Clinical trial NCT00776984: 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 (Study II)
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Asthma
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
Collaborators: name: Pfizer
First posted: 2008-10-22
Enrollment: 453
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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.

Primary outcomes:
measure: Peak Forced Expiratory Volume in 1 Second (FEV1) Response Within 3 Hours Post Dosing (0-3h) After a Treatment Period of 24 Weeks.
timeFrame: Baseline and 24 weeks
measure: Trough FEV1 Response Determined After a Treatment Period of 24 Weeks.
timeFrame: Baseline and 24 weeks
measure: Time to First Severe Asthma Exacerbation During the 48-week Treatment of the Pooled Data From the Two Twin Trials 205.416 (NCT00772538) and the Present 205.417 (NCT00776984).
timeFrame: 48 weeks
Secondary outcomes:
measure: Peak (Within 3 Hours Post-dosing) Forced Vital Capacity (FVC) Response at the End of the 24-week Treatment Period.
timeFrame: Baseline and 24 weeks
measure: Trough FVC Response at the End of the 24-week Treatment Period.
timeFrame: Baseline and 24 weeks
measure: FEV1 Area Under the Curve (AUC0-3h) Response at the End of the 24-week Treatment Period.
timeFrame: Baseline and 24 weeks
measure: FVC (AUC0-3h) Response at the End of the 24-week Treatment Period.
timeFrame: Baseline and 24 weeks
measure: Peak FEV1 0-3h Response at the End of the 48-week Treatment Period.
timeFrame: Baseline and 48 weeks
measure: Trough FEV1 Response at the End of the 48-week Treatment Period.
timeFrame: Baseline and 48 weeks
measure: AUC0-3h FEV1 Response at the End of the 48-week Treatment Period.
timeFrame: Baseline and 48 weeks
measure: Peak FVC 0-3h Response at the End of the 48-week Treatment Period.
timeFrame: Baseline and 48 weeks
measure: Trough FVC Response at the End of the 48-week Treatment Period.
timeFrame: Baseline and 48 weeks
measure: FVC AUC0-3h Response at the End of the 48-week Treatment Period.
timeFrame: Baseline and 48 weeks
measure: Mean Pre-dose Morning Peak Expiratory Flow (PEFa.m.) Response (Diary Data) of Last-7-days-before-week-24-visit .
timeFrame: Baseline and last 7 days before week 24 visit
measure: Mean Pre-dose Evening Peak Expiratory Flow (PEFp.m.) Response (Diary Data) of Last-7-days-before-week 24-visit.
timeFrame: Baseline and last 7 days before week 24 visit
measure: Mean Pre-dose FEV1 a.m. Response (Diary Data) of Last-7-days-before-week 24-visit.
timeFrame: Baseline and last 7 days before week 24 visit
measure: Mean Pre-dose FEV1-p.m.Response (Diary Data) of Last-7-days-before-week 24-visit.
timeFrame: Baseline and last 7 days before week 24 visit
measure: Mean PEF Variability Response (Absolute Difference Between Morning and Evening PEF Value Divided by Their Mean) of Last-7-days-before-week 24-visit.
timeFrame: Baseline and last 7 days before week 24 visit
measure: Time to First Severe Asthma Exacerbation During the 48-week Treatment.
timeFrame: 48 weeks
measure: Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period.
timeFrame: 48 weeks
measure: Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period.
timeFrame: 48 weeks
measure: Number of Patients With at Least One Asthma Exacerbation During the 48-week Treatment Period.
timeFrame: 48 weeks
measure: Number of Patients With at Least One Severe Asthma Exacerbation During the 48-week Treatment Period.
timeFrame: 48 weeks
measure: Time to First Hospitalisation for Asthma Exacerbation During the 48-week Treatment Period.
timeFrame: 48 weeks
measure: Number of Hospitalisations for Asthma Exacerbations Per Patient During the 48-week Treatment Period.
timeFrame: 48 weeks
measure: Number of Patients With at Least One Hospitalisation for Asthma Exacerbation During the 48-week Treatment Period.
timeFrame: 48 weeks
measure: Quality of Life as Assessed by Standardised Asthma Quality of Life Questionnaire (AQLQ(S)) at the End of the 24-week Treatment Period.
timeFrame: 24 weeks
measure: AQLQ(S) Total Score at the End of the 48-week Treatment Period.
timeFrame: 48 weeks
measure: Asthma Control as Assessed by Asthma Control Questionnaire (ACQ) at the End of the 24-week Treatment Period.
timeFrame: 24 weeks
measure: ACQ Score at the End of the 48-week Treatment Period.
timeFrame: 48 weeks
measure: Asthma Symptom Free Days Response During the Last-7-days-before-week-24-visit .
timeFrame: Baseline and last 7 days before week 24 visit
measure: Mean Pro Re Nata (as Needed, PRN) Rescue Medication Use Response During the Last-7-days-before-week-24-visit .
