Clinical trial NCT00350207: Efficacy and Safety of Tiotropium and Salmeterol in Moderate Persistent Asthma Patients Homozygous for B16-Arg/Arg
Official title: A 16-week Randomised, Placebo-controlled, Double-blind, Double-dummy, Parallel-group Study Comparing the Efficacy and Safety of Tiotropium Inhalation Solution Delivered by the Respimat Inhaler (2 Actuations of 2.5 Mcg Once Daily) With That of Salmeterol From the Hydrofluoroalkane Metered Dose Inhaler (2 Actuations of 25 Mcg Twice Daily) in Moderate Persistent Asthma Patients With the B16-Arg/Arg Genotype
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Asthma
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2006-07-10
Enrollment: 388
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a 16 week multicentre, multinational, randomised, double-blind, double-dummy, placebo-controlled, parallel group study to evaluate the long-term efficacy and safety of tiotropium compared to salmeterol in moderate persistent asthmatic (GINA step 3) patients homozygous for arginine at the 16th amino acid position of the beta-adrenergic receptor (ADRB2). Following an initial 4-week run-in period on salmeterol MDI patients will be randomised into the 16 week double-blind treatment period in which they receive either tiotropium once daily administered from the Respimat inhaler or salmeterol twice daily administered from the hydrofluoro-alkane Metered Dose Inhaler (MDI), or placebo twice daily. After the 16 week treatment period all patients will receive salmeterol MDI twice daily for four weeks.

The patients perform daily morning and evening peak flow (PEF) and Forced Expiratory Volume in the First Second (FEV1) measurements with an electronic peak flow meter throughout the study. Daily data on asthma control and use of rescue medication are recorded using an electronic diary included in the electronic peak flow meter. On study visits the Mini-Asthma Quality of Life Questionnaire (Elizabeth Juniper) is administered, pulse and blood pressure and pre-dose pulmonary function testing (FEV1 and Forced Vital Capacity) are performed.


Eligibility criteria: Inclusion_Criteria:

1. Patients homozygous for arginine at the 16th amino acid position of the beta2 adrenergic receptor (B16 Arg/Arg)
2. All patients must sign and date an Informed Consent Form for the study prior to participation in the trial
3. Male or female outpatients with at least 18 years of age, but not older than 65 years
4. Patients must have a documented history of asthma
5. Patients must be current non-smokers or ex-smokers with a cigarette smoking history of \<10 pack-years
6. Patients must be on a maintenance treatment with inhaled corticosteroids with a total daily dose of 400 - 1000 mcg budesonide or equivalent

Exclusion_Criteria:

1. Patients with a significant disease other than asthma
2. Patients with a recent history (i.e., six months or less) of myocardial infarction
3. Patients who have been hospitalized for heart failure (New York Heart Association class III or IV) within the past year
4. Patients with any unstable or life threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year
5. Patients with malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years. Patients with treated basal cell carcinoma are allowed.
6. Patients with a diagnosis of chronic obstructive pulmonary disease (COPD)
7. Patients with a history of life threatening pulmonary obstruction, or a history of cystic fibrosis or clinically evident bronchiectasis
8. Patients with known active tuberculosis
9. Patients who have undergone thoracotomy with pulmonary resection.
10. Patients who have completed a pulmonary rehabilitation program in the six weeks prior to visit 1 or patients who are currently in a pulmonary rehabilitation program that will not be maintained throughout the duration of the study.

