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UK-RES-2101606 August 2021

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UK-RES-2101574 August 2021

INTENDED FOR UK HEALTHCARE PROFESSIONALS ONLY

Trimbow® evidence summary

The following Trimbow evidence summary provides you with information that will assist in your prescribing decision.

Indication[[1,2]]

Trimbow pMDI 87/5/9 and NEXThaler 88/5/9 are indicated for maintenance treatment in adult patients with moderate to severe chronic obstructive pulmonary disease (COPD) who are not adequately treated by a combination of an inhaled corticosteroid and a long-acting β2-agonist or a combination of a long-acting β2-agonist and a long-acting muscarinic antagonist (for effects on symptoms control and prevention of exacerbations see section 5.1 of the SPC).1,2

Three compounds[[1,2]]

Beclometasone
Beclometasone given by inhalation is a corticosteroid with glucocorticoid anti-inflammatory action, which suppresses inflammation in the lungs.1,2

Formoterol
Formoterol is a selective β2-adrenergic agonist that produces relaxation of bronchial smooth muscle in patients with reversible airways obstruction. The bronchodilating effect sets in rapidly, within 1–3 minutes after inhalation, and has a duration of 12 hours after a single dose.1,2

Glycopyrronium
Glycopyrronium is a high-affinity, long-acting muscarinic receptor antagonist (anticholinergic) resulting in a bronchodilator effect on the lungs.1,2

Trimbow pMDI 87/5/9 clinical trials [[1,3–5]]

The Phase III clinical development programme included two 52-week active-controlled studies:1,3,4

  • TRILOGY compared Trimbow pMDI 87/5/9 two inhalations twice daily, with Fostair (beclometasone/formoterol) pMDI 100/6 two inhalations twice daily (n=1,368 randomised patients). There were three co-primary endpoints:1,3
    • pre-dose FEV1
    • 2-h post-dose FEV1
    • transition dyspnoea index (TDI) focal score

    All were assessed at week 26. Superiority of Trimbow pMDI 87/5/9 to Fostair pMDI 100/6 was met in change from baseline in pre-dose FEV1 (p<0.001), change from baseline in 2-h post-dose FEV1 (p<0.001), but unmet for TDI focal score (p=0.160).1,3

    A similar proportion of patients had treatment-emergent adverse events in the two treatment groups, with pneumonia reported in 3% of patients in both treatment arms. Most adverse events were mild or moderate in severity.3

  • TRINITY compared Trimbow pMDI 87/5/9 two inhalations twice daily with Spiriva® HandiHaler® one inhalation once daily, and with a free triple combination made up of Fostair pMDI 100/6 two inhalations twice daily plus Spiriva® HandiHaler® one inhalation once daily (n=2,691 randomised patients).1,4The primary endpoint showed that Trimbow pMDI 87/5/9 resulted in a 20% (95% CI 8-31) reduction in the rate of moderate to severe COPD exacerbations compared with Spiriva® HandiHaler® alone at week 52 (p=0.0025; ARR 0.11).1,4

    Trimbow pMDI 87/5/9 is not licensed as a step-up treatment option for COPD patients on a LAMA only.

    Trimbow pMDI 87/5/9 is indicated for maintenance treatment in adult patients with moderate to severe chronic obstructive pulmonary disease (COPD) who are not adequately treated by a combination of an inhaled corticosteroid and a long-acting β2-agonist or a combination of a long-acting β2-agonist and a long-acting muscarinic antagonist (for effects on symptoms control and prevention of exacerbations see section 5.1 of the SPC).1

    A similar proportion of patients had adverse events in the three treatment groups. Most events were mild or moderate in severity. Pneumonia was reported in a small number of patients, with similar incidence in the three treatment groups (2–3%).4

Both studies were conducted in patients with a clinical diagnosis of COPD with severe to very severe airflow limitation (FEV1 less than 50% predicted), with symptoms assessed as a COPD Assessment Test (CAT®) score of 10 or above, and with at least one moderate or severe COPD exacerbation in the previous year.1,3,4

In addition, Trimbow pMDI 87/5/9 was also studied vs. Ultibro® Breezhaler® in a supporting Phase IIIb trial:1,5

  • TRIBUTE compared Trimbow pMDI 87/5/9 two inhalations twice daily, with Ultibro® Breezhaler®, one inhalation once daily.1,5The primary endpoint was to compare Trimbow pMDI 87/5/9 vs. Ultibro® Breezhaler® in terms of the rate of moderate to severe COPD exacerbations over 52 weeks (n=1,532 randomised patients). Trimbow pMDI 87/5/9 resulted in a 15% reduction in the rate of moderate to severe COPD exacerbations compared with Ultibro® Breezhaler® (rate: 0.50 vs. 0.59 events per patient/year; p=0.043; ARR 0.09).1,5A similar proportion of patients had adverse events in the two treatment groups. Most events were mild or moderate in severity. Pneumonia was reported in a small number of patients, with similar incidence in the two treatment groups (4%).5

TRIBUTE was also conducted in patients with a clinical diagnosis of COPD with severe to very severe airflow limitation (FEV1 less than 50% predicted), with symptoms assessed as a COPD Assessment Test (CAT®) score of 10 or above, and with at least one moderate or severe COPD exacerbation in the previous year.5

Trimbow NEXThaler (DPI) 88/5/9 clinical trial[[2,6]]

The clinical development programme for Trimbow NEXThaler 88/5/9 included one 4-week non-inferiority study:2,6

  • TRI-D compared Trimbow NEXThaler 88/5/9 two inhalations twice daily, with Trimbow pMDI 87/5/9 two inhalations twice daily and Fostair (beclometasone/formoterol) pMDI 100/6 two inhalations twice daily.2,6

    The co-primary efficacy endpoints were non-inferiority between Trimbow NEXThaler 88/5/9 and Trimbow pMDI 87/5/9 in FEV1 AUC0–12h normalised by time and trough FEV1 at 24 hours, both on day 28 (n=366 randomised patients). Changes from baseline in FEV1 AUC0–12h and trough FEV1on day 28 were similar for Trimbow pMDI 87/5/9 and Trimbow NEXThaler 88/5/9 and the CIs for the difference lying entirely within the pre-specified non-inferiority criterion (-50 mL): adjusted mean differences (95% CI) were -20 mL (-35; -6) for FEV1 AUC0–12h, and 3 mL (-15; 20) for trough FEV1 at 24 hours on day 28.2,6

    A similar proportion of patients had adverse events with each treatment. Most were mild or moderate, with few considered related to treatment.6

    Pneumonia was reported as a severe adverse event in a small number of patients on Trimbow NEXThaler 88/5/9 and Trimbow pMDI 87/5/9 (<1%).6

TRI-D was conducted in patients with a diagnosis of COPD ≥12 months prior to entry with FEV1 30–80% predicted, and had been receiving a stable regimen for ≥30 days of LAMA monotherapy, ICS + LABA + LAMA, ICS + LABA, or LABA + LAMA (free or fixed combinations were acceptable).6

COPD exacerbations clinical trial summary[[1,3–5]]

For primary endpoints please see clinical trials section above.

  • Compared with Fostair (beclometasone/formoterol) pMDI 100/6, Trimbow pMDI 87/5/9 reduced the rate of moderate to severe exacerbations over 52 weeks by 23% (rate: 0.41 vs. 0.53 events per patient/year; p=0.005; ARR 0.12). This was a secondary endpoint of the TRILOGY study.1,3 For primary endpoints please see above.
  • Compared with Spiriva® HandiHaler®, Trimbow pMDI 87/5/9 reduced the rate of moderate to severe exacerbations over 52 weeks by 20% (rate: 0.46 vs. 0.57 events per patient/year; p=0.0025; ARR 0.11).1,4
  • Compared with Spiriva® HandiHaler®, Trimbow pMDI 87/5/9 also reduced the rate of severe exacerbations (i.e. excluding moderate exacerbations) by 32% (rate: 0.067 vs. 0.098 events per patient/year; p=0.017; ARR 0.03, secondary endpoint).1,4 For primary endpoints please see above.
  • No differences were observed when comparing Trimbow pMDI 87/5/9 and the free triple combination of Fostair pMDI 100/6 plus Spiriva® HandiHaler® (moderate to severe exacerbation rate: 0.46 vs. 0.45 events per patient/year, secondary endpoint).1,4 For primary endpoints please see above.
  • In addition, compared with both Fostair pMDI 100/6 and with Spiriva® HandiHaler®, Trimbow pMDI 87/5/9 significantly prolonged the time to first moderate to severe exacerbation (hazard ratio 0.80 and 0.84 respectively; p=0.020 and 0.015 respectively, secondary endpoint), with no differences between Trimbow pMDI 87/5/9 and the free triple combination (hazard ratio 1.06, secondary endpoint).1,4 For primary endpoints please see above.
  • Compared with Ultibro® Breezhaler®, Trimbow pMDI 87/5/9 reduced the rate of moderate to severe COPD exacerbations by 15% (rate: 0.50 vs. 0.59 events per patient/year; p=0.043; ARR 0.09).1,5

Effects on lung function (Pre-dose FEV[{1}])[[1,3,4,6]]

For primary endpoints please see clinical trials section above.

  • Compared with Fostair (beclometasone/formoterol) pMDI 100/6, Trimbow pMDI 87/5/9 significantly improved pre-dose FEV1 by 81 mL after 26 weeks of treatment and by 63 mL after 52 weeks of treatment (p<0.001, secondary endpoint).1,3 For primary endpoints please see above.
  • Compared with Spiriva® HandiHaler®, Trimbow pMDI 87/5/9 significantly improved pre-dose FEV, by 51 mL after 26 weeks of treatment and by 61 mL after 52 weeks of treatment (p<0.001, secondary endpoint).1,4 For primary endpoints please see above.
  • No differences were observed when comparing Trimbow pMDI 87/5/9 and the free triple combination of Fostair pMDI 100/6 plus Spiriva® HandiHaler® (p=0.85, difference of 3 mL in pre-dose FEV1 after 52 weeks of treatment, secondary endpoint).1,4 For primary endpoints please see above.
  • No differences were observed when comparing Trimbow NEXThaler 88/5/9 and Trimbow pMDI 87/5/9 for pre-dose morning FEV1, both were superior to Fostair pMDI 100/6. Assay sensitivity demonstrated by statistical superiority of Trimbow NEXThaler 88/5/9 and Trimbow pMDI 87/5/9 vs. Fostair pMDI 100/6 for change from baseline in both FEV1 AUC0–12h and trough FEV1 on day 28 (p<0.001). This was a secondary endpoint of the TRI-D study.6 For primary endpoints please see above.

Safety profile and tolerability[[3-8]]

  • TRILOGY safety and tolerability3,7

  • TRINITY safety and tolerability4,8

  • TRIBUTE safety and tolerability5

  • TRI-D safety and tolerability6

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. Adverse events should also be reported to Chiesi Limited on 0800 0092329 (UK) or PV.UK@Chiesi.com.