HERTFORDSHIRE MEDICINES MANAGEMENT COMMITTEE (HMMC) BECLOMETASONE/FORMOTEROL/GLYCOPYRRONIUM (TRIMBOW®) TRIPLE THERAPY COMBINATION INHALER FOR THE TREATMENT OF COPD AMBER INITITIATION – RECOMMENDED FOR RESTRICTED USE - for initiation by Respiratory Specialists and continuation in Primary Care

Name: generic What it is Indication Date Decision NICE / SMC (trade) decision status Guidance last revised Beclometasone / fixed dose triple therapy treatment of April 2019 Final NICE – no formoterol / combination of an inhaled chronic guidance glycopyrronium corticosteroid (ICS- obstructive SMC - (Trimbow®) beclometasone), a long-acting pulmonary accepted for beta-agonist (LABA- formoterol) disease restricted and long-acting anti-muscarinic (COPD) use (LAMA- glycopyrronium)

HMMC recommendation: Trimbow® is recommended for restricted use as a treatment option in line with local COPD treatment guidelines for stable category D patients where all three components are clinically indicated and effective and MDI (pressurised Metered Dose Inhaler) is an appropriate device AMBER INITITIATION - for initiation by Respiratory Specialists and continuation in Primary Care

Background Information  Trimbow® is a fixed dose triple therapy combination inhaler (containing ICS, LABA & LAMA).  It is licensed for use as maintenance therapy to relieve symptoms and prevent exacerbations in adult patients with moderate to severe COPD who are not adequately treated by an ICS/LABA combination.  Trimbow® has been formulated to deliver extrafine particles of beclometasone, formoterol and glycopyrronium. Each delivered dose (the dose leaving the mouthpiece) contains 87 mcg beclometasone dipropionate, 5 mcg of formoterol fumarate dihydrate and 9 mcg of glycopyrronium (as 11 mcg glycopyrronium bromide).  It is the first triple therapy product available as a pressurised metered dose inhaler (MDI) device  The recommended dose of Trimbow® is two inhalations twice a day  Each pressurised container has 120 actuations (30 day supply) and a shelf life of 22 months. It should be stored in the fridge (2°C-8°C) prior to dispensing. After dispensing, the medicinal product may be stored for a maximum of 4 months at a temperature up to 25°C.  The 30 day cost of each inhaler is £44.50

ASSESSMENT AGAINST THE ETHICAL FRAMEWORK

Evidence of Clinical Effectiveness Patient orientated primary and secondary outcomes (exacerbations): o In an RCT, compared with beclometasone/formoterol (Fostair® 100/6 micrograms), Trimbow® significantly reduced the rate of moderate-to-severe exacerbations of COPD (secondary endpoint) by 23% (p=0.005) after 52 weeks o In an RCT, compared with tiotropium (18 micrograms) in a dry powder inhaler plus a dummy metered dose inhaler and open triple therapy with beclometasone/formoterol (100/ 6 micrograms) in a metered dose inhaler plus tiotropium (18 micrograms), moderate to severe exacerbation rates were 0.46 (95% CI 0.41- 0.51) for Trimbow®, 0.57 (0.52- 0.63) for tiotropium, and 0.45 (0.39-0.52) for open triple therapy. Trimbow® reduced the incidence of moderate and severe exacerbations (the primary endpoint) by 20% vs tiotropium (95% CI 0.69 to 0.92, p=0.0025) o In an RCT, compared with indacaterol/ glycopyrronium bromide (110/ 63 micrograms) in a single matching dry powder inhaler plus a dummy metered dose inhaler the rate of moderate-to-severe exacerbations (the primary outcome) was reduced by 15% over 52 weeks (annualised rate 0.50 compared with 0.59 respectively; RR 0.85, 95% CI 0.72 to 0.99; p=0.043). Reduction was not considered clinically important according to criterion used in the EPAR A 20% reduction in exacerbations was considered clinically important by the European Medicines Agency.

This HMMC recommendation is based upon the evidence available at the time of publication. The recommendation will be reviewed upon request in the light of new evidence becoming available. Page 1 of 3

Disease orientated primary and secondary outcomes (lung function) o In an RCT, compared with beclometasone/formoterol (Fostair® 100/6 micrograms), Trimbow® significantly improved predose FEV1 by 0.081L (95% CI 0.052–0.109, p<0.001) and 2-hour post-dose FEV1 by 0.117L (95% CI 0.086– 0.147, p<0.001) at week 26 (primary outcome). o In an RCT, compared with tiotropium (18 micrograms) in a dry powder inhaler plus a dummy metered dose inhaler and open triple therapy with beclometasone/formoterol (100/ 6 micrograms) in a metered dose inhaler plus tiotropium (18 micrograms) in a dry powder inhaler, at week 52 pre-dose FEV1 for fixed triple was superior to tiotropium (mean difference 0·061 L [0·037 to 0·086]; p<0·0001) and non-inferior to open triple therapy (–0·003L [–0·033 to 0·027]; p=0·85) (secondary end point). General consensus is that an improvement below 0.100 litre is not clinically important although this may vary depending on severity of disease.

Safety: The adverse events reported most frequently during the clinical development of beclomethasone / formoterol / glycopyrronium were: oral candidiasis (0.5%), which is normally associated with ICS, muscle spasms (0.5%), which can be attributed to the long-acting beta-2agonist, and dry mouth (0.5%), which is a typical anticholinergic effect. o study vs beclometasone/formoterol (Fostair® 100/6 micrograms): a similar proportion of participants using beclometasone/formoterol/glycopyrronium and beclometasone/formoterol had treatment-emergent adverse events (54% compared with 56% respectively). Most of these were COPD-related (58% and 63% respectively), and most were mild or moderate in severity. About 3% of participants in each group had pneumonia, and about 2% of participants in each group had major adverse cardiovascular events o study vs tiotropium (18 micrograms) and open triple therapy with beclometasone/formoterol (100/ 6 micrograms): adverse events were reported by 55% of patients on Trimbow®, 58% with tiotropium and, 58% with Fostair® + Tiotropium. Pneumonia was reported in a small number of patients, with similar incidence in the three treatment groups. Most events were mild or moderate in severity o study vs indacaterol/ glycopyrronium bromide (110/ 63 micrograms): a similar proportion of adverse events were reported in participants using beclometasone/formoterol/glycopyrronium and indacaterol/glycopyrronium (64% vs 67% respectively). In both groups, 56% of these were COPD-related, and most were mild or moderate in severity. Pneumonia was seen in 4% of participants in each group, and adverse cardiovascular events were seen in 6% of participants using beclometasone/formoterol/glycopyrronium & 7% of participants using indacaterol/glycopyrronium

General Comments and Study limitations o Limited long term efficacy and safety data. o The RCTs were funded by Chiesi Farmaceutici SpA (the manufacturer) o Patients already on triple therapy (as two separate inhalers- LABA/ICS + LAMA) were excluded from the study and so no direct comparison available o Some differences seen although statistically significant are of uncertain clinical relevance, especially vs LABA/LAMA combination inhaler o No comparison vs alternative fixed dose triple therapy inhaler o It is also not known whether the triple-therapy inhaler has any advantages in terms of patient factors such as adherence to treatment and ease of use of the device o Some treatment escalations eg LAMA to triple therapy would not be in line with local/GOLD treatment guidelines o Studies were in more severe disease and there were many exclusion criteria so outcomes uncertain in the wider population with COPD o Some of the primary outcomes were disease-oriented, rather than patient oriented

Cost of treatment and Cost Effectiveness  No cost-effectiveness analysis available.  Scottish Medicines Consortium (SMC): Trimbow® (beclometasone, formoterol and glycopyrronium) costs less than inhalers containing beclometasone dipropionate / formoterol fumarate 100 micrograms/ 6 micrograms and glycopyrronium 44 micrograms administered separately  The monthly and annual cost of Trimbow® is less than: o inhalers containing beclometasone dipropionate / formoterol fumarate 100 micrograms/ 6 micrograms and glycopyrronium 44 micrograms administered separately o 1st line (licensed) LABA/ICS + LAMA choices administered together as separate inhalers: £541/year vs £548 - £671/year  Where triple therapy is indicated and effective there is a potential for reduced costs by using fixed dose triple therapy (ICS, LABA & LAMA) in a single inhaler versus 2 separate inhalers (e.g. ICS/LABA + LAMA)

The needs of the population  The needs of the population appear to be low as there are a range of single (LAMA, LABA) and dual therapy (LABA/ICS, LAMA/LABA) combination inhalers available to treat COPD.  Like all LABA/ICS combination inhalers (except Relvar) it is administered twice daily  Where triple therapy is indicated, twice daily administration with one inhaler vs two may be an attractive option for

This HMMC recommendation is based upon the evidence available at the time of publication. The recommendation will be reviewed upon request in the light of new evidence becoming available. Page 2 of 3

patient adherence (including difficulty using more than 1 device or who find their medication regimen difficult or confusing) even though the clinical relevance has not been established.  Fixed triple therapy lacks flexibility and makes it difficult to amend the individual medicines if treatment needs changing for any reason.  There are concerns that the availability of a fixed dose triple therapy inhaler may lead to rapid escalation to triple therapy with no assessment of the need, efficacy and safety of the separate individual drugs (especially the ICS – given safety concerns).  Trimbow is a MDI and can be used with a spacer. Alternative fixed dose triple therapy combination (Trelegy) is a DPI  Trimbow contains a medium strength ICS which is preferred 1st line strength for COPD (supports using the lowest effective ICS dose and hence lowering risk of adverse-effects)