timeFrame: Baseline and last 7 days before week 24 visit
Other outcomes:
Locations:
city: Fountain Valley
country: United States
facility: 205.417.01061 Boehringer Ingelheim Investigational Site
state: California
city: Fresno
country: United States
facility: 205.417.01052 Boehringer Ingelheim Investigational Site
state: California
city: Stockton
country: United States
facility: 205.417.01051 Boehringer Ingelheim Investigational Site
state: California
city: Waterbury
country: United States
facility: 205.417.01056 Boehringer Ingelheim Investigational Site
state: Connecticut
city: Pensacola
country: United States
facility: 205.417.01065 Boehringer Ingelheim Investigational Site
state: Florida
city: Chicago
country: United States
facility: 205.417.01059 Boehringer Ingelheim Investigational Site
state: Illinois
city: Normal
country: United States
facility: 205.417.01068 Boehringer Ingelheim Investigational Site
state: Illinois
city: Louisville
country: United States
facility: 205.417.01063 Boehringer Ingelheim Investigational Site
state: Kentucky
city: New Orleans
country: United States
facility: 205.417.01064 Boehringer Ingelheim Investigational Site
state: Louisiana
city: Omaha
country: United States
facility: 205.417.01066 Boehringer Ingelheim Investigational Site
state: Nebraska
city: Ocean
country: United States
facility: 205.417.01069 Boehringer Ingelheim Investigational Site
state: New Jersey
city: Albany
country: United States
facility: 205.417.01062 Boehringer Ingelheim Investigational Site
state: New York
city: Great Neck
country: United States
facility: 205.417.01058 Boehringer Ingelheim Investigational Site
state: New York
city: Rockville Centre
country: United States
facility: 205.417.01055 Boehringer Ingelheim Investigational Site
state: New York
city: High Point
country: United States
facility: 205.417.01067 Boehringer Ingelheim Investigational Site
state: North Carolina
city: Canton
country: United States
facility: 205.417.01070 Boehringer Ingelheim Investigational Site
state: Ohio
city: Upland
country: United States
facility: 205.417.01053 Boehringer Ingelheim Investigational Site
state: Pennsylvania
city: Richmond
country: United States
facility: 205.417.01054 Boehringer Ingelheim Investigational Site
state: Virginia
city: Concord
country: Australia
facility: 205.417.61051 Boehringer Ingelheim Investigational Site
state: New South Wales
city: Mississauga
country: Canada
facility: 205.417.02051 Boehringer Ingelheim Investigational Site
state: Ontario
city: Ottawa
country: Canada
facility: 205.417.02053 Boehringer Ingelheim Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: 205.417.02052 Boehringer Ingelheim Investigational Site
state: Quebec
city: Aalborg
country: Denmark
facility: 205.417.45052 Boehringer Ingelheim Investigational Site
city: Aarhus C
country: Denmark
facility: 205.417.45051 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 205.417.49052 Boehringer Ingelheim Investigational Site
city: Hamburg
country: Germany
facility: 205.417.49054 Boehringer Ingelheim Investigational Site
city: Lübeck
country: Germany
facility: 205.417.49053 Boehringer Ingelheim Investigational Site
city: Rüdersdorf
country: Germany
facility: 205.417.49051 Boehringer Ingelheim Investigational Site
city: Weinheim
country: Germany
facility: 205.417.49055 Boehringer Ingelheim Investigational Site
city: Bussolengo (vr)
country: Italy
facility: 205.417.39052 Boehringer Ingelheim Investigational Site
city: Milano
country: Italy
facility: 205.417.39054 Boehringer Ingelheim Investigational Site
city: Pavia
country: Italy
facility: 205.417.39051 Boehringer Ingelheim Investigational Site
city: Pietra Ligure (sv)
country: Italy
facility: 205.417.39053 Boehringer Ingelheim Investigational Site
city: Himeji, Hyogo
country: Japan
facility: 205.417.81063 Boehringer Ingelheim Investigational Site
city: Hiroshima, Hiroshima
country: Japan
facility: 205.417.81056 Boehringer Ingelheim Investigational Site
city: Itabashi-ku, Tokyo
country: Japan
facility: 205.417.81051 Boehringer Ingelheim Investigational Site
city: Kagoshima, Kagoshima
country: Japan
facility: 205.417.81059 Boehringer Ingelheim Investigational Site
city: Kishiwada, Osaka
country: Japan
facility: 205.417.81053 Boehringer Ingelheim Investigational Site
city: Kitakyusyu, Fukuoka
country: Japan
facility: 205.417.81057 Boehringer Ingelheim Investigational Site
city: Koga, Fukuoka
country: Japan
facility: 205.417.81058 Boehringer Ingelheim Investigational Site
