A Study to Investigate the Safety and Tolerability of Single and Repeat Doses of PC786

Study Overview
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Brief Summary
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This study investigates the safety, tolerability and pharmacokinetics of single and repeat doses of PC786.

Official Title
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A Randomised, Single-blind, Placebo-controlled, Dose-escalation Study to Assess the Safety and Tolerability of Single and Repeat, Inhaled Doses of PC786 in Healthy Subjects Combined With a Randomised, Single-blind, Placebo-controlled, Parallel Group to Assess the Safety and Tolerability of a Single Dose of Inhaled PC786 in Subjects With Mild Asthma

Conditions
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Respiratory Syncytial Virus (RSV)

Intervention / Treatment
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* Drug: PC786 - Single doses
* Drug: Placebo - Single doses
* Drug: PC786 - Repeat doses
* Drug: Placebo - Repeat doses


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All subjects (Cohorts 1, 2, 3 & 4) Must be male or female, aged between 18 and 65 years inclusive (at the time of consent) who fit one of the following criteria: women of childbearing potential who are willing and able to use contraception from screening until 30 days after receipt of the final dose; Women of non-childbearing potential defined as being amenorrhoeic or have been permanently sterilised; Men who are willing and able to use contraception from the time of the first dose, until 90 days after receipt of the final dose of study medication. Females must have a negative serum β human chorionic gonadotropin (β-hCG) test at screening and a negative urinary pregnancy test at Day -1. Subject must be willing and able to adhere to the restrictions and prohibitions required by this protocol. Each subject must sign an informed consent form (ICF) indicating that he or she understands the purpose and requirements of the study and that they are willing to participate. Body weight ≥ 50 kg and body mass index (BMI) within the range 18 - 30 kg/m2 (inclusive). Average QTcF <450 msec at screening and pre-dose. Vital signs assessments within normal ranges at screening and pre-dose. Healthy Subjects (Cohorts 1, 2 & 3) Healthy as determined by a physician based on a full medical examination including medical history, physical examination and laboratory tests performed at screening and pre-dose. Spirometry readings (FEV1 and FVC) to be ≥ 80% of predicted value and FEV1/FVC ratio > 0.7 at screening Subjects with Asthma (Cohort 4) Documented diagnosis of asthma, first diagnosed at least 12 months prior to the screening visit. Subject must demonstrate a PC20 methacholine ≤ 8 mg/mL at the screening visit. Have an FEV1 >60% of predicted normal value at least 6 h after the last use of a short acting β-agonist (SABA). Have stable asthma based on physician assessment at screening and prior to randomisation Subject must be otherwise healthy on the basis of a full medical examination including medical history, physical examination and laboratory tests performed at screening. Exclusion Criteria: All subjects (Cohorts 1, 2, 3 & 4) Any acute illness. Upper or lower respiratory tract infection within 4 weeks of the screening visit or randomisation. Use of prescription medications within 14 days of the Screening visit Are taking over the counter medications other than vitamins or multivitamins and herbal medication, within 14 days prior to Screening History of regular alcohol consumption within 6 months of the study of an average weekly intake of >21 units for males, or >14 units for females Definite or suspected history of drug or alcohol abuse within the previous 5 years. A smoker (regular or irregular), or has smoked or used nicotine-containing products (including e-cigarettes) within the 6 months prior to screening A positive test for HIV-1 & -2 antibodies at screening. A positive pre-study hepatitis B surface antigen or positive hepatitis C antibody result at screening. Positive test for alcohol, smoking or drugs of abuse, at screening or pre-dose Received an experimental drug or used an experimental medical device within 3 months before the first dose of the study drug is scheduled. Allergy to any of the active or inactive ingredients in the study medication. History of drug, or other allergy that would contraindicate participation. Donation of blood in excess of 500 mL within a 3 month period prior to dosing Mentally or legally incapacitated. An employee of the Sponsor or contract research organisation (CRO), or a relative of an employee of the Sponsor or CRO. Unable or unwilling to undergo multiple venepuncture procedures Pregnant or lactating female Any other reason that the Investigator considers makes the subject unsuitable to participate. Healthy Subjects (Cohorts 1, 2 & 3) Any chronic illness or clinically relevant abnormality identified on the screening medical assessment, laboratory tests or ECG Subjects with Asthma (Cohort 4) Has ever had an episode of life-threatening asthma defined as respiratory arrest, intubation for asthma, or ICU admission for asthma. Presence of clinically significant diseases other than asthma, hyper-responsive airways, seasonal allergic rhinitis or atopic diseases Has experienced an acute asthma exacerbation in the 12 months prior to screening requiring hospitalisation or accident and emergency treatment or management with systemic or injectable steroids. Has uncontrolled, or moderate to severe asthma based on PI assessment and/or use of prohibited medications, or has required treatment with these therapies in the previous 12 weeks. History or presence of any known conditions contraindicated for methacholine challenge

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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single dose - healthy subjects<br> | Drug: PC786 - Single doses<br>* Safety and tolerability of single doses<br>Drug: Placebo - Single doses<br>* Safety and tolerability of single doses<br>|
| Experimental: Repeat dose - healthy subjects<br> | Drug: PC786 - Repeat doses<br>* Safety and tolerability of repeat doses<br>Drug: Placebo - Repeat doses<br>* Safety and tolerability of repeat doses<br>|
| Experimental: Single dose - subjects with asthma<br> | Drug: PC786 - Single doses<br>* Safety and tolerability of single doses<br>Drug: Placebo - Single doses<br>* Safety and tolerability of single doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants reporting one or more treatment-emergent adverse events (TEAE) |  | Baseline up to Week 12 | 
| Number of participants who discontinue due to an adverse event (AE) |  | Baseline up to Week 12 | 
| Number of participants who meet the markedly abnormal criteria for safety 12-lead ECG assessment at least once post dose |  | Baseline up to Week 12 | 
| Number of participants who meet the markedly abnormal criteria for vital signs assessment at least once post dose |  | Baseline up to Week 12 | 
| Number of participants who meet the markedly abnormal criteria for safety laboratory assessments at least once once post dose |  | Baseline up to Week 12 | 
| Number of participants who meet the markedly abnormal criteria for safety spirometry assessment (FEV1 & FVC - measured together) at least once once post dose |  | Baseline up to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentration of PC786 | Blood levels of PC786 measured after dosing | Day 1: Pre-dose and at multiple time points (up to 10 days) post final dose | 
| Mucosal lining fluid concentration of PC786 | PC786 concentration data in mucosal lining fluid measured after dosing | Cohort 1 - Day 1 = 3 samples; Day 2 = 2 samples; Day 3 = 1 sample. Cohorts 2 & 3 - Day 1 = 2 samples; Day 6 = 1 sample; Day 7 = 3 samples; Day 8 = 2 samples; Days 9 & 10 - 1 sample |