Evaluation of Tiotropium 5 µg/Day Delivered Via the Respimat® Inhaler Over 48 Weeks in Patients With Severe Persistent Asthma on Top of Usual Care

Condition(s) targeted: Asthma

Intervention: tiotropium 5mcg/day (Drug); tiotropium 5mcg/day (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Boehringer Ingelheim Pharmaceuticals

Official(s) and/or principal investigator(s):
Boehringer Ingelheim, Study Chair, Affiliation: Boehringer Ingelheim Pharmaceuticals

Overall contact:
Boehringer Ingelheim Call Center, Phone: 1-800-243-0127, Email: clintriage.rdg@boehringer-ingelheim.com

The trial is a randomised, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of 5 µg tiotropium over a 48-week treatment period as compared to placebo. Tiotropium inhalation solution delivered by the Respimat® inhaler will be examined as add-on controller therapy on top of usual care in patients with severe persistent asthma. The primary objective of each trial is to evaluate the long term efficacy of tiotropium over placebo on top of usual care in patients with severe persistent asthma as determined by pulmonary function testing, effects on asthma exacerbations, effects on quality of life, on asthma control and health care resource utilisation. The secondary objective of each trial is to compare the long term safety of tiotropium with placebo in this patient population.

Official title: A Phase III Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution Delivered Via Respimat® Inhaler (5 Mcg/Day) Over 48 Weeks as add-on Controller Therapy on Top of Usual Care in Patients With Severe Persistent Asthma

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Primary outcome:

Peak FEV1 response (within 3 hours post dosing) determined after a treatment period of 24 weeks.

Time to first severe asthma exacerbation during the 48-week treatment period. This endpoint will be evaluated on pooled data from the two twin trials 205.416 and 205.417 only.

Trough FEV1 response determined after a treatment period of 24 weeks. Trough FEV1 is defined as the FEV1 measured at the - 10 minute time point at the end of the dosing interval (24 hours post drug administration).

Secondary outcome:

All adverse events.

Amount of analyte that is eliminated in urine from the time point t1 to time point t2.

Amount of tiotropium that is eliminated in urine from the time point t1 to time point t2 at steady-state

Apparent clearance of the analyte in the plasma after extravascular administration

Apparent clearance of tiotropium in the plasma after extravascular administration, steady state

Apparent volume of distribution of the analyte during the terminal phase (z following an extravascular dose

Apparent volume of distribution of tiotropium during the terminal phase Delta-z following an extravascular dose

Area under the concentration time curve of tiotropium in plasma over the time interval t1 to t2, steady state.

Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.

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.

Area under the concentration-time curve of the analyte in plasma over the time interval t1 to t2.

Asthma symptom free days during the 48-week treatment period: Asthma symptom free day is defined as a day with no reported symptoms and no use of rescue medication.

Asthma symptoms as assessed by the patients electronic diary during the 48-week treatment period. Analysis with regard to daytime or night-time symptoms will be done.

B16 and B27 genotype of the beta2 adrenergic receptor

Control of asthma as assessed by the Asthma Control Questionnaire (ACQ) at all time-points during the 48-week treatment period and after 30 days follow-up period.

EQ-5D

FEV1 (AUC0-12h), FEV1 (AUC12-24h), FEV1 (AUC0-24h), FVC (AUC0-12h), FVC (AUC12-24h), FVC (AUC0-24h)

FEV1 (AUC0-3h) and FVC (AUC0-3h) at the end of the 24-week treatment period.

FEV1 a.m./p.m.: mean pre-dose morning and evening peak expiratory flow measured by patients at home (weekly and overall means will be compared).

Fraction of analyte excreted in urine from time point t1 to t2.

Fraction of tiotropium eliminated in urine from time point t1 to time point t2 at steady-state

Further exploratory genetic investigations in respiratory diseases

Health Care Resource Utilisation (HCRU)

Individual FEV1 and FVC measurements at all time-points including peak, trough and AUC0-3h during the 48-week treatment period

Maximum concentration of the analyte in plasma.

Maximum measured concentration of tiotropium in plasma, steady state.

Mean residence time of the analyte in the body after inhalation.

Mean residence time of tiotropium in the body after inhalational administration, steady state.

Minimum concentration of tiotropium in plasma at steady state

Number of asthma exacerbations per patient (exposure adjusted and unadjusted) based on severity of the asthma exacerbation during the 48-week treatment period.

Number of hospitalisations for asthma exacerbations per patient (exposure adjusted and unadjusted) during the 48-week treatment period.

Number of patients with at least one asthma exacerbation based on severity during the 48-week treatment period.

Number of patients with at least one hospitalisation for asthma exacerbation during the 48-week treatment period.

PEF a.m./p.m.: mean pre-dose morning and evening peak expiratory flow measured by patients at home (weekly and overall means will be compared).

PEF variability: PEF variability is the absolute difference between morning and evening PEF value divided by the mean of these two values (weekly and overall means will be compared) during the 48-week treatment period.

Peak (within 3 hours post dosing) and trough Forced Vital Capacity (FVC) determined at the end of the 24-week treatment period (as defined above for FEV1).

Physical examination at Visit 1 and at the end of the randomised treatment period.

Pre-dose concentration of tiotropium in plasma

Pre-dose concentration of tiotropium in plasma

Pre-dose concentration of tiotropium in plasma

Predose concentration of tiotropium in plasma at steady state

Quality of Life as assessed by standardised Asthma Quality of Life Questionnaire (AQLQ (S)) at all time-points during the 48-week treatment period and after 30 days follow-up period.

RA, AUC based on AUC t1-t2

RA, Cmax, 28 based on Cmax

Renal clearance of the analyte in plasma from the time point t1 to time point t2.

Renal clearance of tiotropium from the time point t1 until the time point t2 at steady state

Terminal half-life of the analyte in plasma.

Terminal half-life of the tiotropium in plasma, steady state.

Terminal rate constant in plasma, steady state.

Terminal rate constant of the analyte in plasma.

The area under the plasma concentration-time curve at steady state over a uniform dosing interval , steady state.

The percentage of the AUC0-infinity that is obtained by extrapolation

Time from dosing to maximum concentration

Time from dosing to the maximum concentration of tiotropium in plasma, steady state.

Time to first hospitalisation for asthma exacerbation during the 48-week treatment period.

Time to first severe asthma exacerbation during the 48-week treatment period.

Use of PRN salbutamol (albuterol) rescue medication during the 48-week treatment period: Number of puffs of rescue therapy used per day (i.e. the full 24 hour period, the daytime and the night time; weekly and overall means will be compared)

Vital signs: Pulse rate and blood pressure (seated) recorded in conjunction with spirometry for the first 3 hours post dosing at each visit.

Vital status information of prematurely discontinued patients to be collected for all randomised patients on the originally planned Visit dates for the complete trial period

Minimum age: 18 Years. Maximum age: 75 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

1. All patients must sign and date an Informed Consent Form consistent with 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 5-year history of asthma at the time of enrolment into the trial and the diagnosis of asthma must have been made before the patient´s age of 40.

4. All patients must have a diagnosis of severe persistent asthma and must be symptomatic despite treatment with high, stable doses of inhaled corticosteroids and a long-acting beta adrenergic agent

5. All patients must have a history of one or more asthma exacerbation in the past year.

6. Patients must have evidence of treated, severe, persistent asthma in postbronchodilator pulmonary function tests.

7. Patients should 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

8. Patients must be able to use the Respimat® inhaler correctly

9. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of the electronic diary/peak flow meter.

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 clinically relevant abnormal screening haematology or blood chemistry.

3. Patients with a recent history (i. e. six months or less) of myocardial infarction, hospitalisation for cardiac failure during the past year, any unstable or life threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year, known active tuberculosis, malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years (treated basal cell carcinoma allowed), lung diseases other than asthma (e. g. COPD), significant alcohol or drug abuse within the past two years, patients who have undergone thoracotomy with pulmonary resection. Patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion No. 1.

4. Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to the screening visit (Visit 1).

5. Patients using oral corticosteroid medication at stable doses exceeding 5 mg prednisolone or prednisolone equivalent every day or 10 mg prednisolone or prednisolone equivalent every second day.

6. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the tiotropium inhalation solution.

7. Pregnant or nursing women or women of childbearing potential not using a highly effective method of birth control. Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation/salpingectomy, or post-menopausal for at least two years.

8. Patients who have taken an investigational drug within four weeks or six half-lives (whichever is greater) prior to Visit 1.

9. Patients who have been treated with the long-acting anticholinergic tiotropium (Spiriva®), beta-blocker medication, oral beta-adrenergics, other non-approved and according to international guidelines not recommended ´experimental´ drugs for routine asthma therapy (e. g. TNF-alpha blockers, methotrexate, cyclosporin) within four weeks prior to the Screening Visit (Visit 1) or during the screening period.

10. Patients with any asthma exacerbation or respiratory tract infection in the four weeks prior to the trial.

11. Patients who have previously been randomised in this trial or in the respective twin trial (205. 416 versus 205. 417) or are currently participating in another trial.

12. Patients with a known narrow-angle glaucoma.

Note:

As with other anticholinergic drugs, tiotropium should be used with caution in patients with prostatic hyperplasia or bladder neck obstruction.

As with all predominantly renally excreted drugs, patients with moderate to severe renal impairment (known creatinine clearance of <= 50 mL/min) treated with tiotropium should be monitored closely.

Boehringer Ingelheim Call Center, Phone: 1-800-243-0127, Email: clintriage.rdg@boehringer-ingelheim.com

205.417.45052 Boehringer Ingelheim Investigational Site, Aalborg, Denmark; Active, not recruiting

205.417.45051 Boehringer Ingelheim Investigational Site, Aarhus C, Denmark; Active, not recruiting

205.417.49052 Boehringer Ingelheim Investigational Site, Berlin, Germany; Recruiting

205.417.49054 Boehringer Ingelheim Investigational Site, Hamburg, Germany; Completed

205.417.49053 Boehringer Ingelheim Investigational Site, Lübeck, Germany; Recruiting

205.417.49051 Boehringer Ingelheim Investigational Site, Rüdersdorf, Germany; Recruiting

205.417.49055 Boehringer Ingelheim Investigational Site, Weinheim, Germany; Active, not recruiting

205.417.39052 Boehringer Ingelheim Investigational Site, Bussolengo (vr), Italy; Active, not recruiting

205.417.39054 Boehringer Ingelheim Investigational Site, Milano, Italy; Active, not recruiting

205.417.39051 Boehringer Ingelheim Investigational Site, Pavia, Italy; Active, not recruiting

205.417.39053 Boehringer Ingelheim Investigational Site, Pietra Ligure (sv), Italy; Active, not recruiting

205.417.81063 Boehringer Ingelheim Investigational Site, Himeji, Hyogo, Japan; Active, not recruiting

205.417.81056 Boehringer Ingelheim Investigational Site, Hiroshima, Hiroshima, Japan; Active, not recruiting

205.417.81051 Boehringer Ingelheim Investigational Site, Itabashi-ku, Tokyo, Japan; Active, not recruiting

205.417.81059 Boehringer Ingelheim Investigational Site, Kagoshima, Kagoshima, Japan; Active, not recruiting

205.417.81053 Boehringer Ingelheim Investigational Site, Kishiwada, Osaka, Japan; Active, not recruiting

205.417.81057 Boehringer Ingelheim Investigational Site, Kitakyusyu, Fukuoka, Japan; Active, not recruiting

205.417.81058 Boehringer Ingelheim Investigational Site, Koga, Fukuoka, Japan; Active, not recruiting

205.417.81055 Boehringer Ingelheim Investigational Site, Kurashiki, Okayama, Japan; Active, not recruiting

205.417.81064 Boehringer Ingelheim Investigational Site, Kurume, Fukuoka, Japan; Active, not recruiting

205.417.81062 Boehringer Ingelheim Investigational Site, Morioka, Iwate, Japan; Active, not recruiting

205.417.81052 Boehringer Ingelheim Investigational Site, Osaka-sayama, Osaka, Japan; Recruiting

205.417.81066 Boehringer Ingelheim Investigational Site, Sendai, Miyagi, Japan; Active, not recruiting

205.417.81065 Boehringer Ingelheim Investigational Site, Seto, Aichi, Japan; Recruiting

205.417.81060 Boehringer Ingelheim Investigational Site, Urasoe, Okinawa, Japan; Active, not recruiting

205.417.81061 Boehringer Ingelheim Investigational Site, Urasoe, Okinawa, Japan; Active, not recruiting

205.417.81054 Boehringer Ingelheim Investigational Site, Wakayama, Wakayama, Japan; Active, not recruiting

205.417.31051 Boehringer Ingelheim Investigational Site, Groningen, Netherlands; Recruiting

205.417.31055 Boehringer Ingelheim Investigational Site, Hoofddorp, Netherlands; Recruiting

205.417.31053 Boehringer Ingelheim Investigational Site, Leeuwarden, Netherlands; Recruiting

205.417.31052 Boehringer Ingelheim Investigational Site, Schiedam, Netherlands; Recruiting

205.417.64054 Boehringer Ingelheim Investigational Site, Auckland NZ, New Zealand; Active, not recruiting

205.417.64053 Boehringer Ingelheim Investigational Site, Christchurch, New Zealand; Active, not recruiting

205.417.64051 Boehringer Ingelheim Investigational Site, Tauranga, New Zealand; Active, not recruiting

205.417.64052 Boehringer Ingelheim Investigational Site, Wellington, New Zealand; Active, not recruiting

205.417.07051 Boehringer Ingelheim Investigational Site, St. Petersburg, Russian Federation; Active, not recruiting

205.417.07052 Boehringer Ingelheim Investigational Site, St. Petersburg, Russian Federation; Active, not recruiting

205.417.07053 Boehringer Ingelheim Investigational Site, St. Petersburg, Russian Federation; Active, not recruiting

