Clinical trial NCT04072887: Dose-range Finding Efficacy and Safety Study for QBW251 in COPD Patients
Official title: A 24-week Multi-center, Double-blind, Placebo Controlled Dose-range Finding Study to Investigate the Efficacy and Safety of Oral QBW251 in COPD Patients on Triple Inhaled Therapy (LABA / LAMA / ICS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: COPD
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2019-08-28
Enrollment: 974
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This clinical study was designed to support the dose selection for future studies by evaluating efficacy and safety of different QBW251 doses in Chronic obstructive pulmonary disease (COPD) patients with chronic bronchitis and a history of exacerbations, compared to placebo, when added to a triple inhaled therapy of LABA, LAMA and ICS.

Detailed description: This study used a 6 treatment arm, parallel-group, randomized, double-blind study design. 974 male and female COPD patients were randomized into the trial. The study consisted of four distinct study periods:

* Screening (Weeks -3 to -2): Participants underwent a screening period of 1 week where were assessed for eligibility and tapered off disallowed medications.
* Run-in (Days -14 to 1): Subsequently, participants entered the run-in period of up to 2 weeks to establish baseline values for symptom assessments, to standardize the COPD background therapy (triple combination LABA/LAMA/ICS), and to complete eligibility assessments.
* Treatment (Day 1 to Week 24): Eligible participants moved into the Day 1 visit where they were stratified according to their smoking status (current or ex-smoker) and severity of airflow limitation (FEV1 ≥ 30% to \< 50% and ≥ 50% to \< 80%) and then randomized into 1 of 6 treatment arms with a randomization ratio of 2:2:1:1:1:2 (450 mg b.i.d., 300 mg b.i.d., 150 mg b.i.d., 75 mg b.i.d., 25 mg b.i.d., placebo). The treatment period consisted of 24 weeks, during which the participant returned to the site for regular visits (Day 1 - Week 24). QBW251 450 mg arm was discontinued early based on a pre-defined pharmacokinetic exposure stopping rule.
* Follow-up (Weeks 25-28): Upon completion of the treatment period, participants were followed up for safety assessments for 30 days.

Eligibility criteria: Inclusion Criteria:

* Male and female COPD patients aged ≥40 years, who have signed an Informed Consent Form prior to initiation of any study-related procedure.
* Current or ex-smokers who have a smoking history of at least 10 pack years.
* Patients who have been treated with a triple combination of LABA/LAMA/ICS for the last 3 months prior to screening.
* Patients featuring chronic bronchitis

Exclusion Criteria:

* Patients who have had a COPD exacerbation that required treatment with antibiotics and/or oral corticosteroids and/or hospitalization, or a respiratory tract infection in the 4 weeks prior to screening, or between screening and randomization.
* Patients with any documented history of asthma, or with an onset of chronic respiratory symptoms, including a COPD diagnosis, prior to age 40 years.
* Patients with a body mass index (BMI) of more than 40 kg/m2.
* Use of other investigational drugs (approved or unapproved) within 30 days or 5 half-lives prior to screening, or until the expected pharmacodynamic effect has returned to baseline (e.g., biologics), whichever is longer; or longer if required by local regulations.
* Pregnant or nursing (lactating) women, and women of childbearing potential not willing to use acceptable effective methods of contraception during study participation.

