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Three’s Company - The role of triple therapy in chronic obstructive pulmonary

disease (COPD) October 26th, 2018

Zahava Picado, PharmD PGY1 Pharmacy Resident

Central Texas Veterans Healthcare System Zahava.Picado@va.gov

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Learning Objectives By the end of this session, the learner should be able to…

• Identify COPD patients who are potential candidates for triple therapy

• Compare the use of “fixed” triple therapy with “open” triple therapy

• Explain the role of using inhaled corticosteroids (ICS) in a COPD patient

Assessment Questions Patient HT is a 69-year-old male who presents to your clinic. His most recent pulmonary tests show an FEV1/FVC: 47%,

FEV1: 29% of expected, and 2 exacerbations in previous year, 1 requiring hospitalization. The patient reports that he had

to stop for breath several times to enter your office from the parking lot today (mMRC 3).

1. How would you classify this patient’s COPD?

a. GOLD 1, Group A

b. GOLD 2, Group B

c. GOLD 3, Group C

d. GOLD 4, Group D

2. Which of the following medication regimens would you recommend for HT? a. Albuterol + Tiotropium b. Albuterol + Salmeterol c. Albuterol + Umeclidinium + Vilanterol d. Albuterol + Fluticasone + Salmeterol + Tiotropium

Patient OP is a 71-year-old female who presents to your clinic. Her most recent PFTs show an FEV1/FVC: 45%, FEV1: 28%

of expected, and 1 exacerbation 8 months ago requiring a hospitalization. The patient is extremely upset that she is not

able to run around the backyard and play tag with her grandchildren like she used to (mMRC 2).

3. How would you classify this patient’s COPD?

a. GOLD 1, Group A

b. GOLD 2, Group B

c. GOLD 3, Group C

d. GOLD 4, Group D

4. Which of the following medication regimens would you recommend for HT?

a. Albuterol + Tiotropium b. Albuterol + Salmeterol c. Albuterol + Umeclidinium + Vilanterol d. Albuterol + Fluticasone + Salmeterol + Tiotropium

5. Which of these comorbidities is associated with an increased risk for pneumonia?

I. Morbid Obesity

II. Current Smoker

III. FEV1 30% of predicted

A. I only

B. I and II

C. II and III

D. I, II, and III

E. None of the above

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Background - COPD Epidemiology

• COPD affects approximately 64 million people worldwide and is the 3rd leading cause of death.

• Chronic inflammatory disease with persistent airflow limitation

Classification of COPD

Classification of airflow limitation severity in COPD (based on post-bronchodilator FEV1) in patients with FEV1/FVC < 0.70

GOLD 1 Mild FEV1 > 80% of predicted

GOLD 2 Moderate FEV1 50-79% of predicted

GOLD 3 Severe FEV1 30-49% of predicted

GOLD 4 Very Severe FEV1 < 30% of predicted

Pharmacologic Options

• Beta Agonists o Short acting (SABA) and long acting (LABA)

• Muscarinic Antagonists o Short acting (SAMA) and long acting (LAMA)

• Inhaled Corticosteroids 2018 GOLD Guideline Recommendations

• SABA or SAMA: o Acceptable for occasional dyspnea only (Evidence A)

• LABA + LAMA: o Increases FEV1 and reduces symptoms compared to monotherapy (Evidence A) o Reduces exacerbations compared to monotherapy or ICS + LABA (Evidence B)

• ICS + LABA: o Improves lung function and health status, and reduces exacerbations compared to monotherapy

(Evidence A) • LABA + LAMA + ICS (AKA “triple therapy”):

o Improves lung function, symptoms and health status (Evidence A) and reduces exacerbations (Evidence B) compared to ICS/LABA and LAMA monotherapy

Noxious Air/Particle inhalation

Inflammatory cytokine release

Mucus hypersecretion

Airflow obstruction/air trapping

Gas exchange abnormalities

Pulmonary hypertension

Exacerbation History

> 2 or > 1 leading to hospitalization

GROUP C

GROUP D

0 or 1 (not leading to hospitalization)

GROUP A

GROUP B

mMRC 0-1 CAT < 10

mMRC > 2 CAT > 10

Symptom Severity

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• Role against LAMA/LABA still unclear o Recommended exclusively for patients with group D COPD who continue to have exacerbations despite

dual therapy. o Remains inappropriately prescribed to patients despite GOLD recommendations.

• Overuse of triple therapy results in a waste of limited health resources and increased risk of side effects

Question 1: Which patients will benefit the most from triple therapy?

Trial 1: TRILOGY

Treatment Arms • Beclomethasone + formoterol + glycopyrrolate (ICS/LABA/LAMA) • Beclomethasone + formoterol (ICS/LABA)

Primary Outcome • Change in pre-dose FEV1 and 2-hour post-dose FEV1 at 26 weeks

Select Secondary Outcomes

• COPD exacerbation frequency over 52 weeks

Inclusion Criteria • Age 40+ • Prebronchodilator FEV1 < 60% predicted • 1+ moderate/severe exacerbation within 12 months • Current or former smokers (10 pack-year history) • CAT > 10

Exclusion Criteria • Alpha-1 antitrypsin deficiency • Asthma, allergic rhinitis or Non-COPD pulmonary condition • COPD exacerbation within last 4 weeks • Requiring long term oxygen • Already on ICS/LABA/LAMA regimen

Baseline Characteristics

• 1181 patients completed study • 602 in ICS/LABA/LAMA • 579 in ICS/LABA

• Average age: 63 years old • Average FEV1: ~36% of predicted – severe airflow limitation • Average CAT score 20.8 • 47% active smokers • 1.2 exacerbations in the previous year • COPD medication at study entry

• ICS/LABA or ICS/LAMA – 75% • LABA/LAMA – 14% • LAMA – 11%

Group DLAMA + LABA LABA + ICS LAMA + LABA + ICS

Group CLAMA LAMA + LABA LABA + ICS

Group BLong-acting bronchodilator (LAMA/LABA) LABA + LAMA

Group AShort acting bronchodilator (SABA/SAMA) as needed

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Results Pre-dose FEV1 at 26 weeks • Triple therapy increased FEV1 82 ml; ICS/LABA, increased FEV1 by 1 ml • Adjusted mean difference: 81 ml (p<0.001, CI 52-109 ml)

Post-dose FEV1 at 26 weeks • Triple therapy increased FEV1 261 ml; ICS/LABA, increased FEV1 by 145 ml • Adjusted mean difference: 117 ml (p<0.001, CI 86-147 ml)

Exacerbation rate over 52 weeks • Triple therapy had a 23% lower incidence rate of exacerbations compared to

ICS/LABA (RR 0.77, p = 0.005, CI 0.65-0.92)

Trial 2: IMPACT

Treatment Arms • Fluticasone Furoate + Umeclidinium + Vilanterol (ICS/LAMA/LABA) • Fluticasone + Vilanterol (ICS/LABA) • Umeclidinium + Vilanterol (LAMA/LABA)

Primary Outcome • Moderate-severe exacerbation rate over 52 weeks

Select Secondary Outcomes

• Change in FEV1 over 52 weeks • Change in St Georges Respiratory Questionnaire (SGRQ) over 52 weeks

Inclusion Criteria • Age 40+ • Current or former smokers • COPD CAT Score > 10 • FEV1 <50% of expected AND 1 mod-severe exacerbation in previous year or • FEV1 50-70% of expected AND 2+ moderate exacerbations in previous year

Exclusion Criteria • Alpha-1 antitrypsin deficiency • Severe cardiac dysfunction • Allergic rhinitis or non-COPD pulmonary condition • Requiring long-term oxygen • Chronic use of antibiotics or oral steroids

Baseline Characteristics

• 10,355 patients in study • 4151 in ICS/LABA/LAMA • 4134 in ICS/LABA • 2070 in LABA/LAMA

• Average age: 65 years old • Average CAT score of 20.1 • Average FEV1 ~45% of predicted – severe airflow limitation • 26%: 1 severe COPD exacerbation in previous year • 47%: 2+ moderate COPD exacerbations in previous year • 11%: 3+ moderate-severe exacerbations in previous year • 4%: 2+ Severe COPD exacerbations in previous year

Results Exacerbation rate over 52 weeks • Triple therapy had a 15% lower rate of mod-severe exacerbations compared to

ICS/LABA (RR 0.85, P< 0.001, CI 0.80-0.90), and a 25% lower rate of moderate-severe exacerbations compared to LAMA/LABA (RR 0.75, P <0.001, CI 0.70-0.81).

Change in FEV1 at 52 weeks • Triple therapy increased FEV1 94 ml vs ICS/LABA which decreased FEV1 by 3ml, and

LAMA/LABA, which increased FEV1 by 40 ml. • Adjusted mean difference: 97 ml (P<0.001, CI 85-109); 54 ml (P<0.001, 39-69)

Change in SGRQ Score at 52 weeks • Triple therapy decreased SGRQ score by 5.5 points vs ICS/LABA and LAMA/LABA,

which decreased SGRQ score by 3.7 points. • Adjusted mean difference: 1.8 points (–2.4 to –1.1)

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Trial 3: SUNSET

Treatment Arms 3-week run-in period of Tiotropium + Salmeterol + Fluticasone, then: • Tiotropium + Salmeterol + Fluticasone (LAMA/LABA/ICS) • Indacaterol + glycopyrrolate (LABA/LAMA)

Primary Outcome • Change in FEV1 after 26 weeks of treatment

Select Secondary Outcomes

• Exacerbation rate over 26 weeks

Inclusion Criteria • Age 40+ • FEV1 40-80% predicted • No more than 1 moderate/severe exacerbation within 12 months • Current or former smokers (10 pack-year history) • Receiving ICS/LABA/LAMA for 6+ months

Exclusion Criteria • Alpha-1 antitrypsin deficiency • Asthma, allergic rhinitis or Non-COPD pulmonary condition • Requiring long term oxygen • Blood eosinophil count > 600 cells/µl

Baseline Characteristics

• 1053 patients in study • 527 in ICS/LABA • 526 in ICS/LABA/LAMA

• Average age: 65 years old • Average FEV1 ~56.6% of predicted – moderate airflow limitation • 34.1% had one exacerbation in previous year

Results Difference in FEV1 (Non-inferiority margin: -50 ml) • ICS withdrawal led to a decrease in FEV1 of -26 ml (95% CI -53 to 1) compared to

patients who remained on triple therapy. • De-escalation with dual therapy is not non-inferior to triple therapy.

Exacerbation rate over 26 weeks • Withdrawal of ICS led to 8% higher rate of moderate-severe exacerbations compared

to patients left on triple therapy (RR 1.08, P = 0.58, CI 0.83-1.40)

Triple Therapy

• Class D COPD only

• Severe airflow restriction

• High eosinophil counts (300-600 cells/µL)

Dual Therapy

• Inappropriately escalated

• Stable on triple therapy for > 6 months.

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Question 2: Is “fixed” triple therapy better than “open” triple therapy?

Trial 4: TRINITY

Treatment Arms • Beclomethasone + formoterol + glycopyrrolate (FIXED) • Tiotropium alone • Beclomethasone + formoterol + tiotropium (OPEN)

Primary Outcome • COPD moderate-severe exacerbation rate

Select Secondary Outcomes

• Change in pre-dose FEV1 at week 52

Inclusion Criteria • Age 40-80 • Post-bronchodilator FEV1 <50% predicted • CAT > 10 • Current or former smokers (10 pack-year history) • 1+ moderate/severe exacerbation within 12 months

Exclusion Criteria • Alpha-1 antitrypsin deficiency • Already receiving triple therapy • Asthma, allergic rhinitis or Non-COPD pulmonary condition • COPD exacerbation within last 4 weeks • Requiring long term oxygen

