Asthma Clinical Research Network (ACRN) Trial - Tiotropium Bromide as an Alternative to Increased Inhaled Corticosteroid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid (TALC)

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

210 participants

Study Classification

INTERVENTIONAL

Study Start Date

2008-05-31

Study Completion Date

2010-05-31

Brief Summary

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Typically, people with asthma are initially prescribed a low dose of inhaled corticosteroid (ICS) medication to control asthma symptoms. If a low dose of ICS is ineffective at controlling symptoms, the addition of a second controller medication is recommended. This study will examine the effectiveness of the medication tiotropium bromide combined with a low dose of ICS at maintaining asthma control in people with moderately severe asthma.

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Detailed Description

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National and international asthma treatment guidelines recommend ICS as the initial controller therapy for people with asthma who are in need of daily treatment with a controller medication. If treatment with low to moderate doses of ICS is not sufficient to gain and maintain asthma control, current guidelines recommend adding a second controller medication rather than increasing the dose of ICS. Current options for the second medication include a long-acting beta-agonist, a leukotriene modifier, or theophylline. It is possible that other medications, not yet tested, could fill the role of the second controller medication. Tiotropium bromide is a medication that is used to treat chronic obstructive pulmonary disease (COPD). It works by relaxing and opening the air passages to the lungs to make breathing easier. For people with asthma, the addition of tiotropium bromide may be a good option as a second controller medication. The purpose of this study is to determine if combining tiotropium bromide with a low dose of ICS is more effective than doubling the dose of ICS in people with moderately severe asthma. This study will also examine whether the addition of tiotropium bromide to low dose ICS is as effective as the addition of a long-acting beta-agonist at maintaining asthma control.

This study will begin with a 4-week run-in period during which participants will be monitored while they use an inhaler containing a low dose of ICS medication. Next, participants will be assigned to take part in either the TALC study or the Best Adjustment Strategy for Asthma in Long Term (BASALT) study, which is a separate Asthma Clinical Research Network (ACRN) study.

All TALC participants will then undergo three 16-week treatment periods, which will include the following:

* tiotropium bromide inhalation powder 18 mcg once daily (Tio) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)
* salmeterol xinafoate inhalation powder 50 mcg twice daily (LABA) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)
* beclomethasone dipropionate 160 mcg twice daily (2xICS)

The order in which the three treatment periods will occur will be randomly assigned for each participant. Each of the three 16-week treatment periods will consist of 14 weeks of treatment followed by a 2-week washout period, in which participants will receive a single does of ICS. Study visits will occur at baseline and Weeks 2 and 4 of the 4-week run-in period, and at Weeks 4, 9, 14, and 16 of each 16-week treatment period. Spirometry tests to measure lung function will occur at each study visit and exhaled nitric oxide testing and questionnaires to assess asthma control and symptoms will occur at most visits. During study visits at Week 4 of the run-in period and Week 14 of each treatment period, lung function measurements, sputum collection, questionnaires to assess asthma quality-of-life, and measurements of sleep and daytime alertness will all occur. Participants will also record asthma symptoms, peak flow measurements, and medication usage in a daily diary.

Conditions

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Asthma

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Tio + 1xICS || LABA + 1xICS || 2xICS

Participants will take part in three 16-week treatment periods, which will occur in the following order:

* tiotropium bromide inhalation powder 18 mcg once daily (Tio) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)
* salmeterol xinafoate inhalation powder 50 mcg twice daily (LABA) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)
* beclomethasone dipropionate 160 mcg twice daily (2xICS)

Each of the three 16-week treatment periods will consist of 14 weeks of treatment followed by a 2-week washout period, in which participants will receive beclomethasone dipropionate 80 mcg twice daily (1xICS).

Group Type EXPERIMENTAL

tiotropium bromide

Intervention Type DRUG

tiotropium bromide inhalation powder 18 mcg once daily

salmeterol xinafoate

Intervention Type DRUG

salmeterol xinafoate inhalation powder 50 mcg twice daily

beclomethasone dipropionate

Intervention Type DRUG

beclomethasone dipropionate 80 mcg twice daily (1xICS) or 160 mcg twice daily (2xICS)

TIO + 1xICS || 2xICS || LABA + 1xICS

Participants will take part in three 16-week treatment periods, which will occur in the following order:

* tiotropium bromide inhalation powder 18 mcg once daily (Tio) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)
* beclomethasone dipropionate 160 mcg twice daily (2xICS)
* salmeterol xinafoate inhalation powder 50 mcg twice daily (LABA) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)

Each of the three 16-week treatment periods will consist of 14 weeks of treatment followed by a 2-week washout period, in which participants will receive beclomethasone dipropionate 80 mcg twice daily (1xICS).

Group Type EXPERIMENTAL

tiotropium bromide

Intervention Type DRUG

tiotropium bromide inhalation powder 18 mcg once daily

salmeterol xinafoate

Intervention Type DRUG

salmeterol xinafoate inhalation powder 50 mcg twice daily

beclomethasone dipropionate

Intervention Type DRUG

beclomethasone dipropionate 80 mcg twice daily (1xICS) or 160 mcg twice daily (2xICS)

LABA + 1xICS || Tio + 1xICS || 2xICS

Participants will take part in three 16-week treatment periods, which will occur in the following order:

* salmeterol xinafoate inhalation powder 50 mcg twice daily (LABA) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)
* tiotropium bromide inhalation powder 18 mcg once daily (Tio) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)
* beclomethasone dipropionate 160 mcg twice daily (2xICS)

Each of the three 16-week treatment periods will consist of 14 weeks of treatment followed by a 2-week washout period, in which participants will receive beclomethasone dipropionate 80 mcg twice daily (1xICS).

Group Type EXPERIMENTAL

tiotropium bromide

Intervention Type DRUG

tiotropium bromide inhalation powder 18 mcg once daily

salmeterol xinafoate

Intervention Type DRUG

salmeterol xinafoate inhalation powder 50 mcg twice daily

beclomethasone dipropionate

Intervention Type DRUG

beclomethasone dipropionate 80 mcg twice daily (1xICS) or 160 mcg twice daily (2xICS)

LABA + 1xICS || 2xICS || Tio + 1xICS

Participants will take part in three 16-week treatment periods, which will occur in the following order:

* salmeterol xinafoate inhalation powder 50 mcg twice daily (LABA) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)
* beclomethasone dipropionate 160 mcg twice daily (2xICS)
* tiotropium bromide inhalation powder 18 mcg once daily (Tio) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)

Each of the three 16-week treatment periods will consist of 14 weeks of treatment followed by a 2-week washout period, in which participants will receive beclomethasone dipropionate 80 mcg twice daily (1xICS).

Group Type EXPERIMENTAL

tiotropium bromide

Intervention Type DRUG

tiotropium bromide inhalation powder 18 mcg once daily

salmeterol xinafoate

Intervention Type DRUG

salmeterol xinafoate inhalation powder 50 mcg twice daily

beclomethasone dipropionate

Intervention Type DRUG

beclomethasone dipropionate 80 mcg twice daily (1xICS) or 160 mcg twice daily (2xICS)

2xICS || Tio + 1xICS| || LABA + 1xICS

Participants will take part in three 16-week treatment periods, which will occur in the following order:

* beclomethasone dipropionate 160 mcg twice daily (2xICS)
* tiotropium bromide inhalation powder 18 mcg once daily (Tio) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)
* salmeterol xinafoate inhalation powder 50 mcg twice daily (LABA) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)

Each of the three 16-week treatment periods will consist of 14 weeks of treatment followed by a 2-week washout period, in which participants will receive beclomethasone dipropionate 80 mcg twice daily (1xICS).

Group Type EXPERIMENTAL

tiotropium bromide

Intervention Type DRUG

tiotropium bromide inhalation powder 18 mcg once daily

salmeterol xinafoate

Intervention Type DRUG

salmeterol xinafoate inhalation powder 50 mcg twice daily

beclomethasone dipropionate

Intervention Type DRUG

beclomethasone dipropionate 80 mcg twice daily (1xICS) or 160 mcg twice daily (2xICS)

2xICS || LABA + 1xICS || Tio + 1xICS

Participants will take part in three 16-week treatment periods, which will occur in the following order:

* beclomethasone dipropionate 160 mcg twice daily (2xICS)
* salmeterol xinafoate inhalation powder 50 mcg twice daily (LABA) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)
* tiotropium bromide inhalation powder 18 mcg once daily (Tio) plus beclomethasone dipropionate 80 mcg twice daily (1xICS)

Each of the three 16-week treatment periods will consist of 14 weeks of treatment followed by a 2-week washout period, in which participants will receive beclomethasone dipropionate 80 mcg twice daily (1xICS).

Group Type EXPERIMENTAL

tiotropium bromide

Intervention Type DRUG

tiotropium bromide inhalation powder 18 mcg once daily

salmeterol xinafoate

Intervention Type DRUG

salmeterol xinafoate inhalation powder 50 mcg twice daily

beclomethasone dipropionate

Intervention Type DRUG

beclomethasone dipropionate 80 mcg twice daily (1xICS) or 160 mcg twice daily (2xICS)

Interventions

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tiotropium bromide

tiotropium bromide inhalation powder 18 mcg once daily

Intervention Type DRUG

salmeterol xinafoate

salmeterol xinafoate inhalation powder 50 mcg twice daily

Intervention Type DRUG

beclomethasone dipropionate

beclomethasone dipropionate 80 mcg twice daily (1xICS) or 160 mcg twice daily (2xICS)

Intervention Type DRUG

Other Intervention Names

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SPIRIVA® HandiHaler® Serevent® Diskus® QVAR® Inhalation Aerosol

Eligibility Criteria

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Inclusion Criteria

* Clinical history consistent with asthma
* Forced expiratory volume in one second (FEV1) greater than 40% of predicted value
* Asthma confirmed by one of the following two criteria:

1. Beta-agonist reversibility to 4 puffs albuterol of at least 12% OR
2. Methacholine provocative concentration at 20% (PC20) of 8 milligrams per milliliter (mg/mL) or less when not on an inhaled corticosteroid (ICS), or 16 mg/mL or less when on an ICS
* Need for daily controller therapy (i.e., ICS, leukotriene modifiers, and/or long-acting beta-agonists) based on one or more of the following criteria:

1. Received prescription for or used asthma controller within the 12 months prior to study entry OR
2. Experienced symptoms for more than twice a week and not on asthma controller
* If on inhaled steroids (any drug at any dose not exceeding the equivalent of 1000 micrograms (mcg) of fluticasone daily), participant must have been on a stable dose for at least 2 weeks prior to study entry
* Non-smoker (i.e., total lifetime smoking history less than 10 pack-years; no smoking for at least 1 year prior to study entry)
* Willing to use an effective form of birth control throughout the study

* Ability to measure morning (AM) peak expiratory flow (PEF) on schedule using electronic peak flow meter (EPFM) and to complete the study diary correctly at least 75% of the time during the interval between Weeks 2 and 4 of the run-in period
* Adherence with study medication dosing at least 75% of the time during the interval between Weeks 2 and 4 of the run-in period
* No asthma exacerbation requiring use of oral corticosteroids or additional asthma medications (including an increased dose of ICS) during the run-in period
* FEV1 greater than 40% of the predicted value

Exclusion Criteria

* Lung disease other than asthma, including chronic obstructive pulmonary disease (COPD) and chronic bronchitis
* Established or suspected diagnosis of vocal cord dysfunction
* Significant medical illness other than asthma
* History of respiratory tract infection within the 4 weeks prior to study entry
* History of a significant asthma exacerbation within the 4 weeks prior to study entry
* History of life-threatening asthma requiring treatment with intubation and mechanical ventilation in the 5 years prior to study entry
* Hyposensitization therapy other than an established maintenance regimen
* Inability to coordinate use of the delivery devices used in the study, based on the opinion of the investigator or clinical coordinator
* Pregnant

* Inability to coordinate use of the medication delivery devices used in the study, based on the opinion of the investigator or clinical coordinator

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Vernon M. Chinchilli, PhD

Professor and Chair, Department of Public Health Sciences

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Homer A. Boushey, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Richard J. Martin, MD

Role: PRINCIPAL_INVESTIGATOR

National Jewish Health

Elliot Israel, MD

Role: PRINCIPAL_INVESTIGATOR

Brigham and Women's Hospital

Stephen I. Wasserman, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Diego

Mario Castro, MD

Role: PRINCIPAL_INVESTIGATOR

Washington University School of Medicine

Emily A. DiMango, MD

Role: PRINCIPAL_INVESTIGATOR

Columbia University

Stephen P. Peters, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Wake Forest University Health Sciences

Monica Kraft, MD

Role: PRINCIPAL_INVESTIGATOR

Duke University

William J. Calhoun, MD

Role: PRINCIPAL_INVESTIGATOR

University of Texas

Robert F. Lemanske, MD

Role: PRINCIPAL_INVESTIGATOR

University of Wisconsin, Madison

Reuben M. Cherniack, MD

Role: STUDY_CHAIR

National Jewish Health

Locations

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University of California, San Diego

San Diego, California, United States

Site Status

University of California, San Francisco

San Francisco, California, United States

Site Status

National Jewish Medical and Research Center

Denver, Colorado, United States

Site Status

Brigham & Women's Hospital

Boston, Massachusetts, United States

Site Status

Washington University, St. Louis

St Louis, Missouri, United States

Site Status

Columbia University Health Sciences

New York, New York, United States

Site Status

Duke University Medical Center

Durham, North Carolina, United States

Site Status

Wake Forest University Health Sciences

Winston-Salem, North Carolina, United States

Site Status

University of Texas Medical Branch

Galveston, Texas, United States

Site Status

University of Wisconsin, Madison

Madison, Wisconsin, United States

Site Status

Countries

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United States

References

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Peters SP, Kunselman SJ, Icitovic N, Moore WC, Pascual R, Ameredes BT, Boushey HA, Calhoun WJ, Castro M, Cherniack RM, Craig T, Denlinger L, Engle LL, DiMango EA, Fahy JV, Israel E, Jarjour N, Kazani SD, Kraft M, Lazarus SC, Lemanske RF Jr, Lugogo N, Martin RJ, Meyers DA, Ramsdell J, Sorkness CA, Sutherland ER, Szefler SJ, Wasserman SI, Walter MJ, Wechsler ME, Chinchilli VM, Bleecker ER; National Heart, Lung, and Blood Institute Asthma Clinical Research Network. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med. 2010 Oct 28;363(18):1715-26. doi: 10.1056/NEJMoa1008770. Epub 2010 Sep 19.

Reference Type RESULT

PMID: 20979471 (View on PubMed)

Oba Y, Anwer S, Patel T, Maduke T, Dias S. Addition of long-acting beta2 agonists or long-acting muscarinic antagonists versus doubling the dose of inhaled corticosteroids (ICS) in adolescents and adults with uncontrolled asthma with medium dose ICS: a systematic review and network meta-analysis. Cochrane Database Syst Rev. 2023 Aug 21;8(8):CD013797. doi: 10.1002/14651858.CD013797.pub2.

Reference Type DERIVED

PMID: 37602534 (View on PubMed)

Oba Y, Anwer S, Maduke T, Patel T, Dias S. Effectiveness and tolerability of dual and triple combination inhaler therapies compared with each other and varying doses of inhaled corticosteroids in adolescents and adults with asthma: a systematic review and network meta-analysis. Cochrane Database Syst Rev. 2022 Dec 6;12(12):CD013799. doi: 10.1002/14651858.CD013799.pub2.

Reference Type DERIVED

PMID: 36472162 (View on PubMed)

Lugogo N, Green CL, Agada N, Zhang S, Meghdadpour S, Zhou R, Yang S, Anstrom KJ, Israel E, Martin R, Lemanske RF Jr, Boushey H, Lazarus SC, Wasserman SI, Castro M, Calhoun W, Peters SP, DiMango E, Chinchilli V, Kunselman S, King TS, Icitovic N, Kraft M. Obesity's effect on asthma extends to diagnostic criteria. J Allergy Clin Immunol. 2018 Mar;141(3):1096-1104. doi: 10.1016/j.jaci.2017.04.047. Epub 2017 Jun 15.

Reference Type DERIVED

PMID: 28624608 (View on PubMed)

Peters SP, Bleecker ER, Kunselman SJ, Icitovic N, Moore WC, Pascual R, Ameredes BT, Boushey HA, Calhoun WJ, Castro M, Cherniack RM, Craig T, Denlinger LC, Engle LL, Dimango EA, Israel E, Kraft M, Lazarus SC, Lemanske RF Jr, Lugogo N, Martin RJ, Meyers DA, Ramsdell J, Sorkness CA, Sutherland ER, Wasserman SI, Walter MJ, Wechsler ME, Chinchilli VM, Szefler SJ; National Heart, Lung, and Blood Institute's Asthma Clinical Research Network. Predictors of response to tiotropium versus salmeterol in asthmatic adults. J Allergy Clin Immunol. 2013 Nov;132(5):1068-1074.e1. doi: 10.1016/j.jaci.2013.08.003. Epub 2013 Sep 29.

Reference Type DERIVED

PMID: 24084072 (View on PubMed)

Sutherland ER, Goleva E, Jackson LP, Stevens AD, Leung DY. Vitamin D levels, lung function, and steroid response in adult asthma. Am J Respir Crit Care Med. 2010 Apr 1;181(7):699-704. doi: 10.1164/rccm.200911-1710OC. Epub 2010 Jan 14.

Reference Type DERIVED

PMID: 20075384 (View on PubMed)