Study in Adult Asthmatic Patients With Allergic Bronchopulmonary Aspergillosis

Study Overview
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Brief Summary
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A Randomized, Double-Blind, Multicenter, Placebo-Controlled, Phase 2 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Itraconazole Administered as a Dry Powder for Inhalation (PUR1900) in Adult Asthmatic Patients With Allergic Bronchopulmonary Aspergillosis

Detailed Description
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This is a randomized, double-blind, multicenter, placebo controlled, multiple-arm study. Following screening and confirmation of eligibility, subjects will be randomly assigned (1:1:1:1) into 4 arms of 16 subjects each and will receive 10 mg, 20 mg, or 35 mg of PUR1900 or placebo, administered via dry powder inhalation daily for 28 days. The doses of PUR1900 are stated in this protocol as the respective nominal doses of itraconazole. Subject eligibility for the study will be determined within 28 days before the first dose of study drug (Day 1) and will be confirmed between 9 and 6 days before dosing and again on Day 1. Eligible subjects will begin daily dosing with study drug (PUR1900 or placebo) on Day 1. Subjects will return to the study site for visits on Days 2, 7, 14, and 28 and will be dosed at the study site. The remaining daily doses of study drug will be self-administered at home. A follow-up visit will occur 7 to 10 days after the last dose of study drug.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to Evaluate the Safety, Tolerability, & Pharmacokinetics of Itraconazole Administered as a Dry Powder for Inhalation (PUR1900) in Asthmatic Patients With ABPA

Conditions
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Allergic Bronchopulmonary Aspergillosis

Intervention / Treatment
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* Combination Product: PUR1900
* Combination Product: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is a male or female, 18 to 75 years old (inclusive) at the time of signing the informed consent. Has a body mass index of 18.0 to 35.0 kg/m2 (inclusive) at screening. Has a historical diagnosis of asthma, as per the Global Initiative for Asthma (GINA) 2018 update. Has a confirmed historical diagnosis of ABPA, as per the Modified International Society for Human and Animal Mycology (ISHAM) working group 2013 criteria. 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) Has a serum immunoglobulin (Ig) E ≥1000 IU/mL during screening (Visit 1 or Visit 2). 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. 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. 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 of this protocol. Can demonstrate the correct inhalation technique for the use of the delivery device at screening and before dosing. Exclusion Criteria: Is a female of childbearing potential who is pregnant or lactating or who plans to become pregnant during the study. 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). 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. Had an occurrence of asthma or ABPA exacerbations within the 28 days before screening or during the 28-day period before Day 1. 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. Received any investigational medical product in a clinical research study within the previous 3 months before dosing in this study. Has previously received PUR1900. Has a history of any significant drug or alcohol abuse in the past 2 years before screening, as judged by the investigator. Has current tobacco or inhaled marijuana use or history of smoking tobacco or marijuana within the last 6 months before screening. Is a current user of e-cigarettes or has used these products within the last 6 months before screening. Has a positive urine test result for drugs of abuse, alcohol, or cotinine at screening Has a history of allergies to or hypersensitivity reactions after dosing of itraconazole or other antifungal azoles. Had a major trauma or surgery within the last 28 days before screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Following screening and confirmation of eligibility, subjects will be randomly assigned (1:1:1:1) into 4 arms of 16 subjects each and will receive 10 mg, 20 mg, or 35 mg of PUR1900 or placebo, administered via dry powder inhalation daily for 28 days.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 10 mg PUR1900<br>Study drug (PUR1900) will be administered orally, using a Dry Powder Inhaler (DPI) specific to the study (RS01 Monodose inhaler) | Combination Product: PUR1900<br>* PUR1900 contains itraconazole as the active ingredient, and it is formulated as a dry powder for oral inhalation.<br>|
| Experimental: 20 mg PUR1900<br>Study drug (PUR1900) will be administered orally, using a Dry Powder Inhaler (DPI) specific to the study (RS01 Monodose inhaler) | Combination Product: PUR1900<br>* PUR1900 contains itraconazole as the active ingredient, and it is formulated as a dry powder for oral inhalation.<br>|
| Experimental: 35 mg PUR1900<br>Study drug (PUR1900) will be administered orally, using a Dry Powder Inhaler (DPI) specific to the study (RS01 Monodose inhaler) | Combination Product: PUR1900<br>* PUR1900 contains itraconazole as the active ingredient, and it is formulated as a dry powder for oral inhalation.<br>|
| Placebo Comparator: Placebo<br>Placebo | Combination Product: Placebo<br>* PUR1900 placebo<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 |  | From Day 1 through Follow Up (which is 7 to 10 days after the last dose) | 
| Incidence of intraday FEV1 declines |  | From Day 1 through Follow Up (which is 7 to 10 days after the last dose) | 
| Respiratory rate |  | From Day 1 through Follow Up (which is 7 to 10 days after the last dose) | 
| Blood pressure | Systolic pressure over diastolic pressure | From Day 1 through Follow Up (which is 7 to 10 days after the last dose) | 
| Heart rate | Beats per minute | From Day 1 through Follow Up (which is 7 to 10 days after the last dose) | 
| Oxygen saturation | As a percentage | From Day 1 through Follow Up (which is 7 to 10 days after the last dose) | 
| Physical examination findings | Physician's notes | From Day 1 through Follow Up (which is 7 to 10 days after the last dose) | 
| Clinical laboratory test results | Lab reports with any out of range results flagged | From Day 1 through Follow Up (which is 7 to 10 days after the last dose) | 
| 12-Lead electrocardiogram findings | ECG report and tracing | From Day 1 through Follow Up (which is 7 to 10 days after the last dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sputum concentrations of itraconazole and hydroxy-itraconazole |  | Day 2 to Day 28 | 
| Sputum eosinophils |  | (Day -9 to Day -6) to Day 28 | 
| To evaluate the effect of PUR1900 on pulmonary function following single- and multiple-dose administration of PUR1900 |  | Day 1 to Day 28 | 
| Asthma Control Questionnaire-6 (ACQ 6) | Scores range between 0 (totally controlled) and 6 (severely uncontrolled). | Day 1 to Day 28 | 
| Change from baseline (Day 1) to Day 28 in A fumigatus burden in sputum | As assessed by quantitative PCR and sputum culture | Day 1 to Day 28 | 
| Cmax (maximum observed concentration in plasma) |  | Day 1 to Day 28 | 
| Tmax (time to maximum concentration in plasma) |  | Day 1 to Day 28 | 
| AUC (area under the concentration-time curve) |  | Day 1 to Day 28 | 
| CL/F (clearance) |  | Day 1 to Day 28 | 
| Vz/F (apparent volume of distribution) |  | Day 1 to Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aspergillosis