Study to Evaluate Itraconazole Administered as Inhaled Dry Powder in Adults With Asthma and Allergic Bronchopulmonary Aspergillosis

• ClinicalTrials.gov Identifier: NCT05667662
• Recruitment Status: Recruiting
• First Posted: December 28, 2022
• Last Update Posted: February 2, 2023
• Sponsor: Pulmatrix Inc.
• Information provided by (Responsible Party): Pulmatrix Inc.

Study Description

Brief Summary:

The goal of this clinical trial is to learn about PUR1900 as an inhaled, antifungal therapeutic for the treatment of allergic bronchopulmonary aspergillosis (ABPA) in patients with asthma. The main questions it aims to answer are:

1. Is PUR1900 safe and well tolerated in adults with asthma and ABPA?
2. Is there an effect of daily administration of PUR1900 on potential outcome measures in adults with asthma and ABPA?
3. Is there fungal resistance to A. fumigatus?

This study includes a 28-day screening period, a 112-day (16-week) treatment period, and a 56-day (8 week) observation period.

Participants will take either 40mg of PUR1900, 20 mg of PUR1900 or Placebo for 112 days and complete an eDairy, answer questions about their asthma and complete peak respiratory flow measurements at home. They will come to the clinic approximate once a month during the treatment period and complete study assessments. At the end of the observation period participants will complete one more clinic visit. Participants who complete this study will be given the opportunity to continue on study drug in an open label extension study.

Condition or disease	Intervention/treatment	Phase
ABPA	Drug: Itraconazole Powder; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Study to Evaluate the Effect of Dose and Duration of Treatment of Itraconazole Administered as a Dry Powder for Inhalation (PUR1900) on Safety, Tolerability, and Potential Outcomes in Adult Patients With Asthma and Allergic Bronchopulmonary Aspergillosis
• Actual Study Start Date: February 1, 2023
• Estimated Primary Completion Date: April 13, 2024
• Estimated Study Completion Date: April 13, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: PUR1900 40 mg; 4 PUR1900 (10 mg itraconazole) Capsules with 20 mg total powder (10 mg itraconazole plus 10 mg excipients) administered via oral inhalation, using the RS01 Monodose inhaler once daily for 112 days at approximately the same time each day.	Drug: Itraconazole Powder; Capsules with 20 mg total powder (10 mg itraconazole plus 10 mg excipients); Other Name: PUR1900
Experimental: PUR1900 20 mg; 2 PUR1900 (10 mg itraconazole) Capsules with 20 mg total powder (10 mg itraconazole plus 10 mg excipients) and 2 Placebo Capsules with with 11.8 mg total powder (excipients only) administered via oral inhalation, using the RS01 Monodose inhaler once daily for 112 days at approximately the same time each day.	Drug: Itraconazole Powder; Capsules with 20 mg total powder (10 mg itraconazole plus 10 mg excipients); Other Name: PUR1900
Placebo Comparator: Placebo; 4 Placebo Capsules with with 11.8 mg total powder (excipients only) administered via oral inhalation, using the RS01 Monodose inhaler once daily for 112 days at approximately the same time each day.	Drug: Placebo; Capsules with 11.8 mg total powder (excipients only)

Outcome Measures

Primary Outcome Measures :

1. Incidence of Treatment Emergent Adverse Events (TEAEs) [ Time Frame: 168 days ]
   Review of TEAEs from time of consent to study completion.
2. Safety spirometry assessments [ Time Frame: 168 days ]
   FEV1 (the volume of air (in liters) exhaled in the first second during forced exhalation after maximal inspiration), FVC (liters), and PEFR (L/min) measurements compared to baseline.
3. Vital sign measurements [ Time Frame: 168 days ]
   Vital signs measurements collected before exposure, during and after treatment and compared to baseline. Vital sign measurements will include respiratory rate (bpm), blood pressure (mmHg), heart rate (bpm), oxygen saturation (by pulse oximetry), and oral or tympanic temperature (°C).
4. Physical examinations [ Time Frame: 168 Days ]
   At screening, a complete physical examination will be performed which includes measurement of height (cm), weight (kg) and evaluation of appearance; skin; head and neck; eyes, ears, nose, and throat; chest and lungs; heart; abdomen; neurological system; and extremities.
5. Clinical safety laboratory test results [ Time Frame: 168 days ]
   Hematology, serum chemistry, or urinalysis test results (normal, abnormal, clinical significance) compared to baseline.
6. Cardiac safety monitoring [ Time Frame: 168 days ]
   Electrocardiogram (ECG) recordings collected before exposure, during and after treatment. Electrocardiogram measurements will include heart rate and PR, RR, QRS, and QT intervals, as well as the QTcF and compared to baseline.

Secondary Outcome Measures :

1. Magnitude of effect of daily administration of PUR1900 - Spirometry [ Time Frame: 168 days ]
   Changes in measured Forced Expiratory Volume (FEV1) over time compared to baseline
2. Magnitude of effect of daily administration of PUR1900 - Patient Reported Outcomes (ACQ) [ Time Frame: 168 days ]
   Responses to the Asthma Control Questionnaire (ACQ) sored from 0-6 with 0 being totally controlled and 6 being extremely poorly controlled compared to baseline.
3. Magnitude of effect of daily administration of PUR1900 - Patient Reported Outcomes (AQLQ(s) 12+) [ Time Frame: 168 days ]
   Responses to the Asthma Quality of Life Questionnaire with scores ranging 1-7 and higher scores indicating better quality of life compared to baseline.
4. Frequency of asthma exacerbations versus baseline [ Time Frame: 168 days ]
   Occurrence of asthma exacerbations before, during, and after treatment with PUR1900

Other Outcome Measures:

1. Fungal resistance to Aspergillus fumigatus [ Time Frame: 168 days ]
   Fungal susceptibility of sputum samples collected at the before and after anti-fungal treatment to determine resistance risks using the EUCAST microdilution method

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Is a male or female, ≥18 and ≤80 years old at the time of signing the informed consent.
• BMI of ≥18.0 and <40.0 kg/m2 at screening.
• Has a diagnosis of asthma, as per the Global Initiative for Asthma (GINA) 2018 update
• Has a confirmed diagnosis of ABPA, as per the Modified International Society for Human and Animal Mycology (ISHAM) working group 2013 criteria, including a history of serum IgE ≥1000 IU/mL and a positive immediate skin test or increased IgE antibody to A. fumigatus and at least 2 of the 3 following supportive criteria: eosinophils >500 cells/µL, presence of precipitating antibody (or increased immunoglobulin G [IgG]) to A. fumigatus, consistent radiographic opacities at the time of diagnosis.
• 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).
• At least 1 exacerbation requiring an oral steroid(s) in the last 12 months.
• Has a serum IgE ≥500 IU/mL at screening.
• Has a documented stable asthma medication regimen during the screening period.
• Can perform a valid, reproducible spirometry test with demonstration of a prebronchodilator FEV1 ≥50% of predicted normal for age, sex, race, and height.
• Can demonstrate the correct inhalation technique for the use of the delivery device.
• Subjects who are sexually active, male subjects able to father a child, and female subjects of childbearing potential must agree to follow contraception requirements.

Exclusion Criteria:

