Investigation of the Effect of Inhibition of CYP3A4/5 by Itraconazole on the PK of CHF6001 (Tanimilast)

Study Overview
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Brief Summary
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The objective of this proposed study is to investigate the pharmacokinetics interaction between CHF6001 as substrate and Itraconazole as inhibitor of CYP3A4/5 in a drug-drug interaction study.

Detailed Description
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This clinical trial is a single centre, single dose Phase I study, with a non-randomized, open label, one sequence cross-over design. A total of 24 healthy male and female are planned to be included. Participants will be dosed with CHF6001 before and during co-administration of Itraconazole and will act as their own control. The study will be run with a one-sequence crossover design, where all subjects will be treated with CHF6001 in the first treatment period and CHF6001+Itraconazole in the second treatment period in order to avoid the need of a very long washout from the CYP3A4/5 inhibitor. Standard safety assessments will be conducted during the Study, including safety blood and urine laboratory tests, vital signs, physical examinations, ECGs and observations of any adverse events. Blood samples will be also collected for PK analysis.

Official Title
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Open-label, Non-randomized, One Sequence Cross-over Study to Investigate the Effect of Inhibition of CYP3A4/5 by Itraconazole on the Pharmacokinetics of CHF6001 in Healthy Subjects

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: CHF6001 DPI
* Drug: Itraconazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject's written informed consent obtained prior to any study-related procedure; Healthy male and female subjects aged 18-55 years inclusive; Ability to understand the study procedures, the risks involved and ability to be trained to use the inhalers correctly and to generate sufficient PIF using the In-Check device. Body Mass Index (BMI) between 18,0 and 35,0 kg/m2 extremes inclusive; Non- or ex-smokers who smoked < 5 pack years and stopped smoking > 1 year prior to screening; Good physical and mental status Vital signs within normal limits 12 -lead digitalized Electrocardiogram (12-lead ECG) considered as normal Pulmonary function test within normal limits Women of Childbearing Potential (WOCBP) with fertile male partners: they and/or their partner must be willing to use a highly effective birth control method in addition to a barrier contraception method from the signature of the informed consent and until the follow-up visit. Males with non-pregnant WOCBP partners: they and or/ their partner must be willing to use a highly effective birth control method in addition to the male condom from the signature of the informed consent and until the follow-up visit. Males with pregnant WOCBP partner: they must be willing to use male contraception (condom) from the signature of the informed consent and until the follow-up visit Exclusion Criteria: Participation to another clinical trial where investigational drug was received, and last investigations were performed less than 8 weeks prior to screening; Clinically relevant and uncontrolled respiratory, cardiac, hepatic, gastrointestinal, renal, endocrine, metabolic, neurologic, or psychiatric disorders, gastric surgery recent or in the past, and/or impaired gastric motility Clinically relevant abnormal laboratory values Abnormal liver enzymes at screening Subjects with history of breathing problems Positive HIV1 or HIV2 serology Positive results from the Hepatitis serology Blood donation or blood loss (equal or more than 450 ml) less than 2 months prior to screening or before the first dosing; Positive urine test for cotinine Documented history of alcohol abuse within 12 months prior to screening or a positive alcohol breath test Documented history of drug abuse within 12 months prior to screening or a positive urine drug screen Intake of non-permitted concomitant medications in the predefined period Presence of any current infection, or previous infection that resolved less than 7 days prior to screening or before the first dosing; Known intolerance and/or hypersensitivity to any of the excipients contained in the formulation used in the trial; Known allergy to antifungal medicines; Unsuitable veins for repeated venipuncture; Heavy caffeine drinker For females only: pregnant or lactating women. Serum pregnancy test to be performed at screening and urine pregnancy test to be performed before the first dosing; Subjects receiving treatment with any drug known to have a well-defined potential for hepatotoxicity (e.g. isoniazide, nimesulide, ketoconazole) within the previous 3 months before the screening visit Subjects using e-cigarettes within 6 months before screening. Positive documented COVID-19 test before admission

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: one sequence cross-over design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment R<br>Single dose of CHF6001 | Drug: CHF6001 DPI<br>* Single dose of CHF6001<br>|
| Experimental: Treatment T<br>Single dose of CHF6001 administered after repeated doses of oral Itraconazole | Drug: CHF6001 DPI<br>* Single dose of CHF6001<br>Drug: Itraconazole<br>* Repeated doses of oral Itraconazole<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic parameter (Cmax) | Peak Plasma Concentration (Cmax) for CHF6001 | Over 96 hours after administration in blood | 
| Pharmacokinetic parameter (AUCt) | Area under the plasma concentration versus time curve (AUCt) for CHF6001 | Over 96 hours after administration in blood | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic parameter (AUC0-96) | Area under plasma concentration from 0 to 96 hours (AUC0-96) for CHF6001, CHF5956 and CHF6095 | Over 96 hours after administration in blood | 
| Pharmacokinetic parameter (AUC0-∞) | Area under curve extrapolated to infinity (AUC0-∞) for CHF6001, CHF5956 and CHF6095 | Over 96 hours after administration in blood | 
| Pharmacokinetic parameter (tmax) | Time of the maximum plasma concentration (tmax) for CHF6001, CHF5956 and CHF6095 | Over 96 hours after administration in blood | 
| Pharmacokinetic parameter (t1/2) | Terminal half-life (t1/2) for CHF6001, CHF5956 and CHF6095 | Over 96 hours after administration in blood | 
| Pharmacokinetic parameter (CL/F) | Apparent systemic clearance (CL/F) for CHF6001 | Over 96 hours after administration in blood | 
| Pharmacokinetic parameter (AUCt) | Area under the plasma concentration versus time curve (AUCt) for CHF5956 and CHF6095 | Over 96 hours after administration in blood | 
| Pharmacokinetic parameter (Cmax) | Peak Plasma Concentration (Cmax) for CHF5956 and CHF6095 | Over 96 hours after administration in blood |