Three better than 1 or 2?

Three better than 1 or 2?

DISCLOSURE Pam McLean-Veysey, Team Leader Drug Evaluation Unit DEU funded by the Drug Evaluation Alliance of NS. (DEANS). DEU prepares Drug Evaluation Reports for the Atlantic Common Drug Review (ACDR) Has no conflicts of interest

Faculty: Dr. Brian Moses Relationships with commercial interests: Grants/Research Support: None Speakers Bureau/Honoraria: AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Eli Lilly, Janssen, Novartis, NovoNordisk, Pfizer, Sanofi Aventis, and Servier. Consulting Fees: AstraZeneca, Bayer, BMS/Pfizer, NovoNordisk, Eli Lilly, Novartis. Other: None

OBJECTIVES To review the evidence (benefits and harms) for triple therapy (LAMA+LABA+ICS) in COPD. Based on a case, determine the characteristics of the patient population where triple therapy could be considered. To review the positioning of triple therapy in Clinical Practice Guidelines

AN EXPLOSION OF INHALER DEVICES! Genuair Turbuhaler

Class Generic Long acting Beta 2 agonists (LABA) Salmeterol Formoterol Indacaterol Long Acting Muscarinic Tiotropium Antagonists (LAMA) Aclidinium aka Long Acting Anticholinergic Glycopyrronium (LAAC) Umeclidinium LAMA/LABA Combinations: Aclidinium + Formoterol Glycopyrronium + Indacaterol Tiotropium + Olodaterol Umeclidinium + Vilanterol LABA/ICS Combinations in one Budesonide/ formoterol inhaler Fluticasone/ Salmeterol Fluticasone/ Vilanterol Mometasone/formoterol LAMA+ICS+LAMA Combination in one inhaler Fluticasone, umeclidinium, vilanterol

JB- COPD relevant medical history 74 y.o. male, 5 8 (1.7m) 130 lbs (59 kg); BP 140/90 Heavy smoker x 50 years stopped 5 years ago FEV 1 FVC 50% ; FEV 1 60% predicted; no reversibility > 12% or 200 ml COPD diagnosed 10 years ago; no signs of CHF MRC =3 Treated for hypertension and hyperlipidemia Insured through Pharmacare Image: https://www.google.com/search?q=man+coughing&client=firefoxb&source=lnms&tbm=isch&sa=x&ved=0ahukewib3cpn4jleahvczn8khvvyauqq_auidigb&biw=1280&bih=664#imgrc=vmnhsqceyjfcnm:

Past COPD medications (added therapy in response to persistent dyspnea) Ipratropium 20mcg 2 puffs qid (2008-2012) Tiotropium once daily x 5 years (2012- Dec 2017 (LAMA) Tiotropium + olodaterol 2.5/2.5mcg 2 inhalations once daily (Dec 2017...) (LAMA/LABA) +salbutamol prn First AECOPD 2 weeks ago Increased SOB, cough, sputum volume, purulence x 4 days treated antibiotic doxycycline 200 mg one dose then 100 mg bid x 7 days and prednisone 40 mg x 5 days. Image: https://www.google.com/search?q=man+coughing&client=firefoxb&source=lnms&tbm=isch&sa=x&ved=0ahukewib3cpn4jleahvczn8khvvyauqq_auidigb&biw=1280&bih=664#imgrc=vmnhsqceyjfcnm

Has recovered from exacerbation, and dyspnea and energy almost at baseline You do which of the following? Prescribe the new triple therapy inhaler TRELEGY ELLIPTA (you have samples) Keep on LAMA/LABA Respimat inhaler Update his flu and pneumococcal vaccines Check technique and adherence Add an ICS inhaler - Fluticasone (Flovent) 250 mcg 2 puffs twice daily. Switch to Advair 250mcg 2 puffs twice daily.

Stay on LAMA/LABA Add an ICS (triple therapy) Switch to a LABA/ICS

Exacerbations Mild Moderate Severe (hospitalizations) All combined Symptoms Dyspnea scores (TDI) MCID 1 point SABA use Quality of Life SGRQ SCORES (MCID 4 points) Lung function Trough FEV 1 (MCID? 100-140 ml) Exercise tolerance ADVERSE EFFECTS Key Concepts Clinical vs. statistical significance MCID

PICO FORMAT Population Intervention Comparison Outcome

CONSIDER SWITCH? Wedzicha JA, Banerji D, Chapman KR, et al. Indacaterol glycopyrronium versus salmeterol fluticasone for COPD. N Engl J Med 2016; 374:2222-34.

FLAME TRIAL PRIMARY ENDPOINT N=3362 All (mild, moderate, severe) exacerbations (rate/year) MITT INDACATEROL+ GLYCOPYRRONIUM 110/50 mcg ONCE DAILY n=1680 SALMETEROL+ FLUTICASONE 50/500 mcg BID n=1682 RR 95% CI P VALUE ARR % 3.59% 4.09% 0.88 (0.82, 0.94) p<0.001 ARR 0.50 LABA/LAMA shown to be non inferior to LABA/ICS Met superiority standards also ARR = absolute risk reduction RR = Relative risk

INDACATEROL+ GLYCOPYRRONIUM 110/50 mcg ONCE DAILY n=1680 SALMETEROL+ FLUTICASONE 50/500 mcg BID n=1682 RR 95% CI P VALUE ARR NNT 95% CI Secondary Exacerbation Endpoints (rate/year) Mild 2.46 2.72 Moderate 0.81 0.98 Severe 0.15 0.17 0.91 (0.83, 0.99) 0.83 (0.74, 0.92) 0.87 (0.69, 1.09) 0.030 ARR 0.26 <0.001 ARR 0.17 0.231 - Pts with 1 exacerbation 77% 82% NNT 20 13-44

VS LAMA 3 vs 1? Outcomes with no statistically or clinically relevant difference X Lung function: X Severe exacerbation X Dyspnea - insufficient information Improved QoL: Odds for MCID 50% vs 40% Rojas-Reyes, TRINITY? Moderate to severe exacerbations; vs. TIO: low annualized rates RR 0.80 (0.69-0.92) TRINITY * Reference: Cochrane Review (Triple vs. Tio) Rojas-Reyes MX 2016 and 4 RCTS TRINITY, FULFIL, TRILOGY, GLISTEN

LABA/ICS LAMA/LABA/ICS vs. LABA/ICS *? Lung function: 1 of 4 trials showed clinically relevant difference FULFIL (171 ml) QoL Odds of MCID favored triple: OR1.33 (95%CI 1.11-1.59)? Exacerbations: low annual rates; small ARR; clinical relevance? X Symptoms: no difference both treatments improved dyspnea scores * References: 4 RCTS TRINITY, FULFIL, TRILOGY, GLISTEN

Most relevant comparator vs. triple? After FLAME trial LABA/LAMA or LABA/ICS to confirm FLAME results or Why not LAMA? Insufficient evidence for benefit until these new trials DB, PG, MC Trials IMPACT 2018 TRIBUTE 2018 KRONOS Lipson DA, N Engl J Med. 2018;378:1671-80 Papi A et al Lancet Lancet 2018; 391: 1076 84 2018 Ferguson GT Lancet Respir Med 2018;6: 747-58

Funded by GlaxoSmithKline. Lipson DA, Barnhart F, Brealey N, et al; Once daily single-inhaler triple versus dual therapy in patients with COPD. N Engl J Med. 2018;378:1671-80.

N=10,355, 52 weeks Mean FEV 1 < 56 % PATIENTS: At least 1 moderate or severe exacerbation in the previous year, or an FEV 1 50 to 80% predicted + at least two moderate exacerbations or one severe exacerbation in the-previous year. Baseline: Moderate or severe COPD exacerbation in previous year 1-45% 2-43% 3 or more 11% Severe exacerbations in previous year (hospitalizations) 1 or more 26% 2 or more 4%

Run in Continued own medication, (LAMA, LABA, or an inhaled glucocorticoid alone or in combination), during a 2-week run-in period before randomization. 38% using triple therapy at baseline 29% LABA/ICS 8% LAMA/LABA More patients discontinued prematurely in the dual bronchodilator (27%) and LABA/ICS (25%) than triple therapy (18%) group. 77% completed trial taking medications and overall, 88% completed trial 18% -20% had reversibility of 12% and 200 ml post bronchodilator indicative of asthma.

PICO Intervention and Comparators LABA/ICS/ LAMA: FF 100 mcg, umeclidinium 62.5 mcg, vilanterol 25 mcg (Triple therapy in one inhaler) LABA/ICS: FF 100 mcg, vilanterol25 mcg LAMA/LABA: Umeclidinium 62.5 mcg, vilanterol 25 mcg

PICO Primary outcome Annual rate of moderate or severe COPD exacerbations during treatment Symptoms recorded by patient in electronic diary each morning Symptoms suggestive of an exacerbation over 48 hours - contacted investigator MANY secondary outcomes

IMPACT RESULTS

IMPACT TRIAL Event rates LAMA/LABA /ICS N= 4151 LABA/ LAMA N= 2070 LABA/ICS N= 4134 Rate Ratio/Hazard Ratio/Odds Ratio Triple therapy vs comparators (95% Confidence Interval) LABA/ LAMA LABA/ICS Additional outcomes (not a complete list 16 in total) Not adjusted for multiple comparisons Annual rate of all exacerbations 1.05 1.4 1.25 RR 0.75 (0.70-0.81) RR 0.84 (0.79-0.89) Health Status (SGRQ) Change from baseline MCID -4 pts 5.5 ( 5.9 to 5.0) 3.7 ( 4.4 to 3.0) 3.7 ( 4.2 to 3.2) - - SGRQ proportion with MCID -4 points Lung Function Mean change from baseline (Trough FEV 1 ) 42% 34% 34% 1.41 (1.26 to 1.57) 1.41 (1.29 to 1.55) 94 (86 to 102) 40 (28 to 52 3 ( 12 to 6) Difference 54 ml (39-69) Difference 97 ml (85-109) Dyspnea % with MCID TDI 1 36% 30% 29% OR 1.33 (1.13-1.57) OR 1.36 (1.19-1.55) All cause death on treatment 50 (1%) 39 (2%) 49 (1%) 0.58 (0.38 to 0.88) Authors state a fragile result NNT 121 (71 to 3450) NS All cause death on and off treatment (supplementary info) 89 (2.14)% 60 (2.9%) 97 (2.35) HR 0.71 (0.51-0.99) NS Pneumonia 8% (Serious 4%) 5% (Serious 3%) 7% (Serious 4%) Triple vs LAMA/LABA HR 1.53 (1.22-1.92) NS

CADTH recommendation: July 2018 For the maintenance treatment of COPD, including chronic bronchitis and/or emphysema, if the following criteria and condition are met: Criteria Patients should not be started on triple inhaled therapy as initial therapy for COPD. For use in patients who are not controlled on optimal dual-inhaled therapy for COPD. Condition Drug plan cost of FF/UMEC/VI should not exceed the drug plan cost of treatment with any triple therapies reimbursed for COPD (long-acting muscarinic antagonist [LAMA]/long-acting beta-2 agonist [LABA]/inhaled corticosteroid [ICS]). https://www.cadth.ca/sites/default/files/cdr/complete/sr0562_cdr_complete_trelegy_ellipta_aug_27_18.pdf

Similar design, primary outcome and severity as IMPACT population N=1532, 52 weeks All patients < 50% FEV 1 pred. 20% 2 exacerbations in previous year; 80% 1 exacerbation > 60% used ICS prior to study entry Comparators: triple vs LAMA/LABA: Budesonide extra fine/ formoterol/ glycopyrronium vs. Indacaterol/ glycopyrronium (LAMA/LABA) Funded by Chiesi Farmaceutici

TRIPLE VS LAMA/LABA (TRIBUTE OUTCOMES) No statistically significant difference Moderate exacerbations Severe exacerbations Combined moderate and severe RR 0.85 (0.723-0.995) p=0.043 No difference in lung function or quality of life (SGRQ) outcomes No increased risk of pneumonia Mortality not reported

Patients moderate to severe COPD without a history of exacerbations N=1902 75% - no exacerbations in previous year 20% - 1 exacerbation in previous year FEV 1 % predicted 50% (cut-off for severe) 70% used ICS at baseline ~ 43% reversible (>200 ml and 12%) Baseline inhaler use LABA/ICS ~ 40% LAMA/LABA/ICS ~ 28% LAMA/LABA ~ 20% Remaining - Short acting agents and other combos

PICO Interventions / Comparisons TRIPLE budesonide/glycopyrrolate/formoterol fumarate MDI 320/18/9.6 μg (BGF), Dual Glycopyrrolate/formoterol fumarate mdi 18/9.6 μg (GFF), LABA/ICS budesonide/formoterol fumarate 320/9.6 μg (BFF MDI), Open-label budesonide/formoterol fumarate DPI 400/12 μg (BUD/ FORM DPI). Funded by Astra Zeneca

24 week trial Primary outcomes (lung function) FEV 1 area under curve from 0-4 hours Triple vs LABA/ICS AND Triple vs open label LABA/ICS Pre dose FEV 1 change from baseline Triple vs LAMA/LABA LABA/ICS vs open label LABA/ICS (non-inferiority ) Many secondary outcomes for symptoms, QoL and lung function, time to first moderate or severe exacerbation etc.

OUTCOME LAMA/ LABA/ICS n=639 LAMA/LABA n=625 LABA/ICS n=314 LABA/ICS open label n= 318 FEV 1 AUC 0-4 Difference (LSM) - 16 ml (-6 to 38) P=0.1448 NS 104 ml (77-131) P<0.0001 91 ml (64-117) P<0.001 FEV 1 trough LSM Secondary outcomes Model estimated moderate to severe exacerbations per year (RR triple vs comparator) - 22 ml (4-39) P=0.0139 Clinically Relevant? 0.46 0.95 RR 0.48 (0.37-0.64) P<0.0001 74 (52-95) P< 0.001 0.56 RR 0.82 (0.58-1.17) NS 59 (38-80) P< 0.001 0.55 RR 0.83 (0.59-1.18) NS No statistical and/or clinical relevant difference in dyspnea, health status (SGRQ), or rescue medication use. No increased risk of pneumonia trial short.

GLOBAL INITIATIVE FOR CHRONIC OBSTRUCTIVE LUNG DISEASE CANADIAN THORACIC SOCIETY

GOLD 2018 Therapeutic Options https://goldcopd.org/wp-content/uploads/2017/11/gold-2018-v6.0-final-revised-20-nov_wms.pdf

Symptoms Exacerbations https://cts-sct.ca/wp-content/uploads/2018/01/pharmacotherapy-of-copd-2017.pdf

LAMA LABA LAMA/LABA LABA/ICS ICS $50-53/month $45-59 $60-82 $67-141 $20-85 Triple therapy in one inhaler: Fluticasone furoate/umeclidinium/vilanterol (Trelegy) Wholesale Cost $143.44

Recovered from exacerbation You do which of the following? Prescribe the new triple therapy inhaler TRELEGY ELLIPTA (you have samples)? Keep on LAMA/LABA Respimat inhaler? Update his flu and pneumococcal vaccines Check his inhaler technique and adherence X Prescribe Advair 250 2 puffs twice daily X Add an ICS inhaler - Fluticasone (Flovent) 250 mcg 2 puffs twice daily. ( not likely) X Switch to Advair 250mcg 2 puffs twice daily. (FLAME trial)

Outcome Benefit or Harm Moderate and severe exacerbations Moderate exacerbations IMPACT, TRIBUTE and KRONOS (MODEL ESTIMATED) Absolute differences small ARR 0.3%, 0.09%, 0.5% Not significant in TRIBUTE Not reported in IMPACT, KRONOS Severe exacerbations IMPACT - low rates - clinical relevance of ARR 0.06%? Not TRIBUTE; not reported in KRONOS Health Status SGRQ (% clinically meaningful) IMPACT ARI 8% (mean difference not MCID of 4 points) Not TRIBUTE or KRONOS Dyspnea IMPACT ARI 6% Not TRIBUTE or KRONOS Clinical relevance? Increased Pneumonia IMPACT ARI 3% NNH 33 Not TRIBUTE or KRONOS Mortality IMPACT, reported benefit for triple (low rates questionable outcome - NNT 121 (71 to 3450) KRONOS, TRIBUTE non sign.