How would you treat a severe asthma patient?
SPIRIVA® Respimat® (tiotropium) is indicated as add-on maintenance bronchodilator treatment in patients aged 6 years and older with severe asthma who experienced one or more severe asthma exacerbations in the preceding year. In adult patients with severe asthma, tiotropium should be used in addition to inhaled corticosteroids (≥ 800μg budesonide/day or equivalent) and at least one controller.1
Why SPIRIVA® Respimat® (tiotropium)?
- Efficacy
- Safety Information
Efficacy
Two replicate randomised controlled trials compared SPIRIVA® Respimat® with placebo Respimat® over 48 weeks in 912 adult patients with severe asthma who were symptomatic on ICS (≥800 μg budesonide/day or equivalent) plus LABA, had a post-bronchodilator FEV1 of ≤80% of the predicted value and a history of ≥1 severe exacerbation in the previous year. The co-primary endpoints were lung function measured as peak FEV1(0-3h) and trough FEV1 response at week 24, and time to first severe exacerbation (pooled data) over 48 weeks.2
In adult patients with severe asthma, SPIRIVA® Respimat® has (against placebo Respimat®) demonstrated:
 | Significantly improved lung functionUp to 154mL improvement in peak FEV1 (0-3h) vs placebo Respimat® (95% CI 91-217; p<0.001).2,3* Up to 111mL improvement in trough FEV1 vs placebo Respimat® (95% CI 53-169; p<0.001).2,3* The improvement in lung function was maintained for 24 hours.1 *At 24 weeks, mean difference in improvement in peak FEV1 between Spiriva® Respimat® and placebo Respimat® was 86ml in Trial 1 (p=0.01) and 154ml in Trial 2 (p<0.001); mean difference in improvement in trough FEV1 was 88ml (p=0.01) and 111ml (p<0.01), respectively.2 | ||||||
 | Significantly reduced severe exacerbation risk†Increased time to first severe asthma exacerbation† requiring corticosteroids vs placebo Respimat® by 56 days. (282 days vs. 226 days).2 Reduced severe asthma exacerbation risk by 21% compared to placebo Respimat® (HR 0.79 [95% CI 0.62–1.00]; p=0.03).2 †Severe asthma exacerbation defined as deterioration of asthma necessitating initiation or at least doubling of systemic glucocorticoids for ≥3 days.2 | ||||||
 | Significantly reduced asthma worsening‡Increased the median time to first worsening of asthma by 134 days vs placebo Respimat® (315 days, vs. 181 days).2 31% reduction in risk of asthma worsening vs placebo Respimat® (HR 0.69 [95% CI 0.58–0.82]; p<0.001).2 ‡Asthma worsening defined as either progressive increase in symptoms or ≥30% decline in the best morning PEF from the mean screening morning PEF for 2 or more consecutive days.2 | ||||||
 | Significantly improved asthma symptom controlPatients were 68% more likely to have improved asthma symptom control vs placebo Respimat® (as measured by pooled analysis of ACQ-7 responder rate at week 48 in post hoc analysis) (absolute difference 12.9%; OR 1.68 [95% Cl 1.28–2.21]; p<0.001).4,5§ §A response was defined as a change in ACQ-7 score from study baseline of ≥0.5. | ||||||
SPIRIVA® Respimat® significantly improved lung function (as measured by peak and trough FEV1 response) vs placebo Respimat® in two replicate randomised, placebo-controlled trials in adults with severe asthma.1,2
Peak FEV1 response at week 24 was a prespecified co-primary endpoint.
In Trial 1, the mean improvement in peak FEV1 between SPIRIVA® Respimat® and placebo Respimat was 86 mL at week 24 (95% CI 20−152; p=0.01).1 In Trial 2, the mean improvement in peak FEV1 between SPIRIVA® Respimat® and placebo Respimat® was 154 mL at week 24 (95% CI 91−217; p<0.001).1
*p<0.05; **p<0.01; ***p<0.001.
Adapted from Kerstjens HA et al. 2012 (suppl).2
Trough FEV1 response at week 24 was a pre-specified co-primary endpoint.
At 24 weeks, mean difference in improvement in trough FEV1 between Spiriva® Respimat® and placebo Respimat® was 88ml in Trial 1 (95% CI 27-149; p=0.01) and 111ml (95% CI 53-169; p<0.001) in Trial 2.1
Trial data information
Two replicate randomised controlled trials (PrimoTinA-Asthma 1 and PrimoTinA-Asthma 2) compared SPIRIVA® Respimat® with placebo Respimat® over 48 weeks as add-on controller therapy on top of usual care in adult patients with severe asthma who were symptomatic on maintenance treatment of at least ICS (≥800 μg budesonide/day or equivalent) plus LABA, had a post-bronchodilator FEV1 of ≤80% of the predicted value and a history of ≥1 severe exacerbation in the previous year. In both the SPIRIVA® Respimat® and placebo Respimat® groups, ICS and LABA maintenance therapy was continued. Other asthma medications were allowed if the doses remained stable for ≥4 weeks before study entry and for the duration of the trial. The co-primary endpoints were lung function measured as peak FEV1(0-3h) and trough FEV1 response at week 24, and time to first severe exacerbation (pooled data) over 48 weeks.1
- Abbreviations
- CI, confidence interval; FEV1, forced expiratory volume in 1 second; HR, hazard ratio; LABA, long-acting β2-agonist.
- References: 1. Kerstjens HA et al. N Engl J Med 2012;367:1198–207. 2. Kerstjens HA et al. N Engl J Med 2012;367:1198–207, supplementary appendix.
SPIRIVA® Respimat® significantly delayed the time to first severe asthma exacerbation* by 56 days vs placebo Respimat® in adults with severe asthma.1
Time to the first severe asthma exacerbation (pooled data at 48 weeks) was a prespecified co-primary endpoint.
In the tiotropium group, 122 of 453 patients (26.9%) had at least 1 severe exacerbation, as compared with 149 of 454 (32.8%) in the placebo group.1
* Severe asthma exacerbation was defined as a deterioration of asthma necessitating initiation or at least a doubling of systemic glucocorticoids for ≥3 days.1
Adapted from Kerstjens HA et al. 2012.1
Trial data information
Two replicate randomised controlled trials (PrimoTinA-Asthma 1 and PrimoTinA-Asthma 2) compared SPIRIVA® Respimat® with placebo Respimat® over 48 weeks as add-on controller therapy on top of usual care in adult patients with severe asthma who were symptomatic on maintenance treatment of at least ICS (≥800 μg budesonide/day or equivalent) plus LABA, had a post-bronchodilator FEV1 of ≤80% of the predicted value and a history of ≥1 severe exacerbation in the previous year. In both the SPIRIVA® Respimat® and placebo Respimat® groups, ICS and LABA maintenance therapy was continued. Other asthma medications were allowed if the doses remained stable for ≥4 weeks before study entry and for the duration of the trial. The co-primary endpoints were lung function measured as peak FEV1(0-3h) and trough FEV1 response at week 24, and time to first severe exacerbation (pooled data) over 48 weeks.1
- Abbreviations
- ARR, absolute risk reduction; CI, confidence interval; HR, hazard ratio; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist.
- Reference: 1. Kerstjens HA et al. N Engl J Med 2012;367:1198–207.
SPIRIVA® Respimat® significantly delayed the time to first asthma worsening* by 134 days vs placebo Respimat® in adults with severe asthma.1
Time to first asthma worsening (pooled data at 48 weeks) was a secondary endpoint.
In the tiotropium group, 226 of 453 patients (49.9%) had at least 1 episode of asthma worsening, as compared with 287 of 454 (63.2%) in the placebo group.1
* Asthma worsening was defined as either a progressive increase in symptoms (as compared with usual day-to-day asthma symptoms) or a decline of 30% or more in the best morning PEF from the mean screening morning PEF for 2 or more consecutive days.1
Adapted from Kerstjens HA et al.1
Trial data information
Two replicate randomised controlled trials (PrimoTinA-Asthma 1 and PrimoTinA-Asthma 2) compared SPIRIVA® Respimat® with placebo Respimat® over 48 weeks as add-on controller therapy on top of usual care in adult patients with severe asthma who were symptomatic on maintenance treatment of at least ICS (≥800 μg budesonide/day or equivalent) plus LABA, had a post-bronchodilator FEV1 of ≤80% of the predicted value and a history of ≥1 severe exacerbation in the previous year. In both the SPIRIVA® Respimat® and placebo Respimat® groups, ICS and LABA maintenance therapy was continued. Other asthma medications were allowed if the doses remained stable for ≥4 weeks before study entry and for the duration of the trial. The co-primary endpoints were lung function measured as peak FEV1(0-3h) and trough FEV1 response at week 24, and time to first severe exacerbation (pooled data) over 48 weeks.1
- Abbreviations
- ARR, absolute risk reduction; CI, confidence interval; HR, hazard ratio; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; PEF, peak expiratory flow.
- Reference: 1. Kerstjens HA et al. N Engl J Med 2012;367:1198–207.
Significantly more adult patients with severe asthma achieved an improvement in asthma symptom control (as measured by ACQ-7 responder rate) with SPIRIVA® Respimat® vs placebo Respimat®.1
Post hoc analysis: pooled analysis of ACQ-7† responder rate at week 48.
At week 48, a higher proportion of patients achieved an ACQ-7 response with SPIRIVA® Respimat® vs placebo Respimat® (58.1% vs 45.2%; OR 1.68, 95% CI 1.28-2.21; p<0.001).1,2
†A response was defined as a change in ACQ-7 score from study baseline of ≥0.5.1
Trial data information
Two replicate randomised controlled trials (PrimoTinA-Asthma 1 and PrimoTinA-Asthma 2) compared SPIRIVA® Respimat® with placebo Respimat® over 48 weeks as add-on controller therapy on top of usual care in adult patients with severe asthma who were symptomatic on maintenance treatment of at least ICS (≥800 μg budesonide/day or equivalent) plus LABA, had a post-bronchodilator FEV1 of ≤80% of the predicted value and a history of ≥1 severe exacerbation in the previous year. In both the SPIRIVA® Respimat® and placebo Respimat® groups, ICS and LABA maintenance therapy was continued. Other asthma medications were allowed if the doses remained stable for ≥4 weeks before study entry and for the duration of the trial. The co-primary endpoints were lung function measured as peak FEV1(0-3h) and trough FEV1 response at week 24, and time to first severe exacerbation (pooled data) over 48 weeks.3
- Abbreviations
- ACQ-7, seven-question Asthma Control Questionnaire; CI, confidence interval; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; OR, odds ratio.
- References: 1. Kerstjens HA et al. Respir Med 2016;117:198–206. 2. Murphy K et al. Ann Allergy Asthma Immunol 2013;113(Supl 1):Abstract P294. 3. Kerstjens HA et al. N Engl J Med 2012;367:1198–207.
Trial data information
Two replicate randomised controlled trials (PrimoTinA-Asthma 1 and PrimoTinA-Asthma 2) compared SPIRIVA® Respimat® with placebo Respimat® over 48 weeks as add-on controller therapy on top of usual care in adult patients with severe asthma who were symptomatic on maintenance treatment of at least ICS (≥800 μg budesonide/day or equivalent) plus LABA, had a post-bronchodilator FEV1 of ≤80% of the predicted value and a history of ≥1 severe exacerbation in the previous year. In both the SPIRIVA® Respimat® and placebo Respimat® groups, ICS and LABA maintenance therapy was continued. Other asthma medications were allowed if the doses remained stable for ≥4 weeks before study entry and for the duration of the trial. The primary endpoints were lung function measured as peak FEV1(0-3h) and trough FEV1 response at week 24, and time to first severe exacerbation (pooled data) over 48 weeks.2
Abbreviations
- ACQ-7, seven-question Asthma Control Questionnaire; CI, confidence interval; FEV1, forced expiratory volume in 1 second; HR, hazard ratio; ICS, inhaled corticosteroids; LABA, long-acting β2-agonist; OR, odds ratio; PEF, peak expiratory flow.