• Currently requiring medications that are metabolized via the CYP3A4 isoenzyme system.
• Has evidence of ventricular dysfunction, such as congestive cardiac failure (New York Heart Association functional class III or IV), 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.
• Has used any systemic azole antifungal agent in the 6 weeks before first dose of study drug.
• Has a history of life-threatening asthma within the last 24 months, defined as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest, and/or hypoxic seizures.
• 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 (e.g., 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. Refer to Appendix 4 for definition of bronchiectasis exacerbations.
• 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.
• Had an occurrence of asthma or ABPA exacerbations within the 28 days before screening.
• Has the presence of hoarseness or oropharyngeal candidiasis at screening.
• Had a major trauma or surgery within the last 28-days before screening.
• Has a history of any clinically significant cardiovascular, renal, hepatic, or gastrointestinal disease or neurological or psychiatric disorder endocrine, immunological, or autoimmune disease or other medical condition that would affect the subject's safety or confound the assessment of study endpoints as judged by the Investigator.
• Has a history of any clinically significant drug or alcohol abuse in the past 6 months before screening, as judged by the Investigator.
• Has current tobacco or inhaled marijuana use or history of smoking or vaping including tobacco or marijuana within the last 6 months before screening.
• Has a history of allergic or hypersensitivity reaction or serious adverse reaction after dosing of itraconazole or other antifungal azoles.
• Has a history of serious adverse reaction or known serious hypersensitivity to any of the formulation excipients.
• Has a positive urine test result for drugs of abuse or cotinine at screening (unless, in the opinion of the Investigator, this can be explained by the subject's current medications).
• At screening, has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2x upper limit of normal (ULN), white blood cell (WBC) count > 20,000 X 109/L, absolute neutrophil count <1000 cells/L, platelet counts <100,000 to >500,000 X 109/L, or hemoglobin <10 g/dL
• Has used omalizumab (Xolair®) in the 12 months prior to the first dose of study drug.
• 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 pre dose on Day 1. A woman is of childbearing potential unless she is either permanently sterile (hysterectomy, bilateral salpingectomy, bilateral oophorectomy, bilateral tubal occlusion/ligation, endometrial ablation) or postmenopausal (had no menses for 12 months without an alternative medical cause).
• Has a 12-lead ECG demonstrating a mean QT interval corrected by the Fridericia formula (QTcF) >450 msec for a male subject or >470 msec for a female subject at screening. A repeat triplicate ECG is allowed if a mean QTcF >450 msec for males and >470 msec for females is recorded at Visit 1.
• Has a history of allergic or hypersensitivity reaction or serious adverse reaction after dosing of itraconazole or other antifungal azoles.
• Has a planned or elective surgery, hospitalizations, or participation in other interventional studies any time during the study that may interfere with study logistics or safety.
• Has donated or had a loss of greater than 400 mL of blood within the 3 months before screening.
• Has other social, psychiatric, surgical, or medical conditions or screening laboratory abnormalities that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the judgement of the Investigator, would make the subject inappropriate for entry into the study.
• Received any investigational medical product in a clinical research study within the previous 3 months before first dose of study drug.
• Is a study site employee, an immediate family member of a study site employee, or a Sponsor employee.
• Has previously received PUR1900.

Contacts and Locations

Contacts

Contact: Margaret Wasilewski, MD; 781-357-2333; mwasilewski@pulmatrix.com

Contact: Brent Jones, BS; 781-357-2333; bjones@pulmatrix.com

Locations

United States, Arizona

Medical Research of Arizona; Recruiting

Scottsdale, Arizona, United States, 85251

Contact: Aaliyah Dean 480-675-8982 aaliyah@medicalresearchaz.com

Principal Investigator: Michael E Manning, MD

United States, California

Jonathan Corren, MD; Recruiting

Santa Monica, California, United States, 90025

Contact: Angelica Covarrubias 310-312-5050 angelica@correnmd.com

Principal Investigator: Jonathan Corren, MD

United States, Florida

Renew Health Clinical Research; Recruiting

Tampa, Florida, United States, 33607

Contact: Ebony Owens 706-223-3560 ebony.owens@renewhealthcr.com

Principal Investigator: Eddie Oliver, MD

Sponsors and Collaborators

Pulmatrix Inc.

Investigators

• Study Director: Margaret Wasilewski, MD; Pulmatrix Inc.

More Information

• Responsible Party: Pulmatrix Inc.
• ClinicalTrials.gov Identifier: NCT05667662
• Other Study ID Numbers: 601-0018
• First Posted: December 28, 2022
• Last Update Posted: February 2, 2023
• Last Verified: February 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Pulmatrix Inc.:

Asthma; Allergic Bronchopulmonary Aspergillosis

Additional relevant MeSH terms:

Aspergillosis; Pulmonary Aspergillosis; Aspergillosis, Allergic Bronchopulmonary; Respiratory Tract Diseases; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Mycoses; Bacterial Infections and Mycoses; Infections; Lung Diseases, Fungal; Respiratory Tract Infections; Itraconazole; Antifungal Agents; Anti-Infective Agents; 14-alpha Demethylase Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Steroid Synthesis Inhibitors; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Cytochrome P-450 CYP3A Inhibitors