205.417.38153 Boehringer Ingelheim Investigational Site, Belgrade, Serbia; Active, not recruiting

205.417.38151 Boehringer Ingelheim Investigational Site, Nis, Serbia; Active, not recruiting

205.417.38152 Boehringer Ingelheim Investigational Site, Sremska Kamenica, Serbia; Active, not recruiting

205.417.27051 Boehringer Ingelheim Investigational Site, Bellville, South Africa; Active, not recruiting

205.417.27052 Boehringer Ingelheim Investigational Site, Cape Town, South Africa; Active, not recruiting

205.417.27053 Boehringer Ingelheim Investigational Site, Cape Town, South Africa; Active, not recruiting

205.417.27054 Boehringer Ingelheim Investigational Site, Cape Town, South Africa; Active, not recruiting

205.417.90053 Boehringer Ingelheim Investigational Site, Ankara, Turkey; Active, not recruiting

205.417.90052 Boehringer Ingelheim Investigational Site, Ankara, Turkey; Active, not recruiting

205.417.90051 Boehringer Ingelheim Investigational Site, Izmit, Turkey; Active, not recruiting

205.417.38053 Boehringer Ingelheim Investigational Site, Kharkov, Ukraine; Active, not recruiting

205.417.38051 Boehringer Ingelheim Investigational Site, Kiev, Ukraine; Active, not recruiting

205.417.38052 Boehringer Ingelheim Investigational Site, Vinnytsya, Ukraine; Active, not recruiting

205.417.44051 Boehringer Ingelheim Investigational Site, Chertsey, United Kingdom; Completed

205.417.44053 Boehringer Ingelheim Investigational Site, Exeter, United Kingdom; Completed

205.417.44052 Boehringer Ingelheim Investigational Site, Windsor, United Kingdom; Active, not recruiting

205.417.01061 Boehringer Ingelheim Investigational Site, Fountain Valley, California, United States; Active, not recruiting

205.417.01052 Boehringer Ingelheim Investigational Site, Fresno, California, United States; Terminated

205.417.01051 Boehringer Ingelheim Investigational Site, Stockton, California, United States; Active, not recruiting

205.417.01056 Boehringer Ingelheim Investigational Site, Waterbury, Connecticut, United States; Active, not recruiting

205.417.01065 Boehringer Ingelheim Investigational Site, Pensacola, Florida, United States; Active, not recruiting

205.417.01059 Boehringer Ingelheim Investigational Site, Chicago, Illinois, United States; Active, not recruiting

205.417.01068 Boehringer Ingelheim Investigational Site, Normal, Illinois, United States; Active, not recruiting

205.417.01063 Boehringer Ingelheim Investigational Site, Louisville, Kentucky, United States; Terminated

205.417.01064 Boehringer Ingelheim Investigational Site, New Orleans, Louisiana, United States; Active, not recruiting

205.417.01066 Boehringer Ingelheim Investigational Site, Omaha, Nebraska, United States; Terminated

205.417.01069 Boehringer Ingelheim Investigational Site, Ocean, New Jersey, United States; Active, not recruiting

205.417.61051 Boehringer Ingelheim Investigational Site, Concord, New South Wales, Australia; Active, not recruiting

205.417.01062 Boehringer Ingelheim Investigational Site, Albany, New York, United States; Active, not recruiting

205.417.01058 Boehringer Ingelheim Investigational Site, Great Neck, New York, United States; Active, not recruiting

205.417.01055 Boehringer Ingelheim Investigational Site, Rockville Centre, New York, United States; Active, not recruiting

205.417.01067 Boehringer Ingelheim Investigational Site, High Point, North Carolina, United States; Active, not recruiting

205.417.01070 Boehringer Ingelheim Investigational Site, Canton, Ohio, United States; Active, not recruiting

205.417.02051 Boehringer Ingelheim Investigational Site, Mississauga, Ontario, Canada; Recruiting

205.417.02053 Boehringer Ingelheim Investigational Site, Ottawa, Ontario, Canada; Recruiting

205.417.01053 Boehringer Ingelheim Investigational Site, Upland, Pennsylvania, United States; Active, not recruiting

205.417.02052 Boehringer Ingelheim Investigational Site, Montreal, Quebec, Canada; Recruiting

205.417.01054 Boehringer Ingelheim Investigational Site, Richmond, Virginia, United States; Active, not recruiting

Starting date: October 2008
Last updated: September 14, 2010