Barriers to achieving asthma control in adults: evidence for the role of tiotropium in current management strategies

Figures & data

Figure 1 Asthma management based on a continuous cycle of patient assessment, treatment, and review.

Notes: Treatment should be adjusted to achieve asthma control. *Not for children <12 years. **For children 6–11 years, the preferred Step 3 treatment is medium dose ICS. ^#Low dose ICS/formoterol is the reliever medication for patients prescribed low dose budesonide/formoterol or low dose beclometasone/formoterol maintenance and reliever therapy. ^{^}Tiotropium by mist inhaler is an add-on treatment for patients with a history of exacerbations; it is not indicated in children <12 years. Copyright ©2018. Reproduced from Global Initiative for Asthma. GINA report: global strategy for asthma management and prevention.⁴
Abbreviations: HDM, house dust mite; ICS, inhaled corticosteroid; IgE, immunoglobulin E; IL5, interleukin-5; LABA, long-acting β₂-agonist; LTRA, leukotriene receptor antagonist; OCS, oral corticosteroids; SABA, short-acting beta₂-agonist; SLIT, sublingual immunotherapy.

Table 1 Summary of clinical trials and real-world evidence with tio add-on therapy in adult patients with asthma

Clinical trial	Study design	Duration	Patient population	Treatment armsa	Key endpoints	Summary of findings
Phase III trials
PrimoTinA-asthma^® 1 and 2 (NCT00772538/NCT00776984) Kerstjens et al (2012)^Citation31	Two double-blind, randomized, placebo-controlled, parallel group, replicate studies	48 weeks	Adults (18–75 years old) with symptomatic severe asthma receiving high-dose ICS and LABA	• Tio 5 µg (n=456) • Pbo (n=456)	• Peak FEV1(0–3h) • Trough FEV1 • Time to first severe exacerbation • Asthma control • Safety	• Tio added on to ICS/LABA improves lung function and reduces severe exacerbations and episodes of disease worsening • Improvements in asthma control scores were observed with tio vs placebo, but did not achieve the MCID • Safety and tolerability were comparable with pbo
MezzoTinA-asthma^® 1 and 2 (NCT01172808/NCT01172821) Kerstjens et al (2015)^Citation32	Two double-blind, randomized, double-dummy, placebo-controlled, parallel-group, replicate studies	24 weeks	Adults (18–75 years old) with symptomatic moderate asthma receiving medium-dose ICS±LABA	• Tio 5 µg (n=517) • Tio 2.5 µg (n=519) • Salmeterol 50 µg twice daily (n=541) • Pbo (n=523)	• Peak FEV1(0–3h) • Trough FEV1 • Time to first severe exacerbation • Asthma control • Safety	• Tio add-on treatment significantly improved lung function and asthma control compared with pbo, with similar efficacy and tolerability to the LABA salmeterol • Safety and tolerability were comparable with pbo
GraziaTinA-asthma^® (NCT01316380) Paggiaro et al (2016)^Citation33	Placebo-controlled, randomized, parallel- group study	12 weeks	Adults (18–75 years old) with symptomatic mild-to-moderate asthma receiving low to medium-dose ICS	• Tio 5 µg (n=155) • Tio 2.5 µg (n=154) • Pbo (n=155)	• Peak FEV1(0–3h) • Trough FEV1 • Asthma control • Safety	• Tio add-on therapy was an efficacious bronchodilator • Safety and tolerability were comparable with placebo • No difference in the reduction of ACQ-7 score between tio and pbo groups
CadenTinA-asthma^® (NCT01340209) Ohta et al (2015)^Citation34	Double-blind, randomized, placebo-controlled, parallel-group study	52 weeks	Adults (18–75 years old) from Japan with symptomatic moderate-to-severe asthma receiving medium-dose ICS±LABA	• Tio 5 µg (n=114) • Tio 2.5 µg (n=114) • Pbo (n=57)	• Safety • Trough FEV1 • Asthma control	• No significant difference in adverse events between treatment groups • Tio 5 µg added to ICS±LABA significantly improved lung function (trough FEV1) vs pbo • At Week 52, ACQ-7 responder rates were similar across treatment groups
TALC study (NCT00565266) Peters et al (2010)^Citation45	Three-way, double-blind, triple-dummy, crossover study	52 weeks (each treatment 14 weeks)	Adults with inadequately controlled asthma (FEV1 <70% predicted normal) receiving BDA 80 µg twice daily	• BDA 80 µg twice daily+tio 18 µg+salmeterol pbo twice daily • BDA 80 µg twice daily+salmeterol 50 µg twice daily+tio pbo • BDA 160 µg twice daily+tio pbo+salmeterol pbo twice daily	• Morning PEF	• Tio 18 µg is superior to doubling the ICS dose and non-inferior to salmeterol in patients with uncontrolled asthma
Real-life evidence
Abadoglu and Berk (2016)^Citation46	Retrospective analysis of medical records	2003–2011	Patients with uncontrolled asthma (GINA Step 4/5) with irreversible airway obstruction	High-dose ICS and LABA combination and/or daily oral prednisone, LTRA, and sustained theophylline at least for 1 year	• Lung function • Asthma control	Tio use showed an improvement in lung function and asthma control, and decreased the number of ED visits and hospitalizations
Price et al (2015)^Citation47	Retrospective analysis of medical records	2001–2013	A recorded diagnosis of asthma	At least one prescription for tio	• Exacerbations • Acute respiratory events • Lung function	A significant decrease in the incidence of exacerbations and antibiotic prescriptions for lower respiratory tract infections in the year following the addition of tio

Notes:

a Treated population; tio 5 or 2.5 µg was delivered as two puffs once daily via the Respimat^®.

Abbreviations: ACQ-7, seven-question Asthma Control Questionnaire; BDA, beclomethasone dipropionate aerosol; ED, emergency department; FEV_1(0–3h), FEV₁ within 3 hours post-dose; GINA, Global Initiative for Asthma; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LTRA, leukotriene receptor antagonist; MCID, minimal clinically important difference; pbo, placebo; PEF, peak expiratory flow; TALC, Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid study; tio, tiotropium.

Table 2 Summary of adverse events in Phase III clinical trials of tio in adults (18–75 years old) with mild, moderate, or severe asthma

Clinical trial	Treatment arma	Patients with any AE, n (%)	Patients with SAEs,b n (%)	Patients with investigator- defined treatment- related AEs, n (%)	Patients with AEs leading to discontinuation, n (%)
PrimoTinA-asthma^® 1 and 2 (pooled) (NCT00772538/NCT00776984) Kerstjens et al (2012)^Citation31	Tio 5 µg (n=456)	335 (73.5)	37 (8.1)	26 (5.7)	8 (1.8)
	Pbo (n=456)	366 (80.3)	40 (8.8)	21 (4.6)	14 (3.1)
MezzoTinA-asthma^® 1 and 2 (pooled) (NCT01172808/NCT01172821) Kerstjens et al (2015)^Citation32	Tio 5 µg (n=517)	296 (57.3)	11 (2.1)	38 (7.4)	9 (1.7)
	Tio 2.5 µg (n=519)	302 (58.2)	12 (2.3)	36 (6.9)	6 (1.2)
	Salmeterol 50 µg twice daily (n=541)	294 (54.3)	11 (2.0)	28 (5.2)	10 (1.8)
	Pbo (n=523)	309 (59.1)	14 (2.7)	28 (5.4)	13 (2.5)
GraziaTinA-asthma^® (NCT01316380) Paggiaro et al (2016)^Citation33	Tio 5 µg (n=155)	50 (32.3)	1 (0.6)	2 (1.3)	1 (0.6)
	Tio 2.5 µg (n=154)	48 (31.2)	0	2 (1.3)	2 (1.3)
	Pbo (n=155)	45 (29.0)	1 (0.6)	2 (1.3)	0
CadenTinA-asthma^® (NCT01340209) Ohta et al (2015)^Citation34	Tio 5 µg (n=114)	101 (88.6)	4 (3.5)	10 (8.8)	2 (1.8)
	Tio 2.5 µg (n=114)	99 (86.8)	4 (3.5)	6 (5.3)	1 (0.9)
	Pbo (n=57)	51 (89.5)	9 (15.8)	3 (5.3)	1 (1.8)

Notes: Data are presented as n (%).

a Treated population; tio 5 or 2.5 µg was delivered as two puffs once daily via the Respimat^®.

b SAE was defined as any AE that resulted in death, was immediately life-threatening, resulted in persistent or significant disability/incapacity, required or prolonged patient hospitalization, was a congenital anomaly/ birth defect, or was to be deemed serious for any other reason that might have jeopardized the patient and might have required medical or surgical intervention to prevent one of the other outcomes listed in the above definitions.

Abbreviations: AE, adverse event; pbo, placebo; SAE, serious adverse event; tio, tiotropium.

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