Clinical trial NCT05667662: Study to Evaluate Itraconazole Administered as Inhaled Dry Powder in Adults With Asthma and ABPA
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 ABPA
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: ABPA
Keywords: Asthma
Allergic Bronchopulmonary Aspergillosis
Lead sponsor: Pulmatrix Inc.
Sponsor class: INDUSTRY
First posted: 2022-12-28
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 may be given the opportunity to continue on study drug in an open label extension study.


Eligibility criteria: Inclusion Criteria:

* Is a male or female, ≥18 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, based on the modified International Society for human and Animal Mycology (ISHAM) ABPA working group 2013 and 2021 criteria including a history of or documentation at screening of serum IgE ≥ 500 IU/mL and A. fumigatus-specific IgE\>0.35KUA/L, or above normal IgE antibody to A. fumigatus, or a positive immediate skin test and at least 2 of the 3 following supportive criteria: eosinophil count \>500 cells/µL; A. fumigatus-specific IgG \>27 mgA/L or presence of precipitating (or above normal immunoglobulin G \[IgG\]) antibody to A. fumigatus; consistent radiographic opacities or bronchiectasis on chest CT.
* 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 a systemic glucocorticosteroid(s) in the 12 months prior to Screening. For patients on a biologic agent, at least one exacerbation requiring a systemic glucocorticosteroid(s) must have occurred at least 3 months after the initiation of the biologic agent.
* Has a serum IgE ≥500 IU/mL at screening.
* Has a documented stable asthma medication regimen during the 28 days prior to the first dose of study drug ; applicable asthma medications can include but are not limited to the following: inhaled short-acting beta agonist (SABA), inhaled long-acting beta agonist (LABA), and leukotriene receptor antagonist (LTRA) use and inhaled and/or oral glucocorticosteroids. SABA use during this period should be mostly within a stable range (e.g., 2 puffs 2 to 4 times a day) and should not exceed 8 puffs a day on 2 out of 3 consecutive days.
* Can perform a valid, reproducible spirometry test with demonstration of a prebronchodilator FEV1 ≥50% of predicted normal for age, sex, race, and height at a screening visit.
* Can demonstrate the correct inhalation technique and achieve a minimum inspiratory flow rate of 45 L/min for the use of the delivery device at screening and before dosing on Day 1.
* 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.
* 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 sensitive substrates for CYP3A4-mediated metabolism or medications that are contraindicated with oral itraconazole.
* 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 discontinued previously administered biologic agent(s) in the 3 months prior to screening.
* 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 inhaled tobacco/nicotine 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 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). Note that results that are positive for a drug of abuse or cotinine may be acceptable for drugs that have been obtained by legal means or non-inhaled tobacco/nicotine product use.
* 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 or \>500,000 X 109/L, or hemoglobin \<10 g/dL
* 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, or 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 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.

Primary outcomes:
measure: Incidence of Treatment Emergent Adverse Events (TEAEs)
timeFrame: 168 days
measure: Safety spirometry assessments
timeFrame: 168 days
measure: Vital sign measurements
timeFrame: 168 days
measure: Physical examinations
timeFrame: 168 Days
measure: Clinical safety laboratory test results
timeFrame: 168 days
measure: Cardiac safety monitoring
timeFrame: 168 days
Secondary outcomes:
measure: Magnitude of effect of daily administration of PUR1900 - Spirometry
timeFrame: 168 days
measure: Magnitude of effect of daily administration of PUR1900 - Patient Reported Outcomes (ACQ)
timeFrame: 168 days
measure: Magnitude of effect of daily administration of PUR1900 - Patient Reported Outcomes (AQLQ(s) 12+)
timeFrame: 168 days
measure: Frequency of asthma exacerbations versus baseline
timeFrame: 168 days
Other outcomes:
measure: Fungal resistance to Aspergillus fumigatus
timeFrame: 168 days
Locations:
city: Birmingham
country: United States
facility: University of Alabama Medical Center at Birmingham
state: Alabama
city: Scottsdale
country: United States
facility: Medical Research of Arizona
state: Arizona
city: Santa Monica
country: United States
facility: Jonathan Corren, MD
state: California
city: Stockton
country: United States
facility: Bensch Clinical Research
state: California
city: Springfield
country: United States
facility: Southern Illinois University Center for Clinical Research
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center Research Institute
state: Kansas
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Galveston
country: United States
facility: UTMB Health
state: Texas
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: South Brisbane
country: Australia
facility: Mater Hospital Brisbane, Respiratory Research Group
state: Queensland
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Rennes
country: France
facility: CHU Pontchaillou
state: Cedex 9
city: Strasbourg
country: France
facility: Nouvel Hôpital Civil
state: Strasbourg Cedex
city: Marseille
country: France
facility: CHU de Marseille Hôpital Nord
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham - Heartlands Hospital
state: West Midlands
city: Glasgow
country: United Kingdom
facility: CPS Research Limited
city: London
country: United Kingdom
facility: Royal Brompton Hospital
city: Manchester
country: United Kingdom
facility: University Hospital of South Manchester - Wythenshawe Hospital,
Study officials:
affiliation: Pulmatrix Inc.
name: Chris Cabell, MD
role: STUDY_DIRECTOR
References: