A Thorough QT (TQT) Study of CHF5993 pMDI in Healthy Volunteers (HV)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the potential for cardiac repolarization, according to electrocardiographic monitoring (including QT and QTc intervals), of two dose levels of CHF5993 pMDI (beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB)) and of one dose of CHF5259 (GB) in healthy subjects compared to moxifloxacin and placebo.

Detailed Description
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The main purpose of this study is to evaluate the effect of a single supratherapeutic dose of inhaled BDP/FF/GB on cardiovascular safety. The secondary purposes of the study are to: 1) evaluate the effect of a single supratherapeutic dose of inhaled BDP/FF/GB and GB on cardiovascular safety; 2) establish assay sensitivity by demonstrating the effect of a single oral dose of 400 mg moxifloxacin on cardiovascular safety; 3) determine the pharmacokinetics (PK) of single, inhaled therapeutic and supratherapeutic BDP/FF/GB doses and supratherapeutic GB dose; 4) determine if there is a relationship between the duration of the QTc intervals and the plasma concentrations of the B17MP (beclomethasone 17monopropionate active metabolite of BDP), FF and GB following the administration of BDP/FF/GB and GB pMDIs; 5) generate additional safety and tolerability information.

Official Title
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A Randomized, Double-blind, Positive and Placebo-controlled, Single-dose, Crossover Study of the Effects of CHF5993 pMDI (BDP/FF/GB) at the Proposed Therapeutic and Supratherapeutic Doses, on the Cardiovascular Safety in Healthy Subjects

Conditions
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Asthma, Chronic Obstructive Pulmonary Disease (COPD)

Intervention / Treatment
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* Drug: CHF5993
* Drug: CHF5259
* Drug: Moxifloxacin 400mg
* Drug: CHF5993 Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Subject's written informed consent; 18-55 years of age; Ability to understand the study procedures, the risks involved and ability to be trained to use the inhalers correctly; Body Mass Index (BMI) between 18 and 32 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, determined on the basis of the medical history and a general clinical examination; Vital signs within normal limits at screening and prior to randomization: Diastolic BP 40-89 mmHg, Systolic BP 90-139 mmHg extremes included (mean value of three measures). Body temperature < 37.5°C; 12 -lead digitized Electrocardiogram (12-lead ECG) in triplicate considered as normal (40 ≤ Heart rate ≤ 110bpm, 120 ms ≤ PR ≤ 220 ms, QRS ≤ 110 ms, QTcF ≤ 450 ms); Lung function measurements within normal limits (normal values: forced expiratory volume in the 1st second [FEV1]/forced vital capacity [FVC] > 0.70 and FEV1 > 80% predicted); Female subjects of non-child bearing potential or females of child bearing potential with negative pregnancy test; and acceptable contraceptive methods. Key Exclusion Criteria: Participation in another clinical trial where investigational drug was received and last investigations within the last 8 weeks; Clinically significant abnormal standard ECG at screening; Clinically relevant and uncontrolled respiratory, cardiac, hepatic, gastrointestinal, renal, endocrine, metabolic, neurologic, or psychiatric disorders that may interfere with successful completion of this protocol; Subjects with medical diagnosis of narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that in the opinion of the investigator would prevent use of anticholinergic; Subjects with history of breathing problems (i.e., history of asthma including childhood asthma); Positive urine test for cotinine; Intake of non-permitted concomitant medications in the predefined period prior to screening or prior to randomization, or the subject is expected to take non-permitted concomitant medications during the study; Presence of any current infection, or previous infection that resolved less than 7 days prior to screening or to randomization; Known intolerance and/or hypersensitivity to any of the excipients contained in the formulation used in the trial; Women who are pregnant or lactating; Use of any kind of smoking electronic devices within 6 months before Screening. Other inclusion/exclusion criteria as defined by the protocol.

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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single therapeutic dose of CHF5993 (BDP/FF/GB)<br>Dose: BDP/FF/GB 100/6/12.5 μg, single dose inhalation via pressurized metered dose inhaler (2 puffs from 1 BDP/FF/GB 100/6/12.5 μg pMDI + 2 puffs from 3 placebo pMDI) | Drug: CHF5993<br>* BDP/FF/GB 100/6/12.5 μg pMDI<br>* Other names: BDP/FF/GB;Drug: CHF5993 Placebo<br>* placebo pMDI<br>* Other names: BDP/FF/GB Placebo;|
| Experimental: Single supra-therapeutic dose of CHF5993 (BDP/FF/GB)<br>Dose: BDP/FF/GB 800/48/100 μg single dose inhalation, via pressurized metered dose inhaler (8 puffs from 4 BDP/FF/GB 100/6/12.5 μg pMDI) | Drug: CHF5993<br>* BDP/FF/GB 100/6/12.5 μg pMDI<br>* Other names: BDP/FF/GB;|
| Experimental: Single supra-therapeutic dose CHF5259 (GB)<br>Dose: GB 100 μg single dose inhalation, via pressurized metered dose inhaler (8 puffs from 4 GB 12.5 μg pMDI) | Drug: CHF5259<br>* GB 12.5 μg pMDI<br>* Other names: GB;|
| Placebo Comparator: Single dose Placebo<br>Dose: placebo single dose inhalation, via pressurized metered dose inhaler 8 puffs from 4 CHF5993 placebo pMDI | Drug: CHF5993 Placebo<br>* placebo pMDI<br>* Other names: BDP/FF/GB Placebo;|
| Active Comparator: Moxifloxacin<br>Dose: moxifloxacin 400 mg single dose, for oral use - open label treatment (1 tablet of moxifloxacin 400 mg PO) | Drug: Moxifloxacin 400mg<br>* 400 mg Oral Tablets<br>* Other names: Moxifloxacin hydrochloride;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of BDP/FF/GB pMDI at therapeutic dose on the heart rate-corrected QT interval based on the Fridericia's correction (QTcF). | Placebo-adjusted change in QTc interval based on the Fridericia's correction (ΔΔQTcF) after dosing CHF5993 pMDI (200/12/25 μg). Through digitised 12-lead ECG, extracted from 12-Lead Holter ECG. | time 0 (pre-dose) to 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of BDP/FF/GB pMDI and GB pMDI at supra-therapeutic dose on the heart rate-corrected QT interval based on the Fridericia's correction (QTcF). | Placebo-adjusted change from baseline in QTc interval based on the Fridericia's correction (ΔΔQTcF) after dosing CHF5993 pMDI (800/48/100 μg) and GB pMDI (100 μg). Through digitised 12-lead ECG, extracted from 12-Lead Holter ECG. | time 0 (pre-dose) to 24 hours | 
| Assay sensitivity by demonstrating the effect of a single oral therapeutic dose of moxifloxacin on QTcF. | Placebo-adjusted change from baseline in QTc interval based on the Fridericia's correction (ΔΔQTcF) after dosing 400 mg of moxifloxacin. Through digitised 12-lead ECG, extracted from 12-Lead Holter ECG | time 0 (pre-dose) to 6 hours | 
| Effect of BDP/FF/GB pMDI at therapeutic and supra-therapeutic dose and of GB pMDI at supra-therapeutic dose on Hearth Rate (HR). | Placebo-adjusted change from baseline of HR (ΔΔHR) after dosing BDP/FF/GB pMDI (200/12/25 μg and 800/48/100 μg) and GB pMDI (100 μg) will be summarized by means of descriptive statistics at each analysis time point and by treatment. Through digitised 12-lead ECG, extracted from 12-Lead Holter ECG. | time 0 (pre-dose) to 24 hours | 
| Effect of BDP/FF/GB pMDI at therapeutic and supra-therapeutic dose and of GB pMDI at supra-therapeutic dose on PR interval (PR). | Placebo-adjusted change from baseline of PR (ΔΔPR) after dosing BDP/FF/GB pMDI (200/12/25 μg and 800/48/100 μg) and GB pMDI (100 μg) will be summarized by means of descriptive statistics at each analysis time point and by treatment. Through digitised 12-lead ECG, extracted from 12-Lead Holter ECG. | time 0 (pre-dose) to 24 hours | 
| Effect of BDP/FF/GB pMDI at therapeutic and supra-therapeutic dose and of GB pMDI at supra-therapeutic dose on QRS interval (QRS). | Placebo-adjusted change from baseline of QRS (ΔΔQRS) after dosing BDP/FF/GB pMDI (200/12/25 μg and 800/48/100 μg) and GB pMDI (100 μg) will be summarized by means of descriptive statistics at each analysis time point and by treatment. Through digitised 12-lead ECG, extracted from 12-Lead Holter ECG. | time 0 (pre-dose) to 24 hours | 