Primary outcomes:
measure: Change in Mean Weekly Morning Peak Expiratory Flow From Baseline to the End of the Trial
timeFrame: baseline and after 16 weeks of treatment
Secondary outcomes:
measure: Mean Weekly Morning Peak Expiratory Flow at Week 4
timeFrame: After 4 weeks of treatment
measure: Mean Weekly Morning Peak Expiratory Flow at Week 8
timeFrame: After 8 weeks of treatment
measure: Mean Weekly Morning Peak Expiratory Flow at Week 12
timeFrame: After 12 weeks of treatment
measure: Mean Weekly Morning Peak Expiratory Flow at Week 16
timeFrame: After 16 weeks of treatment
measure: Mean Weekly Evening Peak Expiratory Flow at Week 4
timeFrame: After 4 weeks of treatment
measure: Mean Weekly Evening Peak Expiratory Flow at Week 8
timeFrame: After 8 weeks of treatment
measure: Mean Weekly Evening Peak Expiratory Flow at Week 12
timeFrame: After 12 weeks of treatment
measure: Mean Weekly Evening Peak Expiratory Flow at Week 16
timeFrame: After 16 weeks of treatment
measure: Mean Weekly Morning Forced Expiratory Volume in 1 Second at Week 4
timeFrame: After 4 weeks of treatment
measure: Mean Weekly Morning Forced Expiratory Volume in 1 Second at Week 8
timeFrame: After 8 weeks of treatment
measure: Mean Weekly Morning Forced Expiratory Volume in 1 Second at Week 12
timeFrame: After 12 weeks of treatment
measure: Mean Weekly Morning Forced Expiratory Volume in 1 Second at Week 16
timeFrame: After 16 weeks of treatment
measure: Mean Weekly Evening Forced Expiratory Volume in 1 Second at Week 4
timeFrame: After 4 weeks of treatment
measure: Mean Weekly Evening Forced Expiratory Volume in 1 Second at Week 8
timeFrame: After 8 weeks of treatment
measure: Mean Weekly Evening Forced Expiratory Volume in 1 Second at Week 12
timeFrame: After 12 weeks of treatment
measure: Mean Weekly Evening Forced Expiratory Volume in 1 Second at Week 16
timeFrame: After 16 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "Did You Wake up During the Night Due to Asthma" at Week 4
timeFrame: After 4 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "Did You Wake up During the Night Due to Asthma" at Week 8
timeFrame: After 8 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "Did You Wake up During the Night Due to Asthma" at Week 12
timeFrame: After 12 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "Did You Wake up During the Night Due to Asthma" at Week 16
timeFrame: After 16 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "How Were Your Asthma Symptoms in the Morning" at Week 4
timeFrame: After 4 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "How Were Your Asthma Symptoms This Morning" at Week 8
timeFrame: After 8 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "How Were Your Asthma Symptoms This Morning" at Week 12
timeFrame: After 12 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "How Were Your Asthma Symptoms This Morning" at Week 16
timeFrame: After 16 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "How Were Your Asthma Symptoms During the Day" at Week 4
timeFrame: After 4 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "How Were Your Asthma Symptoms During the Day" at Week 8
timeFrame: After 8 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "How Were Your Asthma Symptoms During the Day" at Week 12
timeFrame: After 12 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "How Were Your Asthma Symptoms During the Day" at Week 16
timeFrame: After 16 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "How Limited Were You in Your Activities Today Because of Your Asthma" at Week 4
timeFrame: After 4 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "How Limited Were You in Your Activities Today Because of Your Asthma" at Week 8
timeFrame: After 8 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "How Limited Were You in Your Activities Today Because of Your Asthma" at Week 12
timeFrame: After 12 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "How Limited Were You in Your Activities Today Because of Your Asthma" at Week 16
timeFrame: After 16 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "How Much Shortness of Breath Did You Experience During the Day" at Week 4
timeFrame: After 4 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "How Much Shortness of Breath Did You Experience During the Day" at Week 8
timeFrame: After 8 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "How Much Shortness of Breath Did You Experience During the Day" at Week 12
timeFrame: After 12 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "How Much Shortness of Breath Did You Experience During the Day" at Week 16
timeFrame: After 16 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "Did You Experience Wheeze or Cough During the Day" at Week 4
timeFrame: After 4 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "Did You Experience Wheeze or Cough During the Day" at Week 8
timeFrame: After 8 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "Did You Experience Wheeze or Cough During the Day" at Week 12
timeFrame: After 12 weeks of treatment
measure: Mean Weekly Score for Asthma Control Diary Question "Did You Experience Wheeze or Cough During the Day" at Week 16
timeFrame: After 16 weeks of treatment
measure: Morning Pre-dose Forced Expiratory Volume in 1 Second as Measured by Spirometry at Visit 3
timeFrame: After 6 weeks of treatment
measure: Morning Pre-dose Forced Expiratory Volume in 1 Second as Measured by Spirometry at Visit 4
timeFrame: After 12 weeks of treatment
measure: Morning Pre-dose Forced Expiratory Volume in 1 Second as Measured by Spirometry at Visit 5
timeFrame: After 16 weeks of treatment
measure: Morning Pre-dose Forced Vital Capacity as Measured by Spirometry at Visit 3
timeFrame: After 6 weeks of treatment
measure: Morning Pre-dose Forced Vital Capacity as Measured by Spirometry at Visit 4
timeFrame: After 12 weeks of treatment
measure: Morning Pre-dose Forced Vital Capacity as Measured by Spirometry at Visit 5
timeFrame: After 16 weeks of treatment
measure: Mini-Asthma Quality of Life Questionnaire (Mini-AQLQ) Overall Score at Visit 3
timeFrame: After 6 weeks of treatment
measure: Mini-AQLQ Overall Score at Visit 4
timeFrame: After 12 weeks of treatment
measure: Mini-AQLQ Overall Score at Visit 5
timeFrame: After 16 weeks of treatment
measure: Systolic Blood Pressure in Conjunction With Spirometry at Visit 3
timeFrame: After 6 weeks of treatment
measure: Systolic Blood Pressure in Conjunction With Spirometry at Visit 4
timeFrame: After 12 weeks of treatment
measure: Systolic Blood Pressure in Conjunction With Spirometry at Visit 5
timeFrame: After 16 weeks of treatment
measure: Diastolic Blood Pressure in Conjunction With Spirometry at Visit 3
timeFrame: After 6 weeks of treatment
measure: Diastolic Blood Pressure in Conjunction With Spirometry at Visit 4
timeFrame: After 12 weeks of treatment
measure: Diastolic Blood Pressure in Conjunction With Spirometry at Visit 5
timeFrame: After 16 weeks of treatment
measure: Pulse Rate in Conjunction With Spirometry at Visit 3
timeFrame: After 6 weeks of treatment
measure: Pulse Rate in Conjunction With Spirometry at Visit 4
timeFrame: After 12 weeks of treatment
measure: Pulse Rate in Conjunction With Spirometry at Visit 5
timeFrame: After 16 weeks of treatment
measure: Mean PEF Variability at Week 4
timeFrame: After 4 weeks of treatment
measure: Mean PEF Variability at Week 8
timeFrame: After 8 weeks of treatment
measure: Mean PEF Variability at Week 12
timeFrame: After 12 weeks of treatment
measure: Mean PEF Variability at Week 16
timeFrame: After 16 weeks of treatment
Other outcomes:
Locations:
city: Graz
country: Austria
facility: 205.342.43002 Boehringer Ingelheim Investigational Site
city: Trofaiach
country: Austria
facility: 205.342.43004 Boehringer Ingelheim Investigational Site
city: Wels
country: Austria
facility: 205.342.43003 Boehringer Ingelheim Investigational Site
city: Wien
country: Austria
facility: 205.342.43001 Boehringer Ingelheim Investigational Site
city: Wien
country: Austria
facility: 205.342.43005 Boehringer Ingelheim Investigational Site
city: Wien
country: Austria
facility: 205.342.43006 Boehringer Ingelheim Investigational Site
city: Wien
country: Austria
facility: 205.342.43007 Boehringer Ingelheim Investigational Site
city: Anderlecht
country: Belgium
facility: 205.342.32010 Boehringer Ingelheim Investigational Site
city: Angleur
country: Belgium
facility: 205.342.32005 Boehringer Ingelheim Investigational Site
city: Brussel
country: Belgium
facility: 205.342.32002 Boehringer Ingelheim Investigational Site
city: Bruxelles
country: Belgium
facility: 205.342.32007 Boehringer Ingelheim Investigational Site
city: Bruxelles
country: Belgium
facility: 205.342.32014 Boehringer Ingelheim Investigational Site
city: Gent
country: Belgium
facility: 205.342.32001 Boehringer Ingelheim Investigational Site
city: Herentals
country: Belgium
facility: 205.342.32003 Boehringer Ingelheim Investigational Site
city: Malmédy
country: Belgium
facility: 205.342.32004 Boehringer Ingelheim Investigational Site
city: Menen
country: Belgium
facility: 205.342.32012 Boehringer Ingelheim Investigational Site
city: Montigny-le-Tilleul
country: Belgium
facility: 205.342.32006 Boehringer Ingelheim Investigational Site
city: Namur
country: Belgium
facility: 205.342.32009 Boehringer Ingelheim Investigational Site
city: Turnhout
country: Belgium
facility: 205.342.32011 Boehringer Ingelheim Investigational Site
city: Yvoir
country: Belgium
facility: 205.342.32013 Boehringer Ingelheim Investigational Site
city: Aalborg
country: Denmark
facility: 205.342.45003 Boehringer Ingelheim Investigational Site
city: Hvidovre
country: Denmark
facility: 205.342.45001 Boehringer Ingelheim Investigational Site
city: Kobenhavn NV
country: Denmark
facility: 205.342.45002 Boehringer Ingelheim Investigational Site
city: Odense C
country: Denmark
facility: 205.342.45004 Boehringer Ingelheim Investigational Site
city: Helsinki
country: Finland
facility: 205.342.35803 Boehringer Ingelheim Investigational Site
city: Jyväskylä
country: Finland
facility: 205.342.35801 Boehringer Ingelheim Investigational Site
city: Lahti
country: Finland
facility: 205.342.35802 Boehringer Ingelheim Investigational Site
city: Tampere
country: Finland
facility: 205.342.35804 Boehringer Ingelheim Investigational Site
city: Brest
country: France
facility: 205.342.3305A Centre Hosp de la Cavale Blanche
city: Chamalières
country: France
facility: 205.342.3304A Cabinet Médical
city: Chauny
country: France
facility: 205.342.3307A Boehringer Ingelheim Investigational Site
city: Grenoble
country: France
facility: 205.342.3301A UCP-X - Clinique Médicale
city: Montpellier
country: France
facility: 205.342.3302A Hôpital Arnaud de Villeneuve
city: Poitiers
country: France
facility: 205.342.3306A Mediscis
city: Saint Pierre la Réunion
country: France
facility: 205.342.3308A Boehringer Ingelheim Investigational Site
city: Saint Pierre la Réunion
country: France
facility: 205.342.3308B Boehringer Ingelheim Investigational Site
city: Beelitz-Heilstätten
country: Germany
facility: 205.342.49016 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 205.342.49004 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 205.342.49006 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 205.342.49013 Boehringer Ingelheim Investigational Site
city: Bruchsal
country: Germany
facility: 205.342.49003 Boehringer Ingelheim Investigational Site
city: Frankfurt/Main
country: Germany
facility: 205.342.49011 Boehringer Ingelheim Investigational Site
city: Kassel
country: Germany
facility: 205.342.49007 Boehringer Ingelheim Investigational Site
city: Köln
country: Germany
facility: 205.342.49009 Boehringer Ingelheim Investigational Site
city: Mainz
country: Germany
facility: 205.342.49010 Boehringer Ingelheim Investigational Site
city: Minden
country: Germany
facility: 205.342.49008 Boehringer Ingelheim Investigational Site
city: Neuruppin
country: Germany
facility: 205.342.49015 Boehringer Ingelheim Investigational Site
city: Rathenow
country: Germany
facility: 205.342.49012 Boehringer Ingelheim Investigational Site
city: Rüdersdorf
country: Germany
facility: 205.342.49005 Boehringer Ingelheim Investigational Site
city: Weinheim
country: Germany
facility: 205.342.49002 Boehringer Ingelheim Investigational Site
city: Athens
country: Greece
facility: 205.342.30001 Boehringer Ingelheim Investigational Site
city: Athens
country: Greece
facility: 205.342.30002 Boehringer Ingelheim Investigational Site
city: Heraklion
country: Greece
facility: 205.342.30005 Boehringer Ingelheim Investigational Site
city: Kavala
country: Greece
facility: 205.342.30006 Boehringer Ingelheim Investigational Site
city: Larisa
country: Greece
facility: 205.342.30004 Boehringer Ingelheim Investigational Site
city: Thessaloniki
country: Greece
facility: 205.342.30003 Boehringer Ingelheim Investigational Site
city: Ferrara
country: Italy
facility: 205.342.39003 Azienda Ospedaliera " S. Anna"
city: Firenze
country: Italy
facility: 205.342.39006 Azienda Ospedaliera Universitaria Careggi
city: Genova
country: Italy
facility: 205.342.39005 Ospedale San Martino
city: Modena
country: Italy
facility: 205.342.39002 Università di Modena e Reggio Emilia
city: Orbassano (to)
country: Italy
facility: 205.342.39010 Boehringer Ingelheim Investigational Site
city: Pavia
country: Italy
facility: 205.342.39007 Policlinico San Matteo
city: Pisa
country: Italy
facility: 205.342.39001 Ospedale di Cisanello
city: Sesto San Giovanni (mi)
country: Italy
facility: 205.342.39009 Boehringer Ingelheim Investigational Site
city: Moscow
country: Russian Federation
facility: 205.342.07001 Boehringer Ingelheim Investigational Site
city: Moscow
country: Russian Federation
facility: 205.342.07002 Boehringer Ingelheim Investigational Site
city: Moscow
country: Russian Federation
facility: 205.342.07003 Boehringer Ingelheim Investigational Site
city: Moscow
country: Russian Federation
facility: 205.342.07004 Boehringer Ingelheim Investigational Site
city: Moscow
country: Russian Federation
facility: 205.342.07005 Boehringer Ingelheim Investigational Site
city: St. Petersburg
country: Russian Federation
facility: 205.342.07006 Boehringer Ingelheim Investigational Site
city: St. Petersburg
country: Russian Federation
facility: 205.342.07007 Boehringer Ingelheim Investigational Site
city: St. Petersburg
country: Russian Federation
facility: 205.342.07008 Boehringer Ingelheim Investigational Site
city: Banska Bystrica
country: Slovakia
facility: 205.342.42101 Boehringer Ingelheim Investigational Site
city: Bratislava
country: Slovakia
facility: 205.342.42102 Boehringer Ingelheim Investigational Site
city: Bratislava
country: Slovakia
facility: 205.342.42104 Boehringer Ingelheim Investigational Site
city: Bratislava
country: Slovakia
facility: 205.342.42105 Boehringer Ingelheim Investigational Site
city: Bratislava
country: Slovakia
facility: 205.342.42107 Boehringer Ingelheim Investigational Site
city: Kosice
country: Slovakia
facility: 205.342.42103 Boehringer Ingelheim Investigational Site
city: Trencin
country: Slovakia
facility: 205.342.42106 Boehringer Ingelheim Investigational Site
city: Zilina
country: Slovakia
facility: 205.342.42108 Boehringer Ingelheim Investigational Site
city: Bellville
country: South Africa
facility: 205.342.27002 Boehringer Ingelheim Investigational Site
city: Bloemfontein
country: South Africa
facility: 205.342.27008 Boehringer Ingelheim Investigational Site
city: Cape Town
country: South Africa
facility: 205.342.27001 Boehringer Ingelheim Investigational Site
city: Cape Town
country: South Africa
facility: 205.342.27004 Boehringer Ingelheim Investigational Site
city: Centurion
country: South Africa
facility: 205.342.27006 Boehringer Ingelheim Investigational Site
city: Durban
country: South Africa
facility: 205.342.27003 Boehringer Ingelheim Investigational Site
city: George
country: South Africa
facility: 205.342.27007 Boehringer Ingelheim Investigational Site
city: Pretoria
country: South Africa
facility: 205.342.27005 Boehringer Ingelheim Investigational Site
city: Barcelona
country: Spain
facility: 205.342.34006 Hospital Clinic i Provincial de Barcelona
city: Centelles
country: Spain
facility: 205.342.34011 Boehringer Ingelheim Investigational Site
city: Guadalajara
country: Spain
facility: 205.342.34004 Hospital General Universitario de Guadalajara
city: Las Palmas de Gran Canaria
country: Spain
facility: 205.342.34002 Hospital de Gran Canaria Dr. Negrín
city: Lleida
country: Spain
facility: 205.342.34007 Hospital Universitari Arnau de Vilanova
city: Madrid
country: Spain
facility: 205.342.34003 Hospital Universitario La Paz
city: Madrid
country: Spain
facility: 205.342.34009 Hospital Universio Puerta del Hierro
city: Santander
country: Spain
facility: 205.342.34008 Hospital Universitario Marqués de Valdecilla
city: Sevilla
country: Spain
facility: 205.342.34005 Hospital Vírgen de la Macarena
city: Valencia
country: Spain
facility: 205.342.34010 Hospital General Universitario de Valencia
city: Ankara
country: Turkey
facility: 205.342.90001 Boehringer Ingelheim Investigational Site
city: Ankara
country: Turkey
facility: 205.342.90006 Boehringer Ingelheim Investigational Site
city: Bursa
country: Turkey
facility: 205.342.90003 Boehringer Ingelheim Investigational Site
city: Istanbul
country: Turkey
facility: 205.342.90007 Istanbul Universitesi Cerrahpasa Tip Fakultesi
city: Izmit
country: Turkey
facility: 205.342.90005 Kocaeli Universitesi Tip Fakultesi
city: Manisa
country: Turkey
facility: 205.342.90004 Celal Bayar Universitesi Tip Fakultesi
city: Aylesbury
country: United Kingdom
facility: 205.342.44002 Boehringer Ingelheim Investigational Site
city: Chertsey
country: United Kingdom
facility: 205.342.44001 Boehringer Ingelheim Investigational Site
city: Greenisland
country: United Kingdom
facility: 205.342.44003 Boehringer Ingelheim Investigational Site
city: Leicester
country: United Kingdom
facility: 205.342.44006 Boehringer Ingelheim Investigational Site
city: Nottingham
country: United Kingdom
facility: 205.342.44005 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: Bateman ED, Kornmann O, Schmidt P, Pivovarova A, Engel M, Fabbri LM. Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma. J Allergy Clin Immunol. 2011 Aug;128(2):315-22. doi: 10.1016/j.jaci.2011.06.004.