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
Overview
- Phase
- Phase 2
- Status
- Terminated
- Sponsor
- Pulmatrix Inc.
- Enrollment
- 8
- Locations
- 18
- Primary Endpoint
- Incidence of Treatment Emergent Adverse Events (TEAEs)
Overview
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:
- Is PUR1900 safe and well tolerated in adults with asthma and ABPA?
- Is there an effect of daily administration of PUR1900 on potential outcome measures in adults with asthma and ABPA?
- 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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
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.
Arms & Interventions
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.
Intervention: Placebo (Drug)
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.
Intervention: Itraconazole Powder (Drug)
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.
Intervention: Itraconazole Powder (Drug)
Outcomes
Primary Outcomes
Incidence of Treatment Emergent Adverse Events (TEAEs)
Time Frame: 168 days
Review of TEAEs from time of consent to study completion.
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.
Clinical safety laboratory test results
Time Frame: 168 days
Hematology, serum chemistry, or urinalysis test results (normal, abnormal, clinical significance) compared to baseline.
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.
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).
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 Outcomes
- Magnitude of effect of daily administration of PUR1900 - Patient Reported Outcomes (ACQ)(168 days)
- Magnitude of effect of daily administration of PUR1900 - Patient Reported Outcomes (AQLQ(s) 12+)(168 days)
- Frequency of asthma exacerbations versus baseline(168 days)
- Magnitude of effect of daily administration of PUR1900 - Spirometry(168 days)