E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Fungal infection of the airway |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10059259 |
E.1.2 | Term | Pulmonary aspergillosis |
E.1.2 | System Organ Class | 100000004862 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To investigate the safety and tolerability of once daily treatment with inhaled PC945 for 28 days in adult subjects with CF who have persistent pulmonary Aspergillus fumigatus infection • To obtain estimates of derived systemic pharmacokinetic parameters of PC945 and the potential circulating metabolite(s), if detectable, following single and repeat doses of PC945 |
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E.2.2 | Secondary objectives of the trial |
To investigate the effect of PC945 on: - A. fumigatus burden in sputum, measured by the number of CFUs, on fungal culture - The conversion of sputum culture from A. fumigatus +ve to A. fumigatus -ve - A. fumigatus burden in sputum measured by qPCR - A. fumigatus-specific IgG levels - Clinically relevant outcome measures, in particular QoL, cough, breathlessness and sputum characteristic - Markers of A. fumigatus sensitisation: total IgE in subjects with elevated Total IgE levels at study entry, A. fumigatus-specific IgE in subjects with elevated levels of A. fumigatus-specific IgE at study entry
To determine if changes in sputum A. fumigatus concentrations on qPCR are related to measures of fungal burden in sputum To investigate correlation between sputum A. fumigatus levels measured by qPCR and clinical variables including CF QoL questionnaire and lung function and to investigate if changes in sputum A. fumigatus measured by qPCR predict clinical response |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject must be male or female, aged 18 years inclusive or older (at the time of consent). 2. Subject must be willing and able to adhere to the restrictions and prohibitions required by this protocol. 3. 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. 4. A confirmed diagnosis of CF by standard criteria. 5. Subject is able to produce sputum. 6. A history of persistently positive A. fumigatus sputum cultures from at least 2 sputum samples in the last year, the most recent of which must have been within the last 6 months. 7. Subject must have a positive sputum fungal culture at screening with one or more colonies of A. fumigatus detected using a modified standard approach. |
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E.4 | Principal exclusion criteria |
1. Any other disease or condition, which in the Investigator’s medical opinion would preclude the subject’s participation in a clinical trial. 2. Is taking inhaled amphotericin B or has taken it within 7 weeks of Day 1. 3. Is taking systemic steroid treatment or has taken it within 4 weeks of Day 1. Subjects considered to be stable on a systemic steroid dose of <15 mg for at least a month will not be excluded. 4. Is taking systemic antifungal treatment (intravenous, oral or inhaled) or has received antifungal therapy (intravenous, oral or inhaled) within 6 weeks of Day 1. 5. If female, the subject is pregnant (e.g., has a positive serum β human chorionic gonadotropin (β-hCG) at screening or a positive urinary pregnancy test pre-dose on Day 1), lactating or breast feeding. 6. Any respiratory exacerbation within 2 weeks of the start of the study. 7. Any upper respiratory tract infection or signs or symptoms thereof within 2 weeks prior to dosing. 8. Positive culture for Mycobacterium abscessus within 12 months before screening or between screening and baseline, or currently receiving treatment for Mycobacterium abscessus. 9. Has chronic, active hepatitis or a positive hepatitis B surface antigen or positive hepatitis C antibody result at screening. 10. Is taking antiretroviral protease inhibitor therapy. 11. Allergy to any of the active or inactive ingredients in the study medication. 12. History of drug (or other) allergy or intolerance that, in the opinion of the Investigator or Pulmocide Medical Monitor, would contraindicate their participation. 13. Clinically significant haemoptysis (>200 mL per episode) within 90 days before screening. 14. Subject is mentally or legally incapacitated. 15. Subject 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. 16. Any other reason that the Investigator considers makes the subject unsuitable to participate. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety and tolerability parameters: • Adverse events (AEs) • Twelve-lead electrocardiogram (ECG; including QT corrected according to Bazett’s formulae interval, QT interval, QRS Interval, PR Interval and ventricular rate). • Vital signs (systolic and diastolic blood pressure, heart rate and respiratory rate) • Clinical laboratory evaluations (haematology, clinical chemistry, and urinalysis) • Spirometry (FEV1, FVC, MEF25-75 and PEFR) • Visual analogue score (VAS) to assess tolerability (cough, breathlessness)
Derived pharmacokinetic parameters for PC945 and the potential circulating metabolite(s), if detectable including: • Maximum plasma concentration • Concentration at the end of the dosage interval (Ctrough) • Area under the curve from time 0 to 2 h post-dose (AUC0–2) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
AEs: study related AEs from consent until Day (D) 1. All AEs from D1 until end of study ECGs: Screening (S), D1 (predose (PD), 0.5, 2 h), D14 (PD, 0.5, 2 h), D32-36, D84 Vitals: S, D1 (PD,0.5, 1, 1.5, 2 h), D14 (PD, 0.5, 1, 1.5, 2 h), D32-36, D84 Clin labs: S, D1, 14, 32-36, 84 Spirometry: S, D1 (PD,0.5 h), D14 (PD, 0.5 h), D32-36, D84 VAS: D1 (PD,0.5 h), D14 (PD, 0.5 h), D32-36, D84
PK: D1 (PD,0.5, 1, 1.5, 2 h), D14 (PD, 0.5, 1, 1.5, 2 h), D32-36, D84 |
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E.5.2 | Secondary end point(s) |
• Change in the number of sputum A. fumigatus CFU from baseline to Visit 3, Visit 4 and at followup (Visit 5) • A. fumigatus status (presence or absence) at Visit 3, Visit 4 and at follow-up Visit 5 in subjects with an A. fumigatus-positive sputum culture at baseline • Change in sputum A. fumigatus measured by qPCR from baseline to Visit 3, Visit 4 and at followup Visit 5 • Change in the serum concentration of A. fumigatus-specific IgG from baseline to Visit 3, Visit 4 and at follow-up Visit 5 • Change in serum Total IgE levels from baseline to Visit 3, Visit 4 and at follow-up Visit 5 • Change in serum Aspergillus-specific IgE levels from baseline to Visit 3, Visit 4 and at follow-up Visit 5 • CFQ-R scores, cough (visual analogue scale), breathlessness (visual analogue scale) and sputum characteristics (e.g. colour, quality) at baseline, Visit 3, Visit 4, and at follow-up at Visit 5 • Correlation between A. fumigatus measured by qPCR and clinical response: e.g., culture, CFQ-R and lung function (FEV1, FVC, MEF25–75 and PEFR) and to investigate if the change in sputum A. fumigatus measured by qPCR predicts clinical response |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Sputum: S, D14, 32-36, 84 Blood samples for circulating biomarkers: D1, 14, 32-36, 84 CFQ-R: D1, 14, 32-36, 84 Lung function: S, D1 (PD,0.5 h), D14 (PD, 0.5 h), D32-36, D84 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |