A Study to Investigate the Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of PC945

Study Overview
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Brief Summary
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PC945 is a new medicine being developed for treatment of fungal lung diseases. The main purpose of this study is to investigate the safety, tolerability and pharmacokinetics of single and repeat doses of PC945

Official Title
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A Randomised, Single-blind, Placebo-controlled, Study to Assess the Safety and Tolerability of Single Escalating and Repeat, Inhaled Doses of PC945 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 PC945 in Subjects With Mild Asthma

Conditions
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Aspergillosis

Intervention / Treatment
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* Drug: PC945 - single doses
* Drug: Placebo - single doses
* Drug: PC945 - 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) 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 required 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 required contraception from the time of the first dose, until 90 days after receipt of the final dose of study medication. Females with a negative pregnancy test at screening and at Day -1. Willing and able to adhere to the restrictions and prohibitions required by this protocol. Signed informed consent form. 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 Healthy Subjects (Cohorts 1 and 2) Healthy as determined by a physician based on a full medical examination. Spirometry readings (FEV1 and FVC) to be ≥ 80% of predicted value and FEV1/FVC ratio > 0.7 at screening. Subjects with Asthma (Cohort 3) Diagnosis of asthma. Positive result to methacholine challenge at the screening visit. FEV1 >60% of predicted normal value at screening. Stable asthma based on physician assessment at screening, with no changes of therapy in the 12 weeks prior to screening and no hospitalization or visit to accident and emergency for asthma in the 12 months prior to screening Otherwise healthy on the basis of a full medical examination at screening Exclusion Criteria: All subjects (Cohorts 1, 2 & 3) 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. Taking over the counter (OTC) medications other than vitamins or multivitamins, within 14 days prior to Screening. History of regular alcohol consumption within 6 months of the study with average weekly intake of >21 units for males, or >14 units for females. History of drug or alcohol abuse within the previous 5 years. Smoker (regular or irregular), or has smoked or used nicotine-containing products (including e-cigarettes) within the 6 months prior to screening or has a smoking history of ≥ 10 pack years. Positive test for HIV-1 & -2 antibodies at screening. 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 Day -1. Received an experimental drug or used an experimental medical device within last 3 months. Allergy to any of the active or inactive ingredients in the study medication. Donation of blood in excess of 500 mL within a 3 month period prior to dosing, or if study participation would result in blood loss in excess of 500 mL in a 3 month period. 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 or poor access to veins suitable for cannulation. Pregnant or lactating female Healthy subjects (Cohorts 1 and 2) Any chronic illness or clinically relevant abnormality identified on the screening medical assessment, laboratory tests or ECG. Subjects with asthma (Cohort 3) Had an episode of life-threatening asthma. Presence of clinically significant diseases other than asthma, hyper-responsive airways, seasonal allergic rhinitis or atopic diseases. 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. 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single dose - healthy volunteers<br> | Drug: PC945 - 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 volunteers<br> | Drug: PC945 - 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 - asthmatic patients<br> | Drug: PC945 - 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 |
| --- | --- | --- |
| Incidence of treatment emergent adverse events | Assessment of number of adverse events reported by subjects following dosing | Cohort 1 - 12 weeks; Cohort 2 - 7 weeks; Cohort 3 - 6 weeks | 
| 12-lead ECG assessment | Change from pre-dose values | Cohort 1 - 12 weeks; Cohort 2 - 7 weeks; Cohort 3 - 6 weeks | 
| Vital signs assessment (blood pressure and heart rate - measured together) | Change for pre-dose values | Cohort 1 - 12 weeks; Cohort 2 - 7 weeks; Cohort 3 - 6 weeks | 
| Clinical laboratory assessments (blood and urine samples - measured together) | Change from pre-dose values | Cohort 1 - 12 weeks; Cohort 2 - 7 weeks; Cohort 3 - 6 weeks | 
| Spirometry assessment (FEV1 & FVC - measured together) | Change from pre-dose values | Cohort 1 - 12 weeks; Cohort 2 - 7 weeks; Cohort 3 - 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentration data of PC945 | Blood levels of PC945 measured after dosing | Cohort 1 (4 treatment periods) & Cohort 3 (1 treatment period) Day1 = 8 samples; Day2 = 2 samples; Day3 = 1 sample; F/U = 1 sample. Cohort 2 - Days1&7 = 10 samples; Days2,5,6 = 1 sample; Day8 = 2 samples; Day9 = 1 sample; F/U = 1 sample | 
| Spirometry assessment (FEV1) | Observed drops in FEV1 assessment after dosing patients with mild asthma | Cohort 3 only - Day 1, 8 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aspergillus species, Filamentous fungi, 14-alpha Demethylase Inhibitors, Anti-Infective Agents, Antifungal Agents, Enzyme Inhibitors, Aspergillosis, Allergic Bronchopulmonary, Asthma