Clinical trial NCT05830071: A Thorough QT (TQT) Study of CHF5993 pMDI in Healthy Volunteers (HV)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Asthma
Chronic Obstructive Pulmonary Disease (COPD)
Lead sponsor: Chiesi Farmaceutici S.p.A.
Sponsor class: INDUSTRY
First posted: 2023-04-26
Enrollment: 95
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Effect of BDP/FF/GB pMDI at therapeutic dose on the heart rate-corrected QT interval based on the Fridericia's correction (QTcF).
timeFrame: time 0 (pre-dose) to 24 hours
Secondary outcomes:
measure: 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).
timeFrame: time 0 (pre-dose) to 24 hours
measure: Assay sensitivity by demonstrating the effect of a single oral therapeutic dose of moxifloxacin on QTcF.
timeFrame: time 0 (pre-dose) to 6 hours
measure: Effect of BDP/FF/GB pMDI at therapeutic and supra-therapeutic dose and of GB pMDI at supra-therapeutic dose on Hearth Rate (HR).
timeFrame: time 0 (pre-dose) to 24 hours
measure: Effect of BDP/FF/GB pMDI at therapeutic and supra-therapeutic dose and of GB pMDI at supra-therapeutic dose on PR interval (PR).
timeFrame: time 0 (pre-dose) to 24 hours
measure: Effect of BDP/FF/GB pMDI at therapeutic and supra-therapeutic dose and of GB pMDI at supra-therapeutic dose on QRS interval (QRS).
timeFrame: time 0 (pre-dose) to 24 hours
measure: 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)
timeFrame: time 0 (pre-dose) to 24 hours
measure: Effect of moxifloxacin at therapeutic dose on individual-corrected QT interval.
timeFrame: time 0 (pre-dose) to 6 hours
measure: Changes in T-wave morphology and U-wave presence.
timeFrame: time 0 (pre-dose) to 24 hours
measure: 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.
timeFrame: time 0 (pre-dose) to 24 hours
measure: Analysis of Maximum plasma concentration (Cmax), pharmacokinetic parameter of FF, GB, BDP and B17MP
timeFrame: time 0 (pre-dose) to 24 hours
measure: Analysis of Area under the curve from 0 to 12 hours post-dose (AUC0-12), pharmacokinetic parameter of FF, GB, BDP and B17MP
timeFrame: time 0 (pre-dose) to 24 hours
measure: 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
timeFrame: time 0 (pre-dose) to 24 hours
measure: Analysis of Area under the curve from time 0 to infinity (AUC0-∞), pharmacokinetic parameter of FF, GB, BDP and B17MP
timeFrame: time 0 (pre-dose) to 24 hours
measure: Analysis of Time to maximum plasma concentration (tmax), pharmacokinetic parameter of FF, GB, BDP and B17MP
timeFrame: time 0 (pre-dose) to 24 hours
measure: Analysis of Terminal half-life (t1/2), pharmacokinetic parameter of FF, GB, BDP and B17MP
timeFrame: time 0 (pre-dose) to 24 hours
measure: Incidence of Adverse events
timeFrame: from study start through study completion, an average of 4 months
measure: Incidence of Adverse Drug Reactions
timeFrame: from study start through study completion, an average of 4 months
measure: Change of systolic and diastolic blood pressure
timeFrame: from study start through study completion, an average of 4 months
measure: Body temperature abnormal values
timeFrame: from study start through study completion, an average of 4 months
measure: Abnormal results of physical examinations
timeFrame: from study start through study completion, an average of 4 months
measure: Abnormal clinical chemistry and haematology laboratory tests
timeFrame: from study start through study completion, an average of 4 months
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: PAREXEL Baltimore Early Phase Clinical Unit
state: Maryland
Study officials:
affiliation: PAREXEL Baltimore Early Phase Clinical Unit
name: Ronald Goldwater, MDCM/M.SC(A)
role: PRINCIPAL_INVESTIGATOR
References: