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31 August 2010
Indacaterol▼ inhaled once daily improved trough FEV1 at 12 weeks compared to placebo in patients with moderate to severe COPD. Results from the 52-week INVOLVE study (n=1732) showed an improvement of 170ml over placebo with indacaterol 300 and 600micrograms daily. An improvement of 180ml over placebo was seen in the 26-week INHANCE study (n=1683). No pre-specified endpoints in either study examined the effect of the drug on patient-oriented outcomes compared with active comparators.
Level of evidence:
Level 3 (other evidence) according to the SORT criteria.
*February 2012 – Please see NICE Evidence Update No 5 February 2012 on COPD for a review of additional indacaterol studies published since this NPC Rapid Review.
Action
Indacaterol was marketed in July 2010 as a maintenance bronchodilator treatment in adult patients with COPD, but is not within the current NICE workplan for a technology appraisal. Commissioners will need to discuss with local specialists the role of the product. Indacaterol may have a place in therapy when symptoms persist after use of when-required bronchodilators or in patients who have frequent exacerbations. However, there are limited data comparing indacaterol to existing long-acting bronchodilators and advantages in terms of clinical efficacy appear marginal.
What is the background to this?
Indacaterol (Onbrez Breezhaler®, Novartis) is a once-daily long-acting inhaled beta2-agonist (LABA) for the management of patients with COPD. The recommended dose is150microgram once daily, the dose may be increased on medical advice to a maximum of 300 microgram daily. Further information on the product can be found in our On the Horizon bulletin. Indacaterol is available as 150 and 300microgram capsules at a cost for either strength of £29.26 per pack of 30 capsules plus inhaler. Currently no NICE appraisal has been proposed for the product. An SMC review is available.
Three key studies were submitted to the European Medicines Agency (EMA) in support of the licence application and two have recently been published, with the third awaiting publication. Both published studies recruited patients with moderate to severe COPD as defined by the NICE and GOLD criteria. However, the patients were not required to have a history of exacerbations. The INVOLVE investigators report on data comparing the efficacy and safety of indacaterol once daily in a placebo–controlled study over 52 weeks which also included an active comparator of twice daily formoterol. The INHANCE study investigators discuss the results of a 26-week placebo-controlled study involving indacaterol which included open-label tiotropium as an active comparator.
What do these studies claim?
The primary endpoint for both studies was the 24 hour post dose (trough) FEV1 after 12 weeks of treatment for indacaterol vs. placebo. In the INVOLVE study both the indacaterol 300 and 600 microgram groups showed a least squares (LS) mean increase in trough FEV1 of 0.17L (95% confidence interval [CI] 0.13 to 0.20, P<0.001) vs. placebo, well in excess of the pre-defined clinically important difference of 0.12L. We note that 600micrograms daily is double the maximum dose of indacaterol licensed in the UK.
The LS mean increase for formoterol 12micrograms twice daily over placebo was 0.07L (95%CI 0.04 to 0.10, P <0.001). The clinical relevance of the 0.1L difference between the two indacaterol doses and formoterol was questioned by the EMA. In addition this particular comparison was not a predefined primary or secondary endpoint, but a predefined exploratory objective of the study. For statistical and methodological reasons, we should be circumspect in evaluating comparisons between indacaterol and formoterol arising from this study. Owing to the design of the trial, such comparisons are hypothesis-generating, not hypothesis testing
A range of clinical outcomes were reported as secondary endpoints (all vs. placebo). These included days of poor control and time to first COPD exacerbation. All active treatments were statistically significantly superior to placebo (see study details)
In the INHANCE study both indacaterol 150 and 300micrograms improved trough FEV1 compared to placebo by 0.18L (98.75% CI 0.14 to 0.22, P<0.001). The improvement for tiotropium 18 micrograms over placebo was 0.14L (98.75% CI 0.10 to 0.18, P< 0.001).
The key secondary objective of this study was to demonstrate the non-inferiority of at least one dose of indacaterol to tiotropium for trough FEV1 at 12 weeks and, if met, then to demonstrate superiority. Both indacaterol doses were stated to be statistically significant for non-inferiority at P<0.001 and for superiority at P≤ 0.01. However, insufficient data are provided in the published report to evaluate this fully.
Other clinical outcomes were measured but not all were reported in the published study (see study details). The EMA Assessment Report states that the number of days of poor control was not statistically significantly better than placebo or tiotropium for either dose of indacaterol.
How do these relate to other studies?
Smoking cessation is the only intervention shown to reduce the rate of decline in lung function. The aim of drug treatment is control of symptoms, prevention of exacerbations and improvement in exercise capacity. The recently updated NICE COPD guideline recommends that in people with stable COPD who remain breathless or have exacerbations, despite use of short-acting bronchodilators as required, the following be considered as maintenance therapy:
– if FEV1 ≥ 50% predicted use either LABA or long-acting muscarinic antagonist (LAMA)
– if FEV1 < 50% predicted use either LABA with an inhaled corticosteroid (ICS) in a combination inhaler, or LAMA. If ICS cannot be tolerated then a LABA plus LAMA combination is an alternative.
In patients with persistent exacerbations or breathlessness various combinations are advised including a LAMA in addition to LABA+ ICS. A short-acting beta agonist as required may continue at all stages.
Further information on COPD can be found on the respiratory tract floor of NPC
So what?
Inhaled indacaterol, administered as a once daily dosing regimen, is an efficacious bronchodilator in terms of improvement of FEV1 over 12 weeks in patients with moderate to severe COPD. However, it should be noted that one of the dosing regimens used in the studies (600micrograms daily) is not licensed. There are limited data comparing indacaterol directly to existing long-acting bronchodilators and the advantages in terms of clinical efficacy appear marginal.
No patient-oriented outcomes (e.g. reduction in exacerbations) have been included as primary outcomes in the studies. The data from symptomatic secondary endpoints suggest a modest and inconsistent benefit for indacaterol over placebo. There are no like for like comparisons with other active comparators. The authors of the papers suggest that more meaningful conclusions on exacerbations are required from long-term studies. One such trial with exacerbations as a secondary endpoint is ongoing at present comparing indacaterol to tiotropium.
The adverse effects reported were typical of LABAs, but on average 17 to 20% of patients experienced a sporadic, transient cough that occurred within 15 seconds of inhaling indacaterol. It was not associated with bronchospasm and did not cause patients to discontinue therapy.
Once daily dosing may offer advantages in terms of patient compliance for patients whose symptoms persist after use of short-acting bronchodilators or who have persistent exacerbations. However, in those patients requiring inhaled corticosteroids in conjunction with a LABA NICE advise the use of a combination inhaler. Such a combination of indacaterol with an ICS is unlikely to be available in the near future.
Design: A phase three, one year, randomised, double-blind, double-dummy, placebo controlled, parallel-group study with formoterol as active comparator.
Patients: 1732 people 40 years of age or older (mean 64 years) with moderate to severe COPD as defined by the GOLD criteria and a smoking history of 20 or more pack-years (mean about 40 years). About 43% of patients had severe COPD. Median baseline prebronchodilator FEV1 was 1.29L and postbronchodilator FEV1 was1.43L. Patients were excluded if they had had a respiratory tract infection or hospitalisation for COPD exacerbation within the previous 6 weeks, oral corticosteroids or change in ICS during the previous month, or history of asthma. Approximately 50% of patients were ICS users.
Intervention and comparison: Indacaterol 300 and 600micrograms once daily, formoterol 12micrograms twice daily and placebo for 52-weeks. Fixed dose combinations of ICS plus long-acting β2-agonist were replaced by monotherapy ICS at an equivalent dose and study regimen. Salbutamol was available as needed. Other bronchodilators or corticosteroids were not allowed unless to treat a COPD exacerbation.
Outcomes and results: The primary objective was to test whether both indacaterol doses were superior to placebo in their effect on the 24-hour trough FEV1 after 12 weeks. The efficacy results are given for a modified intention to treat (ITT) population (excluding subjects from one centre because of non-conformance with good clinical practice, including inability to verify source data) with last observation carried forward for missing data. Both the indacaterol 300microgram (n=405) and 600microgram (n=396) groups showed a least squares (LS) mean increase in trough FEV1 of 0.17L (95%CI 0.13 to 0.20, P< 0.001) vs. placebo (n=399). A treatment difference of 0.12L in trough FEV1 was considered a clinically important benefit. The LS mean increase for formoterol (n=400) over placebo was 0.07L (95%CI 0.04 to 0.10, P <0.001).
The important secondary endpoints (all versus placebo) were ‘days of poor control’ reported over 52 weeks (defined as any day with a score of at least 2 on a 0-3 scale for at least two out of cough, wheeze, production/colour of sputum and breathlessness), St George’s Respiratory Questionnaire (SGRQ) after 12 weeks’ treatment, and on time to first COPD exacerbation during the 52 week period.
COPD exacerbations were defined as onset or worsening of more than one respiratory symptom (dyspnoea, cough, sputum, purulence or volume or wheeze) for more than 3 consecutive days plus intensified treatment (e.g. systemic steroids, antibiotics or oxygen) and /or hospitalization or emergency room visit.
The LS mean difference vs. placebo for days of poor control were -4.7 (95%CI -8.4 to -1.0, P<0.05) for indacaterol 300microgam, -8.3(95%CI -12.0 to -4.6, P<0.001) for indacaterol 600 microgram and -4.8 (95%CI -8.5 to -1.1, P< 0.05) for formoterol.
SGRQ scores improved by 3.8 points (95%CI 2.1 to 5.6), 4.1 (95%CI 2.3 to 5.9) and 3.2 (95%CI 1.5 to 5.0) for indacaterol 300 micrograms, 600 micrograms and formoterol respectively vs. placebo (P<0.001 for all groups) at 12 weeks and by 4.7 (95%CI 2.7 to 6.7), 4.6 (95%CI 2.6 to 6.6) and 4.0 (95%CI 2.0 to 6.0) respectively vs. placebo (P<0.001 for all groups) at 52 weeks. A change of 4 points is regarded as clinically significant.
All active treatments reduced the risk of exacerbations, although there were too few events to calculate event-free time. Hazard ratios versus placebo for 300microgram and 600microgram indacaterol and formoterol were 0.77 (95%CI 0.606 to 0.975); 0.69 (95%CI 0.538 to 0.882) and 0.77 (95%CI 0.605 to 0.981) respectively (P<0.05 for all).
Cough was reported by 7.3% of patients in the indacaterol 300microgram group, 6.4% of those in the indacaterol 600microgram group, 3.9% of the formoterol group and 4.4% of the placebo group. In addition, cough occurring within 5 min of drug administration during clinic visits was observed in an average of 19.1% of patients in the indacaterol groups, 0.8% of the formoterol group and 1.8% of the placebo group. Tremor was reported in 0.2%, 1.9%, 1.2% and 0.5% of the indacaterol 300microgram, 600 microgram, formoterol and placebo groups, respectively. Tachycardia occurred in 0.9%, 0.7%, 0.5% and 1.2% respectively.
Death due to cardiac arrest occurred in a patient who had discontinued indacaterol 300 micrograms three days earlier owing to dyspnoea. The three deaths during formoterol treatment were considered unrelated to formoterol. Four patients randomised to placebo also died
Design: A phase three, 26-week, randomised, double-blind, double-dummy, placebo controlled, parallel-group study using open-label tiotropium as active comparator.
Patients: 1683 patients aged 40 years or older (mean of about 63 years) with moderate to severe COPD as defined by the GOLD criteria and a smoking history of 20 or more pack-years (mean about 49 pack-years). Mean FEV1 30 minutes after bronchodilator use was about 1.5L. Patients were excluded if they had had a respiratory tract infection or hospitalisation for COPD exacerbation within the previous 6 weeks or a history of asthma. Between 35% and 40% (depending on the treatment group) were on ICS.
Intervention and comparison: Indacaterol 150 or 300micrograms or placebo daily (double blind), or open-label tiotropium 18micrograms once daily, for 26 weeks. Treatment with anticholinergic bronchodilators or with beta-agonists was discontinued with appropriate washout. Fixed dose combinations of ICS plus long-acting beta-agonists were replaced by monotherapy ICS at an equivalent dose and regimen. Salbutamol was available as needed.
