Clinical trial NCT03084796: A 6-week Dose Ranging Study of CHF 5259 pMDI in Subjects With Chronic Obstructive Pulmonary Disease
Official title: A 6-week, Multicenter, Randomized, Double-blind, Placebo and Active-controlled, Parallel Group, Dose-ranging Study to Evaluate the Efficacy and Safety of 4 Doses of CHF 5259 pMDI (HFA Glycopyrronium Bromide Via Pressurized Metered Dose Inhaler) in Subjects With Chronic Obstructive Pulmonary Disease (COPD)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: COPD
Chronic Obstructive Pulmonary Disease
Keywords: CHF 5259
Chronic Obstructive Pulmonary Disease (COPD)
pMDI (pressurized metered dose inhaler)
GLIMMER
Lead sponsor: Chiesi Farmaceutici S.p.A.
Sponsor class: INDUSTRY
First posted: 2017-03-21
Enrollment: 733
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: The purpose of this study is to evaluate the dose-response of different doses of CHF 5259 pMDI on lung function and other clinical outcomes, to identify the optimal dose(s) in terms of benefit/ risk ratio for further development in the target subject population.

Detailed description: This is a phase II, multicenter, randomized, double-blind, placebo and active controlled dose-ranging 6-arm parallel group study to identify the optimal dose of CHF 5259 pMDI (pressurized metered dose inhaler) with respect to lung function as well as other clinical efficacy and safety outcomes.

After a 2 week run-in period under rescue albuterol and background inhaled corticosteroid (ICS) as needed, patients were randomized to one of the 6 study treatment groups. Following randomization, subjects were assessed after 3 weeks and 6 weeks of study treatment at the study center. A follow-up phone was performed a week after the last visit.

During the study, daily symptoms, rescue and background medication use and compliance with the study drug were recorded in a subject diary. Treatment-Emergent Adverse Events (TEAEs) were assessed and recorded throughout the study. At screening and subsequent visits, subjects underwent physical and vital signs examinations, spirometry measurements, and 12-lead electrocardiogram (ECG). Symptoms and chronic obstructive pulmonary disease (COPD) health status were assessed through validated questionnaires. Routine hematology, blood chemistry, and pregnancy testing were performed before enrollment and at end of study. 24-hour (24-H) digital recording of ECGs (Holter) was performed before and after the first dose and just before the last dose of study treatment.

Eligibility criteria: Inclusion Criteria:

* Male or female subjects aged ≥ 40 who have signed an Informed Consent Form prior to initiation of any study-related procedure.
* Subjects with a diagnosis of COPD (according to GOLD 2017 Global Strategy for the Diagnosis, Management and Prevention of COPD Report) at least 12 months before the screening visit.
* Current smokers or ex-smokers who quit smoking at least 6 months prior to screening visit, with a smoking history of at least 10 pack years
* A post-bronchodilator forced expiratory volume in the 1st second (FEV1) ≥50% and \<80% of the predicted normal value and,
* a post-bronchodilator FEV1/ Forced Vital Capacity (FVC) \< 0.7 at screening and
* a demonstrated reversibility to ipratropium defined as ΔFEV1 ≥ 5% over baseline 30-45 minutes after inhaling 4 puffs of ipratropium
* Subjects under regular COPD therapy for at least 2 months prior to screening with either inhaled long-acting muscarinic antagonist (LAMA), inhaled ICS/ long-acting β2-agonist (LABA), inhaled ICS + LAMA
* Symptomatic subjects at screening with a CAT score ≥10. This criterion must be confirmed at randomization
* Symptomatic subjects with a BDI focal score ≤ 10. This criterion must be confirmed at randomization
* A cooperative attitude and ability to demonstrate correct use of the inhalers and e-diary.

