Clinical trial NCT03158311: Study to Compare QVM149 and Free Triple Combination of Salmeterol/Fluticasone + Tiotropium
Official title: A Multicenter, Partially-Blinded, Randomized, 24-Week, Parallel-Group, Non-Inferiority, Open-Label Active Controlled Study to Compare the Efficacy and Safety of QVM149 With a Free Triple Combination of Salmeterol/Fluticasone + Tiotropium in Patients With Uncontrolled Asthma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Asthma
Keywords: QVM149
Asthma
Moderate Asthma
Severe Asthma
ICS/LABA/LAMA
ICS/LABA
LAMA
Adult
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2017-05-18
Enrollment: 1426
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel Assignment
Primary purpose: TREATMENT

Brief summary: The purpose of this trial was to demonstrate that the efficacy of two treatment arms of the fixed-dose combination product QVM149 was non-inferior to the efficacy of the free combination arm of salmeterol/ fluticasone+ tiotropium in uncontrolled moderate to severe asthmatic patients.

The planned duration of treatment in this study was 24 weeks, followed up by a 7-day follow-up period.

Detailed description: This study used a randomized, partially-blinded, 24-week, parallel-group, non-inferiority, open-label active controlled design. The study was partially open-label. Investigators and patients had knowledge of treatment allocation between QVM149 and/or comparator, however the QVM149 strength allocation was masked. The global sponsor team responsible for data review and analysis was blinded to all treatment allocations The study consisted of a screening period of up to 1-week, run-in period of 2-weeks, randomized treatment period of 24-weeks, and a follow-up period of 1-week.

At the screening visit, informed consent was obtained, and current and prohibited medications were reviewed. Rescue medication was provided to all patients who met the eligibility criteria and was to be used on an "as needed" basis throughout the study.

At the run-in visit, inclusion and exclusion criteria were reviewed and the patients were supplied with open-label long acting β2-adrenergic agonist/inhaled corticosteroids (LABA/ICS) salmeterol/fluticasone 50/250 μg b.i.d or 50/500 μg b.i.d to match their ICS background medication dose to be stopped at randomization visit.

All patients who met the eligibility criteria were randomized to 1 of 3 treatment arms with a randomization ratio of 1:1:1. The patients were stratified at randomization according to the ICS dose component of background ICS/LABA (medium or high dose) and region.

Treatment period visits were scheduled every 8 weeks. The study used two doses of QVM149 (high dose \[150/50/160 μg\] and a medium dose \[150/50/80 μg\] o.d. delivered via Concept1 inhaler) and a comparator treatment (salmeterol/fluticasone 50/500 μg b.i.d. delivered via Accuhaler® plus tiotropium 5 μg o.d delivered via Respimat®).

All randomized patients were contacted (by telephone) 7 days following the last dose of study medication or last visit, whichever was later, for Safety Follow-up visit.

Eligibility criteria: Inclusion Criteria:

* Patients with a diagnosis of asthma for a period of at least 6 months prior to Visit 1 with current asthma severity ≥ step 4 (GINA 2017).
* Patients who had used ICS/LABA combinations for asthma for at least 3 months and at stable medium or high dose of ICS/LABA for at least 1 month prior to Visit 1.
* Patients were required to be symptomatic at screening despite treatment with medium or high stable doses of ICS/LABA as defined by ACQ-7 score ≥ 1.5 at visits 101 and 201 (randomization visit).
* Patients with history of at least one severe asthma exacerbation which required medical care from a physician, emergency room visit (or local equivalent structure) or hospitalization in the 12 months prior to Visit 1 and required systemic corticosteroid treatment for at least 3 days including physician guided self-management treatment with oral corticosteroids as part of written asthma action plan.
* Pre-bronchodilator FEV1 of \< 85 % of the predicted normal value for the patient after withholding bronchodilators prior to spirometry at both Visit 101 and Visit 201.
* Patients who demonstrated an increase in FEV1 of ≥ 12% and 200 ml.

Exclusion Criteria:

* Patients who had a smoking history of greater than 20 pack years.
* Patients diagnosed with Chronic Obstructive Pulmonary Disease (COPD).
* Patients who had an asthma attack/exacerbation requiring systemic steroids or hospitalization or emergency room visit within 6 weeks of Visit 1 (Screening).
* Patients treated with a LAMA for asthma within 3 months prior to Visit 1.
* Patients who had a respiratory tract infection or clinical significant asthma worsening as defined by Investigator within 4 weeks prior to Visit 1 or between Visit 1 and Visit 201.

