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A Randomised, Double- Blind, Placebo Controlled, Cross-over Efficacy and Safety Comparison of Tiotropium 5 µg Once Daily and Tiotropium 2.5 µg Twice Daily for Four Weeks in Patients With Moderate Persistent Asthma

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ClinicalTrials.gov Identifier: NCT01152450
Recruitment Status : Completed
First Posted : June 29, 2010
Results First Posted : October 30, 2012
Last Update Posted : May 16, 2014
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Boehringer Ingelheim

June 28, 2010
June 29, 2010
August 17, 2012
October 30, 2012
May 16, 2014
July 2010
August 2011   (Final data collection date for primary outcome measure)
Forced Expiratory Volume in One Second (FEV1) Area Under the Curve 0-24 Hours (AUC0-24h) Response [ Time Frame: 10 minutes (min) prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 hours (h) , 3 h, 4 h , 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4 ]
Mixed Model Repeated Measure (MMRM) results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measurements performed in relation to evening dosing. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres.
The primary endpoint is the Forced expiratory Volume in one second (FEV1) area under the curve (AUC) 0-24 hours (AUC0-24h) (L) determined at the end of each 4 week treatment period. All measurements will be performed in relation to evening (p.m.) dosing. [ Time Frame: 4 weeks ]
Complete list of historical versions of study NCT01152450 on ClinicalTrials.gov Archive Site
  • Mean Pre-dose Morning Peak Expiratory Flow (PEF a.m.) Response During the Last Week on Treatment [ Time Frame: Baseline and during week 4 of each treatment period ]
    MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured by patients at home using the AM2+ device.
  • Mean Pre-dose Evening Peak Expiratory Flow (PEF p.m.) Response During the Last Week on Treatment [ Time Frame: Baseline and during week 4 of each treatment period ]
    MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured by patients at home using the AM2+ device.
  • FEV1 Area Under the Curve 0-12 Hours (AUC0-12h) Response [ Time Frame: 10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h and 11 h 50 min related to evening dose at week 4 ]
    MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC0-12h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.
  • FEV1 Area Under the Curve 12-24 Hours (AUC12-24h) Response [ Time Frame: 10 min prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4 ]
    MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC12-24h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.
  • Peak FEV1 Within 24 Hours Post-dose Response [ Time Frame: Baseline and 4 weeks ]
    MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the evening trial-drug inhalation at the end of each 4 week period of randomised treatment.
  • Trough FEV1 Response [ Time Frame: Baseline and 4 weeks ]
    MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Trough FEV1 is defined as FEV1 value (performed at 10 minutes prior to the evening trial-drug inhalation) at the end of each 4 week period of randomised treatment.
  • Trough Forced Vital Capacity (FVC) Response [ Time Frame: Baseline and 4 weeks ]
    MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Trough FVC is defined as FVC value (performed at 10 minutes prior to the evening trial-drug inhalation) at the end of each 4 week period of randomised treatment.
  • FVC Area Under the Curve 0-12 Hours (AUC0-12h) Response [ Time Frame: 10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h and 11 h 50 min related to evening dose at week 4 ]
    MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following each dosing determined at the end of each 4 week treatment period. AUC0-12h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.
  • FVC Area Under the Curve 12-24 Hours (AUC12-24h) Response [ Time Frame: 10 min prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4 ]
    MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following each dosing determined at the end of each 4 week treatment period. AUC12-24h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.
  • Peak FVC Within 24 Hours Post-dose Response [ Time Frame: Baseline and 4 weeks ]
    MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following each dosing determined at the end of each 4 week treatment period.
  • Individual FEV1 Over Time (at Each Timepoint at Visits) Response [ Time Frame: Baseline and 4 weeks ]
    MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.
  • Individual FVC Over Time (at Each Timepoint at Visits) Response [ Time Frame: Baseline and 4 weeks ]
    MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.
  • Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response [ Time Frame: Baseline and 4 weeks ]
    MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.
  • FVC Area Under the Curve 0-24 Hours (AUC0-24h) Response [ Time Frame: 10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h , 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4 ]
    MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres.
  • PEF Area Under the Curve 0-24 Hours (AUC0-24h) Response [ Time Frame: 10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h , 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4 ]
    MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres/min.
  • PEF Variability Response (Last Week on Treatment) [ Time Frame: Baseline and during week 4 ]
    MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. PEF variability is the absolute difference between morning and evening PEF value divided by the mean of these two values, expressed as a percent (weekly means obtained during the last week of each period of randomised treatment will be compared).
