1 helen whamond boucher, m.d. senior associate director clinical development pfizer global research...
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Helen Whamond Boucher, M.D.
Senior Associate Director
Clinical Development
Pfizer Global Research & Development
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Voriconazole Clinical ProgramInvasive Aspergillosis
Global Comparative Aspergillosis Study (307/602) Non-Comparative Aspergillosis Study (304) Contemporaneous Historical Control Study (1003)
Emerging Pathogens Scedosporium Infections Fusarium Infections
Candida Infections Esophageal Candidiasis Study (305) Pooled Efficacy Data
Empirical Therapy Study (603/MSG42)
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The Global Comparative Aspergillosis Study (307/602)
A prospective, randomized, open-label multicenter controlled study
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Global Comparative Aspergillosis Study (307/602)
Two protocols 1997 (US 602, EORTC 307)
Identical patient populations, treatments and assessments
Prospectively planned analysis of the combined interim data: the Umbrella analysis
In agreement with participants, recruitment into studies was discontinued
Final report on Global Comparative Aspergillosis Study (307/602)
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Global Comparative Aspergillosis Study (307/602)Key Inclusion Criteria
Immunocompromised
Definite or probable invasive aspergillosis (radiological, clinical, mycological)
Modified National Institute of Allergy and Infectious Diseases Mycoses Study Group/EORTC criteria*
Less than 96 hours of systemic antifungal treatment at therapeutic doses
*Ascioglu et al, CID, in press
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Global Comparative Aspergillosis Study (307/602) Umbrella Analysis: Sample Size and Statistical Considerations
Assumed overall response rate of 50%
At least 90% power to exclude a difference in DRC-assessed success at Week 12 of -20% (non-inferiority)
Sample size estimate: assumed 25% exclusion, total sample size 368 patients to enroll 276 patients in the Modified Intention to Treat (MITT) population
Stratification at randomization: Site of infection Underlying disease Neutrophil count
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Global Comparative Aspergillosis Study (307/602)
Study Design - Background
Conventional amphotericin B Historically the standard Approved for primary treatment of Invasive
Aspergillosis
Lipid formulations, itraconazole Approved for salvage therapy in Aspergillosis Used more frequently Less toxicity
Other Licensed Antifungal Therapy (OLAT)
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Global Comparative Aspergillosis Study (307/602)
Study Procedures: End of Randomized Therapy
Randomized Therapy
Withdraw from Randomized
Therapy
Switch to Other LicensedAntifungal Therapy
VoriconazoleStandard loading doses, then4 mg/kg IV q 12 h, oral option
200 mg BID p 7 days IV
Amphotericin B 1 mg/kg/d IV x 14 days
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Global Comparative Aspergillosis Study (307/602)
Study Procedures: Week 12
Week 12
DRC Assessmentof Outcome at End ofRandomized Therapy=DRC Assessment at
Week 12
DRC Assessment at
Week 12
Survival through Day 84
Randomized Therapy
Withdraw from Randomized
Therapy
Switch to Other LicensedAntifungal Therapy
DRC Assessmentof Outcome at End ofRandomized Therapy
DRC Assessmentof Outcome at End ofRandomized Therapy
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Global Comparative Aspergillosis Study (307/602) Endpoints
Outcome at Week 12 Test for non-inferiority (DRC-assessed
success) Primary Efficacy Endpoint
Outcome at End Of Randomized Therapy Test for superiority (DRC-assessed success) Secondary Efficacy Endpoint
Survival through Day 84 Secondary Efficacy Endpoint
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Global Comparative Aspergillosis Study (307/602)
Blinded Data Review Committee Composition
12 physicians, including 4 radiologists Expertise in assessment and treatment of
invasive fungal infections in immunocompromised patients
Two sub-groups: European members (elected by the EORTC) US members (Sponsor-selected)
A standard operating procedure was followed when assessing cases
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Global Comparative Aspergillosis Study (307/602) Blinded Data Review Committee Process*
Blinded review of all patients Mycology reports, clinical assessments,
investigator response Digitized radiology studies
Assessed
Certainty of infection at baseline
Outcome at End of Randomized Therapy
Outcome at Week 12
Cause of death
*Patterson et al, ICAAC 2000, Toronto; Denning et al, ICAAC 2000, Toronto
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Global Comparative Aspergillosis Study (307/602)Diagnosis - Patient 3181
Nodular lesion with “halo sign” at baseline
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Global Comparative Aspergillosis Study (307/602)
Results
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Global Comparative Aspergillosis Study (307/602)Enrollment
Number of Centers
Approved
Number of Patients Enrolled
US-Led Study 602 United States 55 112
Canada 16 19 Mexico, Argentina, Brazil, India 16 8
EORTC-Led Study 307 Germany 24 126
France 16 65 Belgium 8 27
Europe, Australia, Israel 64 35
Total 199* 392
*95 of 199 sites enrolled 392 patients
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Global Comparative Aspergillosis Study (307/602)
Patient Disposition
No Treatment
IncorrectRandomization
No Definite or Probable
Aspergillosisper
Blinded Data Review
Committee
196
194
144
Voriconazole Amphotericin B392
Enrolled
185
185
133
Safety Population
Intention to Treat Population
Modified Intention to Treat Population
3 8
2 0
50 52
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Characteristics
Voriconazole
N = 144
Amphotericin B
N = 133
Age – years Mean 48.5 50.5 Range 13 - 79 12 - 75 Sex – N (%) Male 98 (68.1) 89 (66.9) Female 46 (31.9) 44 (33.1) Race – N (%) White 130 (90.3) 126 (94.7) Black 7 (4.9) 1 (0.8) Other 7 (4.9) 6 (4.5)
Global Comparative Aspergillosis Study (307/602) Demographic and Clinical Characteristics (MITT)
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Global Comparative Aspergillosis Study (307/602)Demographics by Stratification Factors as Assessed by the DRC (MITT)
Voriconazole N = 144
Amphotericin B N = 133
Site of Infection n (%) Pulmonary 119 (82.6) 112 (84.2)
Extrapulmonary 25 (17.4) 21 (15.8)
Underlying Disease Allogeneic BMT/PSCT 37 (25.7) 30 (22.5)
Autologous BMT/PSCT or other hematological condition (eg leukemia)
81 (56.3)
84 (63.2)
Other immunosuppression (eg solid organ transplant, HIV/AIDS)
26 (18.0)
19 (14.3)
Neutrophil Status at Baseline ANC < 500 cells/mm3 63 (43.8) 60 (45.1) ANC 500 cells/mm3 81 (56.3) 73 (54.9)
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Global Comparative Aspergillosis Study (307/602)DRC-Assessed Certainty of Infection by Study (MITT)
Certainty of Infection
Voriconazole N = 144
Amphotericin B N = 133
n (%)
Definite 67 (46.5) 41 (30.8)
Probable 77 (53.5) 92 (69.2)
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Global Comparative Aspergillosis Study (307/602)
Study Procedures: Progress Over Time
Randomized Therapy
Withdraw from Randomized
Therapy
Switch to Other LicensedAntifungal Therapy
DRC Assessmentof Outcome at End ofRandomized Therapy
DRC Assessmentof Outcome at End ofRandomized Therapy
Week 12
DRC Assessmentof Outcome at End ofRandomized Therapy=DRC Assessment at
Week 12
DRC Assessment at
Week 12
Survival through Day 84
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Global Comparative Aspergillosis Study (307/602) Disposition Over Time: Voriconazole Arm (MITT)
0
20
40
60
80
100
120
140
160
1 8 15 22 29 36 43 50 57 64 71 78
Day
42
51322
62
Day 84
Voriconazole Randomized Therapy OLAT Died
Post Treatment Follow up Discontinued
Nu
mb
er o
f P
atie
nts
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Global Comparative Aspergillosis Study (307/602) Disposition Over Time: Amphotericin B Arm (MITT)
0
20
40
60
80
100
120
140
1 8 15 22 29 36 43 50 57 64 71 78
Nu
mb
er o
f P
atie
nts
Day 84
56
711
57
2
Amphotericin B Randomized Therapy OLAT Died
Post Treatment Follow up Discontinued
Day
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Global Comparative Aspergillosis Study (307/602)
Endpoints Outcome at Week 12
Test for non-inferiority (DRC-assessed success)
Primary Efficacy Endpoint
Outcome at End Of Randomized Therapy Test for superiority (DRC-assessed success) Secondary Efficacy Endpoint
Survival through Day 84 Secondary Efficacy Endpoint
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Global Comparative Aspergillosis Study (307/602)DRC-Assessed Success at Week 12 (MITT)
Difference (raw) = 21.2%, 95 % CI (9.9, 32.6)Difference (adjusted) = 21.8%, 95% CI (10.5, 33.0)
0
10
20
30
40
50
60
% S
ucc
ess
Voriconazole +/- OLAT*
Amphotericin B +/- OLAT*
76/144
42/133
* OLAT = Other licensed antifungal therapy
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Global Comparative Aspergillosis Study (307/602)DRC-Assessed Success at Week 12 (MITT)
0
10
20
30
40
50
60
Study 602 Study 307
27/58
11/49
49/86
31/84
Study 602 (raw) = 24.1%, 95% CI (6.8, 41.5)Study 307 (raw) = 20.1%, 95% CI (5.4, 34.8)
(raw) = 21.2%
0
10
20
30
40
50
60
% S
ucc
ess
Voriconazole +/- OLAT
Amphotericin B +/- OLAT
76/144
42/133
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26-20 -10 0 10 20 30 40 50 60
Global Comparative Aspergillosis Study (307/602)
DRC-Assessed Success at Week 12 (MITT) Success Voriconazole Ampho B
52.8% 31.6%
55.5% 34.8%
40.0% 14.3%
32.4% 13.3%
63.0% 38.1%
50.0% 31.6%
50.8% 31.7%
54.3% 31.5%
44.8% 19.5%
59.7% 37.0%
Difference in Success Rates (%, 95% CI)
Probable
Non-Neutropenic (ANC 500)
Definite
Neutropenic (ANC < 500)
Allogeneic BMT
Extrapulmonary
Pulmonary
Overall
Other immunosuppressed state (eg solid organ transplant, HIV/AIDS)
Autologous BMT or other hematological condition (eg leukemia)
-20
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Global Comparative Aspergillosis Study (307/602)
Endpoints Outcome at Week 12
Test for non-inferiority (DRC-assessed success)
Primary Efficacy Endpoint
Outcome at End Of Randomized Therapy Test for superiority (DRC-assessed success) Secondary Efficacy Endpoint
Survival through Day 84 Secondary Efficacy Endpoint
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Global Comparative Aspergillosis Study (307/602)DRC-Assessed Success at End of Randomized Therapy (MITT)
Difference (raw) = 31.7%, 95% CI (20.9, 42.4)Difference (adjusted) = 31.9%, 95% CI (21.2, 42.6)
Median Duration ofRandomized Therapy
Voriconazole = 77 days
Amphotericin B = 11 days
0
10
20
30
40
50
60
% S
uc
ce
ss
Voriconazole Amphotericin B
77/144
29/133
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Global Comparative Aspergillosis Study (307/602)
Endpoints Outcome at Week 12
Test for non-inferiority (DRC-assessed success)
Primary Efficacy Endpoint
Outcome at End Of Randomized Therapy Test for superiority (DRC-assessed success) Secondary Efficacy Endpoint
Survival through Day 84 Secondary Efficacy Endpoint
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At Risk (Censored)
Vori 144 (0) 131 (0) 125 (0) 117 (0) 111 (0) 107 (0) 102 (0)
AMB 133 (0) 117 (0) 99 (0) 87 (0) 84 (0) 80 (0) 77 (0)
0 14 28 42 56 70 840.0
0.2
0.4
0.6
0.8
1.0
Global Comparative Aspergillosis Study (307/602) Time to Death (MITT)
Number of days of Therapy
Pro
bab
ilit
y o
f S
urv
ival
Amphotericin B +/- OLAT
Voriconazole +/- OLAT
Hazard ratio = 0.6095% CI (0.40, 0.89)
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Voriconazole +/- OLAT N = 144 n (%)
Amphotericin B +/- OLAT N = 133
n (%)
Mortality 42 (29.2) 56 (42.1)
Death caused by aspergillosis 18 (12.5) 38 (28.6)
Death unrelated to aspergillosis but evidence of active Aspergillus infection
10 (6.9) 8 (6.0)
Death unrelated to aspergillosis and no evidence of residual Aspergillus
infection
7 (4.9) 3 (2.3)
Indeterminate 7 (4.9) 4 (3.0)
Not assessed by DRC 0 3 (2.3)
Global Comparative Aspergillosis Study (307/602)
DRC-Assessed Cause of Death at Day 84 (MITT)
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Global Comparative Aspergillosis Study (307/602)
Conclusions
Voriconazole (+/- OLAT) led to greater DRC-assessed success than did amphotericin B (+/- OLAT) Success
12 Weeks End of Randomized Therapy
Survival Benefit
Robust treatment benefit across relevant subpopulations including component studies
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Success n (%)
ITT
N = 137
Expert Evaluable
N = 112
Per Protocol Primary
Subgroup
5 Days Prior Therapy
N = 50
Success 74 (54.0) 55 (49.1) 26 (52.0)
Failure 61 (44.5) 56 (50.0) 24 (48.0)
No Evaluable Data 2 (1.5) 1 (0.9) 0
Non-Comparative Aspergillosis Study (304)* Outcome
* Denning et al, CID in press
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0 20 40 60 80 100
Non-Comparative Aspergillosis Study (304)
Historical Control Study (1003)
26/50
23/92
% Success(95% Confidence Interval)
Non-Comparative and Historical Control Aspergillosis Studies (304,1003) Success
Success
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Invasive AspergillosisSummary
Superiority in Global Comparative Aspergillosis Study (307/602)
Efficacy in Non-Comparative Aspergillosis Study (304)
Consistent data in contemporaneous Historical Control Study (1003)
In a large pooled efficacy population, success in Central nervous system infections Other poor prognostic risk factors
Total of 476 patients with documented Invasive Aspergillosis treated with voriconazole
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Voriconazole Clinical Efficacy DataInvasive Aspergillosis
Global Comparative Aspergillosis Study (307/602) Non-Comparative Aspergillosis Study (304) Contemporaneous Historical Control Study (1003)
Emerging Pathogens Scedosporium Infections Fusarium Infections
Candida Infections Esophageal Candidiasis Study (305) Pooled Efficacy Data
Empirical Therapy Study (603/MSG42)
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Voriconazole Efficacy Database Emerging Pathogens Infections due to rare pathogens more frequently
recognized and more patients at risk1
Refractory to available agents2
Overall mortality 76 – 87% for Scedosporium3
Fusarium carries 50 – 80% attributable mortality4
1 Perfect, Schell, CID 1996; 2 Hennequin et al, AAC 1997; Espinel-Ingroff et al, Mycologica 20013 Nesky et al, CID 2000; Berenguer et al, Medicine 1997; 4 Boutai et al, Blood 1997; Martino et al, J Infect 1994; Gamis et al, Rev Infect Dis 1991
Fungus
Antifungal Agent
MIC Range
g/ml
MIC50 g/ml
MIC90 g/ml
S. apiospermum (n = 13) Amphotericin B 1 - 8 4 8 Itraconazole 0.125 – 8 0.5 0.5 Miconazole 0.06 - 1 0.12 0.12
S. prolificans (n = 5) Amphotericin B 2 – 16 Itraconazole 2 – 16 Miconazole 0.5 - >16
F. solani (n = 65) Amphotericin B 0.5 - > 16 1 - 4 Itraconazole 1 - > 16 > 16
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38** Jabado et al, CID 1998; Munoz et al, CID 2000; Nesky et al, CID 2000; Poza et al, CID 2000
Success in Scedosporium By Site of Infection
Success n/N
S. apiospermum N = 27
S. prolificans N = 8
Central Nervous System 7/11* 0/2
Disseminated 3/4 1/3
Blood 0 0/1
Pulmonary 5/7 0/1
Cutaneous 0/2 -
Bone/Joint 1/3 1/1
Total 16/27** 2/8
* One patient relapsed; in four patients multiple sites were involved
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Success in Fusarium By Site of Infection
Success n/N
Eye 2/4*
Sinus 2/3**
Skin 1/2
Disseminated 1/6
Total 6/15 (40%)†
* Reis et al, British J Ophtalmol 2000** One patient relapsed† Four patients had Fusarium as part of a mixed fungal infection
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Voriconazole Clinical Efficacy Data
Invasive Aspergillosis Global Comparative Aspergillosis Study (307/602) Non-Comparative Aspergillosis Study (304) Contemporaneous Historical Control Study (1003)
Emerging Pathogens Scedosporium Infections Fusarium Infections
Candida Infections Esophageal Candidiasis Study (305) Pooled Efficacy Data
Empirical Therapy Study (603/MSG42)
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Voriconazole Efficacy Database Candida Infections
Esophageal candidiasis was selected as the proof of concept for efficacy in treating invasive infection
Systemic Candida Infections Experience in 91 patients from across the program
Primary therapy (n = 48) Salvage therapy (n = 43)
Comparative Candidemia Study (Study 608) ongoing
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Esophageal Candidiasis Study (305)*Outcome (Per Protocol)
0
20
40
60
80
100
% S
ucc
ess
113/115134/141
Success (cured + improved): 98.3% Voriconazole, 95.0% Fluconazole Difference 3.23%, 95% CI (-1.08, 7.53)
* Ally et al, CID 2001
Voriconazole Fluconazole
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Systemic Candida Infections Salvage Therapy (N = 43)
Voriconazole Success n/N (%)
Clinical Trial
Patients
Compassionate
Use Patients
Total
Prior Efficacy Failure
10/20 (50) 6/16 (38) 16/36 (44)
Intolerance 2/3 1/1 3/4
Unknown 2/2 1/1 3/3
Total 14/25 (56) 8/18 (44) 22/43 (51)
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Candida Infections Conclusions
Success in esophageal candidiasis proven in a double-blind, double dummy trial vs fluconazole
Experience in treating 91 systemic Candida infections 43 patients received voriconazole as salvage
therapy
Candidemia Study (608) in non-neutropenic patients ongoing (n = 256, target N = 426)
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Voriconazole Clinical Efficacy DataInvasive Aspergillosis
Global Comparative Aspergillosis Study (307/602) Non-Comparative Aspergillosis Study (304) Contemporaneous Historical Control Study (1003)
Emerging Pathogens Scedosporium Infections Fusarium Infections
Candida Infections Esophageal Candidiasis Study (305) Pooled Efficacy Data
Empirical Therapy Study (603/MSG42)
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Empirical Therapy
Significant chance of developing fungal infection among patients with neutropenia and persistent fever despite several days of broad-spectrum antibiotics *
Approved Agents Liposomal amphotericin B (MSG32)** Itraconazole †
* Pizzo et al Am J Med 1982, EORTC Am J Med 1989** Walsh et al N Engl J Med 1999† Boogaerts et al Ann Int Med 2001
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Empirical Therapy Study (603/MSG42) Objectives
Primary:
To evaluate the efficacy of voriconazole compared with liposomal amphotericin B by composite endpoint
Components: Breakthrough fungal infections* Survival* Premature discontinuation from study medication Defervescence during neutropenia* Response in baseline invasive fungal infections
* Secondary efficacy endpoint
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Empirical Therapy Study (603/MSG42) Key Inclusion Criteria
Neutropenia 500/mm3 for at least 96 hours and 250/mm3 within 24 hours prior to randomization
At least 96 hours of parenteral systemic antibiotic therapy
Temperature 38º C within 24 hours of randomization
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Empirical Therapy Study (603/MSG42) Sample Size and Statistical Considerations
Assumed overall response rate of 50%*
At least 80% power to exclude a difference in success in composite endpoint of -10% (non-inferiority)
Sample size estimate: assume 10% exclusion, total sample size 866 patients to enroll 786 patients in the Modified Intention to Treat (MITT) population
* Based on MSG32
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Empirical Therapy Study (603/MSG42)
Stratification at randomization:
Risk of developing invasive fungal infection High risk: allogeneic transplant or relapsed
leukemia Moderate risk: newly diagnosed leukemia,
autologous transplant or other neoplasm
Systemic antifungal prophylaxis: yes vs no
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Empirical Therapy Study (603/MSG42) Blinded Data Review Committee
Eight physicians, including infectious disease specialists and oncologists
Blinded review of all potential infections Mycology reports, clinical assessments, and global
response Radiology studies (films) and reports
Assessed Presence of infection Type of infection (baseline or breakthrough) Certainty of infection Global response at the End of Therapy
A standard operating procedure was followed when assessing cases
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Empirical Therapy Study (603/MSG42)
Results
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Empirical Therapy Study (603/MSG42) Patient Disposition
No Treatment
One dose of randomized
therapy
One dose of randomized therapy and sufficient information to confirm
investigator’s assessment
421
415
428
422
Voriconazole Liposomal
Amphotericin B871
Randomized
Safety Population
Modified Intention to Treat Population
14 8
6 6
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Characteristics
Voriconazole N = 415
Liposomal
Amphotericin B N = 422
Age – years Mean 46.3 45.0 Range 12 – 82 12 - 80
Sex – N (%) Male 233 (56.1) 216 (51.2) Female 182 (43.9) 206 (48.8)
Race – N (%) White 325 (78.3) 333 (78.9) Black 35 (8.4) 32 (7.6) Other 55 (13.3) 57 (13.5)
Empirical Therapy Study (603/MSG42)Demographic and Clinical Characteristics (MITT)
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Characteristics
Voriconazole N = 415 n (%)
Liposomal
Amphotericin B N = 422 n (%)
Risk Category High 143 (34.5) 141 (33.4) Moderate 272 (65.5) 281 (66.6)
Systemic Antifungal Prophylaxis 222 (53.5) 250 (59.2)
Bone Marrow Transplant (BMT)* Allogeneic BMT 76 (18.3) 79 (18.7) Autologous BMT 122 (29.4) 139 (32.9)
Total BMTs 198 (47.7) 217 (51.4)
†
† One subject had both an autologous BMT and an autologous peripheral stem cell transplant
* Includes both BMT and peripheral stem cell transplants
Empirical Therapy Study (603/MSG42) Demographic and Clinical Characteristics (MITT)
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Empirical Therapy Study (603/MSG42) Treatment Duration (MITT)
Voriconazole Liposomal Amphotericin B
Number of Patients
Median Duration Days
(range)
Number of
Patients
Median Duration Days
(range)
IV 415 6 (1 - 46) 422 7 (1 - 81)
Oral + IV 91 6 (1 - 95) N/A N/A
Total 415 7 (1 - 113) 422 7 (1 - 81)
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Empirical Therapy Study (603/MSG42) Analysis of Primary Endpoint (MITT)
Voriconazole
Liposomal Amphotericin B
Number of Patients 415 422
Success (Raw) 108 (26.0%) 129 (30.6%)
Difference between arms - 4.5 (-10.6%, 1.6%)
Primary Analysis
Success (Stratified) 23.7% 30.1%
Difference between arms (Stratified)
- 6.1% (-12.0%, -0.1%)
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Empirical Therapy Study (603/MSG42) Composite Endpoint
Success, all of the following: No breakthrough fungal infection during
neutropenia and for at least 7 days after end of therapy
Survival for at least 7 days after end of therapy No discontinuation from study medication due
to toxicity or lack of efficacy prior to recovery from neutropenia
Defervescence during neutropenia Baseline infections: global response assessed
as complete or partial at end of therapy
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Empirical Therapy Study (603/MSG42) Breakthrough Fungal Infections (MITT)*
Voriconazole
n/N (%)
LiposomalAmphotericin B
n/N (%)
BreakthroughInvasive FungalInfection 8/415 (1.9) 21/422 (5.0)
* Definite or probable according to the blinded DRC
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Organism and Site
Voriconazole
Liposomal Amphotericin B
Aspergillus 4 13 Lung 4 9 Sinuses 0 2 CNS/Skin 0 1 Disseminated 0 1
Candida 2 6 Disseminated 1 0 Blood 1 6
Zygomycetes 2 0 Lung 1 0 Nasal 1 0
Dematiaceous moulds 0 2 Blood 0 1 Lungs 0 1
Total 8 21
Empirical Therapy Study (603/MSG42) Documented Breakthrough Fungal Infections
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Empirical Therapy Study (603/MSG42) Composite Endpoint
Success, all of the following: No breakthrough fungal infection during
neutropenia and for at least 7 days after end of therapy
Survival for at least 7 days after end of therapy No discontinuation from study medication due
to toxicity or lack of efficacy prior to recovery from neutropenia
Defervescence during neutropenia Baseline infections: global response assessed
as complete or partial at end of therapy
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Empirical Therapy Study (603/MSG42) Deaths Within 7 days of End Of Therapy (MITT)
Voriconazole
N = 415 n (%)
Liposomal Amphotericin B
N = 422 n (%)
Deaths
33 (8.0)
25 (5.9)
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Investigator-Assessed Cause of Death* Voriconazole L-AMB
Total Number of Deaths 33 25 Progression of malignancy 13 5
Sepsis 13 9**
Cardiac/respiratory arrest/failure 9 5
Other 8 5
Pneumonia 6
† 0
Multi-organ failure 5 5
Disseminated fungal Infection 2 2
Renal failure 2 1
Ventricular fibrillation 1 0
Hemorrhage 1 6
*More than one cause possible, ** Includes one fungal sepsis† Includes one fungal pneumonia
Empirical Therapy Study (603/MSG42) Deaths Within 7 days of End Of Therapy (MITT)
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Empirical Therapy Study (603/MSG42) Composite Endpoint
Success, all of the following: No breakthrough fungal infection during
neutropenia and for at least 7 days after end of therapy
Survival for at least 7 days after end of therapy No discontinuation from study medication due
to toxicity or lack of efficacy prior to recovery from neutropenia
Defervescence during neutropenia Baseline infections: global response assessed
as complete or partial at end of therapy
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Empirical Therapy Study (603/MSG42) Discontinuation Due to Toxicity or Lack of Efficacy Prior to Recovery from Neutropenia (MITT)*
Voriconazole
N = 415 n
Liposomal Amphotericin B
N = 422 n
Toxicity 19 23
Lack of efficacy 22 5
Total 41 28
* Included only permanent discontinuation. 7 voriconazole and 52 liposomal amphotericin B patients temporarily discontinued study drug or had dose reductions during study
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Voriconazole N = 22*
n
Liposomal
Amphotericin B N = 5
n
Confirmed fungal infection 5 3
Suspected fungal infection 1 0
Pulmonary infiltrates only 2 0
Fever only 14 2
Empirical Therapy Study (603/MSG42) Discontinuation Due to Lack of Efficacy Prior to Recovery from Neutropenia (MITT)
* Six of the 22 patients who discontinued prematurely due to lack of efficacy were from one site
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Empirical Therapy Study (603/MSG42) Composite Endpoint
Success, all of the following: No breakthrough fungal infection during
neutropenia and for at least 7 days after end of therapy
Survival for at least 7 days after end of therapy No discontinuation from study medication due
to toxicity or lack of efficacy prior to recovery from neutropenia
Defervescence during neutropenia Baseline infections: global response assessed
as complete or partial at end of therapy
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68*Temperature less than 38o C for 48 hours prior to recovery from neutropenia (ANC > 250 cells/mm3)
Empirical Therapy Study (603/MSG42) Defervescence*
Number of patients who met defervescence criteria Voriconazole: 135/415 (33.0%) Liposomal amphotericin B: 154/422 (36.0%)
Median time to recovery from neutropenia Voriconazole: 4.8 days Liposomal amphotericin B: 5.4 days
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Empirical Therapy Study (603/MSG42) Composite Endpoint
Success, all of the following: No breakthrough fungal infection during
neutropenia and for at least 7 days after end of therapy
Survival for at least 7 days after end of therapy No discontinuation from study medication due
to toxicity or lack of efficacy prior to recovery from neutropenia
Defervescence during neutropenia Baseline infections: global response assessed
as complete or partial at end of therapy
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Voriconazole Success n/N (%)
Liposomal Amphotericin B
Success n/N (%)
Baseline Infections 6/13 (46) 4/6 (67)
Candida infection 5/10 2/3
Aspergillus infection 1/2 1/2
Other organisms 0/1 1/1
Empirical Therapy Study (603/MSG42) DRC-Assessment of Baseline Infection Outcome at End of Therapy
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71-70 -60 -50 -40 -30 -20 -10 0 10 20 30
Voriconazole L-AMB
% Difference (95% CI)
-10
108/415 129/422
407/415 401/422
382/415 397/422
374/415 394/422
135/415 154/422
6/13 4/6
Empirical Therapy Study (603/MSG42) Response to Empirical Therapy (MITT)
Overall response to empirical therapy (raw)
(stratified)
No breakthrough fungal infections within 7 days of End
of Therapy
Survival through 7 days of End of Therapy
No discontinuation due to toxicity or lack of efficacy before
recovery from neutropenia
Resolution of fever during neutropenia
Global response of baseline fungal infections at End of
Therapy (complete or partial response)
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Prior Antifungal
Prophylaxis n/N (%)
No Prophylaxis n/N (%)
Total n/N (%)
High Risk Voriconazole 1/83 (1.2) 1/60 (1.7) 2/143 (1.4) L-AMB 9/99 (9.1) 4/42 (9.5) 13/141 (9.2)
Moderate Risk Voriconazole 1/139 (0.7) 5/133 (3.8) 6/272 (2.2) L-AMB 4/151 (2.6) 4/130 (3.1) 8/281 (2.8) Total Voriconazole 2/222 (0.9) 6/193 (3.1) 8/415 (1.9) L-AMB 13/250 (5.2) 8/172 (4.7) 21/422 (5.0)
Empirical Therapy Study (603/MSG42) Breakthrough Infections by Risk and Prophylaxis (MITT)
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Voriconazole
n/N (%)
Liposomal Amphotericin B
n/N (%)
Raw Estimate (C.I.)
High Risk 45/143 (32%) 42/141 (30%) + 1.7% (- 9.0%, 12.4%)
Moderate Risk 63/272 (23%) 87/281 (31%) - 7.8% (- 15.2%, - 0.4%)
Empirical Therapy Study (603/MSG42)Overall Response by Randomization Stratum (MITT)
C.I. = 95% Confidence Interval
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-10
High RiskModerate Risk
-100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30 70 80
Empirical Therapy Study (603/MSG42) Response to Empirical Therapy (MITT) High and Moderate Risk
% Difference (95% CI)
Overall response to empirical therapy (raw data)
No breakthrough fungal infections within 7 days of End
of Therapy
Survival through 7 days of End of Therapy
No discontinuation due to toxicity or lack of efficacy before
recovery from neutropenia
Resolution of fever during neutropenia
Global response of baseline fungal infections at End of
Therapy (complete or partial response)
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VoriconazoleN = 415n (%)
LiposomalAmphotericinB
N = 422n (%)
Abnormal Vision 91 (21.9) 3 (0.7)
Chills 57 (13.7) 126 (29.9)
Flushing** 14 (3.4) 46 (10.9)
Dyspnea/Wheezing/Cough/Tachypnea/Hypoxia** 8 (1.9) 50 (11.9)
Chest Pain** 1 (0.2) 17 (4.0)
Abdominal Pain** 1 (0.2) 12 (2.8)
Flank Pain** 1 (0.2) 8 (1.9)
Urticaria** 1 (0.2) 3 (0.7)
Back Pain** 0 14 (3.3)
Anaphylactoid Reaction** 0 7 (1.7)
* 10,398 infusions monitored in 837 patients** Syndrome of sporadic acute infusion related reactions due to liposomal amphotericin B; Roden et al, ICAAC, Chicago 2001
Empirical Therapy Study (603/MSG42)
Infusion Related Reactions (MITT) - All*
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Voriconazole
Superior outcome and survival benefit in primary therapy of acute invasive aspergillosis
Efficacy in patients with Scedosporium and Fusarium infections
Efficacy in Candida infections Appropriate option for empirical therapy Better tolerated than amphotericin B
formulations Acceptable overall safety profile Manageable drug-drug interactions