Dose-range Finding Efficacy and Safety Study for QBW251 in COPD Patients

Pulmonary Disease, Chronic Obstructive Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04072887
• Other study ID #: CQBW251B2201
• Secondary ID: 2018-003197-28
• Status: Completed
• Phase: Phase 2
• Start date: September 12, 2019
• Est. completion date: February 1, 2022

Study information

• Verified date: April 2023
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 974
• Est. completion date: February 1, 2022
• Est. primary completion date: October 8, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• QBW251
QBW251 oral capsules (450, 300, 150, 75 and 25 mg) of identical appearance to ensure blinding administered twice a day (b.i.d) for 24 weeks
• Placebo
Placebo oral capsules administered twice a day for 24 weeks
• COPD maintenance background therapy
Combination of fluticasone furoate, vilanterol and umeclidinium bromide

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Berazategui	Buenos Aires
Argentina	Novartis Investigative Site	Ciudad Autonoma de Bs As
Argentina	Novartis Investigative Site	Concepcion del Uruguay	Entre Ríos
Argentina	Novartis Investigative Site	Mar del Plata	Buenos Aires
Argentina	Novartis Investigative Site	Mendoza
Argentina	Novartis Investigative Site	Mendoza
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Argentina	Novartis Investigative Site	Salta
Argentina	Novartis Investigative Site	Santa Fe
Australia	Novartis Investigative Site	Clayton	Victoria
Australia	Novartis Investigative Site	Footscray	Victoria
Australia	Novartis Investigative Site	South Brisbane	Queensland
Australia	Novartis Investigative Site	Spearwood	Western Australia
Austria	Novartis Investigative Site	Feldbach
Austria	Novartis Investigative Site	Grieskirchen
Austria	Novartis Investigative Site	Thalheim bei Wels
Belgium	Novartis Investigative Site	Erpent
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Liege
Canada	Novartis Investigative Site	Sainte Foy	Quebec
Canada	Novartis Investigative Site	Sherwood Park	Alberta
Canada	Novartis Investigative Site	St-Charles-Borromee	Quebec
Colombia	Novartis Investigative Site	Zipaquira	Cundinamarca
Czechia	Novartis Investigative Site	Liberec	Czech Republic
Czechia	Novartis Investigative Site	Ostrava Poruba	Czech Republic
Czechia	Novartis Investigative Site	Teplice	Czech Republic
Czechia	Novartis Investigative Site	Varnsdorf
Denmark	Novartis Investigative Site	Aalborg
Denmark	Novartis Investigative Site	Copenhagen
Denmark	Novartis Investigative Site	Hvidovre
France	Novartis Investigative Site	Lyon Cedex 04
France	Novartis Investigative Site	Montpellier cedex 5	Herault
France	Novartis Investigative Site	Pessac Cedex
France	Novartis Investigative Site	Reims
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Halle
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Landsberg
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Mainz
Germany	Novartis Investigative Site	Marburg
Germany	Novartis Investigative Site	Mittweida
Germany	Novartis Investigative Site	Witten
Greece	Novartis Investigative Site	Heraklion Crete
Greece	Novartis Investigative Site	Thessaloniki	GR
Guatemala	Novartis Investigative Site	Guatemala City	GTM
Guatemala	Novartis Investigative Site	Guatemala City	GTM
Guatemala	Novartis Investigative Site	Guatemala City
Hong Kong	Novartis Investigative Site	New Territories
Hong Kong	Novartis Investigative Site	Pokfulam
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Godollo
Hungary	Novartis Investigative Site	Komarom
Hungary	Novartis Investigative Site	Mako
Hungary	Novartis Investigative Site	Pecs
Italy	Novartis Investigative Site	Genova	GE
Italy	Novartis Investigative Site	Negrar	VR
Italy	Novartis Investigative Site	Siena	SI
Japan	Novartis Investigative Site	Asahikawa-city	Hokkaido
Japan	Novartis Investigative Site	Chuo ku	Tokyo
Japan	Novartis Investigative Site	Chuo-ku	Tokyo
Japan	Novartis Investigative Site	Chuo-ku	Tokyo
Japan	Novartis Investigative Site	Fukuoka city	Fukuoka
Japan	Novartis Investigative Site	Fukuoka-city	Fukuoka
Japan	Novartis Investigative Site	Kasuga-city	Fukuoka