Exclusion Criteria:

* Pregnant or lactating women and all women physiologically capable of becoming pregnant UNLESS they are willing to use highly effective birth control methods
* Diagnosis of asthma or Asthma-COPD Overlap Syndrome (ACOS) as described in global initiative for asthma (GINA) Report 2016, history of allergic rhinitis or atopy (atopy which may raise contra-indications or impact the efficacy of the study treatment according to Investigator's judgment)
* COPD Exacerbations: a moderate or severe COPD exacerbation that has not resolved ≤14 days prior to screening and ≤30 days following the last dose of any oral/systemic corticosteroid or antibiotic (whichever comes last). A Moderate or Severe COPD exacerbation during the run-in period
* Use of antibiotics for a lower respiratory tract infection in the 4 weeks prior to screening or during run-in
* Subjects treated with non-cardio-selective β-blockers in the month preceding screening or during the run-in period
* Subjects treated with long-acting anti-histamines unless taken at stable regimen at least 2 months prior to screening and to be maintained constant during the study, or if taken as needed
* Subjects requiring long term (at least 12 hours daily) oxygen therapy for chronic hypoxemia
* Known respiratory disorders other than COPD which may impact the efficacy of the study treatment according the Investigator's judgment.
* Subjects who have clinically significant cardiovascular condition
* Subjects who have a clinically significant abnormal 12-lead ECG that results in active medical problem which may impact the safety of the subject according to Investigator's judgement
* Subjects whose 12-lead ECG shows Fridericia corrected QT interval (QTcF) \>450 ms for males or QTcF \>470 ms for females at screening visit
* Medical diagnosis of narrow-angle glaucoma, clinically relevant prostatic hypertrophy or bladder neck obstruction that in the opinion of the Investigator would prevent use of anticholinergic agents
* History of hypersensitivity to M3 receptor antagonists, β2-adrenergic receptor agonist, corticosteroids or any of the excipients contained in any of the formulations used in the study which may raise contra-indications or impact the efficacy of the study treatment according to the Investigator's judgement
* Clinically significant laboratory abnormalities indicating a significant or unstable concomitant disease which may impact the efficacy or the safety of the study treatment according to Investigator's judgement
* Subjects with serum potassium levels \<3.5 mEq/L (or 3.5 mmol/L) at screening
* Use of potent cytochrome P450 2D6 and 3A4 inhibitors within 4 weeks prior to screening
* Unstable or uncontrolled concurrent disease; fever, endocrine disease, gastrointestinal disease; neurological disease; hematological disease; autoimmune disorders, or other which may impact the feasibility of the results of the study according to Investigator's judgment
* History of alcohol abuse and/or substance/drug abuse within 12 months prior to screening
* Subjects who have received an investigational drug within 1 month or 5 half-lives (whichever is greater) prior to screening visit, or have been previously randomized in this trial, or are currently participating in another clinical trial.
* Subjects who are mentally or legally incapacitated, or subjects accommodated in an establishment as a result of an official or judicial order.
* Subjects who have undergone major surgery in the 3 months prior to screening visit or have a planned surgery during the trial.