Primary outcomes:
measure: Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) Total Score
timeFrame: Baseline and Week 24
Secondary outcomes:
measure: Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1)
timeFrame: Baseline, Week 8, Week 16 and Week 24
measure: Change From Baseline in Asthma Control Questionnaire (ACQ-7) Total Score
timeFrame: Baseline, Week 16 and Week 24
measure: Change From Baseline in AQLQ Total Score
timeFrame: Baseline and Week 16
measure: Percentage of Patients Achieving the Minimally Clinically Important Difference (MCID) Decrease From Baseline ACQ-7 ≥ 0.5
timeFrame: Baseline and Week 24
measure: Percentage of Patients Achieving the Minimally Clinically Important Difference (MCID) Change From Baseline AQLQ ≥ 0.5
timeFrame: Baseline and Week 24
measure: Change From Baseline in Forced Vital Capacity (FVC)
timeFrame: Baseline, Week 8, Week 16 and Week 24
measure: Change From Baseline in Forced Expiratory Flow Between 25% and 75% of Forced Vital Capacity (FEF25-75)
timeFrame: Baseline, Week 8, Week 16 and Week 24
Other outcomes:
Locations:
city: Berazategui
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Florida
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Lanus
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Mar del Plata
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Nueve de Julio
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Ranelagh, Partido De Berazate
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Concepcion del Uruguay
country: Argentina
facility: Novartis Investigative Site
state: Entre Rios
city: Santa Rosa
country: Argentina
facility: Novartis Investigative Site
state: La Pampa
city: Buenos Aires
country: Argentina
facility: Novartis Investigative Site
state: Nueve De Julio
city: Rosario
country: Argentina
facility: Novartis Investigative Site
state: Santa Fe
city: Rosario
country: Argentina
facility: Novartis Investigative Site
state: Santa Fe
city: San Miguel de Tucuman
country: Argentina
facility: Novartis Investigative Site
state: Tucuman
city: Bahia Blanca
country: Argentina
facility: Novartis Investigative Site
city: Buenos Aires
country: Argentina
facility: Novartis Investigative Site
city: Buenos Aires
country: Argentina
facility: Novartis Investigative Site
city: Buenos Aires
country: Argentina
facility: Novartis Investigative Site
city: Buenos Aires
country: Argentina
facility: Novartis Investigative Site
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: 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: Santiago
country: Chile
facility: Novartis Investigative Site
state: Region Metropolitana
city: Curico
country: Chile
facility: Novartis Investigative Site
state: VII Region Del Maule
city: Bogota
country: Colombia
facility: Novartis Investigative Site
state: Cundinamarca
city: Bogota
country: Colombia
facility: Novartis Investigative Site
city: Ostrava Poruba
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Prague
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Teplice
country: Czechia
facility: Novartis Investigative Site
state: CZE
city: Lovosice
country: Czechia
facility: Novartis Investigative Site
city: Miroslav
country: Czechia
facility: Novartis Investigative Site
city: Peine
country: Germany
facility: Novartis Investigative Site
state: Niedersachsen
city: Geesthacht
country: Germany
facility: Novartis Investigative Site
state: Schleswig Holstein
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: Berlin
country: Germany
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: Berlin
country: Germany
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: Boehlen
country: Germany
facility: Novartis Investigative Site
city: Bonn
country: Germany
facility: Novartis Investigative Site
city: Darmstadt
country: Germany
facility: Novartis Investigative Site
city: Dortmund
country: Germany
facility: Novartis Investigative Site
city: Einbeck
country: Germany
facility: Novartis Investigative Site
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
city: Furstenwalde
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facility: Novartis Investigative Site
city: Gelsenkirchen
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Hannover
country: Germany
facility: Novartis Investigative Site
city: Hannover
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: Leipzig
country: Germany
facility: Novartis Investigative Site
city: Lubeck
country: Germany
facility: Novartis Investigative Site
city: Ludwigsburg
country: Germany
facility: Novartis Investigative Site
city: Marburg
country: Germany
facility: Novartis Investigative Site
city: Marburg
country: Germany
facility: Novartis Investigative Site
city: Menden
country: Germany
facility: Novartis Investigative Site
city: Mittweida
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facility: Novartis Investigative Site
city: Munchen
country: Germany
facility: Novartis Investigative Site
city: Potsdam
country: Germany
facility: Novartis Investigative Site
city: Rudersdorf
country: Germany
facility: Novartis Investigative Site
city: Schleswig
country: Germany
facility: Novartis Investigative Site
city: Witten
country: Germany
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
state: GR
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
state: GR
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
state: GR
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
state: GR
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Puspokladany
country: Hungary
facility: Novartis Investigative Site
state: HUN
city: Balassagyarmat
country: Hungary
facility: Novartis Investigative Site
city: Godollo
country: Hungary
facility: Novartis Investigative Site
city: Komlo
country: Hungary
facility: Novartis Investigative Site
city: Sellye
country: Hungary
facility: Novartis Investigative Site
city: Siofok
country: Hungary
facility: Novartis Investigative Site
city: Szarvas
country: Hungary
facility: Novartis Investigative Site
city: Szeged
country: Hungary
facility: Novartis Investigative Site
city: Vijayawada
country: India
facility: Novartis Investigative Site
state: Andhra Pradesh
city: Kozhikode
country: India
facility: Novartis Investigative Site
state: Kerala
city: Nagpur
country: India
facility: Novartis Investigative Site
state: Maharashtra
city: Pune
country: India
facility: Novartis Investigative Site
state: Maharashtra
city: Mohali
country: India
facility: Novartis Investigative Site
state: Punjab
city: Coimbatore
country: India
facility: Novartis Investigative Site
state: Tamil Nadu
city: Vellore
country: India
facility: Novartis Investigative Site
state: Tamil Nadu
city: Hyderabad
country: India
facility: Novartis Investigative Site
state: Telangana
city: Kolkata
country: India
facility: Novartis Investigative Site
state: West Bengal
city: Jerusalem
country: Israel
facility: Novartis Investigative Site
city: Jerusalem
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facility: Novartis Investigative Site
city: Ramat Gan
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facility: Novartis Investigative Site
city: Rehovot
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facility: Novartis Investigative Site
city: Mexico
country: Mexico
facility: Novartis Investigative Site
state: Distrito Federal
city: Guadalajara
country: Mexico
facility: Novartis Investigative Site
state: Jalisco
city: Guadalajara
country: Mexico
facility: Novartis Investigative Site
state: Jalisco
city: San Martin de Porres
country: Peru
facility: Novartis Investigative Site
state: Lima
city: Santiago de Surco
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facility: Novartis Investigative Site
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facility: Novartis Investigative Site
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facility: Novartis Investigative Site
city: Poznan
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facility: Novartis Investigative Site
city: Poznan
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facility: Novartis Investigative Site
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facility: Novartis Investigative Site
city: Izhevsk
country: Russian Federation
facility: Novartis Investigative Site
city: Kemerovo
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Nizhny Novgorod
country: Russian Federation
facility: Novartis Investigative Site
city: Novosibirsk
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Saint-Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Saint-Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Saratov
country: Russian Federation
facility: Novartis Investigative Site
city: Saratov
country: Russian Federation
facility: Novartis Investigative Site
city: St Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Ulyanovsk
country: Russian Federation
facility: Novartis Investigative Site
city: Yekaterinburg
country: Russian Federation
facility: Novartis Investigative Site
city: Belgrade
country: Serbia
facility: Novartis Investigative Site
city: Kragujevac
country: Serbia
facility: Novartis Investigative Site
city: Nis
country: Serbia
facility: Novartis Investigative Site
city: Sremska Kamenica
country: Serbia
facility: Novartis Investigative Site
city: Bojnice
country: Slovakia
facility: Novartis Investigative Site
state: Slovak Republic
city: Humenne
country: Slovakia
facility: Novartis Investigative Site
state: Slovak Republic
city: Liptovsky Hradok
country: Slovakia
facility: Novartis Investigative Site
state: Slovak Republic
city: Liptovsky Mikulas
country: Slovakia
facility: Novartis Investigative Site
city: Topolcany
country: Slovakia
facility: Novartis Investigative Site
city: Zilina
country: Slovakia
facility: Novartis Investigative Site
city: Berea
country: South Africa
facility: Novartis Investigative Site
state: Durban
city: Cape Town
country: South Africa
facility: Novartis Investigative Site
city: Cape Town
country: South Africa
facility: Novartis Investigative Site
city: Chatsworth
country: South Africa
facility: Novartis Investigative Site
city: Kempton Park
country: South Africa
facility: Novartis Investigative Site
city: Pretoria
country: South Africa
facility: Novartis Investigative Site
city: Esparraguera
country: Spain
facility: Novartis Investigative Site
state: Barcelona
city: Hostalets De Balenya
country: Spain
facility: Novartis Investigative Site
state: Cataluna
city: Alzira
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Caceres
country: Spain
facility: Novartis Investigative Site
state: Extremadura
city: Benalmadena
country: Spain
facility: Novartis Investigative Site
state: Malaga
city: Kaoshiung
country: Taiwan
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Izmir
country: Turkey
facility: Novartis Investigative Site
city: Mersin
country: Turkey
facility: Novartis Investigative Site
city: Yenisehir/Izmir
country: Turkey
facility: Novartis Investigative Site
city: Ho Chi Minh
country: Vietnam
facility: Novartis Investigative Site
state: VNM
city: Hanoi
country: Vietnam
facility: Novartis Investigative Site
city: Ho Chi Minh
country: Vietnam
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: