Efficacy and Safety of Tiotropium and Salmeterol in Moderate Persistent Asthma Patients Homozygous for B16-Arg/Arg

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Asthma

Intervention / Treatment
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* Drug: Tiotropium bromide
* Drug: Placebo
* Drug: Salmeterol xinafoate


Participation Criteria
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Eligibility Criteria
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Inclusion_Criteria: Patients homozygous for arginine at the 16th amino acid position of the beta2 adrenergic receptor (B16 Arg/Arg) All patients must sign and date an Informed Consent Form for the study prior to participation in the trial Male or female outpatients with at least 18 years of age, but not older than 65 years Patients must have a documented history of asthma Patients must be current non-smokers or ex-smokers with a cigarette smoking history of <10 pack-years Patients must be on a maintenance treatment with inhaled corticosteroids with a total daily dose of 400 - 1000 mcg budesonide or equivalent Exclusion_Criteria: Patients with a significant disease other than asthma Patients with a recent history (i.e., six months or less) of myocardial infarction Patients who have been hospitalized for heart failure (New York Heart Association class III or IV) within the past year Patients with any unstable or life threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year 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. Patients with a diagnosis of chronic obstructive pulmonary disease (COPD) Patients with a history of life threatening pulmonary obstruction, or a history of cystic fibrosis or clinically evident bronchiectasis Patients with known active tuberculosis Patients who have undergone thoracotomy with pulmonary resection. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Parallel Assignment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Tiotropium bromide|nan|
|Drug: Placebo|nan|
|Drug: Salmeterol xinafoate|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mean Weekly Morning Peak Expiratory Flow From Baseline to the End of the Trial | Change from baseline in mean weekly morning peak expiratory flow at 16 weeks. Baseline is defined as the last week prior to the randomisation visit | baseline and after 16 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Weekly Morning Peak Expiratory Flow at Week 4 | Mean weekly morning peak expiratory flow at week 4, pre-dose | After 4 weeks of treatment | 
| Mean Weekly Morning Peak Expiratory Flow at Week 8 | Mean weekly morning peak expiratory flow at week 8, pre-dose | After 8 weeks of treatment | 
| Mean Weekly Morning Peak Expiratory Flow at Week 12 | Mean weekly morning peak expiratory flow at week 12, pre-dose | After 12 weeks of treatment | 
| Mean Weekly Morning Peak Expiratory Flow at Week 16 | Mean weekly morning peak expiratory flow at week 16, pre-dose | After 16 weeks of treatment | 
| Mean Weekly Evening Peak Expiratory Flow at Week 4 | Mean weekly evening peak expiratory flow at week 4, pre-dose | After 4 weeks of treatment | 
| Mean Weekly Evening Peak Expiratory Flow at Week 8 | Mean weekly evening peak expiratory flow at week 8, pre-dose | After 8 weeks of treatment | 
| Mean Weekly Evening Peak Expiratory Flow at Week 12 | Mean weekly evening peak expiratory flow at week 12, pre-dose | After 12 weeks of treatment | 
| Mean Weekly Evening Peak Expiratory Flow at Week 16 | Mean weekly evening peak expiratory flow at week 16, pre-dose | After 16 weeks of treatment | 
| Mean Weekly Morning Forced Expiratory Volume in 1 Second at Week 4 | Mean weekly morning forced expiratory volume in 1 second at week 4, pre-dose | After 4 weeks of treatment | 
| Mean Weekly Morning Forced Expiratory Volume in 1 Second at Week 8 | Mean weekly morning forced expiratory volume in 1 second at week 8, pre-dose | After 8 weeks of treatment | 
| Mean Weekly Morning Forced Expiratory Volume in 1 Second at Week 12 | Mean weekly morning forced expiratory volume in 1 second at week 12, pre-dose | After 12 weeks of treatment | 
| Mean Weekly Morning Forced Expiratory Volume in 1 Second at Week 16 | Mean weekly morning forced expiratory volume in 1 second at week 16, pre-dose | After 16 weeks of treatment | 
| Mean Weekly Evening Forced Expiratory Volume in 1 Second at Week 4 | Mean weekly evening forced expiratory volume in 1 second at week 4, pre-dose | After 4 weeks of treatment | 