The needs of the community  The needs of the community may be low as cost of Trimbow® is less than: 1. Inhalers containing beclometasone dipropionate / formoterol fumarate 100 micrograms/ 6 micrograms (LABA/ICS) and glycopyrronium 44 micrograms (LAMA) administered separately 2. The most commonly prescribed alternative triple therapy regimes prescribed as 2 separate inhalers (LABA/ICS + LAMA)  Costs would be increased if there is rapid escalation to triple therapy and subsequent reduced use of lower cost LABA/ICS or LABA/LAMA inhalers

Policy Drivers o Local COPD Guidelines: triple therapy (currently as separate inhalers) as an option for category D patients if continued frequent exacerbations or persistent breathlessness on LABA/ICS or LAMA/LABA inhalers o SMC (September 2017) following an abbreviated submission: Trimbow® is accepted for restricted use within NHS Scotland. SMC restriction: severe COPD (forced expiratory volume in one second less than 50% predicted normal). o MTRAC evidence review for Trimbow advises that in patients who need triple combination of ICS/LABA/LAMA, there may be benefit in terms of increased patient convenience & compliance with the use of a single inhaler instead of 2. o Local formulary status: • Included in Cambridge and Peterborough CCG Adult COPD pathway as a first line treatment option • Not recommended for primary care prescribing by West Essex CCG (currently on Red list i.e. hospital only prescribing) • Included in Adult COPD guidelines for Bedfordshire CCG • North Central London JFC - not listed as formulary for COPD

Equity: No impact anticipated.

Implementability: No issues identified.

References  NICE Evidence Summary: new medicine (ES17)- Chronic obstructive pulmonary disease: beclometasone, formoterol and glycopyrronium (Trimbow) May 2018– evidence and key issues summary: https://www.nice.org.uk/advice/es17/chapter/Key-points  Hertfordshire COPD treatment guidelines, updated Sept 2018 https://www.enhertsccg.nhs.uk/respiratory-system  Scottish Medicines Consortium (SMC) September 2017 beclometasone dipropionate / formoterol fumarate dihydrate / glycopyrronium 87 micrograms / 5 micrograms / 9 micrograms metered dose inhaler (Trimbow®) product update (accessed 09.12.2018): https://www.scottishmedicines.org.uk/media/1299/beclometasone_trimbow_abbreviated_final_sept_2107_for_website.pdf  Regional drug and therapeutics centre (Newcastle) cost comparison charts august 2018 (accessed 09.12.2018): http://rdtc.nhs.uk/sites/default/files/publications/prescribingsupport/cost_comparison_charts_-_august_2018.pdf  SPC beclometasone dipropionate / formoterol fumarate dihydrate / glycopyrronium 87 micrograms / 5 micrograms / 9 micrograms metered dose inhaler (Trimbow®) (accessed 09.12.2018): https://www.medicines.org.uk/emc/product/761/smpc  MTRAC Commissioning Support:extrafine beclometasone dipropionate / formoterol fumarate dihydrate / glycopyrronium https://ccg.centreformedicinesoptimisation.co.uk/files/MTRAC%20Trimbow_public%20extract%20Sept%202018.pdf  BNF online (accessed 09.12.20118): https://bnf.nice.org.uk/medicinal-forms/beclometasone-with-formoterol-and-glycopyrronium.html  Cambridgeshire and Peterborough CCG Adult COPD Quick Reference Guide (accessed 09.12.18): https://www.cambridgeshireandpeterboroughccg.nhs.uk/easysiteweb/getresource.axd?assetid=11138&type=0&servicetype=1  West Essex CCG formulary (accessed 09.12.18):https://westessexccg.nhs.uk/your-health/medicines-optimisation-and-pharmacy/hospital-only- red-list/9-red-list/file  Bedfordshire CCG COPD guidelines (accessed 09.12.18): http://www.gpref.bedfordshire.nhs.uk/media/209950/BCCG%20COPD%20ACO%20Guidelines.pdf  NCL formulary (accessed 09.12.18): https://www.ncl-mon.nhs.uk/wp-content/uploads/Guidelines/3_RRP_COPD_Guidelines.pdf .

This HMMC recommendation is based upon the evidence available at the time of publication. The recommendation will be reviewed upon request in the light of new evidence becoming available. Page 3 of 3