Primary outcomes:
measure: Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Week 12
timeFrame: Baseline and Week 12
Secondary outcomes:
measure: Change From Baseline in Forced Expiratory Volume in One Second (FEV1)
timeFrame: Baseline, weeks 4, 8, 16, 20 and 24
measure: Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Total Score
timeFrame: Baseline, weeks 12 and 24
measure: Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Cough and Sputum Score
timeFrame: Baseline, weeks 12 and 24
measure: Number of Participants With a "Better" Change in the Patient Global Impression of Severity (PGI-S) From Baseline
timeFrame: Baseline, weeks 12 and 24
measure: Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q)
timeFrame: Baseline, weeks 12 and 24
measure: Change From Baseline in St. George's Respiratory Questionnaire (SGRQ)
timeFrame: Baseline, weeks 12 and 24
measure: Minimum Plasma Concentration (Cmin) for QBW251
timeFrame: Pre-dose on Days 15, 29, 57, 85, 113, 141 and 169
measure: Maximum Plasma Concentration (Cmax) for QBW251
timeFrame: Days 1, 15 and 169
measure: Maximum Plasma Concentration (Cmax) for QBW251 in Serial PK Set
timeFrame: 1, 2, 4, 6, and 8 hours post-dose on Days 1 and 15
measure: Area Under the Curve From Time 0 to 24 Hours (AUC0-24h) of QBW251 in Serial PK Set
timeFrame: 1, 2, 4, 6, and 8 hours post-dose on Days 1 and 15
Other outcomes:
Locations:
city: Andalusia
country: United States
facility: Novartis Investigative Site
state: Alabama
city: Los Angeles
country: United States
facility: Novartis Investigative Site
state: California
city: Westminster
country: United States
facility: Novartis Investigative Site
state: California
city: Ormond Beach
country: United States
facility: Novartis Investigative Site
state: Florida
city: Sarasota
country: United States
facility: Novartis Investigative Site
state: Florida
city: Winter Park
country: United States
facility: Novartis Investigative Site
state: Florida
city: Florence
country: United States
facility: Novartis Investigative Site
state: Kentucky
city: Crowley
country: United States
facility: Novartis Investigative Site
state: Louisiana
city: New Orleans
country: United States
facility: Novartis Investigative Site
state: Louisiana
city: Zachary
country: United States
facility: Novartis Investigative Site
state: Louisiana
city: Livonia
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Edina
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: Minneapolis
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: Saint Charles
country: United States
facility: Novartis Investigative Site
state: Missouri
city: Saint Louis
country: United States
facility: Novartis Investigative Site
state: Missouri
city: Omaha
country: United States
facility: Novartis Investigative Site
state: Nebraska
city: Charlotte
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Gastonia
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Shelby
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Columbus
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Medford
country: United States
facility: Novartis Investigative Site
state: Oregon
city: El Paso
country: United States
facility: Novartis Investigative Site
state: Texas
city: Houston
country: United States
facility: Novartis Investigative Site
state: Texas
city: McKinney
country: United States
facility: Novartis Investigative Site
state: Texas
city: Midlothian
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Berazategui
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Mar del Plata
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Concepcion del Uruguay
country: Argentina
facility: Novartis Investigative Site
state: Entre Ríos
city: Rosario
country: Argentina
facility: Novartis Investigative Site
state: Santa Fe
city: Rosario
country: Argentina
facility: Novartis Investigative Site
state: Santa Fe
city: Ciudad Autonoma de Bs As
country: Argentina
facility: Novartis Investigative Site
city: Mendoza
country: Argentina
facility: Novartis Investigative Site
city: Mendoza
country: Argentina
facility: Novartis Investigative Site
city: Salta
country: Argentina
facility: Novartis Investigative Site
city: Santa Fe
country: Argentina
facility: Novartis Investigative Site
city: South Brisbane
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Clayton
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Footscray
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Spearwood
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Feldbach
country: Austria
facility: Novartis Investigative Site
city: Grieskirchen
country: Austria
facility: Novartis Investigative Site
city: Thalheim bei Wels
country: Austria
facility: Novartis Investigative Site
city: Erpent
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Liege
country: Belgium
facility: Novartis Investigative Site
city: Sherwood Park
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Sainte Foy
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: St-Charles-Borromee
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Zipaquira
country: Colombia
facility: Novartis Investigative Site
state: Cundinamarca
city: Liberec
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Ostrava Poruba
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Teplice
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Varnsdorf
country: Czechia
facility: Novartis Investigative Site
city: Aalborg
country: Denmark
facility: Novartis Investigative Site
city: Copenhagen
country: Denmark
facility: Novartis Investigative Site
city: Hvidovre
country: Denmark
facility: Novartis Investigative Site
city: Montpellier cedex 5
country: France
facility: Novartis Investigative Site
state: Herault
city: Lyon Cedex 04
country: France
facility: Novartis Investigative Site
