Clinical trial review

INSPIRE: LABA/corticosteroid versus tiotropium in COPD

Peter Burrill MRPharmS, DipPresSci, FCPP, FFPMM A randomised controlled trial published in a peer-reviewed journal is considered to be the gold standard of information about the effectiveness of a treatment; however, critical appraisal of trials is required in order to judge the value and implications of the results. Here, the author presents an appraisal of the INSPIRE study, which compared exacerbation rates in COPD patients treated with salmeterol/fluticasone and tiotropium.
Wedzicha JA, Calverley PMA, Seemungal TA, et al, for the INSPIRE Investigators. The prevention of COPD exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med 2008;177:19-26.

range of COPD treatments have been shown to reduce exacerbations. These include long-acting inhaled bronchodilators like salmeterol (Serevent) and tiotropium (Spiriva), as well as inhaled corticosteroids (ICS) alone or when combined with long-acting beta-agonists (LABAs). The effectiveness of an ICS/LABA combination and of a long-acting anticholinergic in preventing exacerbations has not been directly compared. The aim of the Investigating New Standards for Prophylaxis in Reducing Exacerbations (INSPIRE) trial was to compare the effect of the combination of LABA/ICS salmeterol/fluticasone propionate (SFC; Seretide) with the long-acting bronchodilator tiotropium bromide on the rate of moderate and/or severe exacerbations during a two-year treatment period. INSPIRE was a multicentre, ran-

domised, double-blind, doubledummy controlled trial.

Methods

Patients were recruited from 179 centres in 20 countries. Recruited patients were aged 40-80 years with: a smoking histor y of 10 or more pack-years; a clinical history of COPD exacerbations; a postbronchodilator FEV1 below 50 per cent predicted; reversibility to 400g salbutamol 10 per cent or less of predicted FEV1; and a score of 2 or above on the Modified Medical Research Council Dyspnoea Scale. Patients entered a two-week run-in period during which they discontinued all existing COPD maintenance medications and received oral prednisolone 30mg per day and inhaled salmeterol 50g twice daily to standardise their clinical condition prior to randomisation. Patients were then randomised to inhaled SFC (salmeterol 50g plus fluticasone pro-

pionate 500g) twice daily by Diskus/Accuhaler or tiotropium bromide 18g once daily by Handihaler. Subjects randomised to SFC received a once-daily placebo inhalation by Handihaler and those randomised to tiotropium received a twice-daily placebo inhalation by Diskus/Accuhaler. After randomisation, in addition to study medication, patients were allowed short-acting inhaled beta-agonists for relief therapy and standardised short courses of oral systemic corticosteroids and/or antibiotics where indicated for treatment of COPD exacerbations. The randomisation process appears to have been allocation concealed. The primar y efficacy endpoint was the rate of healthcare utilisation exacerbations, defined as those that required treatment with oral corticosteroids and/or antibiotics or required hospitaliPrescriber 5 October 2008 43

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Clinical trial review

sation. Predefined secondar y end-points included health status measured by the St Georges Respirator y Questionnaire (SGRQ), post-dose FEV 1 measured two hours after inhalation of study medication, and study withdrawal rate. All-cause mortality was a tertiary efficacy end-point, while allcause mortality on treatment, up to two weeks after treatment cessation, was an additional end-point. All efficacy and safety analyses used the intent-to-treat (ITT) pop-

ulation, defined as all randomised patients who received at least one dose of study medication. The study was designed to show superiority of either treatment group, and was supported by GlaxoSmithKline.
Results

Of 1499 patients screened, 1323 were randomised. The mean age of participants was 64.5 years, 82.5 per cent were men, 38 per cent were current smokers and 49.5 per cent discontinued ICS at study entry.

Median adherence to treatment was above 99 per cent in both groups. Patients randomised to tiotropium were significantly more likely to withdraw from the study than those randomised to SFC the Kaplan-Meier estimated probability of withdrawing prior to week 104 was 34.5 per cent in the SFC group and 41.7 per cent in the tiotropium group; hazard ratio for tiotropium versus SFC was 1.29 (95% CI 1.081.54, p=0.005; see Figure 1). Withdrawing from the study after receiving tiotropium was

Clinical trial review

unrelated to the subjects prior use of inhaled corticosteroids used by 25 per cent of those withdrawing and 26 per cent of those completing. As a result of this study dropout the mean patient days of study drug exposure was 561 days with SFC and 519 with tiotropium. Over two years, 62 per cent of the SFC group and 59 per cent of the tiotropium group had at least one exacerbation requiring therapeutic inter vention. The estimated overall rates of

exacerbations were 1.28 per year for SFC and 1.32 per year for tiotropium with a ratio of rates of 0.97 (95% CI 0.84-1.12), indicating no difference between rates (p=0.656). Exacerbations requiring antibiotics occurred more frequently in patients treated with SFC (SFC 0.97 per year, tiotropium 0.82 per year, p=0.028), but those requiring systemic corticosteroids were less frequent than in the tiotropiumtreated patients (SFC 0.69 per year, tiotropium 0.85 per year, p=0.039). The incidence of exac-

erbations requiring hospitalisations was 16 per cent for SFC and 13 per cent for tiotropium (p=0.085). Mean SGRQ total score values at screening were 50.3 units for the SFC and 52.3 units for the tiotropium treatment groups, and improved after run-in treatment with systemic steroids and salmeterol to 48.0 units and 48.2 units at baseline respectively. The total SGRQ was significantly lower in the SFC group compared to the tiotropium group at weeks 32, 56, 80 and 104, although this

Clinical trial review

Implications 44 40 36 Probability of withdrawing (%) 32 28 24 20 16 12 8 4 0 0 13 26 39 52 65 78 Time to withdrawal (weeks) 91 104 tiotropium SFC 50/500

Figure 1. Patients taking tiotropium were significantly more likely to withdraw from the study than those randomised to salmeterol/fluticasone

difference did not reach the minimum clinically important difference. At week 104, the adjusted mean treatment difference for SFC versus tiotropium was -2.1 (95% CI -4.0 to -0.1 units, p=0.038). Mortality during the study period was lower in the SFC treatment group (3 per cent) compared with tiotropium (6 per cent), p=0.032. The frequency of adverse events was 66 per cent of patients on SFC and 62 per cent on
Key points

tiotropium (no p-value given but would be a NNH of 25). Serious adverse events were reported during treatment by 30 per cent of SFC-treated and 24 per cent of tiotropium-treated patients (no p-value given but would be a NNH of 17). Pneumonia was reported in 8 per cent and 4 per cent of patients respectively and the hazard ratio for time to reported pneumonia was 1.94 (95% CI 1.19-3.17, p=0.008). The NNH is 25.

INSPIRE is the first study to compare a LABA/ICS combination with a longacting bronchodilator in severe COPD the study was designed to show superiority of either treatment group patients randomised to tiotropium were significantly more likely to withdraw from treatment there was no difference in exacerbation rate between SFC and tiotropium but exacerbations requiring antibiotics occurred more frequently in the SFC group exacerbations requiring hospitalisations were 3 per cent higher for SFC the difference in SGRQ score was not clinically important

The strengths of the INSPIRE trial include its size, long duration and the inclusion of a large number of severe and ver y severe COPD patients, all of which allowed more exacerbation events to be identified. The primar y end-point of healthcare utilisation exacerbation rate was not significantly different between tiotropium and SFC 50/500. As this is what the study was powered for, any significant secondar y end-points are likely to be unreliable, especially if they are of marginal significance. The SGRQ total score was lower at two years with SFC (p=0.038) but only by 2.1 units. As we know 4 is the minimum clinically important difference, the authors conducted a post-hoc responder analysis looking at those that achieved a 4+ unit change. The results were 32 per cent for SFC and 27 per cent for tiotropium (NNT=20). No p-value was given and we have to be wary of this result. Mortality was lower in the SFC group 3 per cent versus 6 per cent ( p =0.032). However, even the authors state this was unexpected, admit that the trial was not powered for mortality, and say that powered studies are needed to confirm this finding. It is likely to be spurious and should be regarded as so until proven otherwise. This is the second RCT to show that inhaled fluticasone 1000g daily increases the risk of pneumonia in patients with COPD. The bottom line is that SFC was not more effective than tiotropium and appears to be less safe. Peter Burrill is specialist pharmaceutical adviser for Public Health, Derbyshire County PCT
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Prescriber 5 October 2008