  • Mean Number of Puffs of Rescue Medication During the Whole Day (Last Week on Treatment, Response Values) [ Time Frame: Baseline and during week 4 ]
    MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared.
  • Mean Number of Puffs of Rescue Medication During Daytime (Last Week on Treatment, Response Values) [ Time Frame: Baseline and during week 4 ]
    MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared.
  • Mean Number of Puffs of Rescue Medication During Nighttime (Last Week on Treatment, Response Values) [ Time Frame: Baseline and during week 4 ]
    MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared.
  • Mean Number of Night Awakenings During the Last Week on Treatment (Score, Response Values) [ Time Frame: Baseline and during week 4 ]
    MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Assessed by the patient's electronic diary (eDiary incorporated in the AM2+ device), obtained during the last week of each period of randomised treatment.
  • Peak expiratory flow (PEF) a.m. / p.m. at the end of each dosing interval (L/min) measured by patients at home using the AM2+® device (weekly means obtained during the last week of each period of randomised treatment will be compared). [ Time Frame: last of 4 week treatment ]
  • FEV1 (AUC0-12h) and FEV1 (AUC12-24h) measured following the respective dosing determined at the end of each 4 week period of randomised treatment. [ Time Frame: 4 weeks ]
  • Peak FEV1 (L) (within 24 hours post-dose) measured following the evening trial-drug inhalation at the end of each 4 week period of randomised treatment. [ Time Frame: 4 weeks ]
  • Trough FEV1 (L) at the end of each 4 week period of randomised treatment. [ Time Frame: 4 weeks ]
  • Trough forced vital capacity (FVC) (L) at the end of each dosing interval (as defined above for FEV1) determined at the end of each 4 week period of randomised treatment. [ Time Frame: 4 weeks ]
  • FVC (AUC0-12h) and FVC (AUC12-24h) and peak FVC (L) (within 24 hours post-dose) measured following each dosing determined at the end of each 4 week treatment period. [ Time Frame: 4 weeks ]
  • Individual FEV1, FVC (L) and PEF (L/min) measurements at each timepoint at visits; AUC0-24h of FVC (L) and PEF (L/min) [ Time Frame: 4 weeks ]
  • PEF variability: PEF variability (L/min) is the absolute difference between morning and evening PEF value divided by the mean of these two values (weekly means obtained during the last week of each period of randomised treatment will be compared). [ Time Frame: last of four week treatment ]
  • Use of prn salbutamol rescue medication during the entire study period: Number of puffs of rescue therapy used per day [ Time Frame: 19 weeks ]
  • Weekly mean number of nighttime awakenings as assessed by the patients electronic diary [ Time Frame: 19 weeks ]
  • Pharmacokinetic evaluation: maximum concentration of the analyte in plasma [ Time Frame: day 1 ]
  • area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point within the first dosing interval [ Time Frame: day 1 ]
  • amount of analyte that is eliminated in urine from the time point t1 to time point t2 [ Time Frame: day 1 ]
  • fraction of analyte excreted in urine from time point t1 to t2 [ Time Frame: day 1 ]
  • area under the concentration-time curve of the analyte in plasma over the time interval t1 to t2 [ Time Frame: day 1 ]
  • area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity [ Time Frame: day 1 ]
  • the percentage of the AUC0-infinity that is obtained by extrapolation [ Time Frame: day 1 ]
  • terminal rate constant of the analyte in plasma [ Time Frame: day 1 ]
  • terminal half-life of the analyte in plasma [ Time Frame: day 1 ]
  • mean residence time of the analyte in the body after inhalation [ Time Frame: day 1 ]
  • apparent clearance of the analyte in the plasma after extravascular administration [ Time Frame: day 1 ]
  • apparent volume of distribution of the analyte during the terminal phase following an extravascular dose [ Time Frame: day 1 ]
  • renal clearance of the analyte in plasma from the time point t1 to time point t2 [ Time Frame: day 1 ]
  • time from dosing to maximum concentration [ Time Frame: day 1 ]
  • area under the concentration-time curve of tiotropium in plasma over the time interval t1 to t2 [ Time Frame: four weeks ]
  • area under the plasma concentration-time curve at steady-state over a uniform dosing interval [ Time Frame: four weeks ]
  • maximum measured concentration of tiotropium in plasma at steady-state [ Time Frame: four weeks ]
  • time from dosing to the maximum concentration of tiotropium in plasma at steady-state [ Time Frame: four weeks ]
  • terminal rate constant in plasma [ Time Frame: four weeks ]
  • terminal half-life of the tiotropium in plasma [ Time Frame: four weeks ]
  • mean residence time of tiotropium in the body after inhalational administration [ Time Frame: four weeks ]
  • apparent clearance of tiotropium in the plasma after extravascular administration [ Time Frame: four weeks ]
  • apparent volume of distribution of tiotropium during the terminal phase following an extravascular dose [ Time Frame: four weeks ]
  • amount of tiotropium that is eliminated in urine from the time point t1 to time point t2 at steady-state [ Time Frame: four weeks ]
  • fraction of tiotropium eliminated in urine from time point t1 to time point t2 at steady-state [ Time Frame: four weeks ]
  • renal clearance of tiotropium from the time point t1 until the time point t2 at steady-state [ Time Frame: four weeks ]
  • pre-dose concentration of tiotropium in plasma at steady-state [ Time Frame: four weeks ]
  • minimum concentration of tiotropium in plasma at steady-state [ Time Frame: four weeks ]
Not Provided
Not Provided
 