Baseline Characteristics

• 2691 patients • 1078 in fixed triple • 1075 in tiotropium • 538 in open triple

• Average age: 63 years old • Average FEV1 ~ 36.6% of predicted – Severe airflow limitation • Average CAT score 21 • 48% active smokers • COPD medication at study entry

• ICS/LABA or ICS/LAMA – 75% • LABA/LAMA – 12% • LAMA – 13%

Results Exacerbation Rate at 52 weeks • 20% lower exacerbation rate with fixed triple therapy compared to tiotropium

alone (RR 0.80, P = 0.0025, CI 0.69-0.92) • 21% lower exacerbation rate with open triple therapy compared to tiotropium

alone (RR = 0.79, P = 0.0095, CI 0.66-0.94) • 1% higher exacerbation rate with fixed triple therapy compared to open triple

therapy (RR = 1.01, P = 0.89, CI 0.85-1.21) Change in FEV1 at 52 weeks

• Fixed triple therapy increased FEV1 by 85 ml (65-100 ml) • Tiotropium therapy increased FEV1 by 21 ml (3-39 ml) • Open Triple therapy increased FEV1 by 85 ml (61-110 ml)

Study Conclusion: When compared to multiple inhalers, “fixed” triple therapy does not appear to have an impact on FEV1 or exacerbation rate.

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Question 3: Which patients are at an increased risk for pneumonia with inhaled steroids? Role of ICS in COPD

• Historically, providers hypothesized that patients with COPD and inflammation would respond to inhaled steroids similar to patients with asthma.

• Data supporting the use of ICS is limited.

• There is evidence that ICS use leads to adverse reactions, such as candidiasis, bruising, and pneumonia.

Trial 5: TORCH

Treatment Arms • Fluticasone Propionate (ICS) • Salmeterol (LABA) • Fluticasone + Salmeterol (ICS/LABA) • Placebo

Primary Outcome • All-cause mortality at 3 years • COPD-related mortality at 3 years

Select Secondary Outcomes

• Rate of exacerbations • Change in FEV1

Inclusion Criteria • Age 40-80 • Prebronchodilator FEV1 <60% predicted • Poor reversibility of airflow obstruction • Current or former smokers (10 pack-year history)

Exclusion Criteria • Alpha-1 antitrypsin deficiency • Asthma or Non-COPD pulmonary condition • COPD exacerbation within last 4 weeks

Baseline Characteristics

• 6112 patients included • 1500 in each treatment arm

• Average age: 65 years old • Average FEV1 ~ 44% of predicted – severe airflow limitation • Average pre-study exacerbation history:

• 1 ± 1.4 exacerbations/year requiring antibiotics/oral steroids • 43% active smokers, 48 pack-year history

Results All-cause mortality at 3 years • ICS/LABA did not significantly reduce risk of death compared to placebo (HR 0.825, CI

0.68-1.00, P=0.052) or salmeterol alone (HR 0.932, CI 0.765-1.134, P=0.48) • ICS/LABA was associated with a 23% reduction in risk of death compared to

fluticasone alone (HR 0.774, CI 0.641-0.934, P=0.007) COPD-related mortality at 3 years

• ICS/LABA was associated with a 22% reduction in risk of COPD-related death compared to placebo (HR 0.78, CI 0.57-1.06, P=0.011)

• ICS/LABA did not significantly reduce risk of COPD-related death compared to salmeterol (HR 0.77, CI 0.56-1.04, P=0.09)

• ICS/LABA was associated with a 33% reduction in risk of COPD-related death compared to fluticasone (HR 0.67, CI 0.50-0.90, P=0.008)

Pneumonia • ICS/LABA had 7.3% more pneumonia events compared to placebo (19.6% vs. 12.3%,

P<0.001) • Fluticasone alone had 6% more pneumonia events compared to placebo (18.3% vs.

12.3% P<0.001) • Salmeterol alone had 1% more pneumonia events compared to placebo (13.3% vs

12.3% P<0.001)

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Trial 6: SUMMIT

Treatment Arms • Fluticasone Furoate • Vilanterol • Fluticasone + vilanterol • Placebo

Primary Outcome • Time to death from any cause

Select Secondary Outcomes

• Cardiovascular death, MI, stroke, UA, and TIA.

Inclusion Criteria • Age 40-80 • FEV1 ≥50 and ≤70% predicted • ≥2 on the mMRC dyspnea scale • History of cardiovascular disease or increased cardiovascular risk • Current or former smokers (10 pack-year history)

Exclusion Criteria • Alpha-1 antitrypsin deficiency • Asthma or Non-COPD pulmonary condition • COPD exacerbation within last 4 weeks • Requiring long term oxygen

Baseline Characteristics

• 16,568 patients included • 4100 in each treatment arm

• Average age: 65 years old • Average FEV1 ~ 59% of predicted – Moderate airflow limitation • Exacerbation History

• 61% patients had 0 exacerbations • 25% of patients had 1 exacerbation • 15% of patients had 2+ exacerbations

• 47% active smokers, 41 pack-year history

Results Time to death from any cause • ICS/LABA did not significantly reduce risk of death compared to placebo (HR 0·88, CI

0·74-1·04, p=0·137) • Fluticasone did not significantly reduce risk of death compared to placebo (HR 0·91,

CI 0·77-1·08, p=0·284) • Vilanterol did not significantly reduce risk of death compared to placebo (HR 0·96, CI

0·81-1·14, p=0·655) Pneumonia

• ICS/LABA had 0.5% more pneumonia events compared to placebo (5.7% vs 5.2%, P<0.001)

• Fluticasone did not have significantly higher pneumonia events compared to placebo (5.5% vs 5.2%, P = 0.716)

• Vilanterol had 1.3% less pneumonia events compared to placebo (3.9% vs 5.2%, P<0.001)

Study Conclusions: Patients at higher risk of pneumonia are:

• Current smokers • Age 55+ • BMI < 25 • Poor mMRC grade and/or severe airflow limitation (FEV1< 50%) • History of exacerbations and/or pneumonia

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Presenter’s Conclusions

• Triple therapy o Recommended exclusively for patients with group D COPD who continue to have exacerbations despite

dual therapy. • Additional patients with high eosinophil counts may benefit from triple therapy.

o Consider de-escalating patients from triple therapy who are stable on their triple therapy for at least 6 months

• Open vs fixed triple therapy o When compared to multiple inhalers, “fixed” triple therapy does not appear to have an impact on FEV1

or exacerbation rate. • Role of ICS and pneumonia

o Use of ICS should be weighed strongly in patients who: are current smokers, age 55+, BMI < 25, are extremely symptomatic with significant airflow limitation, and who have a history of exacerbations and/or pneumonia

o ICS should never be used as monotherapy

Future Studies

1. INTREPID - Investigation of TRELEGY Effectiveness: Usual Practice Design (December 2019) a. Randomized, open-label, effectiveness, phase 4 study b. Fluticasone Furoate/Umeclidinium/Vilanterol single inhaler vs. multiple-inhaler triple therapy

2. TRIVOLVE - Fixed Dose Triple Therapy in Severe COPD in a Real-World Setting (August 2019) a. Prospective, non-interventional study b. Beclomethasone/Formoterol/Glycopyrrolate vs. multiple inhaler triple therapy

3. AIRWISE - Assessment in a Real-World Setting of the Effect of Inhaled Steroid-based Triple Therapy Versus the Combination of Tiotropium and Olodaterol on Reducing COPD Exacerbations (June 2020)

a. Randomized, open-label effectiveness phase 4 study b. Tiotropium/Olodaterol vs multiple inhaler triple therapy

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References

1. Global Initiative for Chonic Obstructive Lung Disease. The Global Strategy for the Diagnosis, Management and Prevention of COPD. 2018 [accessed 2018 August]. Available from: http://goldcopd.org

2. Hatipoglu U, Aboussquan L. Chronic obstructive pulmonary disease: An update for the primary physician. Clev Clin J Med 2014;81(6):373–383.

3. Singh, D., Papi, A., et al. (2016). Single inhaler triple therapy versus inhaled corticosteroid plus long-acting β2-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): A double-blind, parallel group, randomised controlled trial. The Lancet, 388(10048), 963-973. doi:10.1016/s0140-6736(16)31354-x

4. Chapman, K. R., Hurst, J. R., Frent, S., et al. (2018). Long-Term Triple Therapy De-escalation to Indacaterol/Glycopyrronium in Patients with Chronic Obstructive Pulmonary Disease (SUNSET): A Randomized, Double-Blind, Triple-Dummy Clinical Trial. American Journal of Respiratory and Critical Care Medicine, 198(3), 329-339. doi:10.1164/rccm.201803-0405oc

5. Vestbo, J., Papi, A., Corradi, M., et al. (2017). Single inhaler extra fine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): A double-blind, parallel group, randomized controlled trial. The Lancet, 389(10082), 1919-1929. doi:10.1016/s0140-6736(17)30188-5

6. Calverley PM, Anderson JA, Celli B, et al. Salmteterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356(8): 775-89.

7. Vestbo J, Anderson JA, Brook RD et al. Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomized controlled trial. Lance 2016; 387(10030): 1817-26

8. https://clinicaltrials.gov/ct2/show/NCT03467425?term=intrepid&cond=copd&rank=1 9. https://clinicaltrials.gov/ct2/show/NCT03627858?term=trivolve&rank=1 10. https://clinicaltrials.gov/ct2/show/NCT03265145?term=airwise&rank=1

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Supplementary Material

Table 2: Modified Medical Research Council (mMRC) Questionnaire for categorizing COPD severity

Severity Score Level of breathlessness

None 0 Only breathless with strenuous exercise

Mild 1 Shortness of breath hurrying or walking up a slight hill

Moderate 2 Walks slower than age group or must stop for breath when walking on level ground at own pace

Severe 3 Stops for breath after walking 100 meters or a few minutes on level ground

Very Severe 4 Breathless when dressing/too breathless to leave the house

Adapted from: Global Initiative for Chronic Obstructive Lung Disease. 2018

Table 3: Common inhaler formulations/combinations

ICS/LABA LABA/LAMA ICS

Budesonide/Formoterol (Symbicort) Fluticasone/Salmeterol (Advair)

Fluticasone/Vilanterol (Breo) Mometasone/Formoterol (Dulera)

Olodaterol/Tiotropium (Stiolto) Umeclidinium/Vilanterol (Anoro)

Indacterol/Glycopyrrolate (Utibron) Formoterol/Glycopyrrolate (Bevespi)

Fluticasone (Flovent) Flunisolide (Aerospan)

Mometasone (Asmanex) QVAR (Beclomethasone) Budesonide (Pulmicort)

LABA LAMA SABA

Olodaterol (Striverdi) Indacterol (Arcapta)

Salmeterol (Serevent) Formoterol (Foradil, Perforomist)

Tiotropium (Spiriva) Glycopyrrolate (Seebri)

Aclidinium (Tudorza) Umeclidinium (Incruse)

Albuterol (Proair, Ventolin, Proventil)

Levalbuterol (Xopenex)

ICS/LAMA/LABA

Fluticasone/Umeclidinium/Vilanterol (Trelegy)

Table 1: Terms and Abbreviations

COPD – Chronic Obstructive Pulmonary Disease

LABA – Long Acting Beta Agonist

LAMA – Long Acting Muscarinic Antagonist

ICS – Inhaled Corticosteroid

GOLD – Global Initiative for Obstructive Lung Disease

SGRQ – St Georges Respiratory Questionnaire

mMRC – Modified Medical Research Council Dyspnea Scale

CAT – COPD Assessment Test

FEV1 - Volume of air expired in the 1st second during maximal respiratory effort

FVC - total volume of air expired after full inspiration

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Figure 1. COPD Assessment Test