Safety, Tolerability and Pharmacokinetics of PUR1900 (Itraconazole Powder) in Healthy Volunteers and Adults With Asthma

• ClinicalTrials.gov Identifier: NCT03479411
• Recruitment Status: Completed
• First Posted: March 27, 2018
• Last Update Posted: July 27, 2018
• Sponsor: Pulmatrix Inc.
• Information provided by (Responsible Party): Pulmatrix Inc.

Study Description

Brief Summary:

Phase 1, 3-part study to assess safety, tolerability and PK of single and multiple doses of itraconazole administered as a dry powder for inhalation (PUR1900) in healthy subjects (parts 1 and 2) and a 2-period crossover study of single doses of itraconazole administered as a dry powder for inhalation (PUR1900) and an oral solution (Sporanox) in adults with mild to moderate, stable asthma (part 3)

Condition or disease	Intervention/treatment	Phase
Asthma	Drug: Itraconazole Powder; Drug: Itraconazole 200 mg	Phase 1

Detailed Description:

Phase 1, multi-center, 3-part, open-label study in healthy adults (Parts 1 and 2) and adults with mild to moderate, stable asthma (Part 3).

Safety, tolerability and PK will be assessed following either single ascending (SAD) or multiple ascending (MAD) dosing of itraconazole administered as a dry powder for inhalation (PUR1900; Part 1 and Part 2, respectively). Part 1 will comprise 3 separate cohorts planned to receive single doses of 5, 10 and 25 mg itraconzaole, respectively. The study will have an interleaved design; Part 2 will comprise 2 separate cohorts planned to receive daily doses of itraconazole 10 and 20 mg per day for 14 days, respectively. Part 2, Cohort 1 will commence after a review of safety data from Part 1 Cohort 2 suggests it is safe to do so.

Part 3 is a 2-period, randomised, crossover study in adult subjects with mild to moderate stable asthma to assess the safety, tolerability and PK of single doses of itraconazole administered as a dry powder for inhalation (PUR1900) and administered as an oral solution (Sporanox® Oral Solution).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 58 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: The study has 3 parts: 1) Single Ascending Dose Escalation and 2) Multiple Ascending Dose Escalation to be conducted in Normal Healthy Volunteers and 3) A two-period crossover study of single doses of PUR1900 and Sporanox in Adults with Asthma
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 1, 3-Part, Open-Label Study to Assess Safety, Tolerability and PK of Single and Multiple Doses of PUR1900 in Healthy Subjects and Crossover Study of Single Doses of PUR1900 and Sporanox in Adult Subjects With Mild to Moderate Asthma
• Actual Study Start Date: February 9, 2018
• Actual Primary Completion Date: June 28, 2018
• Actual Study Completion Date: June 28, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1 single ascending dose; Intervention: drug Itraconzaole powder: single dose of 5mg, 10mg or 25 mg Other name: PUR1900	Drug: Itraconazole Powder; Itraconazole administered as a dry powder for inhalation (PUR1900); Other Name: PUR1900
Experimental: Part 2 multiple ascending dose; Intervention: drug Itraconzaole powder: 10 mg or 20 mg daily for 14 days Other name: PUR1900	Drug: Itraconazole Powder; Itraconazole administered as a dry powder for inhalation (PUR1900); Other Name: PUR1900
Active Comparator: Part 3 2-period crossover single dose; Intervention: drug Itraconzaole powder: 20 mg single dose and Itraconzaole oral solution 200 mg single dose Other names: PUR1900, Sporanox	Drug: Itraconazole Powder; Itraconazole administered as a dry powder for inhalation (PUR1900); Other Name: PUR1900; Drug: Itraconazole 200 mg; Sporanox® Oral Solution; Other Name: Sporanox®

Outcome Measures

Primary Outcome Measures :

1. Number of participants with treatment-related Adverse Events as assessed by CTCAE v4.0 [ Time Frame: Part 1: Baseline through Day 14, Part 2 and 3: Baseline through Day 28 ]
   Safety and tolerability will be assessed by evaluating the number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Secondary Outcome Measures :