A Randomised, Double- Blind, Placebo Controlled, Cross-over Efficacy and Safety Comparison of Tiotropium 5 µg Once Daily and Tiotropium 2.5 µg Twice Daily for Four Weeks in Patients With Moderate Persistent Asthma
A Phase II, Randomised, Double- Blind, Placebo Controlled, Cross-over Efficacy and Safety Comparison of Tiotropium 5 µg Administered Once Daily (in the Evening) and Tiotropium 2.5 µg Administered Twice Daily Delivered by the Respimat® Inhaler for Four Weeks Versus Placebo in Patients With Moderate Persistent Asthma

Rationale for the current trial is to demonstrate 24 hour bronchodilator efficacy and safety of tiotropium 5 µg administered once daily (in the evening) which is regarded beneficial for the compliance and convenience of the patient in comparison to placebo. Further the rationale is to evaluate efficacy and safety of tiotropium 2.5 µg administered twice daily delivered by the Respimat® inhaler in comparison to placebo and tiotropium 5 µg administered once daily (in the evening) delivered by the Respimat® inhaler in patients with moderate persistent asthma.

Rationale for the pharmacokinetic subinvestigation is to evaluate the 24 hours exposure to tiotropium in patients with moderate persistent asthma when administered 5 µg tiotropium once daily (in the evening) or 2.5 µg tiotropium twice daily.

Not Provided
Interventional
Phase 2
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double
Primary Purpose: Treatment
Asthma
  • Drug: Tiotropium 2.5 µg b.i.d
    2.5 µg (two actuations of 1.25 µg) delivered via Respimat® inhaler
  • Drug: Placebo
    N/A (two actuations of placebo) delivered via Respimat® inhaler
  • Drug: Tiotropium 5 µg q.d.
    5 µg (two actuations of 2.5 µg) delivered via Respimat® inhaler
  • Experimental: Tiotropium daily dose q.d.
    two actuations delivered via Respimat® inhaler
    Intervention: Drug: Tiotropium 5 µg q.d.
  • Experimental: Tiotropium half daily dose b.i.d.
    two actuations delivered via Respimat® inhaler
    Intervention: Drug: Tiotropium 2.5 µg b.i.d
  • Placebo Comparator: Placebo
    N/A (two actuations of placebo) delivered via Respimat® inhaler
    Intervention: Drug: Placebo
Timmer W, Moroni-Zentgraf P, Cornelissen P, Unseld A, Pizzichini E, Buhl R. Once-daily tiotropium Respimat(®) 5 μg is an efficacious 24-h bronchodilator in adults with symptomatic asthma. Respir Med. 2015 Mar;109(3):329-38. doi: 10.1016/j.rmed.2014.12.005. Epub 2014 Dec 27.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
94
90
Not Provided
August 2011   (Final data collection date for primary outcome measure)

Inclusion criteria:

