Ph#2/3#Trial#for#Selepressin#in# the#Treatment#of#Vasopressor6# - - PowerPoint PPT Presentation

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Ph#2/3#Trial#for#Selepressin#in# the#Treatment#of#Vasopressor6# - - PowerPoint PPT Presentation

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Ph#2/3#Trial#for#Selepressin#in# the#Treatment#of#Vasopressor6# Dependent#Sep9c#Shock# # Sco<#Berry,#PhD ! December#4,#2014 # Trial#Basics# Selepressin:# selec9ve#vasopressin#V1a#agonist#for#treatment#of#

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SLIDE 1

Ph#2/3#Trial#for#Selepressin#in# the#Treatment#of#Vasopressor6# Dependent#Sep9c#Shock#

#

Sco<#Berry,#PhD! December#4,#2014#

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SLIDE 2

Trial#Basics#

  • Selepressin:#

– selec9ve#vasopressin#V1a#agonist#for#treatment#of# vasopressor6dependent#sep9c#shock#

  • Arms#created#by#level#of#concentra9on#–#

allowing#mul9ple#“doses”#to#be#blinded#and# infusion#rates#can#vary:#

Dec#4,#2014#

2!

Treatment!! Arm! Star,ng!Dose! (ng/kg/min)! Maximum!Dose! (ng/kg/min)! 0# 0# 0# 1# 1.7# 2.5# 2# 2.5# 3.75# 3# 3.5# 5.25# 4# 5.0# 7.5#

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SLIDE 3

Trial#Basics#

  • Double6blind,#placebo6controlled#
  • “Pivotal#Trial”#Endpoint#

– Composite#mortality/morbidity#endpoint#

Dec#4,#2014#

3!

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SLIDE 4

Possible#Phase#2?#

  • 200#pa9ent#study#of#a#“biomarker”#for#dose#

selec9on#(2#arms#given#fixed#nature?)#

– Then#phase#III#

  • 400#pa9ent#trial#of#doses#on#primary#endpoint#

to#select#dose#and#make#phase#3#go/no6go#

– Then#phase#III#

  • 800#pa9ent#trial#of#doses#on#primary#endpoint#

to#select#dose#and#make#phase#3#go/no6go#

– Then#phase#III#

Dec#4,#2014#

4!

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SLIDE 5

Adap9ve#Phase#2#

##############Phase#26like#

Dec#4,#2014#

5!

Burn6In# PBO# Arm#1# Arm#2# Arm#3# Arm#4# RAR# Part#1# Part#2# 200# 800# 1800#

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SLIDE 6

Part#1:#Burn6In#

  • Start#with#3#doses#+#PBO#during#200#pa9ent#

burn6in#

– 3:2:2:2:0##(Arms#0:1:2:3:4)#

Dec#4,#2014#

6!

Burn6In# PBO# Arm#1# Arm#2# Arm#3# Arm#4# RAR# Part#1# Part#2# 200# 800# 1800#

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SLIDE 7

Part#1:#Adap9ve#

Dec#4,#2014#

7!

Burn6In# PBO# Arm#1# Arm#2# Arm#3# Arm#4# Adap9ve# Part#1# Part#2#

  • Interims#occur#from#2006800#con9nue#

monthly#for#Part#1#

– Create#response#adap9ve#randomiza9on#over# ac9ve#arms#(1/3#:#?#:#?#:#?#:#?)#for#next#month# – Fu9lity#/#Go#to#Part#2#decisions#

200# 800# 1800#

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SLIDE 8

Part#2:#Confirm#

Dec#4,#2014#

8!

Burn6In# PBO# Arm#1# Arm#2# Arm#3# Arm#4# Adap9ve# Part#1# Part#2# 200# 800# 1800#

  • Enroll#1:1#to#PBO#and#selected#‘target’#dose#to#

make#the#final#sample#size#1800#

– Part#2#minimum#is#1000#pa9ents# – Fu9lity#analyses#every#month#

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SLIDE 9

Part#1:#RAR#

Dec#4,#2014#

9!

Burn6In# PBO# Arm#1# Arm#2# Arm#3# Arm#4# Adap9ve# Part#1# Part#2# 200# 800# 1800#

  • Randomiza9on#probability#propor9onal#to#the#

probability#the#arm#maximizes#the#effect#on#the# primary#endpoint#

– Open#“Arm#4”#if#≥#50%#probability#Arm#3#has#be<er# effect#on#the#primary#endpoint#than#Arm#2.#

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SLIDE 10

Part#1:#Decisions#

Dec#4,#2014#

10!

Burn6In# PBO# Arm#1# Arm#2# Arm#3# Arm#4# Adap9ve# Part#1# Part#2# 200# 800# 1800#

  • Go#to#Part#2#if#(n≥300)#

– Predic9ve#probability#of#superiority#@#1800#with# most#likely#maximum#dose#≥#90%#

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SLIDE 11

Part#1:#Decisions#

Dec#4,#2014#

11!

Burn6In# PBO# Arm#1# Arm#2# Arm#3# Arm#4# Adap9ve# Part#1# Part#2# 200# 800# 1800#

  • Stop#for#fu9lity#if#

– Predic9ve#probability#of#superiority#@#1800#with# most#likely#maximum#dose#<#5%#

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SLIDE 12

Part#1:#n=800#Decision#

Dec#4,#2014#

12!

Burn6In# PBO# Arm#1# Arm#2# Arm#3# Arm#4# Adap9ve# Part#1# Part#2# 200# 800# 1800#

  • Go#to#Part#2#if#(n=800)#

– Predic9ve#probability#of#superiority#@#1800#with# most#likely#maximum#dose#≥#25%# – If#not#stop#the#trial#

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SLIDE 13

Final#Analysis#

Dec#4,#2014#

13!

Burn6In# PBO# Arm#1# Arm#2# Arm#3# Arm#4# Adap9ve# Part#1# Part#2# 200# 800# 1800#

  • Pool#all#selepressin#arms#(Part#1#&#Part#2)#in#

final#analysis#vs.#PBO#with#Wilcoxon#Test#(Van# Elteren’s)#at#the#0.025#level#

  • Type#I#error#controlled#analysis#of#superiority#
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SLIDE 14

Bayesian#Sta9s9cal#Model#

  • Sta9s9cal#model#to#drive#all#adapta9ons#
  • Model#mixture#of#death#and#morbidity#
  • utcome#for#survivors#

– Propor9onal#effect#for#selepressin#treatment#arms# (α1,…, α4)#

  • Model#for#morbidity#for#survivors#

– Propor9onal#effect#for#selepressin#treatment#arms# (θ1,…, θ4)#

  • Inverted#U6Dose6Response#models##

Dec#4,#2014#

14!

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SLIDE 15

Opera9ng#Characteris9cs#

Dec#4,#2014#

15!

Scenario! (Effect)! Prop.!Of!Trials! Mean!Sample!Size! Success! Part!2! 1800! Total! Part!1! Part!2! Target! Dose! 0# .016# .148# .043# 770.5# 638.6# 131.9# 709.5# A# .127# .370# .187# 1069.4# 694.6# 374.8# 712.2# B# .497# .680# .569# 1442.2# 665.6# 776.6# 741# C# .854# .895# .875# 1690.3# 582.4# 1107.9# 756.5# D# .983# .986# .985# 1785.2# 501.6# 1283.6# 776.5# E# 1# 1# 1# 1800# 441# 1359# 796.1# F# 1# 1# 1# 1800# 438.3# 1361.7# 806.1#

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SLIDE 16

Individual#Scenarios#

Dec#4,#2014#

16! Arm! True! Effect! Prop!of!Trials! Mean!Sample!Size! Target! Target!&! Win! Total! Part!1! Part!2! PBO! 0! 0! 0! 638.6! 131.9! 709.5! Dose#1# C# .194# .181# 694.6# 374.8# 712.2# Dose#2# C# .456# .440# 665.6# 776.6# 741# Dose#3# C# .234# .225# 582.4# 1107.9# 756.5# Dose#4# C# .011# .008# 501.6# 1283.6# 776.5# PBO! 0! 0! 0! 618.8! 178.9! 439.9! Dose#1# A# .021# .011# 185.2# 173.2# 12.0# Dose#2# B# .206# .155# 266.9# 142.6# 124.3# Dose#3# C# .432# .390# 362.0# 109.7# 252.3# Dose#4# C# .093# .085# 96.8# 45.8# 51.0# PBO! 0! 0! 0! 701.8! 164.3! 537.5! Dose#1# C# .317# .292# 402.6# 215.2# 187.4# Dose#2# C# .489# .468# 427.2# 123.6# 303.6# Dose#3# B# .077# .053# 124.6# 78.1# 46.5# Dose#4# A# 0# 0# 13.4# 13.4# 0#

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SLIDE 17

Simula9on#

  • Trial#conducted#through#extensive#simula9ons#

– Example#trials,#cut6offs,#modeling,#sample#sizes,# power,#dose#selec9on,#etc…#type'I'error''

  • Example#of#value#of#simula9ons#for#fu9lity#

thresholds#prospec9vely…#

Dec#4,#2014#

17!

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SLIDE 18

−5 5 10 −1 1 2 3 4

Primary Endpoint Part 1 Futility = 0

Mortality Benefit Morbidity Benefit Failed at N=1800 : 3356 Success : 6644 Futile, Would Have Lost Anyway : 0 Futile, Would Have Won : 0 Futile for Other Reason : 0 A B C D E Failed at N=1800 : 3356 Futile, Would Have Lost Anyway : 0 Futile for Other Reason : 0 Futile, Would Have Won : 0 Success : 6644 0.0 0.2 0.4 0.6 0.8 1.0 1.2

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SLIDE 19

−5 5 10 −1 1 2 3 4

Primary Endpoint Part 1 Futility = 0.01

Mortality Benefit Morbidity Benefit Failed at N=1800 : 3007 Success : 6644 Futile, Would Have Lost Anyway : 349 Futile, Would Have Won : 0 Futile for Other Reason : 0 A B C D E Failed at N=1800 : 3007 Futile, Would Have Lost Anyway : 349 Futile for Other Reason : 0 Futile, Would Have Won : 0 Success : 6644 0.0 0.2 0.4 0.6 0.8 1.0 1.2

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SLIDE 20

−5 5 10 −1 1 2 3 4

Primary Endpoint Part 1 Futility = 0.05

Mortality Benefit Morbidity Benefit Failed at N=1800 : 2401 Success : 6609 Futile, Would Have Lost Anyway : 955 Futile, Would Have Won : 35 Futile for Other Reason : 0 A B C D E Failed at N=1800 : 2401 Futile, Would Have Lost Anyway : 955 Futile for Other Reason : 0 Futile, Would Have Won : 35 Success : 6609 0.0 0.2 0.4 0.6 0.8 1.0 1.2

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SLIDE 21

−5 5 10 −1 1 2 3 4

Primary Endpoint Part 1 Futility = 0.1

Mortality Benefit Morbidity Benefit Failed at N=1800 : 1963 Success : 6542 Futile, Would Have Lost Anyway : 1393 Futile, Would Have Won : 102 Futile for Other Reason : 0 A B C D E Failed at N=1800 : 1963 Futile, Would Have Lost Anyway : 1393 Futile for Other Reason : 0 Futile, Would Have Won : 102 Success : 6542 0.0 0.2 0.4 0.6 0.8 1.0 1.2

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SLIDE 22

−5 5 10 −1 1 2 3 4

Primary Endpoint Part 1 Futility = 0.15

Mortality Benefit Morbidity Benefit Failed at N=1800 : 1642 Success : 6451 Futile, Would Have Lost Anyway : 1714 Futile, Would Have Won : 193 Futile for Other Reason : 0 A B C D E Failed at N=1800 : 1642 Futile, Would Have Lost Anyway : 1714 Futile for Other Reason : 0 Futile, Would Have Won : 193 Success : 6451 0.0 0.2 0.4 0.6 0.8 1.0 1.2

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SLIDE 23

−5 5 10 −1 1 2 3 4

(Part 1 Rule = 0.05) Primary Endpoint, N=800 Futility = 0

Mortality Benefit Morbidity Benefit Failed at N=1800 : 2401 Success : 6609 Futile, Would Have Lost Anyway : 0 Futile, Would Have Won : 0 Futile for Other Reason : 990 A B C D E Failed at N=1800 : 2401 Futile, Would Have Lost Anyway : 0 Futile for Other Reason : 990 Futile, Would Have Won : 0 Success : 6609 0.0 0.2 0.4 0.6 0.8 1.0 1.2

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SLIDE 24

−5 5 10 −1 1 2 3 4

(Part 1 Rule = 0.05) Primary Endpoint, N=800 Futility = 0.25

Mortality Benefit Morbidity Benefit Failed at N=1800 : 1600 Success : 6492 Futile, Would Have Lost Anyway : 801 Futile, Would Have Won : 117 Futile for Other Reason : 990 A B C D E Failed at N=1800 : 1600 Futile, Would Have Lost Anyway : 801 Futile for Other Reason : 990 Futile, Would Have Won : 117 Success : 6492 0.0 0.2 0.4 0.6 0.8 1.0 1.2

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SLIDE 25

−5 5 10 −1 1 2 3 4

(Part 1 Rule = 0.05) Primary Endpoint, N=800 Futility = 0.3

Mortality Benefit Morbidity Benefit Failed at N=1800 : 1436 Success : 6429 Futile, Would Have Lost Anyway : 965 Futile, Would Have Won : 180 Futile for Other Reason : 990 A B C D E Failed at N=1800 : 1436 Futile, Would Have Lost Anyway : 965 Futile for Other Reason : 990 Futile, Would Have Won : 180 Success : 6429 0.0 0.2 0.4 0.6 0.8 1.0 1.2

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SLIDE 26

−5 5 10 −1 1 2 3 4

(Part 1 Rule = 0.05) Primary Endpoint, N=800 Futility = 0.35

Mortality Benefit Morbidity Benefit Failed at N=1800 : 1288 Success : 6375 Futile, Would Have Lost Anyway : 1113 Futile, Would Have Won : 234 Futile for Other Reason : 990 A B C D E Failed at N=1800 : 1288 Futile, Would Have Lost Anyway : 1113 Futile for Other Reason : 990 Futile, Would Have Won : 234 Success : 6375 0.0 0.2 0.4 0.6 0.8 1.0 1.2

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SLIDE 27

−5 5 10 −1 1 2 3 4

(Part 1 Rule = 0.05) Primary Endpoint, N=800 Futility = 0.4

Mortality Benefit Morbidity Benefit Failed at N=1800 : 1151 Success : 6313 Futile, Would Have Lost Anyway : 1250 Futile, Would Have Won : 296 Futile for Other Reason : 990 A B C D E Failed at N=1800 : 1151 Futile, Would Have Lost Anyway : 1250 Futile for Other Reason : 990 Futile, Would Have Won : 296 Success : 6313 0.0 0.2 0.4 0.6 0.8 1.0 1.2

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SLIDE 28

−5 5 10 −1 1 2 3 4

(Part 1 Rule = 0.05) Primary Endpoint, N=800 Futility = 0.45

Mortality Benefit Morbidity Benefit Failed at N=1800 : 1031 Success : 6228 Futile, Would Have Lost Anyway : 1370 Futile, Would Have Won : 381 Futile for Other Reason : 990 A B C D E Failed at N=1800 : 1031 Futile, Would Have Lost Anyway : 1370 Futile for Other Reason : 990 Futile, Would Have Won : 381 Success : 6228 0.0 0.2 0.4 0.6 0.8 1.0 1.2

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SLIDE 29

−5 5 10 −1 1 2 3 4

(Part 1 Rule = 0.05) Primary Endpoint, N=800 Futility = 0.5

Mortality Benefit Morbidity Benefit Failed at N=1800 : 925 Success : 6164 Futile, Would Have Lost Anyway : 1476 Futile, Would Have Won : 445 Futile for Other Reason : 990 A B C D E Failed at N=1800 : 925 Futile, Would Have Lost Anyway : 1476 Futile for Other Reason : 990 Futile, Would Have Won : 445 Success : 6164 0.0 0.2 0.4 0.6 0.8 1.0 1.2

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SLIDE 30

−5 5 10 −1 1 2 3 4

(Part 1 Rule = 0.05) Primary Endpoint, N=800 Futility = 0.75

Mortality Benefit Morbidity Benefit Failed at N=1800 : 481 Success : 5621 Futile, Would Have Lost Anyway : 1920 Futile, Would Have Won : 988 Futile for Other Reason : 990 A B C D E Failed at N=1800 : 481 Futile, Would Have Lost Anyway : 1920 Futile for Other Reason : 990 Futile, Would Have Won : 988 Success : 5621 0.0 0.2 0.4 0.6 0.8 1.0 1.2

slide-31
SLIDE 31

Summary#

  • Adapta9ons#allow#more#thorough#explora9on#
  • f#dose#range#

– RAR,#Adap9ve#Decisions,#Modeling#

  • Allow#“dose6finding”#to#be#larger#if#needed#
  • Able#to#use#the#subjects#for#dose6finding#and#

confirma9on#

– No#need#to#take#shot6in6the6dark#for#dose#and#go/ no6go#

Dec#4,#2014#

18!