Pharmacology: Clinical Studies:
Asthma: SERETIDE clinical trials: A large twelve-month study (Gaining Optimal Asthma ControL, GOAL) in 3416 asthma patients compared the efficacy and safety of SERETIDE versus inhaled corticosteroid alone in achieving pre-defined levels of asthma control. Treatment was stepped-up every 12 weeks until ##
'Total control' was achieved or the highest dose of study drug was reached. Control needed to be sustained for at least 7 out of the last 8 weeks of treatment. The study showed that: 71% of patients treated with SERETIDE achieved #
'Well-controlled' asthma compared with 59% of patients treated with inhaled corticosteroid alone.
41% of patients treated with SERETIDE achieved ##
'Total control' of asthma compared with 28% of patients treated with inhaled corticosteroid alone.
These effects were observed earlier with SERETIDE compared with inhaled corticosteroid alone and at a lower inhaled corticosteroid dose.
The GOAL study also showed that: The rate of exacerbations was 29% lower with SERETIDE compared to inhaled corticosteroid treatment alone.
Attaining 'Well controlled' and 'Totally controlled' asthma improved Quality of Life (QoL). 61% of patients reported minimal or no impairment on QoL, as measured by an asthma specific quality of life questionnaire, after treatment with SERETIDE compared to 8% at baseline.
Well controlled asthma; occasional symptoms or SABA use or less than 80% predicted lung function plus no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy.
Total control of asthma; no symptoms, no SABA use greater than or equal to 80% predicted lung function, no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy.
Two further studies have shown improvements in lung function, percentage of symptom free days and reduction in rescue medication use, at 60% lower inhaled corticosteroid dose with SERETIDE compared to treatment with inhaled corticosteroid alone, whilst the control of the underlying airway inflammation, measured by bronchial biopsy and bronchoalveolar lavage, was maintained.
Additional studies have shown that treatment with SERETIDE significantly improves asthma symptoms, lung function and reduces the use of rescue medication compared to treatment with the individual components alone and placebo. Results from GOAL show that the improvements seen with SERETIDE, in these endpoints, are maintained over at least 12 months.
SEREVENT clinical trials: The Salmeterol Multi-center Asthma Research Trial (SMART) was a large US study that compared the safety of SEREVENT or placebo added to usual therapy. There were no significant differences in the primary endpoint of the combined number of respiratory-related deaths and respiratory-related life-threatening experiences. The study showed a significant increase in asthma-related deaths in patients receiving SEREVENT (13 deaths out of 13,176 patients treated for 28 weeks on SEREVENT versus 3 deaths out of 13,179 patients on placebo). The study was not designed to assess the impact of concurrent inhaled corticosteroid use. However, post-hoc analyses showed there was no significant difference between treatment groups for asthma-related deaths for those patients using inhaled steroids at baseline (4/6127 on SEREVENT versus 3/6138 on placebo). The numbers of asthma-related deaths in the groups not using inhaled steroids were 9/7049 on SEREVENT versus 0/7041 on placebo. Further, a meta-analysis of 42 clinical studies involving 8,030 patients on SERETIDE and 7,925 patients on FLIXOTIDE did not show a statistical difference between SERETIDE and FLIXOTIDE for serious respiratory-related events or asthma-related hospitalisations.
Safety and efficacy of salmeterol-FP versus FP alone in asthma: Two multi-centre 26-week studies were conducted to compare the safety and efficacy of salmeterol-FP versus FP alone, one in adult and adolescent subjects (AUSTRI trial), and the other in paediatric subjects 4-11 years of age (VESTRI trial). For both studies, enrolled subjects had moderate to severe persistent asthma with history of asthma-related hospitalisation or asthma exacerbation in the previous year. The primary objective of each study was to determine whether the addition of LABA to ICS therapy (salmeterol-FP) was non-inferior to ICS (FP) alone in terms of the risk of serious asthma related events (asthma-related hospitalisation, endotracheal intubation, and death). A secondary efficacy objective of these studies was to evaluate whether ICS/LABA (salmeterol-FP) was superior to ICS therapy alone (FP) in terms of severe asthma exacerbation (defined as deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or an in-patient hospitalisation or emergency department visit due to asthma that required systemic corticosteroids).
A total of 11,679 and 6,208 subjects were randomized and received treatment in the AUSTRI and VESTRI trials, respectively. For the primary safety endpoint, non-inferiority was achieved for both trials (see Table 1 as follows).
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For the secondary efficacy endpoint, reduction in time to first asthma exacerbation for salmeterol-FP relative to FP was seen in both studies, however only AUSTRI met statistical significance: See Table 2.
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Salmeterol Multi-center Asthma Research Trial (SMART): The Salmeterol Multi-center Asthma Research Trial (SMART) was a 28-week US study that evaluated the safety of salmeterol compared to placebo added to usual therapy in adult and adolescent subjects. Although there were no significant differences in the primary endpoint of the combined number of respiratory-related deaths and respiratory-related life-threatening experiences, the study showed a significant increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13,176 patients treated with salmeterol versus 3 deaths out of 13,179 patients on placebo). The study was not designed to assess the impact of concurrent inhaled corticosteroid use.
COPD: Symptomatic COPD patients without restriction to 10% reversibility to a short acting beta-2-agonist: Placebo-controlled clinical trials, over 6 months, have shown that regular use of both SERETIDE 50/250 and 50/500 micrograms rapidly and significantly improves lung function, significantly reduced breathlessness and the use of relief medication. There were also significant improvements in health status. Symptomatic COPD patients who demonstrated less than 10% reversibility to a short acting beta-2-agonist: Placebo-controlled clinical trials, over 6 and 12 months, have shown that regular use of SERETIDE 50/500 micrograms rapidly and significantly improves lung function, significantly reduced breathlessness and the use of relief medication. Over a 12-month period the risk of COPD exacerbations and the need for additional courses of oral corticosteroids was significantly reduced. There were also significant improvements in health status.
