Design of the RESIST Study Program
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![Page 1: Design of the RESIST Study Program](https://reader035.fdocuments.us/reader035/viewer/2022062422/5681325e550346895d98f0c0/html5/thumbnails/1.jpg)
Design of the RESIST Study Program
Dr Kevin Curry
Boehringer Ingelheim, Bracknell, UK
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1182.52Phase IIB500/100500/200750/200
RESIST-1N=500, 24W
TPV/RTV vs. PI/RTV +OBRNA, AUS
RESIST-2N=800, 16W
TPV/RTV vs. PI/RTV +OBREU, SA
1182.513-PI, PK/Safety
RESIST-33-PI, Efficacy
Tipranavir Clinical Development Plan - Phase II-III Program
1182.17/.57 Rollover Studies
Analysis, choose optimal dose
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Tipranavir Trough Concentrations
*Study day 11 (prior to coadministration of RTV)† BLQ = below the limit of quantitation
TPV morning Cmin (minmedianmax µM) after 21 days exposure to TPV/RTV
-----59BLQ 173
60BLQ 102
320.7 71
150.1 47
200 n= 11 to 12
38
BLQ 173
76
BLQ 143
25
BLQ 80
23
BLQ† 66
------100 n= 10 to 14
1.810.13 5.88
0.950.11 4.74
0.690.06 3.13
0.630.25 1.32
0.280.06 0.48
0* n=12 to 25
12501000750500250
TPV (mg BID)
RTV (mg BID)
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TPV 300RTV 200
(1182.3)
TPV 500RTV 100
(1182.2)
TPV 500RTV 100
(1182.4)
TPV 1000RTV 100
(1182.2)
TPV 1200RTV 200
(1182.3)
TPV 1250RTV 100
(1182.4)
Duration 14 days 48 weeks 16 weeks 48 weeks 14 days 16 weeks
N 10 19 21 22 11 21
PatientPopulation
Naïve Multiple PIFailure
Single PIFailure
Multiple PIFailure
Naïve Single PIFailure
Diarrhea(any Grade)
30% 42% 33% 73% 64% 43%
Nausea 0 26% 19% 36% 55% 43%
Vomiting 10% 11% 0 23% 18% 33%
All AEs 80% 100% 71% 100% 81.8% 81%
Tipranavir Adverse Event DataTrials 1182.2, .3, and .4
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Tipranavir Efficacy DataTrials 1182.2, .3, and .4
TPV 300RTV 200
(1182.3)
TPV 500RTV 100
(1182.4)
TPV 1200RTV 200
(1182.3)
Analysis AT/OC ITT AT/OC
Duration 14 days 16 weeks 14 days
N 10 20 11
PatientPopulation
Naïve Single PIFailure
Naïve
Mean VLReduction
1.43 log 1.30 log 1.64 log
% BLQ 400 0.0 38.9% 20.0
% BLQ 50 0.0 22.2% 0.0
CD4 CountChange
+41.5 +80 +83
TPV 500RTV 100
(1182.2)
TPV 1000RTV 100
(1182.2)
TPV 1250RTV 100
(1182.4)
FAS FAS ITT
48 weeks 48 weeks 16 weeks
19 22 21
Multiple PIFailure
Multiple PIFailure
Single PIFailure
2.34 log 1.71 log 1.40 log
78.9% 50.0% 55.0%
68.4% 40.9% 35.0%
+184 +149 -6
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Phase IIB Trial--Dose OptimizationBI 1182.52
DESIGN
Objective: define “maximum tolerated dose”
Primary endpoints
Viral load reduction (efficacy) at 14 days
Incidence of GI adverse events (safety) at 28 days
Patient population
HIV+ adults with >2 PI regimen experience & 3-class experience
>1 major PI mutation & <1 of 82T, 84V, 90M
Duration: up to 32 weeks before rollover
DESIGN
Objective: define “maximum tolerated dose”
Primary endpoints
Viral load reduction (efficacy) at 14 days
Incidence of GI adverse events (safety) at 28 days
Patient population
HIV+ adults with >2 PI regimen experience & 3-class experience
>1 major PI mutation & <1 of 82T, 84V, 90M
Duration: up to 32 weeks before rollover
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Phase IIB Trial--Dose OptimizationBI 1182.52
TREATMENT
All patients receive TPV/RTV + optimized background regimen (OBR)
3 doses of TPV/RTV:
750mg/200mg
500mg/200mg
500mg/100mg
OBR is individually determined for each patient from baseline genotyping and treatment history
TREATMENT
All patients receive TPV/RTV + optimized background regimen (OBR)
3 doses of TPV/RTV:
750mg/200mg
500mg/200mg
500mg/100mg
OBR is individually determined for each patient from baseline genotyping and treatment history
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Phase IIB Trial--Dose OptimizationBI 1182.52
STATUS UPDATE
Trial initiated 29 April 2002 in 9 countries
406 patients screened; 206 enrolled and receiving treatment
Final patient will complete 4 weeks on 31 July
Rapid data collection and analysis to follow
Discussions with regulatory authorities planned for fall 2002
Phase III program to begin following regulatory approval
STATUS UPDATE
Trial initiated 29 April 2002 in 9 countries
406 patients screened; 206 enrolled and receiving treatment
Final patient will complete 4 weeks on 31 July
Rapid data collection and analysis to follow
Discussions with regulatory authorities planned for fall 2002
Phase III program to begin following regulatory approval
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1182.52Phase IIB500/100500/200750/200
RESIST-1N=500, 24W
TPV/RTV vs. PI/RTV +OBRNA, AUS
RESIST-2N=800, 16W
TPV/RTV vs. PI/RTV +OBREU, SA
1182.513-PI, PK/Safety
RESIST-33-PI, Efficacy
Tipranavir Clinical Development Plan - Phase II-III Program
1182.17/.57 Rollover Studies
Analysis, choose optimal dose
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Phase III Trial--Registrational StudyRESIST-1 (BI 1182.12)
DESIGN
Objective
Determine the safety and efficacy of TPV/RTV versus RTV-boosted comparator PI in highly treatment experienced HIV+ adults
Primary endpoints
Proportion of patients with a > 1 log10 reduction in viral load at 48 weeks and the time to treatment failure up to Week 48.
An interim analysis will be conducted to evaluate the proportion of patients with a > 1 log10 reduction in viral load at 24 weeks.
DESIGN
Objective
Determine the safety and efficacy of TPV/RTV versus RTV-boosted comparator PI in highly treatment experienced HIV+ adults
Primary endpoints
Proportion of patients with a > 1 log10 reduction in viral load at 48 weeks and the time to treatment failure up to Week 48.
An interim analysis will be conducted to evaluate the proportion of patients with a > 1 log10 reduction in viral load at 24 weeks.
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Phase III Trial--Registrational StudyRESIST-1 (BI 1182.12)
DESIGN
Patient population
HIV+ adults with >2 PI regimen experience & 3-class experience
>1 major PI mutation (30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M)
<1 of 82L, 82T, 84V, 90M
Duration
48 weeks
Upon the last patient completing 48 weeks, all patients may participate in a rollover trial to receive continued treatment
DESIGN
Patient population
HIV+ adults with >2 PI regimen experience & 3-class experience
>1 major PI mutation (30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M)
<1 of 82L, 82T, 84V, 90M
Duration
48 weeks
Upon the last patient completing 48 weeks, all patients may participate in a rollover trial to receive continued treatment
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Phase III Trial--Registrational StudyRESIST-1 (BI 1182.12)
TREATMENT
Investigators must pre-declare preferred comparator PI and OBR from baseline genotyping and treatment history
Once randomized, patients will receive
TPV/RTV + OBR, or
Comparator PI/RTV +OBR
N= 247 patients per arm
PARTICIPATING COUNTRIES
Canada, USA, Australia (~100 sites)
TREATMENT
Investigators must pre-declare preferred comparator PI and OBR from baseline genotyping and treatment history
Once randomized, patients will receive
TPV/RTV + OBR, or
Comparator PI/RTV +OBR
N= 247 patients per arm
PARTICIPATING COUNTRIES
Canada, USA, Australia (~100 sites)
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1182.52Phase IIB500/100500/200750/200
RESIST-1N=500, 24W
TPV/RTV vs. PI/RTV +OBRNA, AUS
RESIST-2N=800, 16W
TPV/RTV vs. PI/RTV +OBREU, SA
1182.513-PI, PK/Safety
RESIST-33-PI, Efficacy
Tipranavir Clinical Development Plan - Phase II-III Program
1182.17/.57 Rollover Studies
Analysis, choose optimal dose
![Page 14: Design of the RESIST Study Program](https://reader035.fdocuments.us/reader035/viewer/2022062422/5681325e550346895d98f0c0/html5/thumbnails/14.jpg)
Phase III Trial--Registrational StudyRESIST-2 (BI 1182.48)
DESIGN
Objective
Determine the safety and efficacy of TPV/RTV versus RTV-boosted comparator PI in highly treatment experienced HIV+ adults
Primary endpoints
Proportion of patients with a > 1 log10 reduction in viral load at 48 weeks and the time to treatment failure up to Week 48.
An interim analysis will be conducted to evaluate the proportion of patients with a > 1 log10 reduction in
viral load at 16 weeks.
DESIGN
Objective
Determine the safety and efficacy of TPV/RTV versus RTV-boosted comparator PI in highly treatment experienced HIV+ adults
Primary endpoints
Proportion of patients with a > 1 log10 reduction in viral load at 48 weeks and the time to treatment failure up to Week 48.
An interim analysis will be conducted to evaluate the proportion of patients with a > 1 log10 reduction in
viral load at 16 weeks.
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Phase III Trial--Registrational StudyRESIST-2 (BI 1182.48)
DESIGN
N= 404 patients per arm
PARTICIPATING COUNTRIES
France, Germany, Spain, United Kingdom, Sweden, Italy, Portugal, Greece, Denmark, Belgium, Netherlands
Argentina, Mexico
DESIGN
N= 404 patients per arm
PARTICIPATING COUNTRIES
France, Germany, Spain, United Kingdom, Sweden, Italy, Portugal, Greece, Denmark, Belgium, Netherlands
Argentina, Mexico
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1182.52Phase IIB500/100500/200750/200
RESIST-1N=500, 24W
TPV/RTV vs. PI/RTV +OBRNA, AUS
RESIST-2N=800, 16W
TPV/RTV vs. PI/RTV +OBREU, SA
1182.513-PI, PK/Safety
RESIST-33-PI, Efficacy
Tipranavir Clinical Development PlanPhase II-III Program
1182.17/.57 Rollover Studies
Analysis, choose optimal dose
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Phase I-II Trial--1st Companion StudyBI 1182.51
DESIGN
Objective
PK drug interaction between TPV/RTV and APV, LPV, and SQV
Primary endpoints
APV, LPV, SQV Cmin ratio between week 8 and baseline
Safety
DESIGN
Objective
PK drug interaction between TPV/RTV and APV, LPV, and SQV
Primary endpoints
APV, LPV, SQV Cmin ratio between week 8 and baseline
Safety
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Phase I-II Trial--1st Companion StudyBI 1182.51
DESIGN
Patient population
HIV+ adults with >2 PI regimen experience & 3-class experience
>1 major PI mutation (30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M)
>2 of 82L, 82T, 84V, 90M
Duration
48 weeks
Upon the last patient completing 48 weeks, all patients may participate in a rollover trial to receive continued treatment
DESIGN
Patient population
HIV+ adults with >2 PI regimen experience & 3-class experience
>1 major PI mutation (30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M)
>2 of 82L, 82T, 84V, 90M
Duration
48 weeks
Upon the last patient completing 48 weeks, all patients may participate in a rollover trial to receive continued treatment
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Phase I-II Trial--1st Companion StudyBI 1182.51
TREATMENT
Patients will be randomized to one of four arms
TPV/RTV + OBR
TPV/RTV/APV +OBR
TPV/RTV/LPV +OBR
TPV/RTV/SQV + OBR
N= 50 patients per arm
PARTICIPATING COUNTRIES
ALL in either RESIST-1 and RESIST-2
TREATMENT
Patients will be randomized to one of four arms
TPV/RTV + OBR
TPV/RTV/APV +OBR
TPV/RTV/LPV +OBR
TPV/RTV/SQV + OBR
N= 50 patients per arm
PARTICIPATING COUNTRIES
ALL in either RESIST-1 and RESIST-2
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1182.52Phase IIB500/100500/200750/200
RESIST-1N=500, 24W
TPV/RTV vs. PI/RTV +OBRNA, AUS
RESIST-2N=800, 16W
TPV/RTV vs. PI/RTV +OBREU, SA
1182.513-PI, PK/Safety
RESIST-33-PI, Efficacy
Tipranavir Clinical Development Plan - Phase II-III Program
1182.17/.57 Rollover Studies
Analysis, choose optimal dose
![Page 21: Design of the RESIST Study Program](https://reader035.fdocuments.us/reader035/viewer/2022062422/5681325e550346895d98f0c0/html5/thumbnails/21.jpg)
Phase III Trial--2nd Companion StudyRESIST-3 (BI 1182.13)
DESIGN
Objective
Safety and efficacy of a 3-PI regimen in very highly treatment experienced HIV+ adults
Primary endpoints
Viral load reduction at 24/48 weeks
Timing
Will follow analysis of 8-week data from trial 1182.51
DESIGN
Objective
Safety and efficacy of a 3-PI regimen in very highly treatment experienced HIV+ adults
Primary endpoints
Viral load reduction at 24/48 weeks
Timing
Will follow analysis of 8-week data from trial 1182.51
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Phase III Trial--2nd Companion StudyRESIST-3 (BI 1182.13)
DESIGN
Patient population
HIV+ adults with >2 PI regimen experience & 3-class experience
>1 major PI mutation (30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M)
>2 of 82L, 82T, 84V, 90M
Duration
48 weeks
DESIGN
Patient population
HIV+ adults with >2 PI regimen experience & 3-class experience
>1 major PI mutation (30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M)
>2 of 82L, 82T, 84V, 90M
Duration
48 weeks
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Phase III Trial--2nd Companion StudyRESIST-3 (BI 1182.13)
TREATMENT
Patients will be randomized to one of four arms
TPV/RTV/APV +OBR
TPV/RTV/LPV +OBR
TPV/RTV/SQV + OBR
N= ~50 patients per arm
PARTICIPATING COUNTRIES
ALL in either RESIST-1 and RESIST-2
TREATMENT
Patients will be randomized to one of four arms
TPV/RTV/APV +OBR
TPV/RTV/LPV +OBR
TPV/RTV/SQV + OBR
N= ~50 patients per arm
PARTICIPATING COUNTRIES
ALL in either RESIST-1 and RESIST-2
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1182.52Phase IIB
Phase III Program
Tipranavir Clinical Development PlanPhase III, Peds, Naïve, & EA Program
Dose Selection,
PK Analysis
Pediatric PK Trial.14
EXPANDEDACCESS
Naïve Trial.33
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Tipranavir PK Development Program
Completed or ongoing studies
Grid study
Antivirals:
Multiple ARV regimens
NRTIs: ZDV, ddI
NTRTI: tenofovir
NNRTIs: EFV
Oral contraceptive, loperamide
Completed or ongoing studies
Grid study
Antivirals:
Multiple ARV regimens
NRTIs: ZDV, ddI
NTRTI: tenofovir
NNRTIs: EFV
Oral contraceptive, loperamide
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Tipranavir PK Development Program
Planned studies
Other drugs: clarithromycin, fluconazole, rifampin, methadone, rifabutin, atorvastatin
PK/PD: ADME, bioequivalence, GI transit, high fat/antacid
Special populations: hepatic/renal insufficiency
Planned studies
Other drugs: clarithromycin, fluconazole, rifampin, methadone, rifabutin, atorvastatin
PK/PD: ADME, bioequivalence, GI transit, high fat/antacid
Special populations: hepatic/renal insufficiency
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1182.52Phase IIB500/100500/200750/200
RESIST-1N=500, 24W
TPV/RTV vs. PI/RTV +OBRNA, AUS
RESIST-2N=800, 16W
TPV/RTV vs. PI/RTV +OBREU, SA
1182.513-PI, PK/Safety
RESIST-33-PI, Efficacy
Tipranavir Clinical Development Plan - Phase II-III Program
1182.17/.57 Rollover Studies
Analysis, choose optimal dose