Primary outcomes:
measure: Change From Baseline in FEV1 AUC(0-12h) Normalized by Time at Week 6
timeFrame: Baseline, Week 6
Secondary outcomes:
measure: Change From Baseline in FEV1 AUC(0-12h) Normalized by Time on Day 1
timeFrame: Baseline, Day 1
measure: Change From Baseline in FEV1 AUC(0-4h) Normalized by Time on Day 1 and at Week 6
timeFrame: Baseline, Day 1, Week 6
measure: Change From Baseline in FEV1 Peak(0-4h) at Day 1 and Week 6
timeFrame: Baseline, Day 1, Week 6
measure: Change From Baseline in FVC AUC(0-12h), Normalized by Time on Day 1 and at Week 6
timeFrame: Baseline, Day 1, Week 6
measure: Change From Baseline in FVC AUC(0-4h) Normalized by Time on Day 1 and at Week 6
timeFrame: Baseline, Day 1, Week 6
measure: Change From Baseline in FVC Peak(0-4h) on Day 1 and at Week 6
timeFrame: Baseline, Day 1, Week 6
measure: Time to Onset of Action (Change From Baseline in Post-dose FEV1 ≥ 100 mL) on Day 1
timeFrame: Day 1
measure: Number of Patients Achieving Onset of Action - Change From Baseline in Post-dose FEV1 ≥100 mL on Day 1
timeFrame: Day 1
measure: Change From Baseline in Pre-dose Morning FEV1 at Week 3 and Week 6
timeFrame: Baseline, Week 3, Week 6
measure: Change From Baseline in Pre-Dose Morning Inspiratory Capacity (IC) at Week 3 and Week 6
timeFrame: Baseline, Week 3, Week 6
measure: Transition Dyspnea Index (TDI) Response (Focal Score ≥1) at Week 3 and Week 6
timeFrame: Baseline, Week 3, Week 6
measure: Transition Dyspnea Index (TDI) Focal Score at Week 3 and Week 6
timeFrame: Baseline, Week 3, Week 6
measure: Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period
timeFrame: Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period
measure: Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period
timeFrame: Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period
measure: Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period
timeFrame: Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period
measure: Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP)
timeFrame: Baseline, Day 1, Week 6
measure: Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR)
timeFrame: Baseline, Day 1, Week 6
measure: Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval
timeFrame: Baseline, Day 1, Week 6
measure: Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval
timeFrame: Baseline, Day 1, Week 6
measure: Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF)
timeFrame: Baseline, Day 1, Week 6
measure: 24-hour Holter ECG - Prolonged QTcF - Male Subjects
timeFrame: Baseline, Day 1, Week 6
measure: 24-hour Holter ECG - Prolonged QTcF - Female Subjects
timeFrame: Baseline, Day 1, Week 6
measure: 24-hour Holter ECG - Prolonged QTcF - Change From Baseline
timeFrame: Baseline, Day 1, Week 6
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Chiesi Investigational Site
state: Alabama
city: Dothan
country: United States
facility: Chiesi Investigational Site
state: Alabama
city: Montgomery
country: United States
facility: Chiesi Investigational Site
state: Alabama
city: Flagstaff
country: United States
facility: Chiesi Investigational Site
state: Arizona
city: Glendale
country: United States
facility: Chiesi Investigational Site
state: Arizona
city: Phoenix
country: United States
facility: Chiesi Investigational Site
state: Arizona
city: Phoenix
country: United States
facility: Chiesi Investigational Site
state: Arizona
city: Phoenix
country: United States
facility: Chiesi Investigational Site
state: Arizona
city: Surprise
country: United States
facility: Chiesi Investigational Site
state: Arizona
city: Tempe
country: United States
facility: Chiesi Investigational Site
state: Arizona
city: Tucson
country: United States
facility: Chiesi Investigational Site
state: Arizona
city: Anaheim
country: United States
facility: Chiesi Investigational Site
state: California
city: Escondido
country: United States
facility: Chiesi Investigational Site
state: California
city: Fullerton
country: United States
facility: Chiesi Investigational Site
state: California
city: Lincoln
country: United States
facility: Clinical Trials Research
state: California
city: Long Beach
country: United States
facility: Chiesi Investigational Site
state: California
city: Los Angeles
country: United States
facility: Chiesi Investigational Site
state: California
city: Los Angeles
country: United States
facility: Chiesi Investigational Site
state: California
city: Los Angeles
country: United States
facility: Chiesi Investigational Site
