TALC

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Peters SP, et al. "Tiotropium bromide step-up therapy for adults with uncontrolled asthma". The New England Journal of Medicine. 2010. 363(18):1715-1726.
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Clinical Question

In patients with poorly controlled asthma currently using an inhaled corticosteroid alone, does the addition of tiotropium improve symptoms and lung function when compared to increasing the dose of inhaled corticosteroid or adding a long-acting beta-agonist?

Bottom Line

Among patients with poorly controlled asthma receiving inhaled corticosteroid monotherapy, the addition of the long-acting anticholinergic tiotropium may decrease symptoms and improve asthma control when compared to adding a long-acting beta-agonist (LABA).

Major Points

Current treatment options for patients whose asthma is poorly controlled with inhaled corticosteroid (ICS) monotherapy include adding a LABA or montelukast, or increasing the ICS dose. Short- and long-acting anticholinergic agents, which are approved in chronic obstructive pulmonary disease (COPD), had been hypothesized to improve outcomes in asthmatic patients, but their utility compared to LABAs had not been prospectively studied in a large trial.

Published in 2010, the Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid (TALC) trial enrolled 210 adult asthmatic patients whose symptoms were poorly controlled with single-agent ICS. Patients were randomized to one of three arms: 1) doubling their current ICS dose, 2) adding the LABA salmeterol, or 3) adding the long-acting anticholinergic tiotropium. Each patient received the three treatment options for a 14-week period with a 2-week washout between treatments. The primary outcome was morning peak expiratory flow (PEF) between the titropium and increased ICS groups. At the end of the study period, the addition of tiotropium was associated with improved morning PEF when compared to doubling the ICS dose but not when compared to adding salmeterol. Tiotropium outperformed salmeterol in several outcomes including evening PEF and asthma control days.

By virtue of its relatively small size and choice of morning PEF as its primary outcome, TALC has not widely changed clinical practice. Nevertheless, it has challenged the dogma that beta-agonists solely benefit asthmatics and anticholinergics benefit only those with COPD. As such, it has opened the doors for further study of anticholinergic agents as controller agents in patients with poorly controlled asthma.

This trial was run in coordination with BASALT (2012), which studied outcomes of asthma treatment based on physician, patient, and biomarker assessments.[1]

Guidelines

As of February 2015, no guidelines have been published that reflect the results of this trial.

Design

  • Randomized, three-way, double-blind, triple-dummy, crossover trial
  • N=210 patients with poorly controlled asthma receiving ICS mono therapy
    • Tiotropium
    • Salmeterol
    • Doubling ICS dose
  • Setting: 10 medical centers in the United States
  • Enrollment: 2007-2009
  • Analysis: Intention-to-treat
  • Primary outcome: Morning peak expiratory flow (PEF) between tiotropium and doubling the ICS dose

Population

Inclusion Criteria

  • Age ≥18 years
  • History of asthma, confirmed by bronchodilator reversibility or bronchial hyperresponsiveness
  • FEV1 >40% predicted
  • Non-smoker (<10 pack-years)

Exclusion Criteria

  • Use of any prohibited drug including other asthma medications or medications contraindicated in the study insert of study drugs
  • Significant medical illnesses or lung diseases other than asthma
  • Vocal cord dysfunction
  • Respiratory tract infection or significant asthma exacerbation in the previous 4 weeks
  • History of life-threatening asthma in the past 5 years
  • Pregnant or not using acceptable birth control methods if of childbearing potential
  • Hyposensitization therapy other than an established maintenance regimen
  • Inability to effectively use drug delivery devices used in the study

Interventions

Run-in phase

  • All maintenance medicines were stopped and each study participant was started on inhaled beclomethasone 80 μg BID.
  • In order to continue to the study phase, patients had to demonstrate:
    • 75% adherence to the run-in protocol
    • FEV1 ≥40% of the predicted value
    • FEV1 <70% after 4 weeks of inhaled beclomethasone 80 μg BID, symptoms of asthma 6 or more days per week during the last 2 weeks of run-in, or rescue inhaler use ≥6 days per week during the last 2 weeks of the run-in phase, or awakened by symptoms ≥2 nights/week.
    • Patient did not require additional maintenance medication.

Study phase

  • All patients completed a 4-week run-in phase as outlined above
  • All patients cycled through each of the three treatments
  • Each treatment was given in a 14-week cycle, each with a 2-week washout period between of beclomethasone 80 μg BID
    • Cycle 1: Inhaled beclomethasone 80 μg BID plus tiotropium bromide 18 μg every morning plus placebo
    • Cycle 2: Inhaled beclomethasone 160 μg BID plus two placebo inhalers
    • Cycle 3: Inhaled beclomethasone 80 μg BID plus salmeterol 50 μg BID plus placebo

Baseline Characteristics

  • Age (mean): 42.2 years
  • Male: 33%
  • One or more positive skin tests for atopy: 87.5%
  • Duration of asthma (mean): 26 years
  • FEV1 before bronchodilation: 2.31 liters
  • Mean BMI at visit 1: 31.4 kg/m2
  • Mean morning PEF: 377 L/min
  • Mean evening PEF: 384 L/min
  • FEV1 before bronchodilation: 71.5% of predicted
  • FEV1 % reversal of obstruction with albuterol (4 puffs): 14.9
  • Asthma control days: 2.97
  • Daily symptom score: 0.46 (scale of 0 to 3, with a higher score indicating a greater severity of symptoms)
  • Asthma Symptom Utility Index score: 0.78 (scale of 0 to 1, with a higher score indicating better asthma control)
  • Asthma Control Questionnaire score: 1.64 (scale of 0 to 6, with a higher score indicating worse asthma control)
  • Asthma Quality of Life Questionnaire (AQLQ) score: 5.43 (scale of 1 to 7, with a higher score indicating a better quality of life)

Outcomes

Primary Outcomes

Morning peak expiratory flow (PEF) changes
Tiotropium vs. doubling ICS dose: 24.4 vs. -1.4 L/min (P<0.001)

Secondary Outcomes

Morning peak expiratory flow (PEF) changes
Tiotropium vs. salmeterol: 24.4 vs. 18.0 L/min (P=0.26)
Salmeterol vs. doubling ICS dose: 18.0 vs. -1.4 L/min (P<0.001)

Tiotropium vs. doubling ICS dose

Evening PEF change: 29.6 vs. -5.7 L/min (P<0.001)
Pre-bronchodilator FEV1 change: 0.12 vs. 0.02 liters (P=0.004)
Number of additional asthma-control days: 0.131 vs. 0.051 (P=0.01)
Albuterol rescue use: -0.11 vs. -0.07 puffs/day (P=0.63)
FEV1 changes after four puffs of albuterol: 0.02 vs. -0.02 liters (P=0.01)

Tiotropium vs. salmeterol

Evening PEF change: 29.6 vs. 19.0 L/min (P=0.05)
Pre-bronchodilator FEV1 change: 0.12 vs. 0.01 liters (P=0.003)
Number of additional asthma-control days: 0.131 vs. 0.139 (P=0.78)
Albuterol rescue use: -0.11 vs. -0.16 puffs/day (P=0.63)
FEV1 change after four puffs of albuterol: 0.02 vs. -0.05 liters (P<0.001)

Asthma Symptoms and Adverse Events

Tiotropium vs. doubling ICS dose

Mean daily symptom score: -0.09 vs 0.03 (P<0.001)
Asthma symptom utility index score: 0.03 vs. 0.00 (P=0.09)
Asthma control questionnaire score: -0.22 vs. -0.03 (P=0.38)
Asthma quality-of-life questionnaire score: 0.15 vs. 0.05 (P=0.24)

Tiotropium vs. salmeterol

Mean daily symptom score: -0.09 vs. 0.03 (P=0.10)
Asthma symptom utility index score: 0.03 vs. 0.00 (P=0.38)
Asthma control questionnaire score: -0.22 vs. -0.31 (P=0.18)
Asthma quality-of-life questionnaire score: 0.15 vs. 0.28 (P=0.09)
Adverse Events
The reported adverse events were not statistically significantly different between the studied groups.

Criticisms

  • Small sample size.
  • 14-week treatment duration may have been insufficient to determine the efficacy of treatment.
  • Study used a a non-patient–oriented primary outcome (morning PEF) rather than symptom score.
  • Long-term safety issues not assessed.
  • Did not evaluate an increased ICS dose beyond doubling the current dose.

Funding

Funded by the National Heart, Lung, and Blood Institute. Boehringer Ingelheim Pharmaceuticals supplied the tiotropium and were given the opportunity to comment on the design of the study. As a result, the sample size was increased to include more patients with the Arg/Arg polymorphism. This genetic polymorphism influences the response that patient’s have to B2 agonist treatment.

Further Reading

  1. BioLINCC listing for BASALT and TALC