Clinical trial NCT04872231: Single Ascending Dose and Multiple Ascending Dose Study of Voriconazole Inhalation Powder in Healthy Adult Subjects
Official title: A Randomized, Double-Blind, Placebo Controlled, Single-Dose and Multiple Dose Dose-Ranging Study of Voriconazole Inhalation Powder in Healthy Adult Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: voriconazole
inhaled
VFEND
aspergillosis
IPA
fungal infection
pulmonary aspergillosis
Lead sponsor: TFF Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2021-05-04
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Part A: Eight (8) subjects will participate in each of the 4 dose escalations. Subjects will be randomized to receive either Voriconazole Inhalation Powder or placebo by inhalation (6 active, 2 placebo per group of 8).

Part B: Eight (8) subjects will participate in each of the 4 dose escalations. Subjects will be randomized to receive either Voriconazole Inhalation Powder or placebo by inhalation (6 active, 2 placebo per group of 8).
Primary purpose: BASIC_SCIENCE

Brief summary: This is a Phase 1 (healthy adult volunteers), 2-part, double-blind, randomized, placebo controlled trial to evaluate the safety and pharmacokinetic (PK) profiles of escalating single doses of Voriconazole Inhalation Powder versus placebo (SAD part) and escalating multiple doses of Voriconazole Inhalation Powder versus placebo (MAD part). SAD part will be initiated first and includes a sentinel design. MAD part will not utilize a sentinel design and will be initiated once the lowest doses from SAD part are deemed safe.

Detailed description: This is a Phase 1, randomized, 2 part double-blind, placebo-controlled trial to evaluate the safety and PK profiles of Voriconazole Inhalation Powder (VIP) in a SAD/MAD study design.

Part A is a double-blinded, placebo-controlled, randomized, dose- ranging single dose study evaluating four different dose levels.

On Day 1 of each group, two selected subjects (sentinel subjects) will receive either Voriconazole Inhalation Powder or a matching placebo. Blood and sputum samples and safety measurements including Adverse Events (AEs) will be collected over 24 hour period following the drug administration. The safety results to be evaluated include AEs, concomitant medications, out of specification clinical laboratory results, vital signs, Electrocardiograms (ECGs), visual examinations, pulmonary function tests, pulse oximetry results and any new findings on physical examinations. If the administration is safe as deemed by Principal Investigator \& Medical Monitor, the remaining six subjects will be dosed, with identical safety and PK procedures performed after minimum of 3 days interval. A minimum of 3 days will separate each dose escalation, with the remaining dose groups dosed in a sentinel fashion.

Part B is a double-blinded, placebo-controlled, randomized, dose- ranging multi-dose study evaluating four different dose levels. Dose level 1 of Part B can begin in parallel once safety assessments of Part A dose level 2 are complete and indicate safety is present. Voriconazole Inhalation Powder will be administered twice daily (BID) × 13 doses. Blood samples for safety and PK will be collected over 12 hours after the first dose and 24 hours after the last dose. A minimum of 1 week will separate the start of each dose escalation, with the remaining dose groups.

Eligibility criteria: Inclusion Criteria:

1. Provide written informed consent to participate.
2. Healthy, adult males or females (women of non-childbearing potential only).
3. Body mass index (BMI) ≥ 18.0 and ≤ 32.0 kg/m2 at Screening.
4. Medically healthy with no clinically significant abnormalities in medical history, physical and visual examination, laboratory profiles, vital signs or ECGs, as deemed by the PI or designee.
5. Agree to abstain from recreational drug use throughout the study.
6. Must be willing and able to comply with the protocol.
7. Succeed in training on the use of the device for maximum of 12 inhalations in total, with demonstration of at-least 8 successful inhalations of empty capsules during training.
8. Have had a forced expiratory volume in one second (FEV1) ≥80%.

Exclusion Criteria:

1. Is mentally or legally incapacitated or has significant emotional problems in the opinion of the PI.
2. History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the PI.
3. History of any illness that, in the opinion of the PI, might confound the results of the study or poses an additional risk to the subject by their participation in the study.
4. History or presence of alcoholism or drug abuse within the past 2 years.
5. History or presence of hypersensitivity or idiosyncratic reaction to voriconazole or any triazole antifungal.
6. Has had surgery or any medical condition within 6 months prior to first dosing which may affect the absorption, distribution, metabolism, or elimination of the study drug, in the opinion of the PI or designee.
7. Female subjects of childbearing potential.
8. Female subjects with a positive pregnancy test or who are lactating.
9. Positive urine drug or alcohol results at screening or first check-in.
10. Positive cotinine results at screening.
11. Diagnosis of asthma.
12. Use of albuterol or a similar bronchodilator
13. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV).
14. QTcF interval is \>450 msec or has ECG findings deemed abnormal with clinical significance by the PI at screening.
15. Seated blood pressure with systolic less than 90 mmHg or diastolic less than 60 mm/Hg or with a systolic greater than 140 mmHg or diastolic greater than 90 mmHg at screening.
16. Seated heart rate is lower than 60 bpm or higher than 100 bpm at screening.
17. Using any exclusionary medication.
18. Donation or loss of 50 to 499 mL whole blood within 30 days or more than 499 mL whole blood within 56 days prior to the first dosing.
19. Plasma donation within 7 days prior to the first dosing.
20. Has coagulation test outside of normal ranges.
21. Has platelet, hemoglobin, and hematocrit that are below the lower limit of normal.
22. Has liver function tests including alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALP and total bilirubin that are greater than the upper limit of normal. Estimated creatinine clearance \<90 mL/min at screening.
23. Participation in another clinical study within 30 days prior to the first dosing.
24. Had a treatment with other investigational drug within 5 times the elimination half- life, if known (e.g., a marketed product) or within 30 days (if the elimination half-life is unknown) prior to first dosing.
25. Demonstrates an inability to operate the inhalation device after training.
26. Allergy or sensitivity to lactose or milk products.

Primary outcomes:
measure: Number of participants who experience Adverse Events (AEs), Serious Adverse Events (SAEs) and withdrawals due to AEs
timeFrame: Through study completion, an average of 14 days
measure: Number of participants who experience vital sign abnormalities
timeFrame: Baseline through study completion, an average of 14 days
measure: Number of participants who experience pulse oximetry abnormalities
timeFrame: Baseline through study completion, an average of 14 days
measure: Mean change from baseline in forced expiratory volume (FEV1)
timeFrame: Baseline through study completion, an average of 14 days
measure: Mean change from baseline in forced vital capacity (FVC)
timeFrame: Baseline through study completion, an average of 14 days
measure: Mean change from baseline in FEV1/FVC ratio
timeFrame: Baseline through study completion, an average of 14 days
measure: Mean change from baseline in QTcF changes via ECG
timeFrame: Baseline through study completion, an average of 14 days
measure: Number of participants who experience physical examination abnormalities
timeFrame: Baseline through study completion, an average of 14 days
measure: Number of participants who experience laboratory test abnormalities
timeFrame: Baseline through study completion, an average of 14 days
measure: PK of VIP in plasma: Area under the plasma-concentration time curve (AUC)
timeFrame: Predose Day 1 and through 12 hours post last dose (day 6)
measure: PK of VIP in plasma: Area under the concentration time curve, from time 0 to the last observed non-zero concentration (AUC0-tlast)
timeFrame: Predose Day 1 and through 12 hours post last dose (day 6)
measure: PK of VIP in plasma: Maximum observed concentration (Cmax)
timeFrame: Predose Day 1 and through 12 hours post last dose (day 6)
measure: PK of VIP in plasma: Time to maximal observed concentration (tmax)
timeFrame: Predose Day 1 and through 12 hours post last dose (day 6)
measure: PK of VIP in plasma: Area under the plasma-concentration time curve over the first 12 hours after dosing (AUC0-12)
timeFrame: Predose Day 1 and through 12 hours post last dose (day 6)
measure: PK of VIP in plasma: Area under the concentration time curve from time 0 extrapolated to infinity (AUC∞)
timeFrame: Predose Day 1 and through 12 hours post last dose (day 6)
measure: PK of VIP in plasma: Termination elimination half-life (t½)
timeFrame: Predose Day 1 and through 12 hours post last dose (day 6)
measure: PK of VIP in plasma: Apparent total body clearance (CL/F)
timeFrame: Predose Day 1 and through 12 hours post last dose (day 6)
measure: PK of VIP in plasma: Apparent volume of distribution during the terminal elimination phase (Vz/F)
timeFrame: Predose Day 1 and through 12 hours post last dose (day 6)
Secondary outcomes:
Other outcomes:
Locations:
city: Mississauga
country: Canada
facility: Cliantha Research
state: Ontario
Study officials:
affiliation: TFF Pharmaceuticals
name: Dale Christensen, PhD
role: STUDY_DIRECTOR
References: