Evidence Review for NHS Surrey Area Prescribing Committee

Evidence Review for Prescribing Clinical Network

Treatment: Spiriva Respimat ®2.5 microgram, inhalation solution in Asthma

Prepared by: Noreen Devanney

Topic Submitted by: Noreen Devanney

Date: 4th Feb 2015

Summary page

How strong is the evidence for claimed efficacy?

Grade A = > 1 RCT or meta-analysis

Potential advantages:

Spiriva Respimat®1 is a long acting anti-muscarinic antagonist (LAMA) and is the first drug in its class to be licensed for the treatment in asthma.

Is there a clear place in therapy / treatment pathway?

Tiotropium is discussed as an option for add-on therapy at Step 4 of the BTS/SIGN adult asthma management guidelines 20142. This position in the treatment paradigm is consistent with the licensed indication.

Is monitoring for toxicity required? No
Is monitoring for efficacy required? Desirable to assess efficacy.Asthma review annually.
Is dose titration required? No
Traffic light status -Green
Role of the specialist (if applicable)?
Role of GP (if applicable)?
Financial implications?There will be additional cost as addition of LAMA to existing asthma therapy has not currently been an option in the national guidelines. Number of patients who will benefit from treatment is currently unclear.
National Guidance available : BTS/SIGN 3 as above

Recommendation:

Spiriva Respimat®1 may be used within its licensed indication for add-on therapy at Step 4of BTS2in patients with asthma ie in patients who benefit from LABA and ICS(800 micrograms BDP equivalent) but control is still inadequate

and have experienced one or more severe exacerbationsin theprevious year.(Patients in the trial were required to have had at least one exacerbation that was treated with systemic glucocorticoids in the previous year)

Alternative add-on therapy (ieincreasing inhaled corticosteroids to 2,000 micrograms BDP/day

, leukotriene receptor antagonists, theophyllines or slow release β2 agonist (if not on LABA)) is also an option at Step 4 of BTS2.

The license for Spiriva Respimat®1specifies that patients should have had one or more severe exacerbations in the previous year therefore if the patient has not had a severe exacerbation in the previous year alternative add on therapy should beprescribed at Step 4 ( ie. addition of leukotriene receptor antagonist,theophyllines or slow release β2 agonist tablets).

Special Precautions to be noted.1

Cardiovascular

Tiotropium should be used with caution in patients with recent myocardial infarction < 6 months; any unstable or life threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy in the past year; hospitalisation of heart failure (NYHA Class III or IV) within the past year. These patients were excluded from the clinical trials and these conditions may be affected by the anticholinergic mechanism of action.

Renal impairment

Renally impaired patients can use tiotropium bromide at the recommended dose. As plasma concentration increases with decreased renal function in patients with moderate to severe renal impairment (creatinine clearance ≤50 ml/min), tiotropium bromide should be used only if the expected benefit outweighs the potential risk. There is no long-term experience in patients with severe renal impairment.

VERSION CONTROL SHEET

Version / Date / Author / Status / Comment
1 / 26/2/15 / Noreen Devanney / Circulated for specialist comment
2

1. Purpose of the Review

To review the evidence for Spiriva Respimat®2.5 microgram1, inhalation solution in asthma.

The delivered dose is 2.5 microgram tiotropium per puff (2 puffs comprise one medicinal dose) and is equivalent to 3.124 microgram tiotropium bromide monohydrate.

The delivered dose is the dose which is available for the patient after passing the mouthpiece.

The Respimat®Soft Mist inhaler1 is a multi-dose device that uses mechanical power to produce metered doses of inhalation solution as a Soft Mist. The inhaler has a long spray duration and generates a slow-moving aerosol cloud which is independent of inspiratory effort.

2.1Indication:

Asthma

Spiriva Respimat® is indicated as an add-on maintenance bronchodilator treatment, in adult patients over 18 years with asthma who are currently treated with the maintenance combination of inhaled corticosteroids (≥800 µg budesonide/day or equivalent) and long-acting β2 agonists and who experienced one or more severe exacerbations in the previous year.1

NB BTS Step 4 does not stipulate that patient should have had an exacerbation prior to further add on therapy whereas license for Spiriva Respimat ® in asthma is clear that patient should have had a severe exacerbation in the past year.