Japan	Novartis Investigative Site	Kawachinagano	Osaka
Japan	Novartis Investigative Site	Kawasaki-city	Kanagawa
Japan	Novartis Investigative Site	Kishiwada-city	Osaka
Japan	Novartis Investigative Site	Kodaira	Tokyo
Japan	Novartis Investigative Site	Koga city	Fukuoka
Japan	Novartis Investigative Site	Matsusaka-city	Mie
Japan	Novartis Investigative Site	Mizunami-city	Gifu
Japan	Novartis Investigative Site	Nagoya	Aichi
Japan	Novartis Investigative Site	Nagoya	Aichi
Japan	Novartis Investigative Site	Naka-gun	Ibaraki
Japan	Novartis Investigative Site	Osaka
Japan	Novartis Investigative Site	Sagamihara-city	Kanagawa
Japan	Novartis Investigative Site	Sapporo	Hokkaido
Japan	Novartis Investigative Site	Sendai-shi	Miyagi
Japan	Novartis Investigative Site	Setagaya-Ku	Tokyo
Japan	Novartis Investigative Site	Setagaya-ku	Tokyo
Japan	Novartis Investigative Site	Shinagawa	Tokyo
Japan	Novartis Investigative Site	Toshima ku	Tokyo
Japan	Novartis Investigative Site	Toyonaka	Osaka
Japan	Novartis Investigative Site	Yamagata city	Yamagata
Japan	Novartis Investigative Site	Yanagawa-city	Fukuoka
Japan	Novartis Investigative Site	Yokohama-city	Kanagawa
Korea, Republic of	Novartis Investigative Site	Daegu
Korea, Republic of	Novartis Investigative Site	Incheon
Korea, Republic of	Novartis Investigative Site	Seoul	Seocho Gu
Netherlands	Novartis Investigative Site	Eindhoven
Netherlands	Novartis Investigative Site	Harderwijk
Philippines	Novartis Investigative Site	Bulacan
Philippines	Novartis Investigative Site	Iloilo City
Philippines	Novartis Investigative Site	Iloilo city	Iloilo
Philippines	Novartis Investigative Site	Lipa City	Batangas
Philippines	Novartis Investigative Site	Manila
Poland	Novartis Investigative Site	Grudziadz
Poland	Novartis Investigative Site	Katowice
Poland	Novartis Investigative Site	Zawadzkie
Slovakia	Novartis Investigative Site	Bardejov	Slovak Republic
Slovakia	Novartis Investigative Site	Bojnice	Slovak Republic
Slovakia	Novartis Investigative Site	Humenne	Slovak Republic
Slovakia	Novartis Investigative Site	Poprad
Slovakia	Novartis Investigative Site	Presov
Slovakia	Novartis Investigative Site	Spisska Nova Ves
Slovakia	Novartis Investigative Site	Vysne Hagy
Spain	Novartis Investigative Site	Alzira	Comunidad Valenciana
Spain	Novartis Investigative Site	Girona
Spain	Novartis Investigative Site	Marbella	Andalucia
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Khon Kaen	THA
Thailand	Novartis Investigative Site	Songkhla	Hat Yai
Turkey	Novartis Investigative Site	Adana
Turkey	Novartis Investigative Site	Mersin
United Kingdom	Novartis Investigative Site	London
United States	Novartis Investigative Site	Andalusia	Alabama
United States	Novartis Investigative Site	Charlotte	North Carolina
United States	Novartis Investigative Site	Columbus	Ohio
United States	Novartis Investigative Site	Crowley	Louisiana
United States	Novartis Investigative Site	Edina	Minnesota
United States	Novartis Investigative Site	El Paso	Texas
United States	Novartis Investigative Site	Florence	Kentucky
United States	Novartis Investigative Site	Gastonia	North Carolina
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Livonia	Michigan
United States	Novartis Investigative Site	Los Angeles	California
United States	Novartis Investigative Site	McKinney	Texas
United States	Novartis Investigative Site	Medford	Oregon
United States	Novartis Investigative Site	Midlothian	Virginia
United States	Novartis Investigative Site	Minneapolis	Minnesota
United States	Novartis Investigative Site	New Orleans	Louisiana
United States	Novartis Investigative Site	Omaha	Nebraska
United States	Novartis Investigative Site	Ormond Beach	Florida
United States	Novartis Investigative Site	Saint Charles	Missouri
United States	Novartis Investigative Site	Saint Louis	Missouri
United States	Novartis Investigative Site	Sarasota	Florida
United States	Novartis Investigative Site	Shelby	North Carolina
United States	Novartis Investigative Site	Westminster	California
United States	Novartis Investigative Site	Winter Park	Florida
United States	Novartis Investigative Site	Zachary	Louisiana