city: Pessac Cedex
country: France
facility: Novartis Investigative Site
city: Reims
country: France
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
city: Halle
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Landsberg
country: Germany
facility: Novartis Investigative Site
city: Leipzig
country: Germany
facility: Novartis Investigative Site
city: Leipzig
country: Germany
facility: Novartis Investigative Site
city: Leipzig
country: Germany
facility: Novartis Investigative Site
city: Mainz
country: Germany
facility: Novartis Investigative Site
city: Marburg
country: Germany
facility: Novartis Investigative Site
city: Mittweida
country: Germany
facility: Novartis Investigative Site
city: Witten
country: Germany
facility: Novartis Investigative Site
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
state: GR
city: Heraklion Crete
country: Greece
facility: Novartis Investigative Site
city: Guatemala City
country: Guatemala
facility: Novartis Investigative Site
state: GTM
city: Guatemala City
country: Guatemala
facility: Novartis Investigative Site
state: GTM
city: Guatemala City
country: Guatemala
facility: Novartis Investigative Site
city: New Territories
country: Hong Kong
facility: Novartis Investigative Site
city: Pokfulam
country: Hong Kong
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Godollo
country: Hungary
facility: Novartis Investigative Site
city: Komarom
country: Hungary
facility: Novartis Investigative Site
city: Mako
country: Hungary
facility: Novartis Investigative Site
city: Pecs
country: Hungary
facility: Novartis Investigative Site
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Siena
country: Italy
facility: Novartis Investigative Site
state: SI
city: Negrar
country: Italy
facility: Novartis Investigative Site
state: VR
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Fukuoka city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Fukuoka-city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Kasuga-city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Koga city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Yanagawa-city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Mizunami-city
country: Japan
facility: Novartis Investigative Site
state: Gifu
city: Asahikawa-city
country: Japan
facility: Novartis Investigative Site
state: Hokkaido
city: Sapporo
country: Japan
facility: Novartis Investigative Site
state: Hokkaido
city: Naka-gun
country: Japan
facility: Novartis Investigative Site
state: Ibaraki
city: Kawasaki-city
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Sagamihara-city
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Yokohama-city
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Matsusaka-city
country: Japan
facility: Novartis Investigative Site
state: Mie
city: Sendai-shi
country: Japan
facility: Novartis Investigative Site
state: Miyagi
city: Kawachinagano
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Kishiwada-city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Toyonaka
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Chuo ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Chuo-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Chuo-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Kodaira
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Setagaya-Ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Setagaya-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Shinagawa
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Toshima ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Yamagata city
country: Japan
facility: Novartis Investigative Site
state: Yamagata
city: Osaka
country: Japan
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Seocho Gu
city: Daegu
country: Korea, Republic of
facility: Novartis Investigative Site
city: Incheon
country: Korea, Republic of
facility: Novartis Investigative Site
city: Eindhoven
country: Netherlands
facility: Novartis Investigative Site
city: Harderwijk
country: Netherlands
facility: Novartis Investigative Site
city: Lipa City
country: Philippines
facility: Novartis Investigative Site
state: Batangas
city: Iloilo city
country: Philippines
facility: Novartis Investigative Site
state: Iloilo
city: Bulacan
country: Philippines
facility: Novartis Investigative Site
city: Iloilo City
country: Philippines
facility: Novartis Investigative Site
city: Manila
country: Philippines
facility: Novartis Investigative Site
city: Grudziadz
country: Poland
facility: Novartis Investigative Site
city: Katowice
country: Poland
facility: Novartis Investigative Site
city: Zawadzkie
country: Poland
facility: Novartis Investigative Site
city: Bardejov
country: Slovakia
facility: Novartis Investigative Site
state: Slovak Republic
city: Bojnice
country: Slovakia
facility: Novartis Investigative Site
state: Slovak Republic
city: Humenne
country: Slovakia
facility: Novartis Investigative Site
state: Slovak Republic
city: Poprad
country: Slovakia
facility: Novartis Investigative Site
city: Presov
country: Slovakia
facility: Novartis Investigative Site
city: Spisska Nova Ves
country: Slovakia
facility: Novartis Investigative Site
city: Vysne Hagy
country: Slovakia
facility: Novartis Investigative Site
city: Marbella
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Alzira
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Girona
country: Spain
facility: Novartis Investigative Site
city: Songkhla
country: Thailand
facility: Novartis Investigative Site
state: Hat Yai
city: Khon Kaen
country: Thailand
facility: Novartis Investigative Site
state: THA
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Adana
country: Turkey
facility: Novartis Investigative Site
city: Mersin
country: Turkey
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
References: