E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Asthma with Allergic Bronchopulmonary Aspergillosis |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10006474 |
E.1.2 | Term | Bronchopulmonary aspergillosis allergic |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 |
The primary objective of the study is to evaluate the safety and tolerability of multiple dose administration of PUR1900 given to adult asthmatic subjects with Allergic Bronchopulmonary Aspergillosis (ABPA). |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
To characterize the pharmacokinetics of multiple doses of inhaled PUR1900 in plasma and sputum
To evaluate the effect of PUR1900 on biomarkers of inflammation (sputum eosinophils and serum IgE)
To evaluate the effect of PUR1900 on pulmonary function following single- and multiple-dose administration of PUR1900
To evaluate the impact of PUR1900 on respiratory symptoms, as measured by the ACQ 6
To evaluate the effect of PUR1900 on the Aspergillus fumigatus burden in the sputum, as assessed by quantitative PCR and sputum culture |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Participants must meet all of the following criteria to be enrolled into this study: 1.Can provide written informed consent before the performance of any study-specific procedures. 2.Is a male or female, 18 to 75 years old (inclusive) at the time of signing the informed consent. 3.Has a body mass index of 18.0 to 35.0 kg/m2 (inclusive) at screening. 4.Has a historical diagnosis of asthma, as per the Global Initiative for Asthma (GINA) 2018 update (Section 13.1). 5.Has a confirmed historical diagnosis of ABPA, as per the Modified International Society for Human and Animal Mycology (ISHAM) working group 2013 criteria (Section 13.2). 6.Is currently considered to be in one of the following stages of ABPA: Stage 2 (Response), Stage 4 (Remission), Stage 5a (Treatment-dependent ABPA), or Stage 5b (Glucocorticoid-dependent asthma) (Section 13.3). 7.Has a serum immunoglobulin (Ig) E ≥1000 IU/mL during screening (Visit 1 or Visit 2). 8.Can perform a valid, reproducible spirometry test with demonstration of a prebronchodilator FEV1 ≥50% of predicted normal for age, sex, race, and height (Quanjer et al 2012) at a screening visit. 9.Has a documented stable asthma medication regimen during screening (Day 28 to Day 1), including SABA, LABA, and LTRA use and inhaled and/or oral GCS. 10.Subjects who are sexually active, male subjects able to father a child, and female subjects of childbearing potential must agree to follow the contraception requirements outlined in Section 5.8.4 of this protocol. 11.Can demonstrate the correct inhalation technique for the use of the delivery device at screening and before dosing on Day 1. 12.Is willing and able to comply with all study procedures and assessments, including scheduled visits, drug dosing plan, study procedures, laboratory tests, and study restrictions.
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E.4 | Principal exclusion criteria |
A participant who meets any of the following criteria will be excluded from the study: 1.Has used any anti-IgE (eg, Xolair® [omalizumab]) or anti-interleukin-5 (IL-5) biologics (eg, Cinqair® [reslizumab], Nucala® [mepolizumab], or Fasenra® [benralizumab]) in the 6 months before first dose of study drug. 2.Is a female of childbearing potential who is pregnant or lactating or who plans to become pregnant during the study (all female subjects must have a negative pregnancy test at screening and predose on Day 1). A woman is considered to be of childbearing potential unless she is either permanently sterile (hysterectomy, bilateral salpingectomy, bilateral oophorectomy, bilateral tubal occlusion/ligation) or postmenopausal (had no menses for 12 months without an alternative medical cause). 3.Is taking or has taken any prescribed or over-the-counter (OTC) drug that is a CYP3A4 inhibitor or substrate in the 14 days (or 5 half-lives, whichever is longer) before first dose of study drug and for the duration of the study (Section 13.4) (exclusion also applies to the whole fruit or juices of grapefruit and Seville or pomelo oranges). 4.Is taking or has taken any herbal remedies or CYP3A4 inducers in the 28 days before first dose of study drug (Section 13.4). 5.Has used any systemic azole antifungal agent in the 6 months before first dose of study drug. 6.Has a history of life-threatening asthma within the last 5 years, defined as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest, and/or hypoxic seizures. 7.Had an occurrence of asthma or ABPA exacerbations (as defined in Section 13.5) within the 28 days before screening or during the 28-day period before Day 1. 8.Had an occurrence of clinically significant bacterial, viral, or fungal infection that required systemic (oral or intravenous) antibiotics, antivirals, or antifungals within the 28 days before screening. Topical treatments, other than antifungals, are allowed. 9.Received any investigational medical product in a clinical research study within the previous 3 months before dosing in this study. 10.Is a study site employee, an immediate family member of a study site employee, or a sponsor employee. 11.Has previously received PUR1900. 12.Has a history of any significant drug or alcohol abuse in the past 2 years before screening, as judged by the investigator. 13.Has current tobacco or inhaled marijuana use or history of smoking tobacco or marijuana within the last 6 months before screening. 14.Is a current user of e-cigarettes or has used these products within the last 6 months before screening. 15.Has the absence of suitable veins for multiple venipunctures/cannulation as assessed by the investigator or designee at screening. 16.Has evidence or history of clinically significant abnormal serum chemistry, hematology, or urinalysis at screening, as judged by the investigator (particularly elevation of liver enzymes or bilirubin). 17.Has a positive urine test result for drugs of abuse, alcohol, or cotinine at screening (unless, in the opinion of the investigator, this can be explained by the subject’s current medications). 18.Has a positive human immunodeficiency virus (HIV; type A and type B) antibody result: a subject who is HIV antibody positive is not excluded if a subsequent CD4 count is ≥200 cells/µL. 19.Has evidence or a history of clinically significant cardiovascular, renal, hepatic, or gastrointestinal disease or neurological or psychiatric disorder, as judged by the investigator. 20.Has evidence or a history of endocrine, immunological, or autoimmune disease that would affect the subject’s safety or confound the assessment of study endpoints in the opinion of the investigator. 21.Has a current diagnosis of any chronic airway disease other than asthma, ABPA, or bronchiectasis believed to be related to ABPA, such as chronic obstructive pulmonary disease, pulmonary fibrosis, cystic fibrosis, or Churg-Strauss syndrome. A subject whose predominating clinical disease burden is related to bronchiectasis (eg, a subject with 2 or more infective exacerbations of bronchiectasis in the past 12 months or a subject with chronic colonization with Pseudomonas aeruginosa) will be excluded. 22.Has evidence of ventricular dysfunction, such as congestive cardiac failure, or a history of congestive cardiac failure. N-terminal pro B-type natriuretic peptide (NT pro BNP) will be checked at screening only. A subject with a confirmed value of >400 pg/mL will not be eligible to participate. 23.Has a 12-lead ECG demonstrating a mean QT interval corrected by the Fridericia formula (QTcF) >450 ms for a male subject or >470 ms for a female subject at screening. A repeat triplicate ECG is allowed if a mean QTcF >450 ms is recorded at Visit 1 or Visit 2. 24.Has a serious adverse reaction or serious hypersensitivity to any of the formulation excipients. See protocol for remaining exclusion criteria. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoints on this study are: - Incidence of treatment-emergent adverse events - Incidence of intraday FEV1 declines (from pre-dose to post-dose) of >=10%, >=15% and >=20% - Vital sign measurements (respiratory rate, blood pressure, heart rate, oxygen saturation by pulse oximetry, oral or tympanic temperature) - Physical examination findings - Clinical laboratory parameters - 12-Lead electrocardiogram findings |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
•Pharmacokinetic parameters of itraconazole and hydroxy-itraconazole in plasma, including, but not limited to, Cmax, Tmax, AUC, CL/F, and Vz/F •Sputum concentrations of itraconazole and hydroxy-itraconazole on Day 2, on Day 14, and at follow-up •Change from baseline (Day -9 to Day -6) to Day 28 in sputum eosinophil count •Change from baseline (Day -9 to Day -6) to Day 28 in percentage of sputum eosinophils •Change from baseline (Day 1) to Day 28 in IgE plasma concentration •Change from baseline (Day 1) to Day 28 in FEV1 •Change from baseline (Day 1) to Day 28 in FVC, PEF, and FEV1/FVC •Change from baseline (Day 1) to Day 28 in ACQ-6 score •Change from baseline (Day 1) to Day 28 in A fumigatus burden in sputum as assessed by quantitative PCR and sputum culture |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
India |
Poland |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 28 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 27 |