Evaluation of Tiotropium 2.5 and 5 mcg Once Daily Delivered Via the Respimat® Inhaler Compared to Placebo and Salmeterol HydroFluoroAlkane (HFA) Metered Dose Inhaler (MDI) (50 mcg Twice Daily) in Patient With Moderate Persistent Asthma II

NCT ID: NCT01172821

Last Updated: 2014-06-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 1032 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-08-31
• Study Completion Date: 2012-11-30

Brief Summary

The aim of this trial is to evaluate the efficacy and safety of 2.5 and 5 mcg tiotropium over a 24-week treatment period as compared to placebo and salmeterol (50 mcg twice daily). Tiotropium inhalation solution delivered by the Respimat® inhaler will be examined on top of maintenance treatment with inhaled corticosteroid controller medication in patients with moderate persistent asthma. Efficacy and safety will be assessed by measuring effects on lung function, effects on asthma exacerbations, effects on quality of life, effects on asthma control, effects on health care resource utilisation, and number of adverse events.

Conditions

Asthma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

tiotropium low dose

Once daily, delivered with Respimat® inhaler (+ inhalation of placebo HFA MDI twice daily)

Group Type: EXPERIMENTAL

placebo

Intervention Type: DRUG

Placebo that represents comparator

tiotropium Respimat® low dose

Intervention Type: DRUG

IMP

tiotropium high dose

Once daily, delivered with Respimat® inhaler (+ inhalation of placebo HFA MDI twice daily)

Group Type: EXPERIMENTAL

tiotropium Respimat® high dose

Intervention Type: DRUG

IMP

placebo

Intervention Type: DRUG

Placebo that represents comparator

50 mcg salmeterol

Twice daily, delivered with HFA MDI (+ inhalation of placebo Respimat® inhaler once daily)

Group Type: ACTIVE_COMPARATOR

placebo

Intervention Type: DRUG

Placebo that represents BI drug

50 mcg salmeterol HFA MDI

Intervention Type: DRUG

Active comparator

placebo

Once daily, delivered with Respimat® inhaler + twice daily delivered with HFA MDI

Group Type: PLACEBO_COMPARATOR

placebo

Intervention Type: DRUG

Placebo that represents BI drug

placebo

Intervention Type: DRUG

Placebo that represents comparator

Interventions

placebo

Placebo that represents BI drug

Intervention Type: DRUG

placebo

Placebo that represents comparator

Intervention Type: DRUG

placebo

Placebo that represents comparator

Intervention Type: DRUG

tiotropium Respimat® low dose

IMP

Intervention Type: DRUG

placebo

Placebo that represents BI drug

Intervention Type: DRUG

tiotropium Respimat® high dose

IMP

Intervention Type: DRUG

50 mcg salmeterol HFA MDI

Active comparator

Intervention Type: DRUG

placebo

Placebo that represents comparator

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. All patients must sign and date an Informed Consent Form consistent with International Conference on Harmonisation - 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 month history of asthma at the time of enrolment into the trial. The diagnosis should be confirmed at Visit 1 by fulfilling inclusion criterion 5.

4. The initial diagnosis of asthma must have been made before the patient's age of 40.

5. The diagnosis of asthma has to be confirmed at Visit 1 with a bronchodilator reversibility (15 minutes after 400 mcg salbutamol (albuterol)) resulting in a Forced Expiratory Volume in one second (FEV1) increase of at least 12% and at least 200mL.

6. All patients must have been on maintenance treatment with a medium, stable dose of inhaled corticosteroids for at least for 4 weeks prior to Visit 1. 7. All patients must be symptomatic at Visit 1 (screening) and prior to randomisation at Visit 2 as defined by an Asthma Control Questionnaire (ACQ) mean score of at least 1.5.

8. All patients must have a pre-bronchodilator FEV1 at least 60% and less than or equal to 90% of predicted normal at Visit 1.

9. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator) as compared to Visit 2 (pre-dose) must be within ± 30%.

10. Patients must be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment (Visit 0) and who have a smoking history of less than 10 pack years.

11. Patients must be able to use the Respimat® inhaler and metered dose inhaler correctly.

12. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of 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 a clinically relevant abnormal screening (Visit 1) haematology or blood chemistry if the abnormality defines a significant disease as defined in exclusion criterion 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 Pulmonary 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. Patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion no. 1.

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 Visit 1 (screening).

12. Patients with known hypersensitivity to anticholinergic drugs, benzalkonium chloride (BAC), ethylenediamineteraacetic acid (EDTA), salmeterol xinafoate or any other components of the study medication delivery systems.

13. Pregnant or nursing woman.

14. Women of childbearing potential not using a highly effective method of birth control.

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

16. Patients who have been treated with beta-blocker medication within four weeks prior to Visit 1 and/or during the screening period. Topical cardio-selective beta-blocker eye medications for non-narrow angle glaucoma are allowed.

17. Patients who have been treated with the long-acting anticholinergic tiotropium (Spiriva®) within four weeks prior to Visit 1 and/or during the screening period.

18. Patients who have been treated with oral or patch beta-adrenergics within four weeks prior to Visit 1 and/or during the Screening period.

19. Patients who have been treated with oral corticosteroids within four weeks prior to Visit 1 and/or during the screening period.

20. Patients who have been treated with anti-IgE antibodies, e.g. omalizumab (Xolair®), within 6 months prior to Visit 1 and/or during the screening period.

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

22. Patients who have been treated with methylxanthines or phosphodiesterase 4 inhibitors within two weeks prior to Visit 1 and/or during the screening period.

23. Patients who have been treated with other non-approved and according to international guidelines not recommended "experimental" drugs for routine asthma therapy within four weeks prior to Visit 1 and/or during the screening period.

24. Patients with any asthma exacerbation or any respiratory tract infection iin the four weeks prior to Visit 1 and/or during the screening period.

25. Patients who have previously been randomised in this trial or in the respective twin trial (205.418) or are currently participating in another trial.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pfizer

INDUSTRY

Sponsor Role: collaborator

Boehringer Ingelheim

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Boehringer Ingelheim

Role: STUDY_CHAIR

Boehringer Ingelheim

Locations

205.419.01058 Boehringer Ingelheim Investigational Site

Los Angeles, California, United States

205.419.01053 Boehringer Ingelheim Investigational Site

Stockton, California, United States

205.419.01061 Boehringer Ingelheim Investigational Site

Centennial, Colorado, United States

205.419.01066 Boehringer Ingelheim Investigational Site

Denver, Colorado, United States

205.419.01064 Boehringer Ingelheim Investigational Site

Panama City, Florida, United States

205.419.01060 Boehringer Ingelheim Investigational Site

Winter Park, Florida, United States

205.419.01068 Boehringer Ingelheim Investigational Site

Novi, Michigan, United States

205.419.01054 Boehringer Ingelheim Investigational Site

Plymouth, Minnesota, United States

205.419.01062 Boehringer Ingelheim Investigational Site

St Louis, Missouri, United States

205.419.01070 Boehringer Ingelheim Investigational Site

Bozeman, Montana, United States

205.419.01067 Boehringer Ingelheim Investigational Site

Skillman, New Jersey, United States

205.419.01071 Boehringer Ingelheim Investigational Site

Raleigh, North Carolina, United States

205.419.01055 Boehringer Ingelheim Investigational Site

Cincinnati, Ohio, United States

205.419.01065 Boehringer Ingelheim Investigational Site

Portland, Oregon, United States

205.419.01069 Boehringer Ingelheim Investigational Site

Greenville, South Carolina, United States

205.419.01056 Boehringer Ingelheim Investigational Site

Union, South Carolina, United States

205.419.01063 Boehringer Ingelheim Investigational Site

El Paso, Texas, United States

205.419.01051 Boehringer Ingelheim Investigational Site

San Antonio, Texas, United States

205.419.55053 Boehringer Ingelheim Investigational Site

Florianópolis, , Brazil

205.419.55054 Boehringer Ingelheim Investigational Site

Porto Alegre, , Brazil

205.419.55052 Boehringer Ingelheim Investigational Site

São Paulo, , Brazil

205.419.55055 Boehringer Ingelheim Investigational Site

São Paulo, , Brazil

205.419.86061 Boehringer Ingelheim Investigational Site

Chengdu, , China

205.419.86053 Boehringer Ingelheim Investigational Site

Chongqing, , China

205.419.86056 Boehringer Ingelheim Investigational Site

Guangzhou, , China

205.419.86062 Boehringer Ingelheim Investigational Site

Guangzhou, , China

205.419.86054 Boehringer Ingelheim Investigational Site

Haikou, , China

205.419.86059 Boehringer Ingelheim Investigational Site

Kunming, , China

205.419.86058 Boehringer Ingelheim Investigational Site

Nanchang, , China

205.419.86064 Boehringer Ingelheim Investigational Site

Nanjing, , China

205.419.86051 Boehringer Ingelheim Investigational Site

Shanghai, , China

205.419.86052 Boehringer Ingelheim Investigational Site

Shanghai, , China

205.419.86055 Boehringer Ingelheim Investigational Site

Shanghai, , China

205.419.86066 Boehringer Ingelheim Investigational Site

Shanghai, , China

205.419.86057 Boehringer Ingelheim Investigational Site

Xi'an, , China

205.419.86065 Boehringer Ingelheim Investigational Site

Xi'an, , China

205.419.86063 Boehringer Ingelheim Investigational Site

Xuzhou, , China

205.419.86067 Boehringer Ingelheim Investigational Site

Yangzhou, , China

205.419.86068 Boehringer Ingelheim Investigational Site

Yinchuan, , China

205.419.57051 Boehringer Ingelheim Investigational Site

Bogotá, , Colombia

205.419.57052 Boehringer Ingelheim Investigational Site

Bogotá, , Colombia

205.419.57053 Boehringer Ingelheim Investigational Site

Bogotá, , Colombia

205.419.57054 Boehringer Ingelheim Investigational Site

Medellín, , Colombia

205.419.49061 Boehringer Ingelheim Investigational Site

Bamberg, , Germany

205.419.49051 Boehringer Ingelheim Investigational Site

Berlin, , Germany

205.419.49052 Boehringer Ingelheim Investigational Site

Berlin, , Germany