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Canada,  Colombia,  Czechia,  Denmark,  France,  Germany,  Greece,  Guatemala,  Hong Kong,  Hungary,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Philippines,  Poland,  Slovakia,  Spain,  Thailand,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Week 12	The primary efficacy analysis assessed the effect of QBW251 on the absolute change from baseline in trough FEV1 in liters on Week 12. Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Baseline measurement was defined as the baseline visit pre-bronchodilator spirometry assessment.; Change from baseline in the FEV1 mean scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + run-in FEV1 + airflow limitation severity + region + time interval + treatment*time interval interaction + baseline score*time interval interaction.	Baseline and Week 12
Secondary	Change From Baseline in Forced Expiratory Volume in One Second (FEV1)	The primary efficacy analysis assessed the effect of QBW251 on the absolute change from baseline in trough FEV1 in liters compared to placebo on Weeks 4, 8, 16, 20 and 24. Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Baseline measurement was defined as the baseline visit pre-bronchodilator spirometry assessment. A positive trend for change from baseline in FEV1 across the dose range is considered a favorable outcome.	Baseline, weeks 4, 8, 16, 20 and 24
Secondary	Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Total Score	The E-RS assesses overall daily respiratory COPD symptoms (Total score) and it is derived as the sum of 11 severity items; a higher scores indicate more severe symptoms. E-RS total score has a range of 0 to 40.; Change from baseline in the E-RS Total weekly mean scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + run-in E-RS + airflow limitation severity + region + time interval + treatment*time interval interaction + baseline score*time interval interaction.; The mean baseline E-RS Total score was the average of the corresponding daily scores from the run-in period.; A negative change from baseline corresponds to improvement in symptoms severity.	Baseline, weeks 12 and 24
Secondary	Change From Baseline in Evaluating Respiratory Symptoms (E-RS); Cough and Sputum Score	The E-RS assesses both overall daily respiratory COPD symptoms (Total score) and specific respiratory symptoms using 3 subscales (Breathlessness, Cough & Sputum, and Chest Symptoms). The E-RS comprises 11 severity items and higher scores indicate more severe symptoms. The Cough and Sputum subscale score has a range of 0 to 11 and was derived as the sum of items 2 - 4.; Change from baseline in the E-RS Cough and Sputum weekly mean scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + run-in E-RS + airflow limitation severity + region + time interval + treatment*time interval interaction + baseline score*time interval interaction.; The mean baseline E-RS Cough & Sputum subscale score was the average of the corresponding daily scores from the run-in period. Lower scores in the change from baseline correspond to lower symptom severity.	Baseline, weeks 12 and 24
Secondary	Number of Participants With a "Better" Change in the Patient Global Impression of Severity (PGI-S) From Baseline	The PGI-S questionnaire is a patient-reported outcomes score that rates the severity of the respiratory symptoms and of cough and mucus. The change in severity scores (Better, No change and Worse) from baseline were reported at weeks 12 and 24. Thus, the number of participants with a Better change in the severity score are reported in the table below.	Baseline, weeks 12 and 24
Secondary	Change From Baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q)	The CASA-Q is a validated questionnaire instrument used to measure cough and sputum production, and their impact in patients COPD and/or chronic bronchitis. It contains a total of 20 items on a 5-step scale distributed in 4 domains: Cough symptoms, Cough impact, Sputum symptoms and Sputum impact. All items are rescored from 1-5 to 0-4 and then reverse scored such that better responses have higher scores. The four domains are ranged from 0-100 where higher scores associated with fewer symptoms/less impact due to cough or sputum.; Change from baseline in the CASA-Q cough and symptoms scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + run-in E-RS + airflow limitation severity + region + time interval + treatment*time interval interaction + baseline score*time interval interaction.	Baseline, weeks 12 and 24
Secondary	Change From Baseline in St. George's Respiratory Questionnaire (SGRQ)	SGRQ measures health impairment and contains 50 items divided into three components: Symptoms, Activity and Impacts. A score was calculated for each component and a "Total" score was also calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of quality of life.; Change from baseline in the SGRQ scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + baseline SGRQ score + airflow limitation severity + region + time interval + treatment*time interval interaction + baseline score*time interval interaction.	Baseline, weeks 12 and 24
Secondary	Minimum Plasma Concentration (Cmin) for QBW251	Venous whole blood samples were collected for pharmacokinetics characterization. Cmin was measured pre dose at all visits and was summarized using descriptive statistics. All concentrations below the lower limit of quantification (LLOQ) were treated as zero.	Pre-dose on Days 15, 29, 57, 85, 113, 141 and 169
Secondary	Maximum Plasma Concentration (Cmax) for QBW251	Venous whole blood samples were collected for pharmacokinetics characterization. Cmax was calculated from plasma concentration data using non-compartmental methods and summarized using descriptive statistics. Cmax was measured in the samples taken at 3 hours post-dose with the exception of the participants included in the Serial PK set on Days 1 and 15 for whom all samples (1, 2, 4, 6, and 8 hours post-dose) were taken into consideration for the measurement of Cmax. All concentrations below the lower limit of quantification (LLOQ) were treated as zero.	Days 1, 15 and 169
Secondary	Maximum Plasma Concentration (Cmax) for QBW251 in Serial PK Set	Venous whole blood samples were collected for pharmacokinetics characterization. Cmax was calculated from plasma concentration data using non-compartmental methods and summarized using descriptive statistics. All concentrations below the lower limit of quantification (LLOQ) were treated as zero.	1, 2, 4, 6, and 8 hours post-dose on Days 1 and 15
Secondary	Area Under the Curve From Time 0 to 24 Hours (AUC0-24h) of QBW251 in Serial PK Set	Venous whole blood samples were collected for pharmacokinetics characterization. AUC0-24h was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics. All concentrations below the lower limit of quantification (LLOQ) were treated as zero.	1, 2, 4, 6, and 8 hours post-dose on Days 1 and 15