: HH-120;Drug: Placebo<br>* Placebo to match<br>|
| Experimental: Multiple Ascending Doses Cohort B1<br>Subjects will receive multiple doses of either Dose level 1of HH-120 or placebo | Biological: HH-120 Dose 1<br>* Dose level 1 of HH-120<br>* Other names: HH-120;Drug: Placebo<br>* Placebo to match<br>|
| Experimental: Multiple Ascending Doses Cohort B2<br>Subjects will receive multiple doses of either Dose level 2 of HH-120 or placebo | Biological: HH-120 Dose 2<br>* Dose level 2 of HH-120<br>* Other names: HH-120;Drug: Placebo<br>* Placebo to match<br>|
| Experimental: Multiple Ascending Doses Cohort B3<br>Subjects will receive multiple doses of either Dose level 3 of HH-120 or placebo | Biological: HH-120 Dose 3<br>* Dose level 3 of HH-120<br>* Other names: HH-120;Drug: Placebo<br>* Placebo to match<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment emergent adverse events (TEAEs) | An Adverse Event (AE) is any event, side-effect or any untoward medical occurrence in a clinical study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE that started on or after the first study treatment or that worsened after the first study treatment will be regarded as TEAEs. | Day 1- Day 15 (SAD) or Day 22 (MAD) | 
| Severity of treatment emergent adverse events (TEAEs)as assessed by CTCAE v5.0 | An Adverse Event (AE) is any event, side-effect or any untoward medical occurrence in a clinical study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE that started on or after the first study treatment or that worsened after the first study treatment will be regarded as TEAEs. | Day 1- Day 15 (SAD) or Day 22 (MAD) | 
| Duration of treatment emergent adverse events (TEAEs) | An Adverse Event (AE) is any event, side-effect or any untoward medical occurrence in a clinical study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE that started on or after the first study treatment or that worsened after the first study treatment will be regarded as TEAEs. | Day 1- Day 15 (SAD) or Day 22 (MAD) | 
| Number of participants with serious adverse events (SAEs) | A serious adverse event (SAE) is defined as an AE occurring during any study phase and at any dose of IP (active or placebo) that results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; results in congenital anomaly/birth defect | Day 1- Day 15 (SAD) or Day 22 (MAD) | 
| Severity of serious adverse events (SAEs) as assessed by CTCAE v5.0 | A serious adverse event (SAE) is defined as an AE occurring during any study phase and at any dose of IP (active or placebo) that results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; results in congenital anomaly/birth defect | Day 1- Day 15 (SAD) or Day 22 (MAD) | 
| Duration of serious adverse events (SAEs) | A serious adverse event (SAE) is defined as an AE occurring during any study phase and at any dose of IP (active or placebo) that results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; results in congenital anomaly/birth defect | Day 1- Day 15 (SAD) or Day 22 (MAD) | 
| Number of participants with abnormal clinically significant physical examination findings | Complete and symptom directed physical examination will be performed | Day 1- Day 15 (SAD) or Day 22 (MAD) | 
| Number of participants with abnormal clinically significant electrocardiogram (ECG) | Single resting 12- lead ECGs will be collected | Day 1- Day 15 (SAD) or Day 22 (MAD) | 
| Number of participants with clinically significant change in vital signs from baseline | Vital signs include heart rate, blood pressure, respiratory rate and tympanic temperature | Day 1- Day 15 (SAD) or Day 22 (MAD) | 
| Changes in the spirometry score from Baseline | Measured by Forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) after dosing | Day 1- Day 15 (SAD) or Day 22 (MAD) | 
| Number of participants with abnormal clinically significant clinical laboratory parameters | Clinical laboratory test include hematology, coagulation, biochemistry and urinalysis | Day 1- Day 15 (SAD) or Day 22 (MAD) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax in SAD and MAD | Maximum observed HH-120 concentration | Day 1- Day 15 (SAD) or Day 22 (MAD) | 
| Tmax in SAD and MAD | Time to the maximum observed HH-120 concentration | Day 1- Day 15 (SAD) or Day 22 (MAD) | 
| t1/2 in SAD and MAD part | Terminal elimination half life calculated as ln (2)/λz | Day 1- Day 15 (SAD) or Day 22 (MAD) | 
| AUC0-last | Area under the plasma concentration-time curve from time zero (from the start of inhalation time) to the last time point with measurable analyte concentration | Day 1- Day 15 (SAD) or Day 22 (MAD) | 
| AUC0-inf | AUC from time zero (from the start of inhalation time) extrapolated to infinity | Day 1- Day 15 (SAD) or Day 22 (MAD) | 
| %AUCextrap | The percentage of the AUC that has been extrapolated beyond the last observed data point | Day 1- Day 15 (SAD) or Day 22 (MAD) | 
| Kel or λz | Apparent terminal elimination rate constant, calculated by linear regression of the terminal linear portion of the log concentration vs time curve | Day 1- Day 15 (SAD) or Day 22 (MAD) | 
| CL/F | Apparent total body clearance | Day 1- Day 15 (SAD) or Day 22 (MAD) | 
| Vz/F in SAD | Apparent volume of distribution during the terminal phase | Day 1- Day 15 (SAD) or Day 22 (MAD) | 
| CL/Fss in MAD | Apparent total plasma clearance at steady state | Day 1-Day 22 | 
| Vz/Fss in MAD | Apparent terminal volume of distribution at steady state | Day1- Day 22 | 
| Accumulation ratio (RA) | AUC0-24 hours on Day 7/AUC0-24 hours on Day 1 | Day 1- Day 7 | 
| Immunogenicity of HH-120 | To determine the presence and levels of anti-drug antibody (ADA). | Day 1- Day 15 (SAD) or Day 22 (MAD) |