205.419.49062 Boehringer Ingelheim Investigational Site

Berlin, , Germany

205.419.49063 Boehringer Ingelheim Investigational Site

Berlin, , Germany

205.419.49064 Boehringer Ingelheim Investigational Site

Berlin, , Germany

205.419.49054 Boehringer Ingelheim Investigational Site

Frankfurt, , Germany

205.419.49058 Boehringer Ingelheim Investigational Site

Hamburg, , Germany

205.419.49057 Boehringer Ingelheim Investigational Site

Koblenz, , Germany

205.419.49056 Boehringer Ingelheim Investigational Site

Lübeck, , Germany

205.419.49059 Boehringer Ingelheim Investigational Site

Rüdersdorf, , Germany

205.419.49053 Boehringer Ingelheim Investigational Site

Wiesbaden, , Germany

205.419.49055 Boehringer Ingelheim Investigational Site

Witten, , Germany

205.419.91057 Boehringer Ingelheim Investigational Site

Ahmedabad, , India

205.419.91056 Boehringer Ingelheim Investigational Site

Coimbatore, , India

205.419.91055 Boehringer Ingelheim Investigational Site

Hyderabad, , India

205.419.91051 Boehringer Ingelheim Investigational Site

Jaipur, , India

205.419.91058 Boehringer Ingelheim Investigational Site

Jaipur, , India

205.419.91054 Boehringer Ingelheim Investigational Site

Mumbai, , India

205.419.91059 Boehringer Ingelheim Investigational Site

Mysore, , India

205.419.91053 Boehringer Ingelheim Investigational Site

Nagpur, , India

205.419.81085 Boehringer Ingelheim Investigational Site

Aira, Kagoshima, , Japan

205.419.81062 Boehringer Ingelheim Investigational Site

Chuo-ku, Tokyo, , Japan

205.419.81073 Boehringer Ingelheim Investigational Site

Fukuoka, Fukuoka, , Japan

205.419.81074 Boehringer Ingelheim Investigational Site

Fukuoka, Fukuoka, , Japan

205.419.81072 Boehringer Ingelheim Investigational Site

Fukuyama, Hiroshima, , Japan

205.419.81069 Boehringer Ingelheim Investigational Site

Habikino, Osaka, , Japan

205.419.81071 Boehringer Ingelheim Investigational Site

Hiroshima, Hiroshima, , Japan

205.419.81058 Boehringer Ingelheim Investigational Site

Itabashi-ku, Tokyo, , Japan

205.419.81064 Boehringer Ingelheim Investigational Site

Iwata, Shizuoka, , Japan

205.419.81063 Boehringer Ingelheim Investigational Site

Kanazawa, Ishikawa, , Japan

205.419.81054 Boehringer Ingelheim Investigational Site

Kishiwada, Osaka, , Japan

205.419.81075 Boehringer Ingelheim Investigational Site

Kitakyushu, Fukuoka, , Japan

205.419.81070 Boehringer Ingelheim Investigational Site

Kobe, Hyogo, , Japan

205.419.81061 Boehringer Ingelheim Investigational Site

Koto-ku, Tokyo, , Japan

205.419.81067 Boehringer Ingelheim Investigational Site

Kyoto, Kyoto, , Japan

205.419.81080 Boehringer Ingelheim Investigational Site

Matsusaka, Mie, , Japan

205.419.81081 Boehringer Ingelheim Investigational Site

Meguro-ku, Tokyo, , Japan

205.419.81060 Boehringer Ingelheim Investigational Site

Minato-ku, Tokyo, , Japan

205.419.81077 Boehringer Ingelheim Investigational Site

Minato-ku, Tokyo, , Japan

205.419.81056 Boehringer Ingelheim Investigational Site

Morioka, Iwate, , Japan

205.419.81055 Boehringer Ingelheim Investigational Site

Naka-gun, Ibaraki, , Japan

205.419.81078 Boehringer Ingelheim Investigational Site

Nakano-ku,Tokyo, , Japan

205.419.81084 Boehringer Ingelheim Investigational Site

Oita,Oita, , Japan

205.419.81068 Boehringer Ingelheim Investigational Site

Osaka-Sayama, Osaka, , Japan

205.419.81053 Boehringer Ingelheim Investigational Site

Sapporo, Hokkaido, , Japan

205.419.81057 Boehringer Ingelheim Investigational Site

Sendai, Miyagi, , Japan

205.419.81059 Boehringer Ingelheim Investigational Site

Seto, Aichi, , Japan

205.419.81082 Boehringer Ingelheim Investigational Site

Shinagawa-ku, Tokyo, , Japan

205.419.81065 Boehringer Ingelheim Investigational Site

Shizuoka, Shizuoka, , Japan

205.419.81066 Boehringer Ingelheim Investigational Site

Toyota, Aichi, , Japan

205.419.81051 Boehringer Ingelheim Investigational Site

Urasoe, Okinawa, , Japan

205.419.81052 Boehringer Ingelheim Investigational Site

Urasoe, Okinawa, , Japan

205.419.81076 Boehringer Ingelheim Investigational Site

Urasoe, Okinawa, , Japan

205.419.81083 Boehringer Ingelheim Investigational Site

Yokohama, Kanagawa, , Japan

205.419.81079 Boehringer Ingelheim Investigational Site

Yotsukaido, Chiba, , Japan

205.419.52051 Boehringer Ingelheim Investigational Site

Mexico City, , Mexico

205.419.52052 Boehringer Ingelheim Investigational Site

Mexico City, , Mexico

205.419.52053 Boehringer Ingelheim Investigational Site

Monterrey, , Mexico

205.419.51051 Boehringer Ingelheim Investigational Site

Lima, , Peru

205.419.51052 Boehringer Ingelheim Investigational Site

Lima, , Peru

205.419.51053 Boehringer Ingelheim Investigational Site

Lima, , Peru

205.419.51054 Boehringer Ingelheim Investigational Site

Lima, , Peru

205.419.51055 Boehringer Ingelheim Investigational Site

Lima, , Peru

205.419.48052 Boehringer Ingelheim Investigational Site

Bialystok, , Poland

205.419.48054 Boehringer Ingelheim Investigational Site

Bydgoszcz, , Poland

205.419.48055 Boehringer Ingelheim Investigational Site

Gorzów Wielkopolski, , Poland

205.419.48051 Boehringer Ingelheim Investigational Site

Krakow, , Poland

205.419.48057 Boehringer Ingelheim Investigational Site

Poznan, , Poland

205.419.48058 Boehringer Ingelheim Investigational Site

Sopot, , Poland

205.419.48056 Boehringer Ingelheim Investigational Site

Wroclaw, , Poland

205.419.48053 Boehringer Ingelheim Investigational Site

Włoszczowa, , Poland

205.419.40055 Boehringer Ingelheim Investigational Site

Brasov, , Romania

205.419.40056 Boehringer Ingelheim Investigational Site

Brasov, , Romania

205.419.40051 Boehringer Ingelheim Investigational Site

Bucharest, , Romania

205.419.40052 Boehringer Ingelheim Investigational Site

Bucharest, , Romania

205.419.40053 Boehringer Ingelheim Investigational Site

Bucharest, , Romania

205.419.40054 Boehringer Ingelheim Investigational Site

Bucharest, , Romania

205.419.40058 Boehringer Ingelheim Investigational Site

Bucharest, , Romania

205.419.40060 Boehringer Ingelheim Investigational Site

Bucharest, , Romania

205.419.40059 Boehringer Ingelheim Investigational Site

Constanța, , Romania

205.419.40057 Boehringer Ingelheim Investigational Site

Iași, , Romania

Countries

United States; Brazil; China; Colombia; Germany; India; Japan; Mexico; Peru; Poland; Romania

References

Halpin DMG, Hamelmann EH, Frith PA, Moroni-Zentgraf PM, van Hecke B, Unseld A, Kerstjens HAM, Szefler SJ. Comparative Responses in Lung Function Measurements with Tiotropium in Adolescents and Adults, and Across Asthma Severities: A Post Hoc Analysis. Pulm Ther. 2020 Jun;6(1):131-140. doi: 10.1007/s41030-020-00113-w. Epub 2020 Mar 16.

Reference Type: DERIVED

PMID: 32180164 (View on PubMed)

Casale TB, Aalbers R, Bleecker ER, Meltzer EO, Zaremba-Pechmann L, de la Hoz A, Kerstjens HAM. Tiotropium Respimat(R) add-on therapy to inhaled corticosteroids in patients with symptomatic asthma improves clinical outcomes regardless of baseline characteristics. Respir Med. 2019 Oct-Nov;158:97-109. doi: 10.1016/j.rmed.2019.09.014. Epub 2019 Sep 30.

Reference Type: DERIVED

PMID: 31654891 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31319851 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29174062 (View on PubMed)

Kerstjens HA, Casale TB, Bleecker ER, Meltzer EO, Pizzichini E, Schmidt O, Engel M, Bour L, Verkleij CB, Moroni-Zentgraf P, Bateman ED. Tiotropium or salmeterol as add-on therapy to inhaled corticosteroids for patients with moderate symptomatic asthma: two replicate, double-blind, placebo-controlled, parallel-group, active-comparator, randomised trials. Lancet Respir Med. 2015 May;3(5):367-76. doi: 10.1016/S2213-2600(15)00031-4. Epub 2015 Feb 12.

Reference Type: DERIVED

PMID: 25682232 (View on PubMed)

Other Identifiers

2009-018005-43

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

205.419

Identifier Type: -

Identifier Source: org_study_id