2.2 The problem:

Background:

Asthma affects approximately 5.4 million people in the UK and costs the NHS around £1 billion per year3.
Figures from asthma UK indicate that approximately 5.4 million people in the UK are currently receiving treatment for asthma ;1.1 million children and 4.3 million adults4
In the UK, during 2011–2012, there were over 65,000 hospital admissions for asthma 8.

It is estimated that as many as 75% of all hospital admissions for asthma are avoidable through good asthma management and routine care5.
Asthma is estimated to account for 1,000 deaths per year in the UK and Ireland, about 90% of which are associated with preventable factors6, 7.
The annual cost of hospital in-patient care, GP consultations and community prescriptions for asthma in the UK are estimated to be more than £63 million per year9.

Most hospital admissions are emergencies and 70% may have been preventable with appropriate early interventions6,7

2.3 The Intervention:

Tiotropium bromide is a long acting muscarinic antagonist with affinity to the receptor subtypes M1 to M51

In the airways, tiotropium bromide competitively and reversibly binds to the M3 receptors in the bronchial smooth musculature, antagonising the cholinergic (bronchoconstrictive) effects of acetylcholine(released from the parasympathetic nerve endings)resulting in bronchial smooth muscle relaxation1

2.4 Alternative treatments:

Tiotropium bromide is the only LAMA available for the treatment of asthma.

3. Effectiveness

The pharmacological effect of tiotropium on bronchial smooth muscle should theoretically confer benefit in the treatment of asthma.

The Respimat®inhaler is a multi-dose device that uses mechanical energy from a coiled spring to produce metered doses of inhalation solution as a Soft Mist. The inhaler has a long spray duration and generates a slow-moving aerosol cloud which is independent of inspiratory effort. The slow moving mist may simplify co-ordination of inhalation10,11.

The mist moves through the airways slowly and is associated with a high lung deposition and reduced oropharyngeal deposition compared to a pressurised metered dose inhaler.10, 11

The Respimat® inhaler also has a dose counter and automatic locking mechanism, which locks the device once all of the doses have been used as a patient feedback mechanism.12, 13

3.1 Review of evidence

The PrimoTinA-asthmastudies14 comprised two replicate, phase III, randomised, double-blind, placebo-controlled, 48-week trials investigating the efficacy and safety of tiotropium administered via the Respimat inhaler compared with placebo, when added to a treatment regimen of ICS (≥ 800mcg budesonide/day or equivalent) and LABAs in patients with symptomatic asthma.

The studies included 912 eligible patients with asthma of ≥5 years duration and at least one exacerbation requiring systemic corticosteroids in the previous year.Patients were required to be either lifelong nonsmokers or to have a smoking history of fewer than 10 pack-years, with no smoking in the last 10 years. Patients were randomised in a 1:1 ratio to two puffs of tiotropium 2.5mcg (5mcg total) once daily (n=456; 237 in trial 1 and 219 in trial 2), or placebo (n=456; 222 in trial 1 and 234 in trial 2), both administered via the Respimat inhaler, as add-on therapy to individual pre-trial maintenance asthma therapy consisting of ICS (≥ 800mcg budesonide/day or equivalent) and LABAs. Continued use of sustained-release theophylline, leukotriene modifiers, anti-IgE antibody, and oral corticosteroids (≤ 5mg per day) was also permitted if the dose of each remained stable for at least 4 weeks before study entry and for the duration of the trial. An open-label metered-dose inhaler of salbutamol (100mcg per puff) or albuterol (90mcg per puff) was provided as rescue medication for use during the trials.

The two co-primary lung-function end points for each trial were the peak FEV1 response (within 3 hours after administration of the maintenance and study drugs [0-3h]) and the trough FEV1 response at week 24, both expressed as the change from the baseline FEV1. A pre-specified third co-primary end point, the time to the first severe asthma exacerbation*, was evaluated from 48-week pooled trial data. Secondary endpoints included peak and trough FEV1 at other time points during the trial, forced vital capacity (FVC), worsening of asthma (pre-specified as the time to the first asthma exacerbation**), asthma control, quality of life and safety. Baseline characteristics were similar in the two trials and were balanced between the treatment groups.

* Severe asthma exacerbation was defined as a deterioration of asthma necessitating initiation or at least a doubling of systemic corticosteroids for ≥3 days.

**Worsening of asthma was defined as either a progressive increase in 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.

