A Study of the Safety and Efficacy of Posaconazole Versus Voriconazole for the Treatment of Invasive Aspergillosis (MK-5592-069)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01782131
• Collaborator: (none)
• Enrollment: 585
• Arms: 2
• Actual Duration (Months): 71.5

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety and efficacy of posaconazole (POS) versus voriconazole (VOR) in the treatment of adults and adolescents with invasive aspergillosis (IA). The primary hypothesis is that the all-cause mortality through Day 42 in the POS treatment group is non-inferior to that in the VOR treatment group.

Condition or Disease	Intervention/Treatment	Phase
Fungal Infections; Invasive Pulmonary Aspergillosis	Drug: Posaconazole; Drug: Voriconazole; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 585 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Randomized Study of the Efficacy and Safety of Posaconazole Versus Voriconazole for the Treatment of Invasive Aspergillosis in Adults and Adolescents (Phase 3; Protocol No. MK-5592-069)
• Actual Study Start Date: Sep 25, 2013
• Actual Primary Completion Date: Jul 10, 2019
• Actual Study Completion Date: Sep 10, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Posaconazole (POS) Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.	Drug: Posaconazole; POS IV: Day 1: 300 mg BID Day 2-84: 300 mg QD POS oral: Day 1: 300 mg BID Day 2-84: 300 mg QD; Other Names: SCH 056592 MK-5592 Noxafil® ; Drug: Placebo; Matching placebo received for Posaconazole (IV and oral) or Voriconazole (oral)
Active Comparator: Voriconazole Participants received 6 mg/kg voriconazole (VOR) IV twice per day (BID) on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.	Drug: Voriconazole; VOR IV: Day 1: 6 mg/kg per body weight administered BID Day 2-84: 4 mg/kg per body weight administered BID VOR oral: Day 1: 300 mg BID Day 2-84: 200 mg BID; Other Names: VFEND® ; Drug: Placebo; Matching placebo received for Posaconazole (IV and oral) or Voriconazole (oral)

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Who Died Through Day 42 in the Intention to Treat Population [Up to ~42 days]

   The percentage of participants who died with posaconazole (POS) compared to voriconazole (VOR) in the first line treatment of invasive aspergillosis (IA) in the Intention to Treat (ITT) population through Day 42 was assessed.

Secondary Outcome Measures

1. Percentage of Participants Who Died Through Day 42 in the Full Analysis Set Population [Up to ~42 days]

   The percentage of participants who died with POS compared to VOR in the first line treatment of invasive aspergillosis (IA) in the Full Analysis Set (FAS) population through Day 42 was assessed.

2. Percentage of Participants Who Died Through Day 84 in the ITT Population [Up to ~84 days]

   The percentage of participants who died with POS compared to VOR in the first line treatment of invasive aspergillosis (IA) in the ITT population through Day 84 was assessed.

3. Percentage of Participants Who Died Through Day 84 in the FAS Population [Up to ~ 84 days]

   The percentage of participants who died with POS compared to VOR in the first line treatment of invasive aspergillosis (IA) in the FAS population through Day 84 was assessed.

4. Percentage of Participants Achieving Global Clinical Response at Week 12 in the FAS Population [Up to 12 weeks (± 4 weeks)]

   The global clinical response of POS compared to VOR in the first line treatment of invasive aspergillosis (IA) was assessed. The percentage of participants achieving adjudicated global clinical response (complete or partial) at Week 12 was reported. Complete response was classified as survival with resolution of fungal disease evidence; Partial response was survival and improvement of fungal disease.

5. Percentage of Participants Achieving Global Clinical Response at Week 6 in the FAS Population [Up to 6 weeks (± 2 weeks)]

   The global clinical response of POS compared to VOR in the first line treatment of invasive aspergillosis (IA) was assessed. The percentage of participants achieving adjudicated global clinical response (complete or partial) at Week 6 was reported. Complete response was classified as survival with resolution of fungal disease evidence; Partial response was survival and improvement of fungal disease.

6. Number of Participants Experiencing Mortality at Day 42, Day 84, and Day 114 in the FAS Population (Kaplan-Meier Time To Death Estimate) [Up to ~16 weeks (± 2 weeks)]

   The number of participants experiencing mortality at Day 42, Day 84 and Day 114 in participants with proven or probable IA receiving POS versus VOR were assessed. The Kaplan-Meier estimate reports the number of participants who experienced death (all causes) through Day 114 or ~16 weeks. Participants who did not have any endpoint event until last visit or who were lost to follow-up and had no event were censored at the time of last available information (last study visit). For Day 42 and Day 84, missing or 'unable to determine' responses were considered as failures (dead).

7. Number of Participants Who Died Due to Invasive Aspergillosis Through Day 42 in the FAS Population [Up to 42 days]

   The number of participants who died due to IA receiving POS versus VOR through Day 42 was assessed.

8. Number of Participants Who Died Due to Invasive Aspergillosis Through Day 84 in the FAS Population [Up to 84 days]

   The number of participants who died due to IA receiving POS versus VOR in the FAS population through Day 84 was assessed.

9. Percentage of Participants With Tier 1 Treatment Emergent Adverse Events [Up to ~16 weeks (± 2 weeks)]

   The percentage of participants with Tier 1 treatment-emergent adverse events (TEAEs) was determined. The Tier 1 TEAEs included hepatic safety (elevated aspartate serum transaminase [AST] or alanine serum transaminase [ALT] value ≥3x upper limit of normal (ULN) and an elevated total bilirubin value ≥2x ULN and, at the same time, an alkaline phosphatase value <2 ULN); central nervous system (CNS) and visual disturbances (eye disorders, nervous system disorders, psychiatric disorders), dermatologic reactions, and adrenal insufficiency or temporally associated TEAEs of hypotension.

10. Percentage of Participants With at Least One Adverse Event [Up to ~16 weeks (± 2 weeks)]

    An adverse event (AE) was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product.

11. Percentage of Participants With at Least One Drug Related Adverse Event [Up to ~16 weeks (± 2 weeks)]

    An adverse event (AE) was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product.

12. Percentage of Participants With at Least One Serious Adverse Event [Up to ~16 weeks (± 2 weeks)]

    A serious adverse event (SAE) was an AE that resulted in death, was life threatening, required or prolonged an existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, or was another important medical event deemed such by medical or scientific judgment.

13. Percentage of Participants With at Least One Serious Drug Related Adverse Event [Up to ~16 weeks (± 2 weeks)]

    An SAE was an AE that resulted in death, was life threatening, required or prolonged an existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, or was another important medical event deemed such by medical or scientific judgment.

14. Percentage of Participants Who Discontinued Study Treatment Due to an Adverse Event [Up to ~12 weeks]

    An AE was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product.

15. Steady State Average Concentration (Cavg) of Posaconazole With Food Intake [Baseline, and at pre-dose on Day 7, Week 2, Week 4, Week 6, and Week 12]

    The characterization of the pharmacokinetics (PK) parameters of POS was determined from plasma samples taken at steady-state after receiving oral tablet of POS. Steady-state Cavg, where Cavg is defined as area under the concentration time-curve from 0 to 24 hours (AUC0-24hr) divided by the dosing interval. Data is presented in POS group column only. No evaluation of food intake on the VOR capsule was presented.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 13 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Weight >40 kg (88 lb) and ≤150 kg (330 lb); if between 13 and 14 years of age must weigh >= 50 kg (110 lb)

• Must meet the criteria for proven, probable, or possible IA as per 2008 European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) disease definitions at the time of randomization. Proven IA will include those participants with the demonstration of fungal elements (by cytology, microscopy, or culture) in diseased tissue (sterile sampling). Probable IA includes participants with at least 1 host factor, clinical criteria, as well as mycological criteria including both direct and indirect methods. Possible IA includes participants with at least 1 host factor and clinical criteria but without mycological criteria. A modification to the 2008 EORTC/MSG criteria regarding risk factors has been made to allow for the inclusion of participants with any duration of neutropenia as an acceptable inclusion host factor.

• If with possible IA at time of randomization must be willing or be in process of an ongoing diagnostic work up which is anticipated to result in a mycological diagnosis of proven or probable IA postrandomization.

• Must have a central line (e.g., central venous catheter, peripherally-inserted central catheter, etc.) in place or planned to be in place prior to beginning IV study therapy. If without central catheter access, must be clinically stable and able to receive oral study therapy.

• Acute IA defined as duration of clinical syndrome of <30 days.

• Must be willing to adhere to dosing, study visit schedule, and mandatory procedures as outlined in the protocol. The participant must be willing to continue on study therapy for up to 12 weeks and remain in the study through the 1-month follow-up visit.

• The participant must have the ability to transition to oral study therapy during the course of the study.

• Female participants of child-bearing potential must be using a medically accepted method of birth control before beginning study-drug treatment and agree to continue its use for 30 days after stopping study medication

• Is not taking prohibited antifungal prophylaxis or treatment

Exclusion Criteria:

• Chronic (>1 month duration) IA, relapsed/recurrent IA, or refractory IA which has not responded to antifungal therapy.

• Has pulmonary sarcoidosis, aspergilloma, or allergic bronchopulmonary aspergillosis (ABPA).

• Known mixed invasive mold fungal infection including Zygomycetes, and/or a known invasive Aspergillus fungal infection in which either study drug may not be considered active.