References
- SPIRIVA® Respimat® (tiotropium) 2.5 μg Summary of Product Characteristics.
- Kerstjens HA et al. N Engl J Med 2012;367:1198–207.
- Kerstjens HA et al. N Engl J Med 2012;367:1198–207, supplementary appendix.
- Kerstjens HA et al. Respir Med 2016;117:198–206.
- Murphy K et al. Annals of Allery Asthma and Immunology Abstract P294. 2014;113:Suppl 1.
Safety Information
Summary of the safety profile
Many of the listed undesirable effects can be assigned to the anticholinergic properties of tiotropium bromide.1
In asthma the incidence of dry mouth was 0.83%. No discontinuations due to dry mouth were reported.1
Serious undesirable effects consistent with anticholinergic effects include glaucoma, constipation, intestinal obstruction including ileus paralytic and urinary retention.1
An increase in anticholinergic effects may occur with increasing age.1
Tabulated summary of adverse reactions
The frequencies assigned to the undesirable effects listed below are based on crude incidence rates of adverse drug reactions (i.e. events attributed to tiotropium) observed in the tiotropium group pooled from 12 placebo controlled clinical trials in adult and paediatric patients with asthma (1,930 patients) with treatment periods ranging from four weeks to one year.1
Frequency is defined using the following convention:
Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).1
| System Organ Class / MedDRA Preferred Term | Frequency |
|---|---|
| Metabolism and nutrition disorders | |
| Dehydration | Not known |
| Nervous system disorders | |
| Dizziness | Uncommon |
| Headache | Uncommon |
| Insomnia | Uncommon |
| Eye disorders | |
| Glaucoma | Not known |
| Intraocular pressure increased | Not known |
| Vision blurred | Not known |
| Cardiac disorders | |
| Atrial fibrillation | Not known |
| Palpitations | Uncommon |
| Supraventricular tachycardia | Not known |
| Tachycardia | Not known |
| Respiratory, thoracic and mediastinal disorders | |
| Cough | Uncommon |
| Pharyngitis | Uncommon |
| Dysphonia | Uncommon |
| Epistaxis | Rare |
| Bronchospasm | Uncommon |
| Laryngitis | Not known |
| Sinusitis | Not known |
| Gastrointestinal disorders | |
| Dry Mouth | Uncommon |
| Constipation | Rare |
| Oropharyngeal candidiasis | Uncommon |
| Dysphagia | Not known |
| Gastroesophageal reflux disease | Not known |
| Dental caries | Not known |
| Gingivitis | Rare |
| Glossitis | Not known |
| Stomatitis | Rare |
| Intestinal obstruction, including ileus paralytic | Not known |
| Nausea | Not known |
| Skin and subcutaneous tissue disorders, immune system disorders | |
| Rash | Uncommon |
| Pruritus | Rare |
| Angioneurotic oedema | Rare |
| Urticaria | Rare |
| Skin infection/skin ulcer | Not known |
| Dry skin | Not known |
| Hypersensitivity (including immediate reactions) | Rare |
| Anaphylactic reaction | Not known |
| Musculoskeletal and connective tissue disorders | |
| Joint swelling | Not known |
| Renal and urinary disorders | |
| Urinary retention | Not known |
| Dysuria | Not known |
| Urinary tract infection | Rare |
Abbreviations
MedDRA, Medical Dictionary for Regulatory Activities.
Reference
1.
SPIRIVA® Respimat® (tiotropium) 2.5 μg Summary of Product Characteristics.
PC-GB-107376 V1
April 2023