Data from the phase III PrimoTinA-asthma studies demonstrated the following:

Primary endpoints results

Airflow obstruction was significantly reduced with the addition of tiotropium, as compared with the addition of placebo

Peak FEV1 (0–3h) response at 24 weeks was 86±34 ml in Trial 1 (p=0.01) and 154±32 in Trial 2 (p0.001).
Trough FEV1 response after 24 weeks was 88±31 ml in Trial 1 (p=0.01) and 111±30 ml in Trial 2 (p0.001).

Time to first exacerbation was significantly increased with the addition of tiotropium, as compared with the addition of placebo

At 48 weeks, time to first severe asthma exacerbation was delayed by 56 days with tiotropium as compared with placebo (282 days vs 226 days), corresponding to a risk reduction of 21% (hazard ratio [HR] 0.79; 95% CI 0.62-1.0; p=0.03).

Secondary endpoints results

Lung function

Significant improvement in spirometric measurements were recorded among patients in the tiotropium group, as compared with those in the placebo group at week 24.
In a subgroup of patients in whom 24-hour spirometry was performed, the improvement in lung function was maintained over the full day (24 hours). Furthermore, improvements in peak FEV1 were sustained over the 48-week period.

Significantly greater improvements in weekly morning and evening PEF values in the tiotropium group were recorded at 24 weeks (p0.001). These improvements were sustained over the full 48-week period.

Asthma exacerbations

Total number of severe exacerbations per patient-year was significantly lower in the tiotropium group than in the placebo group (0.53 vs 0.66, p=0.046).

Asthma worsenings

Median time to the first worsening of asthma was increased with addition of tiotropium (315 days vs. 181 days with placebo) with a corresponding reduction of 31% in risk for asthma worsening (hazard ratio, 0.69; 95% CI, 0.58-0.82; p0.001) and a 24% (p=0.0031) risk reduction in the mean number of asthma worsenings per patient year.

49.9% of patients (n=226) in the tiotropium group compared with 63.2% (n=287) had a least one asthma worsening (odds ratio 0.58; p<0.001).

Asthma control and quality of life

Both asthma control (evaluated by the Asthma Control Questionnaire-7 [ACQ-7]) and asthma-related quality of life (evaluated by the Asthma Quality of Life Questionnaire [AQLQ]) were improved in both studies. At week 24, for both asthma control and asthma-related quality of life, there was a trend towards improvement in trial 1 and a statistically significant improvement in trial 2. The minimal clinically important difference of 0.5 units for both the ACQ-7 score and the AQLQ score was not achieved in either trial.
Patients recorded morning and evening PEF, asthma symptoms and medication use in an electronic diary (Asthma Monitor AM3) twice daily. There were small and non-significant differences in the number of symptom-free days, as recorded in the AM3 electronic diary while the use of rescue medication was similar in the two study groups.

Safety and tolerability

Tiotropium Respimat is well tolerated in the treatment of asthma14

In the PrimoTinA-asthma studies, reported adverse events (AEs) were similar between treatment groups (i.e. patients treated with addition of tiotropium, as compared with addition of placebo [ICS plus LABA only])

AEs were reported in 73.5% of patients in the tiotropium group and 80.3% of patients in the placebo group.
Asthma, decreased rate of PEF and nasophyaryngitis were the most commonly reported AEs in both the tiotropium and placebo groups.
Of the AEs reported by at least 2% of patients in any study group, only allergic rhinitis occurred at a significantly higher rate in the tiotropium group. Asthma events and insomnia were significantly more common in the placebo group.
AEs in the 456 patients were assessed as drug-related in 5.7% of patients (n=26) in the tiotropium group as compared with 4.6% (n=21) in the placebo group.
Dry mouth was reported in 1.8 % of patients (n=8) in the tiotropium group as compared with 0.7% (n=3) in the placebo group.
Serious AEs were reported in 8.1% of patients (n=37) in the tiotropium group and 8.8% of patients (n=40) in the placebo group.

Cardiac AEs occurred in less than 2% of patients and were well balanced between the study groups. Drug-related cardiac events were reported in two patients (0.4%) in the tiotropium group and one patient (0.2%) in the placebo group.

Special Warnings and Precautions for Use 1

Cardiovascular

Tiotropium should be used with caution in patients with recent myocardial infarction < 6 months; any unstable or life threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy in the past year; hospitalisation of heart failure (NYHA Class III or IV) within the past year. These patients were excluded from the clinical trials and these conditions may be affected by the anticholinergic mechanism of action.