| Effect of BDP/FF/GB pMDI at therapeutic and supra-therapeutic dose and of GB pMDI at supra-therapeutic dose on individual-corrected QT interval (QTcI) | Placebo-adjusted change from baseline in individual-corrected QT interval (ΔΔQTcI) after dosing BDP/FF/GB pMDI (200/12/25 μg and 800/48/100 μg) and GB pMDI (100 μg). Through digitised 12-lead ECG, extracted from 12-Lead Holter ECG. | time 0 (pre-dose) to 24 hours | 
| Effect of moxifloxacin at therapeutic dose on individual-corrected QT interval. | Placebo-adjusted change from baseline in individual-corrected QT interval (ΔΔQTcI) after dosing 400 mg of moxifloxacin. Through digitised 12-lead ECG, extracted from 12-Lead Holter ECG. | time 0 (pre-dose) to 6 hours | 
| Changes in T-wave morphology and U-wave presence. | Frequency of treatment-emergent changes in T-wave morphology and U-wave presence after dosing BDP/FF/GB pMDI (200/12/25 μg and 800/48/100 μg) and GB pMDI (100 μg). Through digitised 12-lead ECG, extracted from 12-Lead Holter ECG. | time 0 (pre-dose) to 24 hours | 
| Analysis of categorical outliers of Hearth Rate (HR), PR interval (PR), QRS interval (QRS) and QTcF interval (QTcF), after BDP/FF/GB pMDI dosing at therapeutic and supra-therapeutic dose, and after GB dosing at supra-therapeutic dose. | Results of categorical outliers will be summarized by treatment in frequency tables reporting: counts and percentages for number of subjects and number of time points with 1) abnormal actual QTcF values, and 2) abnormal change from baseline of HR, PR, QRS and QTcF. Through digitised 12-lead ECG, extracted from 12-Lead Holter ECG. | time 0 (pre-dose) to 24 hours | 
| Analysis of Maximum plasma concentration (Cmax), pharmacokinetic parameter of FF, GB, BDP and B17MP | Analysis of Cmax after dosing BDP/FF/GB pMDI (200/12/25 μg and 800/48/100 μg) and GB pMDI (100 μg). | time 0 (pre-dose) to 24 hours | 
| Analysis of Area under the curve from 0 to 12 hours post-dose (AUC0-12), pharmacokinetic parameter of FF, GB, BDP and B17MP | Analysis of AUC0-12, after dosing BDP/FF/GB pMDI (200/12/25 μg and 800/48/100 μg) and GB pMDI (100 μg). | time 0 (pre-dose) to 24 hours | 
| Analysis of Area under the plasma concentration-time curve from time 0 to time t (AUC0 t), pharmacokinetic parameter of FF, GB, BDP and B17MP | Analysis of AUC0-t after dosing BDP/FF/GB pMDI (200/12/25 μg and 800/48/100 μg) and GB pMDI (100 μg). | time 0 (pre-dose) to 24 hours | 
| Analysis of Area under the curve from time 0 to infinity (AUC0-∞), pharmacokinetic parameter of FF, GB, BDP and B17MP | Analysis of AUC0-∞ after dosing BDP/FF/GB pMDI (200/12/25 μg and 800/48/100 μg) and GB pMDI (100 μg). | time 0 (pre-dose) to 24 hours | 
| Analysis of Time to maximum plasma concentration (tmax), pharmacokinetic parameter of FF, GB, BDP and B17MP | Analysis of tmax, after dosing BDP/FF/GB pMDI (200/12/25 μg and 800/48/100 μg) and GB pMDI (100 μg). | time 0 (pre-dose) to 24 hours | 
| Analysis of Terminal half-life (t1/2), pharmacokinetic parameter of FF, GB, BDP and B17MP | Analysis of t1/2, after dosing BDP/FF/GB pMDI (200/12/25 μg and 800/48/100 μg) and GB pMDI (100 μg). | time 0 (pre-dose) to 24 hours | 
| Incidence of Adverse events | Number and percentage of subjects with at least one event and number of treatment emergent events | from study start through study completion, an average of 4 months | 
| Incidence of Adverse Drug Reactions | Number and percentage of subjects with at least one event and number of treatment emergent events | from study start through study completion, an average of 4 months | 
| Change of systolic and diastolic blood pressure | Number and percentage of subjects with with abnormal changes from baseline | from study start through study completion, an average of 4 months | 
| Body temperature abnormal values | Number and percentage of subjects with at least one event and number of treatment emergent events | from study start through study completion, an average of 4 months | 
| Abnormal results of physical examinations | Number and percentage of subjects with at least one event and number of treatment emergent events | from study start through study completion, an average of 4 months | 
| Abnormal clinical chemistry and haematology laboratory tests | Number and percentage of subjects with at least one event and number of treatment emergent events | from study start through study completion, an average of 4 months |