Tiotropium bromide step-up therapy for adults with uncontrolled asthma (talc trial)

Tiotropium bromide Step-Up Therapy for Adults with Uncontrolled Asthma (TALC trial)
Peters, S. et al. NEJM 363(18)1715-1726. Oct. 28, 2010
Rationale:
- short acting anticholinergics have been around for decades and have been used for acute and chronic
management of both COPD and asthma
- Cochrane review 2004 “no justification for routinely introducing anticholinergics as part of add-on
treatment for patients whose asthma is not well controlled on standard therapies.” This review looked at
short acting anticholinergics (ipratropium) only.
- Tiotropium approved for use in 2004 for COPD only
- Recent (controversial) safety concerns of LABAs has fueled interest in looking for alternative step up
therapies for asthma
Methods:
Hypothesis 1: In patients with asthma that is inadequately controlled by an inhaled glucocorticoid alone,
the addition of tiotropium would be superior to doubling the dose of ICS
Hypothesis 2: In such patients, the addition of tiotropium would not be inferior to the addition of a LABA
Patient enrollment:
(See figure 1) Enrolled 826 patient to two common trials (BASALT, TALC), 210 were randomized to
TALC if FEV1 <70% predicted or had symptoms or rescue inhaler use 6 or more days per week or were
awakened by asthma symptoms 2 or more nights/week
Inclusion criteria
- use of prohibited medications (other asthma meds, other - clinical history consistent with asthma - significant medical illnesses or lung diseases other than asthma - asthma confimed by : 1) reversibility ≥12% with 4 puffs albuterol 2) PC20≤8 not on ICS or ≤16 on ICS - RTI or significant asthma exacerbation in the past 4 weeks - need for daily controller therapy (used or received prescription - history of life-threatening asthma in the past 5 years for asthma controller in the past year OR symptoms more than - pregnant or not using acceptable birth control - hyposensitization therapy other than established regimen - If on steroid, not exceeding equivalent of 1000 mcg fluticasone - inability to use drug delivery devices effectively - Nonsmoker (<10 pk years, no smoking in past year) - able to provide informed consent Protocol: Outcomes:
Primary outcome: morning PEF
Secondary outcomes: FEV1 before bronchodilation, number of asthma-control days (days without
symptoms or use of rescue inhaler), asthma symptoms, rescue bronchodilator use, asthma exacerbations,
use of health care services, biomarkers of inflammation, questionnaires on symptoms and quality of life
Study oversight:
Study funded by the National Heart, Lung and Blood Institute’s Asthma Clinical Research Network (not
pharma)
Statistical analysis:
Intention to treat
Results:
√ Hypothesis #1: Tiotropium is superior to doubling dose of glucocorticoid
Morning PEF was 25.8 L/min higher in patients receiving tiotropium compared with double dose
glucocorticoid (P<0.001). Other indices also superior: higher prebronchodilator FEV1 0.1 L (P=0.004),
increase in proportion of asthma control days of 0.079 (P=0.01), FEV1 after four puffs of albuterol 0.04
(P=0.01)
√ Hypothesis #2: Tiotropium is not inferior to salmeterol as add-on
Addition of tiotropium was noninferior to the addition of salmeterol for all assessed outcomes and
increased the prebronchodilator FEV1 more than did salmeterol, with a difference of 0.11 liters (P=0.003).
12 adverse events (3 for tiotropium, 4 for double dose beclomethasone, 4 for salmeterol and one during run
in)
Discussion and Critical Analysis:
1. Are the results valid?
- Method of randomization not described.
- All patients were accounted for in figure 1.
– Intention to treat
- Three way, double-blind, triple dummy crossover trial
- All groups treated similarly
2. What were the results?
- Superiority of tiotropium over double dose glucocorticoid significant but ?clinically significant
- No significant difference between tiotropium and salmeterol for primary outcome and most measures.
Prebronchodilator FEV1 favoured tiotropium, though this was a small difference and a secondary outcome
so ?clinical relevance.
3. Will the results help me in caring for pts?
- inclusion/exclusion criteria themselves reasonable and fairly inclusive, but subsequent selection of
patients for TALC vs BASALT selected significantly obstructed population for TALC. This may be
reasonable for a noninferiority trial
- trial done in ideal circumstances – frequent visits, excellent compliance (beclomethasone 84% of doses,
salmeterol 93%, tiotropium 93%). Poor compliance (<75%) excluded
Were all clinically NB outcomes considered?
- PEF as primary endpoint is less clinically meaningful. Secondary endpoints were more clinically
meaningful – FEV1, asthma control days
- Limited duration of study does not permit evaluation of whether tiotropium reduces asthma exacerbations
Was noninferiority appropriate design?
- Design of noninferiority trial implies that we do not care if tiotropium is better, as long as it is equivalent
we would consider using it over salmeterol – big and potentially untrue assumption. Safety concerns with
LABAs highly controversial.
- May be ethically challenging to design superiority trial for tiotropium without doing this study first. This
may create clinical equipoise to perform longer term superiority study using clinically relevant outcomes.

Source: http://www.dom-uoft.com/resp/jc/JC1011LauraDiscussion.pdf