state: California
city: Newport Beach
country: United States
facility: Chiesi Investigational Site
state: California
city: San Diego
country: United States
facility: Chiesi Investigational Site
state: California
city: Tustin
country: United States
facility: Chiesi Investigational Site
state: California
city: Westminster
country: United States
facility: Chiesi Investigational Site
state: California
city: Boulder
country: United States
facility: Chiesi Investigational Site
state: Colorado
city: Centennial
country: United States
facility: Chiesi Investigational Site
state: Colorado
city: Denver
country: United States
facility: Chiesi Investigational Site
state: Colorado
city: Lafayette
country: United States
facility: Chiesi Investigational Site
state: Colorado
city: Brandon
country: United States
facility: Chiesi Investigational Site
state: Florida
city: Clearwater
country: United States
facility: Chiesi Investigational Site
state: Florida
city: Daytona Beach
country: United States
facility: Chiesi Investigational Site
state: Florida
city: Edgewater
country: United States
facility: Chiesi Investigational Site
state: Florida
city: Hialeah
country: United States
facility: Chiesi Investigational Site
state: Florida
city: Kissimmee
country: United States
facility: Chiesi Investigational Site
state: Florida
city: Miami
country: United States
facility: Chiesi Investigational Site
state: Florida
city: Miami
country: United States
facility: Chiesi Investigational Site
state: Florida
city: Miami
country: United States
facility: Chiesi Investigational Site
state: Florida
city: Miami
country: United States
facility: Chiesi Investigational Site
state: Florida
city: Orlando
country: United States
facility: Chiesi Investigational Site
state: Florida
city: Panama City
country: United States
facility: Chiesi Investigational Site
state: Florida
city: Blue Ridge
country: United States
facility: Chiesi Investigational Site
state: Georgia
city: Dacula
country: United States
facility: Chiesi Investigational Site
state: Georgia
city: Duluth
country: United States
facility: Chiesi Investigational Site
state: Georgia
city: Lawrenceville
country: United States
facility: Chiesi Investigational Site
state: Georgia
city: Marietta
country: United States
facility: Chiesi Investigational Site
state: Georgia
city: Savannah
country: United States
facility: Chiesi Investigational Site
state: Georgia
city: Chicago
country: United States
facility: Chiesi Investigational Site
state: Illinois
city: Evansville
country: United States
facility: Chiesi Investigational Site
state: Indiana
city: Valparaiso
country: United States
facility: Chiesi Investigational Site
state: Indiana
city: Louisville
country: United States
facility: Chiesi Investigational Site
state: Kentucky
city: Louisville
country: United States
facility: Chiesi Investigational Site
state: Kentucky
city: Crowley
country: United States
facility: Chiesi Investigational Site
state: Louisiana
city: Lake Charles
country: United States
facility: Chiesi Investigational Site
state: Louisiana
city: Lutherville
country: United States
facility: Chiesi Investigational Site
state: Maryland
city: Fall River
country: United States
facility: Chiesi Investigational Site
state: Massachusetts
city: Fall River
country: United States
facility: Chiesi Investigational Site
state: Massachusetts
city: Ann Arbor
country: United States
facility: Chiesi Investigational Site
state: Michigan
city: Farmington Hills
country: United States
facility: Chiesi Investigational Site
state: Michigan
city: Minneapolis
country: United States
facility: Chiesi Investigational Site
state: Minnesota
city: Saint Charles
country: United States
facility: Chiesi Investigational Site
state: Missouri
city: Saint Louis
country: United States
facility: Chiesi Investigational Site
state: Missouri
city: Missoula
country: United States
facility: Chiesi Investigational Site
state: Montana
city: Omaha
country: United States
facility: Chiesi Investigational Site
state: Nebraska
city: Las Vegas
country: United States
facility: Chiesi Investigational Site
state: Nevada
city: Summit
country: United States
facility: Chiesi Investigational Site
state: New Jersey
city: Albuquerque
country: United States
facility: Chiesi Investigational Site
state: New Mexico
city: Bronx
country: United States
facility: Chiesi Investigational Site
state: New York
city: Charlotte
country: United States
facility: Chiesi Investigational Site
state: North Carolina
city: Gastonia
country: United States
facility: Chiesi Investigational Site
state: North Carolina
city: Hendersonville
country: United States
facility: Chiesi Investigational Site
state: North Carolina
city: Mooresville
country: United States
facility: Chiesi Investigational Site
state: North Carolina
city: Raleigh
country: United States
facility: Chiesi Investigational Site
state: North Carolina
city: Shelby
country: United States
facility: Chiesi Investigational Site
state: North Carolina
city: Wilmington
country: United States
facility: Chiesi Investigational Site
state: North Carolina
city: Winston-Salem
country: United States
facility: Chiesi Investigational Site
state: North Carolina
city: Cincinnati
country: United States
facility: Chiesi Investigational Site
state: Ohio
city: Columbus
country: United States
facility: Chiesi Investigational Site
state: Ohio
city: Columbus
country: United States
facility: Chiesi Investigational Site
state: Ohio
city: Dayton
country: United States
facility: Clinical Research Solutions
state: Ohio
city: Grove City
country: United States
facility: Chiesi Investigational Site
state: Ohio
city: Edmond
country: United States
facility: Chiesi Investigational Site
state: Oklahoma
city: Oklahoma City
country: United States
facility: Chiesi Investigational Site
state: Oklahoma
city: Medford
country: United States
facility: Chiesi Investigational Site
state: Oregon
city: Portland
country: United States
facility: Chiesi Investigational Site
state: Oregon
city: Philadelphia
country: United States
facility: Chiesi Investigational Site
state: Pennsylvania
city: East Providence
country: United States
facility: Chiesi Investigational Site
state: Rhode Island
city: Anderson
country: United States
facility: Chiesi Investigational Site
state: South Carolina
city: Charleston
country: United States
facility: Chiesi Investigational Site
state: South Carolina
city: Easley
country: United States
facility: Chiesi Investigational Site
state: South Carolina
city: Fort Mill
country: United States
facility: Chiesi Investigational Site
state: South Carolina
city: Gaffney
country: United States
facility: Chiesi Investigational Site
state: South Carolina
city: Greenville
country: United States
facility: Chiesi Investigational Site
state: South Carolina
city: Mount Pleasant
country: United States
facility: Chiesi Investigational Site
state: South Carolina
city: Orangeburg
country: United States
facility: Chiesi Investigational Site
state: South Carolina
city: Rock Hill
country: United States
facility: Chiesi Investigational Site
state: South Carolina
city: Seneca
country: United States
facility: Chiesi Investigational Site
state: South Carolina
city: Spartanburg
country: United States
facility: Chiesi Investigational Site
state: South Carolina
city: Union
country: United States
facility: Chiesi Investigational Site
state: South Carolina
city: Rapid City
country: United States
facility: Chiesi Investigational Site
state: South Dakota
city: Franklin
country: United States
facility: Chiesi Investigational Site
state: Tennessee
city: Jackson
country: United States
facility: Chiesi Investigational Site
state: Tennessee
city: Knoxville
country: United States
facility: Chiesi Investigational Site
state: Tennessee
city: Tullahoma
country: United States
facility: Chiesi Investigational Site
state: Tennessee
city: Boerne
country: United States
facility: Chiesi Investigational Site
state: Texas
city: Cypress
country: United States
facility: Chiesi Investigational Site
state: Texas
city: New Braunfels
country: United States
facility: Chiesi Investigational Site
state: Texas
city: Sherman
country: United States
facility: Chiesi Investigational Site
state: Texas
city: Tomball
country: United States
facility: Chiesi Investigational Site
state: Texas
city: South Burlington
country: United States
facility: Chiesi Investigational Site
state: Vermont
city: Richmond
country: United States
facility: Chiesi Investigational Site
state: Virginia
city: Everett
country: United States
facility: Chiesi Investigational Site
state: Washington
city: Richland
country: United States
facility: Chiesi Investigational Site
state: Washington
city: Tacoma
country: United States
facility: Chiesi Investigational Site
state: Washington
Study officials:
affiliation: Crisor LLC c/o Clinical Research Institute of Southern Oregon, Inc.
name: Edward Kerwin, MD
role: PRINCIPAL_INVESTIGATOR
References:
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