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
Overview
- Phase
- Phase 1
- Intervention
- CHF5993
- Conditions
- Asthma
- Sponsor
- Chiesi Farmaceutici S.p.A.
- Enrollment
- 95
- Locations
- 1
- Primary Endpoint
- Effect of BDP/FF/GB pMDI at therapeutic dose on the heart rate-corrected QT interval based on the Fridericia's correction (QTcF).
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
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.
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;
Arms & Interventions
Single therapeutic dose of CHF5993 (BDP/FF/GB)
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)
Intervention: CHF5993
Single therapeutic dose of CHF5993 (BDP/FF/GB)
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)
Intervention: CHF5993 Placebo
Single supra-therapeutic dose of CHF5993 (BDP/FF/GB)
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)
Intervention: CHF5993
Single supra-therapeutic dose CHF5259 (GB)
Dose: GB 100 μg single dose inhalation, via pressurized metered dose inhaler (8 puffs from 4 GB 12.5 μg pMDI)
Intervention: CHF5259
Single dose Placebo
Dose: placebo single dose inhalation, via pressurized metered dose inhaler 8 puffs from 4 CHF5993 placebo pMDI
Intervention: CHF5993 Placebo
Moxifloxacin
Dose: moxifloxacin 400 mg single dose, for oral use - open label treatment (1 tablet of moxifloxacin 400 mg PO)
Intervention: Moxifloxacin 400mg
Outcomes
Primary Outcomes
Effect of BDP/FF/GB pMDI at therapeutic dose on the heart rate-corrected QT interval based on the Fridericia's correction (QTcF).
Time Frame: time 0 (pre-dose) to 24 hours
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.
Secondary Outcomes
- Assay sensitivity by demonstrating the effect of a single oral therapeutic dose of moxifloxacin on QTcF.(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).(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)(time 0 (pre-dose) to 24 hours)
- Effect of moxifloxacin at therapeutic dose on individual-corrected QT interval.(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 PR interval (PR).(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).(time 0 (pre-dose) to 24 hours)
- Changes in T-wave morphology and U-wave presence.(time 0 (pre-dose) to 24 hours)
- Analysis of Maximum plasma concentration (Cmax), pharmacokinetic parameter of FF, GB, BDP and B17MP(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(time 0 (pre-dose) to 24 hours)
- Analysis of Terminal half-life (t1/2), pharmacokinetic parameter of FF, GB, BDP and B17MP(time 0 (pre-dose) to 24 hours)
- Incidence of Adverse Drug Reactions(from study start through study completion, an average of 4 months)
- 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).(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(time 0 (pre-dose) to 24 hours)
- Analysis of Time to maximum plasma concentration (tmax), pharmacokinetic parameter of FF, GB, BDP and B17MP(time 0 (pre-dose) to 24 hours)
- Change of systolic and diastolic blood pressure(from study start through study completion, an average of 4 months)
- Body temperature abnormal values(from study start through study completion, an average of 4 months)
- Abnormal results of physical examinations(from study start through study completion, an average of 4 months)
- 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.(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(time 0 (pre-dose) to 24 hours)
- Incidence of Adverse events(from study start through study completion, an average of 4 months)
- Abnormal clinical chemistry and haematology laboratory tests(from study start through study completion, an average of 4 months)