Outcomes and results: The primary endpoint was 24 hour post dose (trough) FEV1 after 12 weeks of treatment for indacaterol vs. placebo. Results are given for a selected efficacy population as least square means, with last observation carried forward for missing data. Both the indacaterol 150 microgram (n=389) and 300microgram (n=389) regimens improved trough FEV1 compared to placebo (n=376) by 0.18L (98.75%CI 0.14 to 0.22, P<0.001). The improvement for tiotropium (n=393) over placebo was 0.14L (98.75%CI 0.10 to 0.18, P< 0.001).
The key secondary objective of the study was to demonstrate the non-inferiority of at least one dose of indacaterol to tiotropium for trough FEV1 at 12 weeks and, if met, then to demonstrate superiority. Both indacaterol doses were stated to be statistically significant for non-inferiority at P<0.001 and for superiority at P≤ 0.01
Other secondary endpoints (all comparing indacaterol with placebo) in this study included the percentage of days of poor control during the 26 weeks of treatment, the time to first COPD exacerbation over 26 weeks,health status at week 12 as assessed by the St George’s Respiratory Questionnaire (SGRQ), breathlessness (transitional dyspnoea index) scores and the percentage of days no use of as-needed salbutamol over 26 weeks.
Data for the days of poor control are not presented in the paper. However, the EMA Assessment Report states the LS mean for the days of poor control over 26 weeks for patients receiving indacaterol 150micrograms, 300micrograms, tiotropium and placebo were 31.5 days (Standard Error, SE, 1.51), 30.8 days (SE 1.51), 31.0 days (SE 1.50) and 34.0 days (SE 1.53) respectively. The numerical advantage in days of poor control was not significant for either indacaterol dose.
The LS mean difference in SGRQ scores vs. placebo were as follows -2.8 (95%CI -4.5 to -1.1, P≤0.001), -2.5 (95%CI -4.4 to -1.0, P value not stated in paper) and -1.1 (95%CI -2.8 to 0.6, P value not stated in paper) for indacaterol 150 micrograms, 300 micrograms and tiotropium respectively. A change of 4 or more points had been defined as clinically relevant.
Breathlessness scores vs. placebo, as measured by the transitional dyspnoea index, were as follows at 26 weeks: 1.00 (95%CI 0.55 to 1.46, P<0.001), 1.18 (95%CI 0.73 to 1.62, P<0.001), 0.87 (95%CI 0.42 to 1.32, P<0.001) for indacaterol 150 micrograms, indacaterol 300 micrograms and tiotropium respectively. A change of 1 point or greater had been defined as clinically relevant.
The percentage of days with no use of as-needed salbutamol were as follows: 56.7 (SE 1.97, P<0.001), 57.8 (SE 1.97, P<0.001), 46.1 (SE 1.96, P=0.051), 41.8 (2.01) for indacaterol 150 micrograms, 300 micrograms, tiotropium and placebo respectively.
The effect on time to first exacerbation showed inconsistent results with a reduced risk relative to placebo for indacaterol 150 micrograms (HR 0.69, 95%CI 0.51 to 0.94, P=0.019) but the reductions were not statistically significant for indacaterol 300 micrograms (HR 0.74, 95%CI 0.55 to 1.01, P=0.054) or tiotropium (HR 0.76, 95% CI 0.56 to 1.03, P=0.080).
The main adverse effect reported was COPD worsening in 17.5% of patients in the indacaterol 150 microgram group and 18.3% in the 300 microgram group as compared to 19.5% with tiotropium and 21.8% of those receiving placebo. Nasopharyngitis occurred in 8% to 9% of patients in each group. The rate of cough was similar (about 7%) across the treatment groups. Tremor was reported in 0.5% of patients in both indacaterol groups. Tachycardia occurred in 1.2% and 0.2% of patients in the indacaterol 150 and 300microgram groups, respectively, in 1.4% of tiotropium patients and 0.7% of placebo. Sudden death occurred in a patient receiving indacaterol 150micrograms and who was diagnosed with cardiac failure. No causal relationship to the drug was established. Two deaths were reported with tiotropium; one due to an unspecified event secondary to arteriosclerosis and another due to severe acute bronchopneumonia.
Sponsorship: Both studies were sponsored by Novartis
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