Clinical trial NCT03084718: An 8-week Dose Ranging Study of CHF 718 pMDI in Asthmatic Subjects
Official title: An 8-week, Multicenter, Randomized, Double-blind, Placebo and Active-controlled, Parallel Group, Dose-ranging Study to Evaluate the Efficacy and Safety of 3 Doses of CHF 718 pMDI (HFA Beclomethasone Dipropionate Via Pressured Metered Dose Inhaler) in Asthmatic Subjects.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Asthma
Lead sponsor: Chiesi Farmaceutici S.p.A.
Sponsor class: INDUSTRY
First posted: 2017-03-21
Enrollment: 610
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
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 781 Pressurized Metered Dose Inhaler (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 patient population.

Detailed description: This is a phase II, multicenter, randomized, double-blind, placebo and active controlled dose ranging 5-arm parallel group study to identify the optimal dose of CHF 781 pMDI with respect to lung function and other clinical efficacy and safety outcomes.

After a 2 week run-in period under rescue albuterol as needed and background inhaled corticosteroid (ICS), patients will be randomized to one of the 5 study treatment groups. After randomization, patients will be assessed after 4 and 8 weeks of study treatment at the center. A follow-up phone call will be performed a week after the last visit.

During the study, daily asthma symptoms, peak expiratory flow, rescue and background medication use, and compliance with the study medication will be recorded via subject diary. Treatment-Emergent Adverse Events (TEAEs) will be assessed and recorded throughout the study. At screening and subsequent visits, patients will undergo physical and vital signs examinations, spirometry measurements, and 12-lead ECG. Routine hematology, blood chemistry, and pregnancy testing will be performed before enrollment and at end of study. 24-hr urine cortisol and creatinine will be assessed before and after the first dose and just before the last dose of study treatment.

Eligibility criteria: Inclusion Criteria:

* Male or female subjects aged ≥18 and ≤75 years who have signed an Informed Consent form prior to initiation of any study-related procedure.
* A diagnosis of asthma as defined in the Global Initiative for Asthma (GINA) Report, 2016, documented for at least 1 year prior to screening.
* Subjects with poorly controlled or uncontrolled asthma evidenced by a score at the Asthma Control Questionnaire 7 © (ACQ-7) ≥1.5 (this criterion must be met at screening and at randomization visits).
* Subjects with a pre-bronchodilator Forced Expiratory Volume in the 1st Second (FEV1) ≥50% and \<85% of their predicted normal value, after appropriate washout from bronchodilators, at the screening and randomization visits.
* Subjects with a positive response to a reversibility test at screening (pre - post BD), within 1 year prior to or at screening defined as ΔFEV1≥12% and ≥200 mL over baseline within 30 minutes after inhaling 4 puffs of albuterol HFA 90µg/actuation.
* Use of inhaled corticosteroids (low/medium dose according to GINA Report 2016) with or without a long-acting bronchodilator (LABD) for 3 months (stable dose in the last 4 weeks) before screening visit (V).
* A cooperative attitude and ability to demonstrate correct use of the diary, peak flow meter, and pMDI inhalers.
* A basal morning (7-10 am) serum cortisol level between 7-28 µg/dL at screening visit (V1).
* A Body Mass Index (BMI): 18.5 ≤ BMI \<35 kg/m\^2.

Exclusion Criteria:

* Pregnant (as evident by a positive urine human chorionic gonadotropin (hCG) or serum β-hCG test) or lactating women and all women physiologically capable of becoming pregnant (i.e. women of childbearing potential) UNLESS they are willing to use a highly effective birth control method
* Subjects who suffer from chronic obstructive pulmonary disease (COPD) as defined by the GOLD Report 2017, or are suspected of having Asthma COPD Overlap Syndrome (ACOS) as defined in GINA Report, 2016.
* Inability to carry out pulmonary lung function testing, to comply with study procedures or with study drug intake.
* Current smokers or ex-smokers (tobacco, vapor cigarettes, marijuana) with a smoking history of \>10 pack-years or having stopped smoking one year or less prior to screening visit.
* History of life-threatening asthma, clinically significant uncontrolled disease or respiratory infection.
* An asthma exacerbation requiring oral corticosteroids within 3 months or hospitalization within 6 months prior to screening.
* Subjects with unresolved bacterial or viral respiratory tract, sinus or middle ear infection affecting asthma status within 2 weeks prior to screening.
* Subjects who received a vaccination within 2 weeks prior to screening or during the run-in.
* Subjects with oral candidiasis at screening or at randomization.
* Subjects with any clinically significant, uncontrolled condition
* 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 and randomization visits.
* Subjects with known intolerance/hypersensitivity or contra-indication to treatment with ß2-adrenergic receptor agonists, inhaled corticosteroids or propellant gases/excipients.
* Subjects with concomitant immunosuppressive therapy, use of oral or injected corticosteroids, anti-Immunoglobulin E (IgE), anti-Interleukin 5 (IL5), or other monoclonal or polyclonal antibodies within 12 weeks prior to screening.
* Use of potent cytochrome P450 3A4 inhibitors and inducers within 4 weeks prior to screening.
* 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: Pre-dose Morning FEV1 at Week 8 - Change From Baseline
timeFrame: Baseline, Week 8
Secondary outcomes:
measure: Pre-dose Morning FEV1 at Week 4 - Change From Baseline
timeFrame: Baseline, Week 4
measure: Pre-dose Morning FVC at Week 4 and 8 - Change From Baseline
timeFrame: Baseline, Week 4, Week 8
measure: Asthma Control Questionnaire-7© (ACQ-7) Score at Week 4 and Week 8 - Change From Baseline
timeFrame: Baseline, Week 4, Week 8
measure: Average Use of Rescue Medication - Change From Baseline
timeFrame: Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)
measure: Percentage (%) of Rescue Medication-free Days - Change From Baseline
timeFrame: Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)
measure: Overall Daily Asthma Symptoms Scores - Change From Baseline
timeFrame: Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)
measure: Percentage (%) of Asthma Symptoms-free Days - Change From Baseline
timeFrame: Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)
measure: Percentage (%) of Asthma Control Days - Change From Baseline
timeFrame: Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)
measure: Pre-dose Peak Expiratory Flow (PEF) (L/Min) (Morning and Evening) - Change From Baseline
timeFrame: Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)
measure: Vital Signs (Systolic and Diastolic Blood Pressure) - Change From Baseline
timeFrame: Baseline, Week 4, Week 8
measure: 12-lead ECG Parameters - Heart Rate - Change From Baseline
timeFrame: Baseline, Week 8
measure: 12-lead ECG Parameters - PR, QRS, QTcF - Change From Baseline.
timeFrame: Baseline, Week 8
measure: 12-lead ECG Parameters - Prolonged QTcF - Change From Baseline
timeFrame: Baseline, Week 8
measure: 24-hr Urine Free Cortisol - Change From Baseline
timeFrame: Baseline, Week 8
measure: 24-hr Creatinine - Change From Baseline.
timeFrame: Baseline, Week 8
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Chiesi Investigational Site
state: Alabama
city: Montgomery
country: United States
facility: Chiesi Investigational Site
state: Alabama
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: Little Rock
country: United States
facility: Chiesi Investigational Site
state: Arkansas
city: Anaheim
country: United States
facility: Chiesi Investigational Site
state: California
city: Encinitas
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: Huntington Beach
country: United States
facility: Chiesi Investigational Site
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: North Hollywood
country: United States
facility: Chiesi Investigational Site
state: California
city: Rolling Hills Estates
country: United States
facility: Chiesi Investigational Site
state: California
city: Sacramento
country: United States
facility: Chiesi Investigational Site
state: California
city: San Diego
country: United States
facility: Chiesi Investigational Site
state: California
city: San Diego
country: United States
facility: Chiesi Investigational Site
state: California
city: San Jose
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: Colorado Springs
country: United States
facility: Chiesi Investigational Site
state: Colorado
city: Denver
country: United States
facility: Chiesi Investigational Site
state: Colorado
city: Greenwood
country: United States
facility: Chiesi Investigational Site
state: Colorado
city: Wheat Ridge
country: United States
facility: Chiesi Investigational Site
state: Colorado
city: Aventura
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: Doral
country: United States
facility: Chiesi Investigational Site
state: Florida
city: Gainesville
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: Lauderdale Lakes
country: United States
facility: Chiesi Investigational Site
state: Florida
city: Loxahatchee Groves
country: United States
facility: Chiesi Investigational Site
state: Florida
city: Maitland
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: Miami
country: United States
facility: Chiesi Investigational Site
state: Florida
city: Orlando
country: United States
facility: Chiesi Investigational Site
state: Florida
city: Palmetto Bay
country: United States
facility: Chiesi Investigational Site
state: Florida
city: Plantation
country: United States
facility: Chiesi Investigational Site
state: Florida
city: Pompano Beach
country: United States
facility: Chiesi Investigational Site
state: Florida
city: Saint Cloud
country: United States
facility: Chiesi Investigational Site
state: Florida
city: Sarasota
country: United States
facility: Chiesi Investigational Site
state: Florida
city: Winter Park
country: United States
facility: Chiesi Investigational Site
state: Florida
city: Dacula
country: United States
facility: Chiesi Investigational Site
state: Georgia
city: Duluth
country: United States
facility: Chiesi Investigational Site
state: Georgia
city: Gainesville
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: Chicago
country: United States
facility: Chiesi Investigational Site
state: Illinois
city: Crowley
country: United States
facility: Chiesi Investigational Site
state: Louisiana
city: New Orleans
country: United States
facility: Chiesi Investigational Site
state: Louisiana
city: Baltimore
country: United States
facility: Chiesi Investigational Site
state: Maryland
city: Bethesda
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: North Dartmouth
country: United States
facility: Chiesi Investigational Site
state: Massachusetts
city: South Dartmouth
country: United States
facility: Chiesi Investigational Site
state: Massachusetts
city: Detroit
country: United States
facility: Chiesi Investigational Site
state: Michigan
city: Minneapolis
country: United States
facility: Chiesi Investigational Site
state: Minnesota
city: Columbia
country: United States
facility: Chiesi Investigational Site
state: Missouri
city: Festus
country: United States
facility: Chiesi Investigational Site
state: Missouri
city: Rolla
country: United States
facility: Chiesi Investigational Site
state: Missouri
city: Saint Louis
country: United States
facility: Chiesi Investigational Site
state: Missouri
city: Saint Louis
country: United States
facility: Chiesi Investigational Site
state: Missouri
city: Warrensburg
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: Las Vegas
country: United States
facility: Chiesi Investigational Site
state: Nevada
city: Skillman
country: United States
facility: Chiesi Investigational Site
state: New Jersey
city: Albuquerque
country: United States
facility: Chiesi Investigational Site
state: New Mexico
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: Brooklyn
country: United States
facility: Chiesi Investigational Site
state: New York
city: New York
country: United States
facility: Chiesi Investigational Site
state: New York
city: New York
country: United States
facility: Chiesi Investigational Site
state: New York
city: Charlotte
country: United States
facility: Chiesi Investigational Site
state: North Carolina
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: Hickory
country: United States
facility: Chiesi Investigational Site
state: North Carolina
city: Monroe
country: United States
facility: Chiesi Investigational Site
state: North Carolina
city: Mooresville
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: Cincinnati
country: United States
facility: Chiesi Investigational Site
state: Ohio
city: Dayton
country: United States
facility: Chiesi Investigational Site
state: Ohio
city: Dayton
country: United States
facility: Chiesi Investigational Site
state: Ohio
city: Grove City
country: United States
facility: Chiesi Investigational Site
state: Ohio
city: Munroe Falls
country: United States
facility: Chiesi Investigational Site
state: Ohio
city: Toledo
country: United States
facility: Chiesi Investigational Site
state: Ohio
city: Edmond
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: East Providence
country: United States
facility: Chiesi Investigational Site
state: Rhode Island
city: East Providence
country: United States
facility: Chiesi Investigational Site
state: Rhode Island
city: Warwick
country: United States
facility: Chiesi Investigational Site
state: Rhode Island
city: Anderson
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: Rock Hill
country: United States
facility: Chiesi Investigational Site
state: South Carolina
city: Spartanburg
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: Chattanooga
country: United States
facility: Chiesi Investigational Site
state: Tennessee
city: Chattanooga
country: United States
facility: Chiesi Investigational Site
state: Tennessee
city: Knoxville
country: United States
facility: Chiesi Investigational Site
state: Tennessee
city: Smyrna
country: United States
facility: Chiesi Investigational Site
state: Tennessee
city: Spring Hill
country: United States
facility: Chiesi Investigational Site
state: Tennessee
city: Allen
country: United States
facility: Chiesi Investigational Site
state: Texas
city: Beaumont
country: United States
facility: Chiesi Investigational Site
state: Texas
city: Cypress
country: United States
facility: Chiesi Investigational Site
state: Texas
city: Dallas
country: United States
facility: Chiesi Investigational Site
state: Texas
city: Dallas
country: United States
facility: Chiesi Investigational Site
state: Texas
city: El Paso
country: United States
facility: Chiesi Investigational Site
state: Texas
city: McKinney
country: United States
facility: Chiesi Investigational Site
state: Texas
city: Pearland
country: United States
facility: Chiesi Investigational Site
state: Texas
city: Plano
country: United States
facility: Chiesi Investigational Site
state: Texas
city: San Antonio
country: United States
facility: Chiesi Investigational Site
state: Texas
city: Sherman
country: United States
facility: Chiesi Investigational Site
state: Texas
city: Saint George
country: United States
facility: Chiesi Investigational Site
state: Utah
city: South Burlington
country: United States
facility: Chiesi Investigational Site
state: Vermont
city: Norfolk
country: United States
facility: Chiesi Investigational Site
state: Virginia
city: Everett
country: United States
facility: Chiesi Investigational Site
state: Washington
city: Greenfield
country: United States
facility: Chiesi Investigational Site
state: Wisconsin
Study officials:
affiliation: Bernstein Clinical Research Center, LLC
name: David Bernstein, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Dahl R, Chung KF, Buhl R, Magnussen H, Nonikov V, Jack D, Bleasdale P, Owen R, Higgins M, Kramer B; INVOLVE (INdacaterol: Value in COPD: Longer Term Validation of Efficacy and Safety) Study Investigators. Efficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twice-daily formoterol in COPD. Thorax. 2010 Jun;65(6):473-9. doi: 10.1136/thx.2009.125435.
citation: Keating GM. Tiotropium bromide inhalation powder: a review of its use in the management of chronic obstructive pulmonary disease. Drugs. 2012 Jan 22;72(2):273-300. doi: 10.2165/11208620-000000000-00000.
citation: Casaburi R, Kukafka D, Cooper CB, Witek TJ Jr, Kesten S. Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD. Chest. 2005 Mar;127(3):809-17. doi: 10.1378/chest.127.3.809.
citation: Kesten S, Casaburi R, Kukafka D, Cooper CB. Improvement in self-reported exercise participation with the combination of tiotropium and rehabilitative exercise training in COPD patients. Int J Chron Obstruct Pulmon Dis. 2008;3(1):127-36. doi: 10.2147/copd.s2389.
citation: Karner C, Chong J, Poole P. Tiotropium versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012 Jul 11;(7):CD009285. doi: 10.1002/14651858.CD009285.pub2.
citation: Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers RT, Thach C, Fogel R, Patalano F, Vogelmeier CF; FLAME Investigators. Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD. N Engl J Med. 2016 Jun 9;374(23):2222-34. doi: 10.1056/NEJMoa1516385. Epub 2016 May 15.
citation: Yang IA, Clarke MS, Sim EH, Fong KM. Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012 Jul 11;2012(7):CD002991. doi: 10.1002/14651858.CD002991.pub3.
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