  1. All patients must sign and date an Informed Consent Form consistent with International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice ( ICH-GCP) guidelines and local legislation prior to participation in the trial (i.e. prior to any trial procedures, including any pre-trial washout of medications and medication restrictions for pulmonary function test at Visit 1).
  2. Male or female patients aged at least 18 years but not more than 75 years.
  3. All patients must have at least a 3 months history of asthma at the time of enrolment into the trial. The diagnosis of asthma has to be confirmed at Visit 1 with a bronchodilator reversibility resulting in a Forced Expiratory Volume in 1 Second (FEV1) increase of equal above 12% and equal above 200mL.
  4. The initial diagnosis of asthma must have been made before the patient's age of 40.
  5. All patients must have a diagnosis of moderate persistent asthma and must be symptomatic despite their current maintenance treatment with medium doses of inhaled corticosteroids.
  6. All patients must have been on maintenance treatment with a medium, stable dose of inhaled corticosteroids (alone or in a fixed combination with a Long Acting Betaadrenergic (LABA) or Short Acting Betaadrenergic (SABA)) for at least 4 weeks prior to Visit 1.
  7. All patients must be symptomatic at Visit 1 (screening) and Visit 2 as defined by an Asthma Control Questionnaire (ACQ) Score
  8. All patients must have a pre-bronchodilator FEV1 above equal 60% predicted and below equal 90% of predicted normal at Visit 1. Predicted normal values will be calculated according to the European Coal and Steel Community Guidelines (ECSC).
  9. All patients must have an increase in FEV1 of equal above 12% and equal above 200 mL 15 minutes after 400 µg salbutamol at Visit 1.
  10. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator) as compared to Visit 2 (pre-dose) must be within ± 30% .
  11. Patients must be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment and who have a smoking history of less than 10 pack years.
  12. Patients must be able to use the Respimat® inhaler correctly.
  13. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of the e-Diary/peak flow meter.
  14. Patients taking a chronic pulmonary medication allowed by the study protocol must be willing to continue this therapy for the entire duration of the study (exception: times of acute disease deterioration).

Exclusion criteria:

  1. Patients with a significant disease other than asthma.A significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the trial, or (ii) influence the results of the trial, or (iii) cause concern regarding the patient's ability to participate in the trial.
  2. Patients with a clinically relevant abnormal screening hematology or blood chemistry if the abnormality defines a significant disease as defined in exclusion criterion no. 1.
  3. Patients with a recent history (i.e. six months or less) of myocardial infarction.
  4. Patients who have been hospitalised for cardiac failure during the past year.
  5. Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year.
  6. Patients with lung diseases other than asthma (e.g. Chronic Obstructive Lung Disease (COPD)).
  7. Patients with known active tuberculosis.
  8. 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.
  9. Patients who have undergone thoracotomy with pulmonary resection.
  10. Patients with significant alcohol or drug abuse within the past two years.
  11. Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to V 1.
  12. Patients with known hypersensitivity to anticholinergic drugs, Benzalconiumchloride (BAC), Ethylenediaminetetraacetate (EDTA) or any other components of the study medication delivery systems.
  13. Pregnant or nursing women.
  14. Women of childbearing potential not using a highly effective method of birth control.
  15. Patients who have been treated with beta-blocker medication within four weeks prior to Visit 1 or during the screening period. Topical cardio-selective beta-blocker eye medications for non-arrow angle glaucoma are allowed.
  16. Patients who have been treated with the long-acting anticholinergic tiotropium (Spiriva®) within four weeks prior to Visit 1 or during the screening period.
  17. Patients who have been treated with oral beta-adrenergics within four weeks prior to Visit 1 or during the screening period.
  18. Patients who have been treated with oral corticosteroids within four weeks prior to Visit 1 or during the screening period.
  19. Patients who have been treated with anti-IgE antibodies, e.g. omalizumab (Xolair®), within 6 months prior to Visit 1 or during the screening period.20. Patients who have been treated with cromolyn sodium or nedocromil sodium within two weeks prior to Visit 1 or during the screening period.

21. Patients who have been treated with methylxanthines within two weeks prior to Visit 1 or during the screening period.

22. Patients who have taken an investigational drug within four weeks prior to Visit 1.

23. Patients who have been treated with other non-approved and according to international guidelines not recommended "experimental" drugs for routine asthma therapy (e.g. TNFalpha blockers, methotrexate, cyclosporin) within four weeks prior to Visit 1 or during the screening period.

24. Patients with any asthma exacerbation or any respiratory tract infection in the four weeks prior to Visit 1 or during the screening period. Visit 1 and/or Visit 2 should be postponed in case of an asthma exacerbation or respiratory tract infection.

25. Patients who have previously been randomised in this trial or are currently participating in another trial.

26.Patients who have been treated with depot corticosteroids within six months prior to Visit 1 or during the screening period.

27.Patients who have been treated with leukotriene modifiers within two weeks prior to Visit 1 or during the screening period.

Sexes Eligible for Study: All
18 Years to 75 Years   (Adult, Older Adult)
No
Contact information is only displayed when the study is recruiting subjects
Austria,   Czech Republic,   Estonia,   Germany,   Latvia
 
 
NCT01152450
205.420
2009-018006-21 ( EudraCT Number: EudraCT )
Not Provided
Not Provided
Not Provided
Boehringer Ingelheim
Boehringer Ingelheim
Pfizer
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
Boehringer Ingelheim
February 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP