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Fluticasone Furoate, Umeclidinium and Vilanterol (Trelegy)

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pat hways Chronic obstructive pulmonary disease: fluticasone furoate, umeclidinium and vilanterol (Trelegy) Evidence summary Published: 14 June 2018 nice.org.uk/guidance/es18 Key points The content of this evidence summary was up-to-date in June 2018. See summaries of product characteristics (SPC), British national formulary (BNF) or the MHRA or NICE websites for up- to-date information. Regulatory status: Fluticasone furoate/umeclidinium/vilanterol (Trelegy, GlaxoSmithKline UK) received a European marketing authorisation in November 2017. This triple-therapy inhaler contains an inhaled corticosteroid (ICS), long-acting beta-2 agonist (LABA) and long-acting muscarinic antagonist (LAMA). It is licensed for maintenance treatment of adults with moderate- to-severe chronic obstructive pulmonary disease (COPD) who are not adequately treated by a combination of an ICS and a LABA (summary of product characteristics). Overview This evidence summary discusses 2 randomised controlled trials (RCTs) looking at the safety and efficacy of fluticasone furoate/umeclidinium/vilanterol (an ICS/LAMA and LABA combination inhaler) in people with COPD who were symptomatic despite regular maintenance treatment and who either had a history, or were at risk, of exacerbations. © NICE 2018. All rights reserved. Subject to Notice of rights (https://www.nice.org.uk/terms-and- Page 1 of conditions#notice-of-rights). 54 Chronic obstructive pulmonary disease: fluticasone furoate, umeclidinium and vilanterol (Trelegy) (ES18) Fluticasone furoate/umeclidinium/vilanterol (Trelegy) is licensed for maintenance treatment of adults with moderate-to severe COPD who are not adequately treated by a combination of an ICS and a LABA. Fluticasone furoate/umeclidinium/vilanterol has been shown to reduce the annual rate of moderate or severe exacerbations by 15% compared with fluticasone furoate/vilanterol. The NICE COPD full guideline considers 20% to be the minimum clinically important difference. There was no statistically significant difference between fluticasone furoate/umeclidinium/ vilanterol and fluticasone furoate/vilanterol for the annual ater of severe COPD exacerbations. Compared with umeclidinium/vilanterol, fluticasone furoate/umeclidinium/vilanterol reduced the annual rate of moderate or severe exacerbations by 25% and the annual rate of severe exacerbations by 34%. However, 39% of the participants in the umeclidinium/vilanterol group were previously using an ICS, LABA and a LAMA and stopped ICS treatment upon randomisation. It is unclear whether or not this abrupt cessation of ICS treatment may have had an effect on exacerbation outcomes. There were improvements in the St George's Respiratory Questionnaire total score (SGRQ; a health-related quality of life score) with fluticasone furoate/umeclidinium/vilanterol compared with budesonide/formoterol after 24 weeks' treatment, however there was no difference between the 2 groups after 52 weeks' treatment. There were also improvements in SGRQ total score with fluticasone furoate/umeclidinium/vilanterol compared with both fluticasone furoate/vilanterol and umeclidinium/vilanterol although the differences were less than what is considered to be the minimum clinically important difference. More participants had a clinically significant improvement in dyspnoea (defined as a rT ansitional Dyspnoea Index (TDI), focal score of at least a 1-unit increase) with fluticasone furoate/ umeclidinium/vilanterol compared with fluticasone furoate/vilanterol (36% compared with 29% respectively). There was an increase of 171 ml in change from baseline in trough forced expiratory volume in 1 second (FEV1) with fluticasone furoate/umeclidinium/vilanterol compared with budesonide/ formoterol. However, the European Public Assessment Report (EPAR) highlighted that the results for the fluticasone furoate/umeclidinium/vilanterol group may be unduly flattering as people in the comparator group were undertreated for their degree of severity of COPD and may have benefited from additional treatment. The EPAR stated that the safety profile of fluticasone furoate/umeclidinium/vilanterol was in line with the pharmacologic class of each component and with the dual combination products fluticasone furoate/vilanterol and umeclidinium/vilanterol, and no new safety signals emerged in the populations studied. However, the EPAR highlighted that pneumonia occurred more frequently © NICE 2018. All rights reserved. Subject to Notice of rights (https://www.nice.org.uk/terms-and- Page 2 of conditions#notice-of-rights). 54 Chronic obstructive pulmonary disease: fluticasone furoate, umeclidinium and vilanterol (Trelegy) (ES18) with fluticasone furoate/umeclidinium/vilanterol than with budesonide/formoterol. There was no difference between fluticasone furoate/umeclidinium/vilanterol and fluticasone furoate/vilanterol for risk of pneumonia. There was a statistically significant higher risk of pneumonia with fluticasone furoate/umeclidinium/vilanterol compared with umeclidinium/vilanterol. There were fewer all- cause mortality deaths in the fluticasone furoate/umeclidinium/vilanterol group than the umeclidinium/vilanterol group, although the overall number of deaths in the study was low. It is not known from these studies how the efficacy and safety of fluticasone furoate/umeclidinium/ vilanterol compares with other treatments for COPD such as other combinations of an ICS/LABA (alone or with a separate LAMA) or beclometasone/formoterol/glycopyrronium (Trimbow). Fluticasone furoate/umeclidinium/vilanterol may be suitable for some people with moderate-to- severe COPD who have found triple therapy beneficial using more than 1 inhaler, who have difficulty using multiple inhalers and can use a dry powder inhaler. A summary to inform local decision-making is shown in table 1. Table 1 Summary of the evidence on effectiveness, safety, patient factors and resource implications © NICE 2018. All rights reserved. Subject to Notice of rights (https://www.nice.org.uk/terms-and- Page 3 of conditions#notice-of-rights). 54 Chronic obstructive pulmonary disease: fluticasone furoate, umeclidinium and vilanterol (Trelegy) (ES18) Effectiveness In Lipson et al. 2018 (IMPACT), there was a statistically significant 15% reduction in the annual rate of moderate or severe exacerbations with fluticasone furoate/umeclidinium/ vilanterol compared with fluticasone furoate/vilanterol (0.91 compared with 1.07 per eary , rate ratio [RR] 0.85, 95% confidence interval [CI] 0.80 to 0.90; p<0.001). There was a 25% reduction compared with umeclidinium/vilanterol (0.91 compared with 1.21, RR 0.75, 95% CI 0.70 to 0.81; p<0.001, RCT, primary outcome, n=10,355, 52 weeks). In Lipson et al. 2018, there was no statistically significant difference between fluticasone furoate/umeclidinium/vilanterol and fluticasone furoate/vilanterol for the annual ater of severe exacerbations (0.13 compared with 0.15 per year, RR 0.87, 95% CI 0.76 to 1.01; p=0.06) and a statistically significant 34% reduction compared with umeclidinium/ vilanterol (0.13 compared with 0.19 per year, RR 0.66, 95% CI 0.56 to 0.78; p<0.001). In Lipson et al. 2017 (FULFIL), there was a statistically significant improvement in the change from baseline in SGRQ total score with fluticasone furoate/umeclidinium/vilanterol compared with budesonide/formoterol after 24 weeks treatment (−2.2 units, 95% CI −3.5 to −1.0 units; p<0.001). However there was no statistically significant difference between the 2 groups after 52 weeks' treatment (−2.7 units, 95% CI −5.5 to 0.2 units; p=0.065, RCT, co-primary outcome, n=1,811 and n=430 for 52-week data). In Lipson et al. 2018, there were statistically significant improvements in the change from baseline in SGRQ total score with fluticasone furoate/umeclidinium/vilanterol compared with both fluticasone furoate/vilanterol (−1.8 units, 95% CI −2.4 to −1.1 units; p<0.001) and umeclidinium/vilanterol (−1.8 units, 95% CI −2.6 to −1.0 units; p<0.001; secondary outcome). However, the differences between the groups were less than the 4 units' decrease considered to be the minimum clinically important difference. In Lipson et al. 2017, there was a statistically significant improvement in the change from baseline in trough forced expiratory volume in 1 second (FEV1) with fluticasone furoate/ umeclidinium/vilanterol compared with budesonide/formoterol (142 ml compared with −29 ml respectively; difference 171 ml, 95% CI 148 ml to 194 ml; p<0.001, co-primary outcome). In Lipson et al. 2018, more participants had a clinically significant improvement in TDI focal score with fluticasone furoate/umeclidinium/vilanterol compared with fluticasone furoate/ vilanterol (36% compared with 29% respectively, odds ratio 1.36; 95% CI 1.19 to 1.55, p<0.001, RCT, additional outcome in a subset of participants, n=5,058, 52 weeks). © NICE 2018. All rights reserved. Subject to Notice of rights (https://www.nice.org.uk/terms-and- Page 4 of conditions#notice-of-rights). 54 Chronic obstructive pulmonary disease: fluticasone furoate, umeclidinium and vilanterol (Trelegy) (ES18) Safety The EPAR highlighted that pneumonia occurred more frequently in the fluticasone furoate/ umeclidinium/vilanterol group than the budesonide/formoterol group in the Lipson et al. 2017 study (2.2% participants compared with 0.8% participants). The EPAR further added that the significance of this, if any, is uncertain as both groups contained an ICS and it is unknown if there are differences within the class for ICS propensity to cause pneumonia. The Medicines
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    (19) & (11) EP 2 162 125 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/136 (2006.01) A61K 31/01 (2006.01) 19.10.2011 Bulletin 2011/42 A61P 1/00 (2006.01) A61K 45/06 (2006.01) A61K 31/56 (2006.01) A61K 31/573 (2006.01) (2006.01) (21) Application number: 08768441.1 A61K 31/606 (22) Date of filing: 13.06.2008 (86) International application number: PCT/US2008/007401 (87) International publication number: WO 2008/156671 (24.12.2008 Gazette 2008/52) (54) Composition for rectal administration combined with an oral alpha-lipoic acid composition for the treatment of inflammatory bowel disease Zusammensetzung zur rektalen Verabreichung kombiniert mit einer oralen Zusammentzung enthaltend alpha Liponsäure zur Behandlung von entzündlicher Darmerkrankung Composition pour l’administration rectale en combinaison avec une composition orale de l’ acide alpha- lipoique pour le traitment des maladies intestinales inflammatoires (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR EP-B1- 0 671 168 WO-A2-02/089796 HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT US-A- 4 657 900 US-A- 5 082 651 RO SE SI SK TR US-A- 5 378 470 (30) Priority: 13.06.2007 US 934505 P • MULDER CJ. ET AL.: ’Beclomethasone 06.02.2008 US 63745 P dipropionate (3mg) versus 5- aminosalicylic acid (2g) versus the combination of both (3mg/2g)as (43) Date of publication of application: retention enemas in active ulcerative proctitis’ 17.03.2010 Bulletin 2010/11 EUR.J.GASTROENTEROL HEPATOL vol.
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