1. Area under the serum concentration vs time curve from time 0 to infinity (AUC0-inf) of single dose of itraconazole [ Time Frame: Part 1: Baseline through Day 14, Part 2 and 3: Baseline through Day 28 ]
   The area under the serum concentration vs time curve from time 0 to infinity (AUC0-inf)
2. Time of the maximum measured serum concentration (Tmax) of single dose of itraconazole [ Time Frame: Part 1: Baseline through Day 14, Part 2 and 3: Baseline through Day 28 ]
   Time of the maximum measured serum concentration (Tmax)
3. Area under the serum concentration vs time curve within the dosing interval (AUCtau) of single dose of itraconazole [ Time Frame: Part 1: Baseline through Day 14, Part 2 and 3: Baseline through Day 28 ]
   The area under the serum concentration vs time curve within the dosing interval (AUCtau)
4. Apparent first-order terminal elimination half-life (t1/2 ) of single dose of itraconazole [ Time Frame: Part 1: Baseline through Day 14, Part 2 and 3: Baseline through Day 28 ]
   Apparent first-order terminal elimination half-life (t1/2 )
5. Apparent first-order terminal elimination rate constant calculated from a semi-log plot of the serum concentration vs time curve (Kel) of single dose of itraconazole [ Time Frame: Part 1: Baseline through Day 14, Part 2 and 3: Baseline through Day 28 ]
   Apparent first-order terminal elimination rate constant calculated from a semi-log plot of
6. Apparent clearance (CL/F) of single dose of itraconazole [ Time Frame: Part 1: Baseline through Day 14, Part 2 and 3: Baseline through Day 28 ]
   Apparent clearance (CL/F)
7. Apparent volume of distribution (Vz/F) of single dose of itraconazole [ Time Frame: Part 1: Baseline through Day 14, Part 2 and 3: Baseline through Day 28 ]
   Apparent volume of distribution (Vz/F)

Other Outcome Measures:

1. Maximum Concentration [Cmax] of itraconazole and hydroxyitraconazole in sputum [ Time Frame: Part 3: baseline through 28 days ]
   Exploratory objective: To characterize the concentrations of itraconazole in induced sputum after single doses of inhaled PUR1900 and oral Sporanox® solution in subjects with mild to moderate stable asthma
2. Area under the Curve [AUC] of itraconazole and hydroxyitraconazole in sputum [ Time Frame: Part 3: baseline through 28 days ]
   Exploratory objective: To characterize the concentrations of itraconazole in induced sputum after single doses of inhaled PUR1900 and oral Sporanox® solution in subjects with mild to moderate stable asthma

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

Part 1 (SAD) and Part 2 (MAD):

1. Healthy males or non-pregnant, non-lactating healthy females.
2. Age 18 to 60 years
3. Screening forced expiratory volume in 1 sec (FEV1) ≥80% of the predicted value
4. Screening FEV1/forced vital capacity (FVC) >0.70.
5. Able to demonstrate the correct inhalation technique for use of delivery device during the study.

Part 3 (Asthmatic Subjects):

1. Males or non-pregnant, non-lactating females with a physician-confirmed diagnosis of asthma for at least 3 months. Asthma must be assessed by investigator as being stable for at least 4 weeks prior to screening.
2. Age 18 to 60 years
3. Subject is being treated with either inhaled corticosteroids (ICS) or inhaled corticosteroids plus long-acting beta-agonists (ICS/LABA). Only GINA STEP 2 and 3 patients will be enrolled.
4. Pre-bronchodilator, clinic measured, FEV1 ≥70% of predicted normal at screening
5. Able to perform the required spirometric testing.
6. Able to produce a sputum sample of a quality required for drug concentration assessments (a single repeat is permitted).

Exclusion Criteria:

1. Subjects who have received any IMP in a clinical research study within the previous 3 months prior to dosing on this study
2. Subjects who have previously received IMP in this study. Subjects who have participated in Part 1 are not permitted to participate in Part 2 or Part 3.
3. History of any drug or alcohol abuse in the past 2 years prior to screening.
4. Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months
5. Females of childbearing potential who are pregnant or lactating, or who plan to become pregnant during the study (all female subjects must have a negative pregnancy test at screening). A woman is considered of childbearing potential unless she is permanently sterile (hysterectomy, bilateral salpingectomy, bilateral oophorectomy, bilateral tubal occlusion/ligation) or is postmenopausal (had no menses for 12 months without an alternative medical cause (will be re-assessed at admission/pre-dose).
6. Positive drugs of abuse test result at screening or admission
7. Subjects with congestive heart failure or a history of congestive heart failure
8. History of severe cough or bronchospasm upon inhalation of any dry powder inhalation product
9. Subjects who are taking or have taken any herbal remedies or CYP3A4 inducers in the 28 days prior to the first IMP administration
10. Upper respiratory tract infection (excluding otitis media), fever, acute or chronic cough within 14 days of the first IMP administration, or lower respiratory tract infection within the last 3 months prior to IMP administration
11. Recent (last 4 weeks prior to IMP administration) clinically significant bacterial, viral or fungal infection that required systemic (oral or intravenous) antibiotics, antivirals or antifungals; topical treatments, other than antifungals, are allowed.

Contacts and Locations

Locations

United Kingdom

Medicines Evaluation Unit

Manchester, United Kingdom

Quotient Sciences

Nottingham, United Kingdom

Sponsors and Collaborators

Pulmatrix Inc.

Investigators

• Study Director: James Roach, MD; Pulmatrix Inc.

More Information

• Responsible Party: Pulmatrix Inc.
• ClinicalTrials.gov Identifier: NCT03479411
• Other Study ID Numbers: 601-0013
• First Posted: March 27, 2018
• Last Update Posted: July 27, 2018
• Last Verified: July 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

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

Additional relevant MeSH terms:

Asthma; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Itraconazole; Hydroxyitraconazole; 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