city: Kurashiki, Okayama
country: Japan
facility: 205.417.81055 Boehringer Ingelheim Investigational Site
city: Kurume, Fukuoka
country: Japan
facility: 205.417.81064 Boehringer Ingelheim Investigational Site
city: Morioka, Iwate
country: Japan
facility: 205.417.81062 Boehringer Ingelheim Investigational Site
city: Osaka-sayama, Osaka
country: Japan
facility: 205.417.81052 Boehringer Ingelheim Investigational Site
city: Sendai, Miyagi
country: Japan
facility: 205.417.81066 Boehringer Ingelheim Investigational Site
city: Seto, Aichi
country: Japan
facility: 205.417.81065 Boehringer Ingelheim Investigational Site
city: Urasoe, Okinawa
country: Japan
facility: 205.417.81060 Boehringer Ingelheim Investigational Site
city: Urasoe, Okinawa
country: Japan
facility: 205.417.81061 Boehringer Ingelheim Investigational Site
city: Wakayama, Wakayama
country: Japan
facility: 205.417.81054 Boehringer Ingelheim Investigational Site
city: Groningen
country: Netherlands
facility: 205.417.31051 Boehringer Ingelheim Investigational Site
city: Leeuwarden
country: Netherlands
facility: 205.417.31053 Boehringer Ingelheim Investigational Site
city: Schiedam
country: Netherlands
facility: 205.417.31052 Boehringer Ingelheim Investigational Site
city: Auckland NZ
country: New Zealand
facility: 205.417.64054 Boehringer Ingelheim Investigational Site
city: Christchurch
country: New Zealand
facility: 205.417.64053 Boehringer Ingelheim Investigational Site
city: Newtown Wellington NZ
country: New Zealand
facility: 205.417.64052 Boehringer Ingelheim Investigational Site
city: Tauranga
country: New Zealand
facility: 205.417.64051 Boehringer Ingelheim Investigational Site
city: St. Petersburg
country: Russian Federation
facility: 205.417.07051 Boehringer Ingelheim Investigational Site
city: St. Petersburg
country: Russian Federation
facility: 205.417.07052 Boehringer Ingelheim Investigational Site
city: St. Petersburg
country: Russian Federation
facility: 205.417.07053 Boehringer Ingelheim Investigational Site
city: Belgrade
country: Serbia
facility: 205.417.38153 Boehringer Ingelheim Investigational Site
city: Nis
country: Serbia
facility: 205.417.38151 Boehringer Ingelheim Investigational Site
city: Sremska Kamenica
country: Serbia
facility: 205.417.38152 Boehringer Ingelheim Investigational Site
city: Bellville
country: South Africa
facility: 205.417.27051 Boehringer Ingelheim Investigational Site
city: Cape Town
country: South Africa
facility: 205.417.27052 Boehringer Ingelheim Investigational Site
city: Cape Town
country: South Africa
facility: 205.417.27053 Boehringer Ingelheim Investigational Site
city: Cape Town
country: South Africa
facility: 205.417.27054 Boehringer Ingelheim Investigational Site
city: Ankara
country: Turkey
facility: 205.417.90052 Boehringer Ingelheim Investigational Site
city: Ankara
country: Turkey
facility: 205.417.90053 Boehringer Ingelheim Investigational Site
city: Izmit
country: Turkey
facility: 205.417.90051 Boehringer Ingelheim Investigational Site
city: Kharkov
country: Ukraine
facility: 205.417.38053 Boehringer Ingelheim Investigational Site
city: Kiev
country: Ukraine
facility: 205.417.38051 Boehringer Ingelheim Investigational Site
city: Vinnytsya
country: Ukraine
facility: 205.417.38052 Boehringer Ingelheim Investigational Site
city: Chertsey
country: United Kingdom
facility: 205.417.44051 Boehringer Ingelheim Investigational Site
city: Exeter
country: United Kingdom
facility: 205.417.44053 Boehringer Ingelheim Investigational Site
city: Windsor
country: United Kingdom
facility: 205.417.44052 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: Halpin DMG, Meltzer EO, Pisternick-Ruf W, Moroni-Zentgraf P, Engel M, Zaremba-Pechmann L, Casale T, FitzGerald JM. Peak expiratory flow as an endpoint for clinical trials in asthma: a comparison with FEV1. Respir Res. 2019 Jul 18;20(1):159. doi: 10.1186/s12931-019-1119-6.
citation: Casale TB, Bateman ED, Vandewalker M, Virchow JC, Schmidt H, Engel M, Moroni-Zentgraf P, Kerstjens HAM. Tiotropium Respimat Add-on Is Efficacious in Symptomatic Asthma, Independent of T2 Phenotype. J Allergy Clin Immunol Pract. 2018 May-Jun;6(3):923-935.e9. doi: 10.1016/j.jaip.2017.08.037. Epub 2017 Nov 22.
citation: Kerstjens HA, Engel M, Dahl R, Paggiaro P, Beck E, Vandewalker M, Sigmund R, Seibold W, Moroni-Zentgraf P, Bateman ED. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med. 2012 Sep 27;367(13):1198-207. doi: 10.1056/NEJMoa1208606. Epub 2012 Sep 2.