| Mean Weekly Evening Forced Expiratory Volume in 1 Second at Week 8 | Mean weekly evening forced expiratory volume in 1 second at week 8, pre-dose | After 8 weeks of treatment | 
| Mean Weekly Evening Forced Expiratory Volume in 1 Second at Week 12 | Mean weekly evening forced expiratory volume in 1 second at week 12, pre-dose | After 12 weeks of treatment | 
| Mean Weekly Evening Forced Expiratory Volume in 1 Second at Week 16 | Mean weekly evening forced expiratory volume in 1 second at week 16, pre-dose | After 16 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question Did You Wake up During the Night Due to Asthma at Week 4 | Unit on a scale 1-5. 1: Did not wake up, 2: Woke up once, 3: Woke up 2-5 times, 4: Woke up more than 5 times, 5: Was awake all night. 1 is the best value | After 4 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question Did You Wake up During the Night Due to Asthma at Week 8 | Unit on a scale 1-5. 1: Did not wake up, 2: Woke up once, 3: Woke up 2-5 times, 4: Woke up more than 5 times, 5: Was awake all night. 1 is the best value | After 8 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question Did You Wake up During the Night Due to Asthma at Week 12 | Unit on a scale 1-5. 1: Did not wake up, 2: Woke up once, 3: Woke up 2-5 times, 4: Woke up more than 5 times, 5: Was awake all night. 1 is the best value | After 12 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question Did You Wake up During the Night Due to Asthma at Week 16 | Unit on a scale 1-5. 1: Did not wake up, 2: Woke up once, 3: Woke up 2-5 times, 4: Woke up more than 5 times, 5: Was awake all night. 1 is the best value | After 16 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question How Were Your Asthma Symptoms in the Morning at Week 4 | Unit on a scale 1-5. 1: No asthma symptoms, 2: Mild asthma symptoms, 3: Moderate asthma symptoms, 4: Severe asthma symptoms, 5: Very severe asthma symptoms. 1 is the best value | After 4 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question How Were Your Asthma Symptoms This Morning at Week 8 | Unit on a scale 1-5. 1: No asthma symptoms, 2: Mild asthma symptoms, 3: Moderate asthma symptoms, 4: Severe asthma symptoms, 5: Very severe asthma symptoms. 1 is the best value | After 8 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question How Were Your Asthma Symptoms This Morning at Week 12 | Unit on a scale 1-5. 1: No asthma symptoms, 2: Mild asthma symptoms, 3: Moderate asthma symptoms, 4: Severe asthma symptoms, 5: Very severe asthma symptoms. 1 is the best value | After 12 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question How Were Your Asthma Symptoms This Morning at Week 16 | Unit on a scale 1-5. 1: No asthma symptoms, 2: Mild asthma symptoms, 3: Moderate asthma symptoms, 4: Severe asthma symptoms, 5: Very severe asthma symptoms. 1 is the best value | After 16 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question How Were Your Asthma Symptoms During the Day at Week 4 | Unit on a scale 1-5. 1: No asthma symptoms, 2: Mild asthma symptoms, 3: Moderate asthma symptoms, 4: Severe asthma symptoms, 5: Very severe asthma symptoms. 1 is the best value | After 4 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question How Were Your Asthma Symptoms During the Day at Week 8 | Unit on a scale 1-5. 1: No asthma symptoms, 2: Mild asthma symptoms, 3: Moderate asthma symptoms, 4: Severe asthma symptoms, 5: Very severe asthma symptoms. 1 is the best value | After 8 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question How Were Your Asthma Symptoms During the Day at Week 12 | Unit on a scale 1-5. 1: No asthma symptoms, 2: Mild asthma symptoms, 3: Moderate asthma symptoms, 4: Severe asthma symptoms, 5: Very severe asthma symptoms. 1 is the best value | After 12 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question How Were Your Asthma Symptoms During the Day at Week 16 | Unit on a scale 1-5. 1: No asthma symptoms, 2: Mild asthma symptoms, 3: Moderate asthma symptoms, 4: Severe asthma symptoms, 5: Very severe asthma symptoms. 1 is the best value | After 16 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question How Limited Were You in Your Activities Today Because of Your Asthma at Week 4 | Unit on a scale 1-5. 1: Not limited at all, 2: A little limited, 3: Moderately limited, 4: Severely limited, 5: Totally limited. 1 is the best value | After 4 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question How Limited Were You in Your Activities Today Because of Your Asthma at Week 8 | Unit on a scale 1-5. 1: Not limited at all, 2: A little limited, 3: Moderately limited, 4: Severely limited, 5: Totally limited. 1 is the best value | After 8 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question How Limited Were You in Your Activities Today Because of Your Asthma at Week 12 | Unit on a scale 1-5. 1: Not limited at all, 2: A little limited, 3: Moderately limited, 4: Severely limited, 5: Totally limited. 1 is the best value | After 12 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question How Limited Were You in Your Activities Today Because of Your Asthma at Week 16 | Unit on a scale 1-5. 1: Not limited at all, 2: A little limited, 3: Moderately limited, 4: Severely limited, 5: Totally limited. 1 is the best value | After 16 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question How Much Shortness of Breath Did You Experience During the Day at Week 4 | Unit on a scale 1-5. 1: None, 2: A very little, 3: A moderate amount, 4: Quite a lot, 5: A very great deal. 1 is the best value | After 4 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question How Much Shortness of Breath Did You Experience During the Day at Week 8 | Unit on a scale 1-5. 1: None, 2: A very little, 3: A moderate amount, 4: Quite a lot, 5: A very great deal. 1 is the best value | After 8 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question How Much Shortness of Breath Did You Experience During the Day at Week 12 | Unit on a scale 1-5. 1: None, 2: A very little, 3: A moderate amount, 4: Quite a lot, 5: A very great deal. 1 is the best value | After 12 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question How Much Shortness of Breath Did You Experience During the Day at Week 16 | Unit on a scale 1-5. 1: None, 2: A very little, 3: A moderate amount, 4: Quite a lot, 5: A very great deal. 1 is the best value | After 16 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question Did You Experience Wheeze or Cough During the Day at Week 4 | Unit on a scale 1-5. 1: Not at all, 2: A little of the time, 3: A moderate amount of the time, 4: Most of the time, 5: All the time. 1 is the best value | After 4 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question Did You Experience Wheeze or Cough During the Day at Week 8 | Unit on a scale 1-5. 1: Not at all, 2: A little of the time, 3: A moderate amount of the time, 4: Most of the time, 5: All the time. 1 is the best value | After 8 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question Did You Experience Wheeze or Cough During the Day at Week 12 | Unit on a scale 1-5. 1: Not at all, 2: A little of the time, 3: A moderate amount of the time, 4: Most of the time, 5: All the time. 1 is the best value | After 12 weeks of treatment | 
| Mean Weekly Score for Asthma Control Diary Question Did You Experience Wheeze or Cough During the Day at Week 16 | Unit on a scale 1-5. 1: Not at all, 2: A little of the time, 3: A moderate amount of the time, 4: Most of the time, 5: All the time. 1 is the best value | After 16 weeks of treatment | 
| Morning Pre-dose Forced Expiratory Volume in 1 Second as Measured by Spirometry at Visit 3 | Morning pre-dose forced expiratory volume in 1 second as measured by spirometry after 6 weeks of treatment | After 6 weeks of treatment | 
| Morning Pre-dose Forced Expiratory Volume in 1 Second as Measured by Spirometry at Visit 4 | Morning pre-dose forced expiratory volume in 1 second as measured by spirometry after 12 weeks of treatment | After 12 weeks of treatment | 
| Morning Pre-dose Forced Expiratory Volume in 1 Second as Measured by Spirometry at Visit 5 | Morning pre-dose forced expiratory volume in 1 second as measured by spirometry after 16 weeks od treatment | After 16 weeks of treatment | 
| Morning Pre-dose Forced Vital Capacity as Measured by Spirometry at Visit 3 | Morning pre-dose forced vital capacity as measured by spirometry after 6 weeks of treatment | After 6 weeks of treatment | 
| Morning Pre-dose Forced Vital Capacity as Measured by Spirometry at Visit 4 | Morning pre-dose forced vital capacity as measured by spirometry after 12 weeks of treatment | After 12 weeks of treatment | 
| Morning Pre-dose Forced Vital Capacity as Measured by Spirometry at Visit 5 | Morning pre-dose forced vital capacity as measured by spirometry after 16 weeks of treatment | After 16 weeks of treatment | 
| Mini-Asthma Quality of Life Questionnaire (Mini-AQLQ) Overall Score at Visit 3 | Mean of the responses to 15 questions from 4 domains: Symptoms (1), Activity Limitations (2), Emotional Function (3), Environmental Stimuli (4). Unit on a scale 1-7. For domain (2): 1: totally limited, 2: extremely limited, 3: very limited, 4: moderate limitation, 5: some limitation, 6: a little limitation, 7: not at all limited. For other domains: 1: all of the time, 2: most of the time, 3: a good bit of the time, 4: some of the time, 5: a little of the time, 6: hardly any of the time, 7: none of the time. 7 is the best value | After 6 weeks of treatment | 
| Mini-AQLQ Overall Score at Visit 4 | Mean of the responses to 15 questions from 4 domains: Symptoms (1), Activity Limitations (2), Emotional Function (3), Environmental Stimuli (4). Unit on a scale 1-7. For domain (2): 1: totally limited, 2: extremely limited, 3: very limited, 4: moderate limitation, 5: some limitation, 6: a little limitation, 7: not at all limited. For other domains: 1: all of the time, 2: most of the time, 3: a good bit of the time, 4: some of the time, 5: a little of the time, 6: hardly any of the time, 7: none of the time. 7 is the best value | After 12 weeks of treatment | 
| Mini-AQLQ Overall Score at Visit 5 | Mean of the responses to 15 questions from 4 domains: Symptoms (1), Activity Limitations (2), Emotional Function (3), Environmental Stimuli (4). Unit on a scale 1-7. For domain (2): 1: totally limited, 2: extremely limited, 3: very limited, 4: moderate limitation, 5: some limitation, 6: a little limitation, 7: not at all limited. For other domains: 1: all of the time, 2: most of the time, 3: a good bit of the time, 4: some of the time, 5: a little of the time, 6: hardly any of the time, 7: none of the time. 7 is the best value | After 16 weeks of treatment | 
| Systolic Blood Pressure in Conjunction With Spirometry at Visit 3 | Systolic blood pressure collected in conjunction with spirometry at 6 weeks | After 6 weeks of treatment | 
| Systolic Blood Pressure in Conjunction With Spirometry at Visit 4 | Systolic blood pressure collected in conjunction with spirometry at 12 weeks | After 12 weeks of treatment | 
| Systolic Blood Pressure in Conjunction With Spirometry at Visit 5 | Systolic blood pressure collected in conjunction with spirometry at 16 weeks | After 16 weeks of treatment | 
| Diastolic Blood Pressure in Conjunction With Spirometry at Visit 3 | Diastolic blood pressure collected in conjunction with spirometry at 6 weeks | After 6 weeks of treatment | 
| Diastolic Blood Pressure in Conjunction With Spirometry at Visit 4 | Diastolic blood pressure collected in conjunction with spirometry at 12 weeks | After 12 weeks of treatment | 
| Diastolic Blood Pressure in Conjunction With Spirometry at Visit 5 | Diastolic blood pressure collected in conjunction with spirometry at 16 weeks | After 16 weeks of treatment | 
| Pulse Rate in Conjunction With Spirometry at Visit 3 | Pulse rate collected in conjunction with spirometry at 6 weeks | After 6 weeks of treatment | 
| Pulse Rate in Conjunction With Spirometry at Visit 4 | Pulse rate collected in conjunction with spirometry at 12 weeks | After 12 weeks of treatment | 
| Pulse Rate in Conjunction With Spirometry at Visit 5 | Pulse rate collected in conjunction with spirometry at 16 weeks | After 16 weeks of treatment | 
| Mean PEF Variability at Week 4 | PEF (Peak expiratory flow) variability is defined as the difference between the highest morning PEF value and the highest evening PEF value of one day divided by the arithmetic mean of these two PEF values and multiplied by 100% | After 4 weeks of treatment | 
| Mean PEF Variability at Week 8 | PEF (Peak expiratory flow) variability is defined as the difference between the highest morning PEF value and the highest evening PEF value of one day divided by the arithmetic mean of these two PEF values and multiplied by 100% | After 8 weeks of treatment | 
| Mean PEF Variability at Week 12 | PEF (Peak expiratory flow) variability is defined as the difference between the highest morning PEF value and the highest evening PEF value of one day divided by the arithmetic mean of these two PEF values and multiplied by 100% | After 12 weeks of treatment | 
| Mean PEF Variability at Week 16 | PEF (Peak expiratory flow) variability is defined as the difference between the highest morning PEF value and the highest evening PEF value of one day divided by the arithmetic mean of these two PEF values and multiplied by 100% | After 16 weeks of treatment |