# Presentation: 670347

## Helen Whamond Boucher, M.D.

**Senior Associate Director**
**Clinical Development**
**Pfizer Global Research & Development**

## Voriconazole Clinical Program

**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)**

## The Global Comparative Aspergillosis Study (307/602)

**A prospective, randomized, open-label multicenter controlled study**

## 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)**

## 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**

## 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**

## 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)**

## Global Comparative Aspergillosis Study (307/602) Study Procedures: End of Randomized Therapy

**Global Comparative Aspergillosis Study ****(307/602)**** ****Study Procedures: End of Randomized Therapy**

**Randomized Therapy **

**Withdraw from Randomized Therapy**** **

**Switch to Other Licensed**
**Antifungal Therapy**

**Voriconazole**
**Standard loading doses, then**
**4 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 **

## Global Comparative Aspergillosis Study (307/602) Study Procedures: Week 12

**Week 12**

**DRC Assessment****of Outcome at End of**
**Randomized Therapy**
**=**
**DRC Assessment at **
**Week 12**** **

**DRC Assessment at **
**Week 12**** **

**Survival through Day 84**** **

**Randomized Therapy **

**Withdraw from **
**Randomized Therapy**** **

**Switch to Other Licensed**
**Antifungal Therapy**

**DRC Assessment****of Outcome at End of**
**Randomized Therapy **

**DRC Assessment****of Outcome at End of**
**Randomized Therapy **

## 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**

## 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  **

## 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**

## Global Comparative Aspergillosis Study (307/602)Diagnosis - Patient 3181

**Nodular lesion with “halo sign” at baseline**

## Global Comparative Aspergillosis Study (307/602)

**Results**

## Global Comparative Aspergillosis Study (307/602)Enrollment

***95 of 199 sites enrolled 392 patients**

## Global Comparative Aspergillosis Study (307/602) Patient Disposition

**No Treatment**

**Incorrect****Randomization**

**No Definite or Probable Aspergillosis****per  ****Blinded Data Review Committee**

**196**

**194**

**144**

**Voriconazole**

**Amphotericin B**

**392****Enrolled**

**185**

**185**

**133**

**Safety Population**
**Intention to Treat Population**
**Modified Intention to Treat Population**

**3**

**8**

**2**

**0**

**50**

**52**

## Global Comparative Aspergillosis Study (307/602) Demographic and Clinical Characteristics (MITT)

**Global Comparative Aspergillosis Study (307/602)**** ****Demographic and Clinical Characteristics (MITT)**

## Global Comparative Aspergillosis Study (307/602)Demographics by Stratification Factors as Assessed by the DRC (MITT)

## Global Comparative Aspergillosis Study (307/602)DRC-Assessed Certainty of Infection by Study (MITT)

## Global Comparative Aspergillosis Study (307/602) Study Procedures: Progress Over Time

**Randomized Therapy **

**Withdraw from **
**Randomized Therapy**** **

**Switch to Other Licensed**
**Antifungal Therapy**

**DRC Assessment****of Outcome at End of**
**Randomized Therapy **

**DRC Assessment****of Outcome at End of**
**Randomized Therapy **

**Week 12**

**DRC Assessment****of Outcome at End of**
**Randomized Therapy**
**=**
**DRC Assessment at **
**Week 12**** **

**DRC Assessment at **
**Week 12**** **

**Survival through Day 84**** **

## Global Comparative Aspergillosis Study (307/602) Disposition Over Time: Voriconazole Arm (MITT)

**Day**

**42**

**5**

**13**

**22**

**62**

**Day 84**

**Voriconazole Randomized Therapy****	****OLAT ****	****	****Died **
**Post Treatment Follow up****	****	****Discontinued****	****	**

**Number of Patients**

## Global Comparative Aspergillosis Study (307/602) Disposition Over Time: Amphotericin B Arm (MITT)

**Number of Patients**

**Day 84**

**56**

**7**

**11**

**57**

**2**

**Day**

## 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 **

## 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) **

**76/144**

**42/133**

*** OLAT = Other licensed antifungal therapy**

## Global Comparative Aspergillosis Study (307/602)DRC-Assessed Success at Week 12 (MITT)

-  **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%**

**76/144**

**42/133**

## Global Comparative Aspergillosis Study (307/602) DRC-Assessed Success at Week 12 (MITT)

**Global Comparative Aspergillosis Study (307/602)**** ****DRC-Assessed Success at Week 12 (MITT)**

**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**

## 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**

## 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 of**
**Randomized Therapy**
**Voriconazole      = 77 days**
**Amphotericin B  = 11 days**** **

**77/144**

**29/133**

## 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**

## Global Comparative Aspergillosis Study (307/602) Time to Death (MITT)

**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)**

**Global Comparative Aspergillosis Study (307/602)**** ****Time to Death (MITT)**

**Number of days of Therapy**

**Probability of Survival**

**Hazard ratio = 0.60**
**95% CI (0.40, 0.89)**

## Global Comparative Aspergillosis Study (307/602) DRC-Assessed Cause of Death at Day 84 (MITT)

**Global Comparative Aspergillosis Study (307/602) ****DRC-Assessed Cause of Death at Day 84 (MITT)**

## 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**

## Non-Comparative Aspergillosis Study (304)* Outcome

**Non-Comparative Aspergillosis Study (304)***** ****Outcome**

*** Denning et al, CID in press**

## Non-Comparative and Historical Control Aspergillosis Studies (304,1003) Success

**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**

## Invasive AspergillosisSummary

**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**

## 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)**

## Voriconazole Efficacy Database Emerging Pathogens

**Infections due to rare pathogens more frequently recognized and more patients at risk****1**
**Refractory to available agents****2**
**Overall mortality 76 – 87% for *****Scedosporium******3***
***	******Fusarium***** carries 50 – 80% attributable mortality****4**

**1**** Perfect, Schell, CID 1996; ****2 ****Hennequin et al, AAC 1997; Espinel-Ingroff et al, Mycologica 2001**
**3**** 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**

## Success in Scedosporium By Site of Infection

**Success in *****Scedosporium***** ****By Site of Infection**

*** One patient relapsed; in four patients multiple sites were involved**

## Success in Fusarium By Site of Infection

*** Reis et al, British J Ophtalmol 2000**
**** One patient relapsed**
**†**** ****Four patients had *****Fusarium***** as part of a mixed fungal infection**

## 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)**

## 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**

## Esophageal Candidiasis Study (305)*Outcome (Per Protocol) 

**113/115**

**134/141**

**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**

## Systemic Candida Infections Salvage Therapy (N = 43)

## 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)**

## 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)**

## 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**

## 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**

## Empirical Therapy Study (603/MSG42) Key Inclusion Criteria

**Neutropenia ******** 500/mm****3 ****for at least 96 hours and ******** 250/mm****3**** within 24 hours prior to randomization**
**At least 96 hours of parenteral systemic antibiotic therapy**
**Temperature ******** 38o C within 24 hours of randomization**

## 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**

## 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**

## 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  **

## Empirical Therapy Study (603/MSG42) 

**Results**

## 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 B**

**871****Randomized**

**Safety Population**
**Modified Intention to Treat Population**

**14**

**8**

**6**

**6**

## Empirical Therapy Study (603/MSG42)Demographic and Clinical Characteristics (MITT)

**Empirical Therapy Study ****(603/MSG42)****Demographic and Clinical Characteristics (MITT)**

## Empirical Therapy Study (603/MSG42) Demographic and Clinical Characteristics (MITT)

**†**** ****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)**

## Empirical Therapy Study (603/MSG42) Treatment Duration (MITT)

## Empirical Therapy Study (603/MSG42) Analysis of Primary Endpoint (MITT)

## 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**

## Empirical Therapy Study (603/MSG42) Breakthrough Fungal Infections (MITT)*

*** Definite or probable according to the blinded DRC**

## Empirical Therapy Study (603/MSG42) Documented Breakthrough Fungal Infections

**Empirical Therapy Study ****(603/MSG42)**** ****Documented Breakthrough Fungal Infections**

## 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**

## Empirical Therapy Study (603/MSG42) Deaths Within 7 days of End Of Therapy (MITT) 

## Empirical Therapy Study (603/MSG42) Deaths Within 7 days of End Of Therapy (MITT)

***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)**

## 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**

## Empirical Therapy Study (603/MSG42) Discontinuation Due to Toxicity or Lack of Efficacy Prior to Recovery from Neutropenia (MITT)*

*** Included only permanent discontinuation.  7 voriconazole and 52 liposomal amphotericin B patients temporarily discontinued study drug or had dose reductions during study**

## Empirical Therapy Study (603/MSG42) Discontinuation Due to Lack of Efficacy Prior to Recovery from Neutropenia (MITT)

**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**

## 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**

## Empirical Therapy Study (603/MSG42) Defervescence*

**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**

## 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**

## Empirical  Therapy Study (603/MSG42) DRC-Assessment of Baseline Infection Outcome at End of Therapy

**Empirical  Therapy Study ****(603/MSG42)**** ****DRC-Assessment of Baseline Infection Outcome at End of Therapy**

## Empirical Therapy Study (603/MSG42) Response to Empirical Therapy (MITT)

**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)**

## Empirical Therapy Study (603/MSG42) Breakthrough Infections by Risk and Prophylaxis (MITT)

**Empirical Therapy Study (603/MSG42)**** ****Breakthrough Infections by Risk and Prophylaxis (MITT)**

## Empirical Therapy Study (603/MSG42)Overall Response by Randomization Stratum (MITT)

**Empirical Therapy Study (603/MSG42)****Overall Response by Randomization Stratum (MITT)**

**C.I. = 95% Confidence Interval**

## Empirical Therapy Study (603/MSG42) Response to Empirical Therapy (MITT) High and Moderate Risk 

**-10**

**Empirical Therapy Study ****(603/MSG42)**** ****Response to Empirical Therapy (MITT) High and Moderate Risk**** **

**% Difference (95% CI)**

## Empirical Therapy Study (603/MSG42) Infusion Related Reactions (MITT) - All*

*** 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***

## 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**