SERETIDE 50/500 micrograms was effective in improving lung function, health status and reducing the risk of COPD exacerbations, in both current and ex-smokers.
TORCH study (TOwards a Revolution in COPD Health): TORCH was a 3-year study to assess the effect of treatment with SERETIDE ACCUHALER 50/500 micrograms twice daily, salmeterol ACCUHALER 50 micrograms twice daily, FP Accuhaler 500 micrograms twice daily or placebo on all-cause mortality in patients with COPD. Patients with moderate to severe COPD with a baseline (pre-bronchodilator) FEV1
<60% of predicted normal were randomised to double-blind medication. During the study, patients were permitted usual COPD therapy with the exception of other inhaled corticosteroids, long-acting bronchodilators, and long-term systemic corticosteroids. Survival status at 3 years was determined for all patients regardless of withdrawal from study medication. The primary endpoint was reduction in all-cause mortality at 3 years for SERETIDE vs placebo. (See Table 3.)
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SERETIDE reduced the risk of dying at any time during the 3 years by 17.5% compared to placebo (Hazard Ratio 0.825 (95% CI 0.68, 1.00, p=0.052; all adjusted for interim analyses). There was a 12% reduction in the risk of dying at any time within 3 years from any cause for salmeterol compared with placebo (p=0.180) and a 6% increase for FP compared with placebo (p=0.525).
A supporting analysis using Cox's Proportional Hazards model gave a hazard ratio of 0.811 (95% CI 0.670, 0.982, p=0.031) for SERETIDE vs placebo which represented a 19% reduction in the risk of dying at any time within 3 years. The model adjusted for important factors (smoking status, age, sex, region, baseline FEV1
and Body Mass Index). There was no evidence that treatment effects varied for these factors.
The percentage of patients who died within 3 years due to COPD-related causes was 6.0% for placebo, 6.1% for salmeterol, 6.9% for FP and 4.7% for SERETIDE.
SERETIDE reduced the rate of moderate to severe exacerbations by 25% (95% CI: 19% to 31%; p<0.001) compared with placebo. SERETIDE reduced the exacerbation rate by 12% compared with salmeterol (95% CI: 5% to 19%, p=0.002) and 9% compared with FP (95% CI: 1% to 16%, p=0.024). Salmeterol and FP significantly reduced exacerbation rates compared with placebo by 15% (95% CI: 7% to 22%; p<0.001) and 18% (95% CI: 11% to 24%; p<0.001) respectively.
Health Related Quality of Life, as measured by the St George's Respiratory Questionnaire (SGRQ) was improved by all active treatments in comparison with placebo. The average improvement over three years for SERETIDE compared with placebo was -3.1 units (95% CI: -4.1 to -2.1; p<0.001), compared with salmeterol was -2.2 units (p<0.001) and compared with FP was -1.2 units (p=0.017).
Over the 3 year treatment period, FEV1
values were higher in subjects treated with SERETIDE than for those treated with placebo (average difference over 3 years 92mL, 95% CI: 75 to 108 mL; p<0.001). SERETIDE was also more effective than salmeterol or FP in improving FEV1
(average difference 50 mL, p<0.001 for salmeterol and 44mL, p<0.001 for FP).
The estimated 3 year probability of having pneumonia reported as an adverse event was 12.3% for placebo, 13.3% for salmeterol, 18.3% for FP and 19.6% for SERETIDE (Hazard ratio for SERETIDE vs placebo: 1.64, 95% CI: 1.33 to 2.01, p<0.001). There was no increase in pneumonia related deaths; deaths while on treatment that were adjudicated as primarily due to pneumonia were 7 for placebo, 9 for salmeterol, 13 for FP and 8 for SERETIDE. There was no significant difference in probability of bone fracture (5.1% placebo, 5.1% salmeterol, 5.4% FP and 6.3% SERETIDE; Hazard ratio for SERETIDE vs placebo: 1.22, 95% CI: 0.87 to 1.72, p=0.248). The incidence of adverse events of eye disorders, bone disorders, and HPA axis disorders was low and there was no difference observed between treatments. There was no evidence of an increase in cardiac adverse events in the treatment groups receiving salmeterol.
Fluticasone propionate containing medications in asthma during pregnancy: An observational retrospective epidemiological cohort study utilising electronic health records from the United Kingdom was conducted to evaluate the risk of MCMs following first trimester exposure to inhaled FP alone and salmeterol-FP combination relative to non-FP containing ICS. No placebo comparator was included in this study. As an epidemiologic study, biases may not have been controlled to the same extent as in a clinical trial.
Within the asthma cohort of 5362 first trimester ICS-exposed pregnancies in which MCMs were diagnosed by one year of age, 131 major MCMs were identified; in the 1612 (30%) pregnancies which were exposed to FP or salmeterol-FP, 42 diagnosed MCMs were identified. In 3750 (70%) pregnancies which were exposed to non-FP inhaled corticosteroid (ICS), 89 diagnosed MCMs were identified. The adjusted odds ratio for MCMs diagnosed by 1 year was 1.1 (95%CI: 0.5 - 2.3) for FP exposed vs non-FP ICS exposed women with moderate asthma and 1.2 (95%CI: 0.7 - 2.0) for women with considerable to severe asthma. No difference in the risk of MCMs was identified following first trimester exposure to FP alone versus salmeterol-FP combination. Absolute risks of MCMs across the asthma severity strata ranged from 2.0 to 2.9 per 100 FP-exposed pregnancies.