Renal impairment

Renally impaired patients can use tiotropium bromide at the recommended dose. As plasma concentration increases with decreased renal function in patients with moderate to severe renal impairment (creatinine clearance ≤50 ml/min), tiotropium bromide should be used only if theexpected benefit outweighs the potential risk. There is no long-term experience in patients with severe renal impairment.

4. Guidelines

BTS/SIGN adult asthma management guidelines 20142

Step 4: POOR CONTROL ON MODERATE DOSE OF INHALED

CORTICOSTEROID + ADD-ON THERAPY: addition of fourth drug

increasing inhaled corticosteroids to 2,000 micrograms BDP/day

(adults)

leukotriene receptor antagonists
theophyllines
slow release β2 agonist tablets, although caution needs to be used

in patients already on long-acting β2 agonists.

“Long-acting muscarinic antagonists appear to be as effective as salmeterol in the short term and may be superior to doubling the dose of ICS in fixed airways obstruction. Longer term studies are required to confirm this evidence.There would also appear to be benefit in adding tiotropium to ICS and salmeterol in patients who remain symptomatic despite these medications.2

5. Budgetary Impact

Cost:

The cost of one month’s treatment with Spiriva Respimat ® 2.5 microgram 5micrograms (2 puffs) daily is £33.50

This is an additional cost per patient when Spiriva Respimat ®2.5 microgram is used as indicated per guidelines. There are no equivalent LAMAs licensed in asthma with which to compare this cost.

Patients may use tiotropium as an alternative to one of the other strategies advised at Step 4 (ie. increasing steroid dose, addition of leukotriene receptor antagonist, theophyllines or slow release β2 agonist tablets). This may partially offset the additional cost.

6. Summary of evidence:

Efficacy Evidence

Primary endpoints were met
Airflow obstruction was significantly reduced with the addition of tiotropium, as compared with the addition of placebo
Time to first exacerbation was significantly increased with the addition of tiotropium, as compared with the addition of placebo
Significant improvement in spirometric measurements and PEF were recorded among patients in the tiotropium group, as compared with those in the placebo group at week 24.In a subgroup of patients lung function was maintained over the full day (24 hours)and improvements in peak FEV1 were sustained over the 48-week period.
Total number of severe exacerbations per patient-year was significantly lower in the tiotropium group than in the placebo group and median time to the first worsening of asthma was increased with addition of tiotropium

Both asthma control and asthma-related quality of life were improved in both studies. At week 24, for both asthma control and asthma-related quality of life, there was a trend towards improvement in trial 1 and a statistically significant improvement in trial 2.
The minimal clinically important difference of 0.5 units for both the scores was not achieved in either trial.
Patients recorded morning and evening PEF, asthma symptoms and medication use twice daily. There were small and non-significant differences in the number of symptom-free days, while the use of rescue medication was similar in the two study groups.

Adverse Effects

AEs were reported in 73.5% of patients in the tiotropium group and 80.3% of patients in the placebo group.
Asthma, decreased rate of PEF and nasophyaryngitis were the most commonly reported AEs in both the tiotropium and placebo groups.
Of the AEs reported by at least 2% of patients in any study group, only allergic rhinitis occurred at a significantly higher rate in the tiotropium group. Asthma events and insomnia were significantly more common in the placebo group.
AEs in the 456 patients were assessed as drug-related in 5.7% of patients (n=26) in the tiotropium group as compared with 4.6% (n=21) in the placebo group.
Dry mouth was reported in 1.8 % of patients (n=8) in the tiotropium group as compared with 0.7% (n=3) in the placebo group.
Serious AEs were reported in 8.1% of patients (n=37) in the tiotropium group and 8.8% of patients (n=40) in the placebo group.
Cardiac AEs occurred in less than 2% of patients and were well balanced between the study groups. Drug-related cardiac events were reported in two patients (0.4%) in the tiotropium group and one patient (0.2%) in the placebo group.
It should be noted that patients with recent myocardial infarction; any unstable or life threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy in the past year; hospitalisation of heart failure (NYHA Class III or IV). These patients were excluded from the trials.
Special precautions in patients with GFR ≤50ml/min

Recommendation: