separating the dynamic components of placebo effect, disease … · 2018-06-07 · literature model...

Literature Model for FEV1 in COPD Trials Separating the Dynamic Components of Placebo Effect,

Disease Progression and Interacting Drug Effects

GlobalPharmacometrics

Jakob Ribbing, Christine Falcoz,Itzela Correa and Steven W Martin

21st PAGE meeting, Venice (Italy)6th June 2012

Acknowledgements

• Lutz Harnisch

• Margherita Bennetts

• Tracy Higgins

• Thomas Kerbusch

• John C Lukas

2

The FEV1 biomarker in COPD

• Chronic obstructive pulmonary disease (COPD)– Third leading cause of death in US and

projected to increase world-wide due toprojected to increase world wide due to smoking

• Forced expiratory volume in one second (FEV1)– Important endpoint for diagnosis and the

primary biomarker for dose selection in ph2b– Ph3 need to show reduced exacerbations 3

Example of how literature analysis aids internal development at PfizerInternal Data Literature Data

FEV1

Model prediction of Drugs X/Y Dose-

Response in FEV1

Model prediction of FEV1-treatment effects

across published compounds

FEV1 comparison to competitor drugs (MDI)

4

Exac

erba

tion

rate

(ER

) Model prediction of FEV1-ER relation across

published compounds

Predicted efficacy in ER across published

compounds

Model prediction of Drugs X/Y Dose-Response in ER

ER comparison to competitor drugs (MDI)

Drug Class of interest in COPD

• Long-acting bronchodilators (inhaled)– Long-acting β2 agonists (LABA)

L ti ti h li i (LAAC)– Long-acting anticholinergics (LAAC)

• Anti-inflammatory therapy– Inhaled corticosteroids (ICS)– PDE4-inhibitors (PDE4i)

5

Literature FEV1 in COPD Change from baseline trough FEV1 (up to wk 26)

by treatment classICS ICS LABA ICS LABA LAAC

0.0

0.1

0.2

LAAC

FB (L

)

Absolute FEV1 is

analysed, but displayed as

6

0.0

0.1

0.2

0 5 10 15 20 25

LABA LABA LAAC

0 5 10 15 20 25

PBO PDE4i

Time (weeks)

Trou

gh F

EV

1 C

F displayed as change from baseline, due

to dominating variability in

baseline!

Linear disease progressionDisease modifying effects?

-0.2

-0.1

0.0

Pauwels (1999) Ref=637 Trial ID=43 N=1277 Post-BD

1 1 11 1 1

11

1 1 11

1

-0.1

0.0

0.1

Tashkin (2008) NCT00144339 Ref=661 Trial ID=75 N=5993 Pre-BD

1

1 1 11

11 1 1

1

UPLIFT study

7

0 50 100 150

-0.3

PBOBudesonide 800 UG/DAY 1

Time (weeks)

CFB

FEV

1 (L

)

0 50 100 150 200-0

.2-

PBOTiotropium 18 UG/DAY 1

Time (weeks)

CFB

FEV

1 (L

)

0 50 100 150

-0.2

-0.1

0.0

0.1

Celli (2008) NCT00268216, SCO30003 Ref=663 Trial ID=81 N=6112 Post-BD

PBO

1

1 11

1 11

Fluticasone/Salmeterol 1000/100 UG/DAY 1

2

22 2

22

2

Fluticasone 1000 UG/DAY 2

3

33 3

33

3

Salmeterol 100 UG/DAY 3

Time (weeks)

CFB

FEV

1 (L

)

0 50 100 150 200

-0.3

-0.2

-0.1

0.0

UNK (2000) Ref=741 Trial ID=60 N=1116 Pre-BD

PBO

1 1

11

11

11

1

Triamcinolone 1200 UG/DAY 1

Time (weeks)

CFB

FEV

1 (L

)

48 / LIKE COPD 110621 l / f 1 19 / 04J 2012

y

TORCH study

Week

CFB

in F

EV

1(L)

Illustration of ISV in placebo effect at typical disease progression

1.22

Short study duration Long study duration

Pre-SABA/SAAC

Placebo95% Conf. Int.

Legend

FEV1active = Baseline + Effplacebo + Progressiondisease

Graph illustrates gradual placebo

8Week

FEV

1 (L

)

1.18

1.19

1.20

1.21

0 1 2 3 4 5 6

Year

1.05

1.10

1.15

1.20

0 1 2 3 4

gradual placebo response, but

mixture component allowed immediate placebo response

as well

Placebo, Salmeterol (LABA) and Fluticasone (ICS)

1.40

Short study duration1.4

Long study duration

Pre-SABA/SAAC

PlaceboSalmeterol 50 mcg BIDFluticasone 250 mcg BID

Legend

FEV1active = Baseline + Effplacebo + Progressiondisease + Effdrug

9Week

FEV

1 (L

)

1.20

1.25

1.30

1.35

0 1 2 3 4 5 6

Year

1.1

1.2

1.3

0 1 2 3 4

Salmeterol interaction with FEV1 post-SABA/SAAC

1.40

Short study duration1.4

Long study duration

Pre-SABA/SAAC

PlaceboSalmeterol 50 mcg BIDFluticasone 250 mcg BID

Post-SABA/SAACLegend

FEV1active = Baseline + Effplacebo + Progressiondisease + Effdrug

10Week

FEV

1 (L

)

1.20

1.25

1.30

1.35

0 1 2 3 4 5 6

Year

1.1

1.2

1.3

0 1 2 3 4

Covariates

• Pre-specified– baseline parameter, based on inclusion criteria:

• Min/max disease severity:mild/moderate/severe/v. severe• Restricted medical history limits more severe patients• min/max #exacerbations in previous year (no, any#, ≥1, ≥2)

– Disease prog. proportional to (ipred) baselineuntreated

• Selected at p<0.001:– Baseline decline with Age– Baseline < 1.2 L: Linear decline in anti-inflammatory

efficacy11

η-diagnostics: Base modelBaseline affects drug response

typi

cal e

ffica

cy

1.2

1.4ETA on AI efficacy

1.0 1.5 2.0ETA on BD efficacy

12

Untreated study baseline (L)

Rat

io: i

pred

effi

cacy

ove

r

0.4

0.6

0.8

1.0

1.0 1.5 2.0

η-diagnostics: Base modelBaseline affects drug response

typi

cal e

ffica

cy

1.2

1.4 fluticasone trialsbudesonide trials

roflumilast trials599

648

637165663 668684

714577308

261

ETA on AI efficacy

1.0 1.5 2.0

salmeterol trialsformoterol trialstiotropium trials

indacaterol trials693

353573490

ETA on BD efficacy

13


Rat

io: i

pred

effi

cacy

ove

r

0.4

0.6

0.8

1.0

1.0 1.5 2.0

785649

649

648573750

679

657

647

609

695 664

668

779

786708706

666164 251

270

288328 509 609621695 664

663 668779684708706

714577308709

353

605

639

610261

573 653659

660673690 776778

807

679657

678

664647 656 1536536 765

251 607658767686

683

288455488492493

494

621

653659

660 662673690695

762676

661664

668779 687647 656 667694807798790

ETA diagnostics: Final modelty

pica

l effi

cacy

1 05

1.10

1.15 fluticasone trialsbudesonide trials

roflumilast trials649 648

663261

ETA on AI efficacy

1.0 1.5 2.0

salmeterol trialsformoterol trialstiotropium trials

indacaterol trials

693

684714

353639573

653807536 765

490

494653676 807

ETA on BD efficacy

14


Rat

io: i

pred

effi

cacy

ove

r

0.85

0.90

0.95

1.00

1.05

1.0 1.5 2.0

599

785649

648

573 637750

679

657

647

165

609695

664

668779

684

786708706

714666577308

164

261

251

270

288328509

609

621695

664

663 668779

708706

714

577

308

709605

610261659

660

673690776

778

807

679657

678

664

647656

1536

765

251 607

658767

686

683

288455488492

493621659

660

662

673690

695762

676

661

664

668779 687647

656 667

694807

798

790

Efficacy in moderate COPD

formoterol9 mcg BID

indacaterol75 mcg QD

SX 50mcg BID andSpiriva 18 mcg QD

SXFP 50/250 mcg BID

86 ml

149 ml

162 ml

154 ml

Pre-SABA/SAAC

LABA + ICS same efficacy as the sum

of the two mono components

15Placebo-corrected FEV1 (L)

roflumilast500 mcg QD

budesonide400/320 mcg BID

Fluticasone250 mcg BID

Spiriva18 mcg QD

Respimat5 mcg QD

salmeterol50 mcg BID

0.05 0.10 0.15

36 ml

61 ml

83 ml

92 ml

128 ml

116 ml

Efficacy in moderate COPD

formoterol9 mcg BID



SXFP 50/250 mcg BID

86 ml

149 ml

162 ml

154 ml

Pre-SABA/SAAC

LABA+LAACinteraction estimated as a relative reduction

in LABA effect





Spiriva18 mcg QD

Respimat5 mcg QD


0.05 0.10 0.15

36 ml

61 ml

83 ml

92 ml

128 ml

116 ml

Efficacy in moderate COPD95% CI excluding treatment heterogeneity

Indacaterol (QD) has superior trough efficacy in comparison

to the two BID LABAs.formoterol9 mcg BID



SXFP 50/250 mcg BID

86 ml

149 ml

162 ml

154 ml

95% CI: 131-167 ml

95% CI: 135-195 ml

95% CI: 136-171 ml

95% CI: 68-106 ml

Pre-SABA/SAAC

17

Several large studies indicating poor efficacy for budesonide.Due to protocol/study conduct

or compound?

Placebo-corrected FEV1 (L)




Spiriva18 mcg QD

Respimat5 mcg QD


0.05 0.10 0.15

36 ml

61 ml

83 ml

92 ml

128 ml

116 ml

95% CI: 117-139 ml

95% CI: 101-131 ml

95% CI: 22-51 ml

95% CI: 48-72 ml

95% CI: 71-97 ml

95% CI: 80-106 ml

Efficacy in moderate COPD95% CI including treatment heterogeneity (ISV Emax)

formoterol9 mcg BID



SXFP 50/250 mcg BID

86 ml

149 ml

162 ml

154 ml

95% CI: 57-123 ml

95% CI: 100-196 ml

95% CI: 112-224 m

95% CI: 115-187 ml

Pre-SABA/SAAC





Spiriva18 mcg QD

Respimat5 mcg QD


0.05 0.10 0.15 0.20

36 ml

61 ml

83 ml

92 ml

128 ml

116 ml

95% CI: 20-57 ml

95% CI: 38-77 ml

95% CI: 57-113 ml

95% CI: 65-127 ml

95% CI: 87-167 ml

95% CI: 78-154 ml

Efficacy with untreated baseline 1 L95% CI including treatment heterogeneity

formoterol9 mcg BID



SXFP 50/250 mcg BID

82 ml

142 ml

156 ml

127 ml

95% CI: 53-119 ml

95% CI: 92-191 ml

95% CI: 108-212 m

95% CI: 92-161 ml

Pre-SABA/SAAC





Spiriva18 mcg QD

Respimat5 mcg QD


0.05 0.10 0.15 0.20

23 ml

39 ml

54 ml

88 ml

122 ml

110 ml

95% CI: 13-38 ml

95% CI: 23-54 ml

95% CI: 35-76 ml

95% CI: 60-121 ml

95% CI: 81-159 ml

95% CI: 74-148 ml

Predicted efficacy: Morning trough Pre- vs. Post-SABA/SAAC

LABA and LAAC efficacy when FEV1 is measured post-

SABA/SAAC

Spiriva

Respimat5 mcg QD


formoterol9 mcg BID


48 ml

83 ml

52 ml

65 ml

Post-SABA/SAAC

In TORCH (ref 650) reports a disappointing 40

20

LABA and LAAC efficacy when FEV1

is measured pre-SABA/SAAC

Placebo-corrected FEV1 (L)

Spiriva18 mcg QD

Respimat5 mcg QD


formoterol9 mcg BID


0.05 0.10 0.15

86 ml

149 ml

92 ml

128 ml

116 ml

Pre-SABA/SAAC

Spiriva18 mcg QD 72 ml

reports a disappointing 40 ml efficacy for salmeterol.

Low efficacy due to measuring post SABA

Model Predicts LABA/LAAC Interaction LABA with LAAC background and vice versa

indacaterol75 mcg QD 95 ml

60% background

Spiriva18 mcg QD

Respimat5 mcg QD


formoterol9 mcg BID


34 ml59 ml

36 ml

72 ml60 ml

100% background

UPLIFT (661) reports 87-103 ml efficacy for

Spiriva. Canadian study


Spiriva18 mcg QD

Respimat5 mcg QD


formoterol9 mcg BID


0.05 0.10 0.15

86 ml149 ml

92 ml

128 ml116 ml

No DD interaction

Spiriva18 mcg QD

Respimat5 mcg QD


formoterol9 mcg BID

75 mcg QD

55 ml59 ml

95 ml83 ml

Canadian study (686) reports 80-120 ml. 60% and

54% LABA background, respectively.

Discussion

• Placebo effect has no typical direction– Still important to account for: individual

studies have marked placebo effect• Dropout due to lack of efficacyp y

– Masks any disease progression– Reduce signs of disease modifying effects

• Low study baselinelower efficacy of anti-inflammatory drugsWeak trend towards lower efficacy in

bronchodilators (LABA or LAAC)• Mixed message in literature on individual data 22

Conclusion

• DD-interactions and covariates account for the sometimes disappointing results on FEV1 in late-stage trials

TORCH UPLIFT & rolumilast exacerbation trials– TORCH, UPLIFT & rolumilast exacerbation trials– Except LABA/LAAC interaction (UPLIFT) these do

not necessarily translate into lower effect on exacerbations!

• Model provides efficacy bench mark for published compounds, accounting for treatment heterogeneity (ISV Emax) 23

separating the dynamic components of placebo effect, disease … · 2018-06-07 · literature model...

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