The Effect of Early Treatment of PC945 on Aspergillus Fumigatus Lung Infection in Lung Transplant Patients.

Study Overview
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Brief Summary
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This study tests the effects of pre-emptive treatment with an experimental drug PC945 in lung transplant recipients whose lungs are infected by the fungus Aspergillus fumigatus. PC945 may be useful in treating patients infected with Aspergillus fumigatus as, unlike the usual treatments, it is inhaled into the lung and has been designed to stay there and treat the infection. Participants will be monitored for up-to 12 weeks for the presence of Aspergillus in their lungs. Suitable participants will receive PC945 for an initial 28 days (Pre-emptive treatment phase) and, if needed, a further 8-weeks (Extended treatment phase).The amount of fungus in the patients' lungs will be measured over the course of the study. Participants with lung infections but not eligible for PC945 will be followed-up for 16-weeks on standard of care treatment. The study will take place at multiple sites in UK and 10 participants will receive PC945. The maximum study duration will be about 28 weeks.

Official Title
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An Open-label, Pilot Study to Assess Safety, Tolerability, Pharmacokinetics and Effects of Inhaled PC945 in the Pre-emptive Treatment of Aspergillus Fumigatus Colonisation in Lung Transplant Recipients

Conditions
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Aspergillosis, Lung Transplant Infection

Intervention / Treatment
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* Drug: PC945
* Drug: Standard of Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (Surveillance Phase) Between the ages of 18 and 85 years. Received a single or bilateral lung transplant. Provided written informed consent prior to transplant Exclusion Criteria (Surveillance Phase) Is precluded from participating in this study as a result of treatment with another investigational drug or participation in another clinical trial. If female, the subject is pregnant, lactating or breast feeding. Any other clinically significant disease or condition, which in the Investigator's medical opinion would preclude the subject's participation in a clinical trial (e.g., recent myocardial infarction). Is employed or is a first-degree relative of anyone employed by Pulmocide, a participating clinical trial site, or any contract research organisation involved in the study. Is receiving antiretroviral protease inhibitor therapy. Has human immunodeficiency virus or chronic, active hepatitis infection, or had a positive hepatitis B surface antigen or hepatitis C virus RNA test prior to transplant. Any known history or current evidence of alcohol or drug abuse that, in the Investigator's opinion, would exclude the subject from participation in the study Inclusion Criteria (Pre-emptive Treatment Phase) A positive test for A. fumigatus in BAL during the Surveillance Phase of the study Provided written informed consent for participating in the Pre-Emptive Treatment Phase. Exclusion Criteria (Pre-emptive Treatment Phase) Clinical, endobronchial and/or radiological features of fungal disease.* Any other disease or condition, which in the Investigator's medical opinion would preclude the subject's participation in the Pre-Emptive Treatment Phase of the study (e.g., recent myocardial infarction). Inclusion Criteria (Follow-up Phase - SOC Antifungal Treatment) Subject is not eligible to receive pre-emptive PC945 treatment due to either clinical, endobronchial and/or radiological features of fungal disease OR a fungal infection other than A. fumigatus in BAL, that requires SoC antifungal treatment to be started during the Surveillance Phase of the study. Provided written informed consent for participating in the Follow-Up Phase for SoC antifungal treatment. Exclusion Criteria (Follow-up Phase - SOC Antifungal Treatment) Any other disease or condition, which in the Investigator's medical opinion would preclude the subject's participation in the Follow-Up Phase for SoC antifungal treatment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subjects in the surveillance phase with detectable Aspergillus fumigatus lung infections WITHOUT clinical symptoms will be eligible to receive PC945 for 28 days. Following 28 days on PC945, subjects with ongoing A. fumigatus lung infections may receive a further 56 days of PC945. Subjects in the surveillance phase with EITHER detectable Aspergillus fumigatus lung infections WITH clinical symptoms, OR other fungal lung infection, will be eligible to be followed up for 16 weeks on Standard of Care.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PC945<br> | Drug: PC945<br>* Nebulized PC945 5mg OD for 28 days with an optional extended treatment period of a further 56 days.<br>|
| Other: Standard of Care<br>Standard of care anti-fungal medication | Drug: Standard of Care<br>* Standard of Care antifungal medication<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events (AEs) |  | 48 hours Post Transplant to Week 16 post treatment | 
| Proportion of participants receiving PC945 who meet the markedly abnormal criteria for 12-lead ECG assessment at lease once post dose |  | Baseline to Week 16 | 
| Proportion of participants receiving PC945 who meet the markedly abnormal criteria for vital signs assessment at lease once post dose |  | Baseline to Week 16 | 
| Proportion of participants receiving PC945 who meet the markedly abnormal criteria for safety laboratory assessment at lease once post dose |  | Baseline to Week 16 | 
| Predicted post bronchodilator forced expiratory volume in 1 second (FEV1) values from participants receiving PC945 |  | Baseline to Week 16 | 
| Forced vital capacity (FVC) values from participants receiving PC945 |  | Baseline to Week 16 | 
| Area under the curve from time 0 to 2 h post-dose (AUC0-2) | Derived pharmacokinetic parameters for PC945 and the potential circulating metabolite(s), if detectable | Baseline to Week 16 | 
| Maximum plasma concentration | Derived pharmacokinetic parameters for PC945 and the potential circulating metabolite(s), if detectable | Baseline to Week 16 | 
| Concentration at the end of the dosage interval (Ctrough) | Derived pharmacokinetic parameters for PC945 and the potential circulating metabolite(s), if detectable | Baseline to Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lung Concentration of PC945 |  | Baseline to Week 16 | 
| A. fumigatus fungal culture status (presence or absence) in subjects with a baseline A. fumigatus-positive bronchoalveolar lavage (BAL) |  | Baseline to Week 16 | 
| Change in BAL A. fumigatus measured by quantitative polymerase chain reaction (qPCR) |  | Baseline to Week 16 | 
| Change in the number of sputum A. fumigatus colony forming units (CFU) in cultured BAL. |  | Baseline to Week 16 | 
| Galactomannan levels in BAL |  | Baseline to Week 16 | 
| Aspergillus status (Presence or absence) of BAL using an Aspergillus immunochromatographic lateral flow device (AspLFD). |  | Baseline to Week 16 | 
| Status of fungal hyphae or pseudohyphae (presence or absence) on cytological examination |  | Baseline to Week 16 | 
| Subject experience of inhaled PC945 | Assessed by a standardised study-specific questionnaire assessing participants' subjective experience across a number of domains including taste, smell and overall acceptability following inhalation of PC945. | Baseline to Week 16 | 
| Subject experience of inhaled amphotericin B | Assessed by a standardised study-specific questionnaire assessing participants' subjective experience across a number of domains including taste, smell and overall acceptability, following inhalation of amphotericin B. | Baseline to Week 16 |