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!

Turbuhaler

Genuair

Class GenericLong acting Beta2 agonists (LABA) Salmeterol

Formoterol

Indacaterol

Long Acting Muscarinic

Antagonists (LAMA)

aka Long Acting Anticholinergic

(LAAC)

Tiotropium

Aclidinium

Glycopyrronium

Umeclidinium

LAMA/LABA Combinations: Aclidinium + Formoterol

Glycopyrronium + Indacaterol

Tiotropium + Olodaterol

Umeclidinium + Vilanterol

LABA/ICS Combinations in one

inhaler

Budesonide/ formoterol

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

FEV1 FVC 50% ; FEV1 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=firefox-b&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=firefox-b&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 FEV1 (MCID? 100-140 ml)

Exercise tolerance

ADVERSE EFFECTS

Key ConceptsClinical 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 mcgONCE DAILY

n=1680

SALMETEROL+FLUTICASONE

50/500 mcg BIDn=1682

RR 95% CI P VALUE

ARRNNT

95% CI

Secondary Exacerbation Endpoints (rate/year)

Mild 2.46 2.720.91

(0.83, 0.99)0.030 ARR 0.26

Moderate 0.81 0.980.83

(0.74, 0.92)<0.001 ARR 0.17

Severe 0.15 0.170.87

(0.69, 1.09)0.231 -

Pts with ≥ 1 exacerbation

77% 82%NNT 2013-44

VS LAMA

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

3 vs 1?

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 Lipson DA, N Engl J Med. 2018;378:1671-80

TRIBUTE 2018 Papi A et al Lancet Lancet 2018; 391: 1076–84

KRONOS 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 FEV1 < 56 %

PATIENTS: At least 1 moderate or severe exacerbation in the previous year, or an FEV1 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.

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

PICO

IMPACT RESULTS

IMPACT TRIAL

Event rates Rate Ratio/Hazard Ratio/Odds Ratio

Triple therapy vs comparators

(95% Confidence Interval)

LAMA/LABA

/ICS

N= 4151

LABA/

LAMA

N= 2070

LABA/ICS

N= 4134

LABA/

LAMALABA/ICS

Additional outcomes (not a complete list – 16 in total) Not adjusted for multiple comparisons

Annual rate of all

exacerbations1.05 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 points42% 34% 34% 1.41 (1.26 to 1.57) 1.41 (1.29 to 1.55)

Lung Function Mean

change from baseline

(Trough FEV1)

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 ≥ 136% 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% FEV1 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

FEV1 % 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

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

PICO

24 week trial

Primary outcomes (lung function)

FEV1 area under curve from 0-4 hours

Triple vs LABA/ICS AND Triple vs open label LABA/ICS

Pre dose FEV1 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

FEV1 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

FEV1 trough

LSM

- 22 mL (4-39)

P=0.0139

Clinically

Relevant?

74 (52-95)

P< 0.001

59 (38-80)

P< 0.001

Secondary outcomes

Model estimated

moderate to severe

exacerbations

per year (RR triple vs

comparator)

0.46 0.95

RR 0.48 (0.37-0.64)

P<0.0001

0.56

RR 0.82 (0.58-1.17)

NS

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 IMPACT, TRIBUTE and KRONOS (MODEL ESTIMATED)

Absolute differences small ARR 0.3%, 0.09%, 0.5%

Moderate exacerbations 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.