• Receipt of any systemic (oral, intravenous, or inhaled) antifungal therapy for this infection episode for 4 or more consecutive days (>= 96 hours) immediately before randomization.

• Developed the current episode of IA infection during receipt of >13 days of antifungal prophylaxis with an agent considered to be a mold-active antifungal agent.

• Receipt of posaconazole or voriconazole as empirical treatment for this infection for 4 days (96 hours) or more within the 15 days immediately before randomization.

• Has condition that, in the opinion of the investigator, may interfere with optimal participation in the study.

• Known hypersensitivity or other serious adverse reaction to any azole antifungal therapy or to any other ingredient of the study medication used.

• Females who are pregnant, intend to become pregnant, or are nursing at the time of randomization.

• Known history of Torsade de Pointes, unstable cardiac arrhythmia or proarrhythmic conditions, or a history of recent myocardial infarction within 90 days of study entry.

• Has significant liver dysfunction

• Hepatic cirrhosis or a Child-Pugh score of C (severe hepatic impairment) at the time of randomization.

• Severe renal insufficiency (estimated creatinine clearance <20 mL/min) or on hemodialysis at the time of randomization or likely to require dialysis during the study.

• Known hereditary problem of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

• Acute symptomatic pancreatitis within 6 months of study entry or a diagnosis of chronic pancreatitis at the time of randomization.

• Active skin lesion consistent with squamous cell carcinoma at the time of randomization, or a current or prior history of malignant melanoma within 5 years of study entry.

• On artificial ventilation or receiving acute Continuous Positive Airway Pressure (CPAP)/Bilevel Positive Airway Pressure (BPAP) at the time of randomization.

• Known or suspected Gilbert's disease at the time of randomization.

• Requires treatment with other medications that cannot be stopped and for which there is a known contraindication to co-administration of one or more of the study drugs.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 7, 2019

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT01782131
• Other Study ID Numbers: P06200; 2011-003938-14; 5592-069
• First Posted: Feb 1, 2013
• Last Update Posted: Sep 10, 2020
• Last Verified: Aug 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Mycoses; Aspergillosis; Pulmonary Aspergillosis; Invasive Pulmonary Aspergillosis; Voriconazole; Posaconazole

Study Results

Participant Flow

Recruitment Details	After a screening phase of up to 7 days, 585 participants were enrolled/randomized, but only 575 began treatment (288 in the posaconazole [POS] group and 287 in the voriconazole [VOR] group).

Arm/Group Title	Posaconazole	Voriconazole
Arm/Group Description	Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.	Participants received 6 mg/kg voriconazole (VOR) IV twice per day (BID) on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
Period Title: Overall Study
STARTED	293	292
Treated	288	287
COMPLETED	184	177
NOT COMPLETED	109	115

Baseline Characteristics

Arm/Group Title	Posaconazole	Voriconazole	Total
Arm/Group Description	Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.	Participants received 6 mg/kg voriconazole (VOR) IV twice per day (BID) on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.	Total of all reporting groups
Overall Participants	288	287	575
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.5 (16.7)	53.0 (15.9)	53.3 (16.3)
Sex: Female, Male (Count of Participants)
Female	116 40.3%	115 40.1%	231 40.2%
Male	172 59.7%	172 59.9%	344 59.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	48 16.7%	57 19.9%	105 18.3%
Not Hispanic or Latino	220 76.4%	219 76.3%	439 76.3%
Unknown or Not Reported	20 6.9%	11 3.8%	31 5.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	4 1.4%	6 2.1%	10 1.7%
Asian	62 21.5%	60 20.9%	122 21.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 1%	4 1.4%	7 1.2%
White	194 67.4%	192 66.9%	386 67.1%
More than one race	25 8.7%	25 8.7%	50 8.7%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Who Died Through Day 42 in the Intention to Treat Population
Description	The percentage of participants who died with posaconazole (POS) compared to voriconazole (VOR) in the first line treatment of invasive aspergillosis (IA) in the Intention to Treat (ITT) population through Day 42 was assessed.
Time Frame	Up to ~42 days

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who received at least one dose of study treatment.

Arm/Group Title	Posaconazole	Voriconazole
Arm/Group Description	Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.	Participants received 6 mg/kg voriconazole (VOR) IV twice per day (BID) on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
Measure Participants	288	287
Number [Percentage of Participants]	15.3 5.3%	20.6 7.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Posaconazole, Voriconazole
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Based on Miettinen and Nurminen's method stratified by the risk for mortality/poor outcome (high risk, not high risk) and using Cochran-Mantel-Haenszel weighting scheme. The p-Value is based on the one-sided non-inferiority test. Non-inferiority of posaconazole vs. voriconazole is established if the upper limit of the 95% confidence interval is less than 10%.
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Miettinen and Nurminen
	Comments
Method of Estimation	Estimation Parameter	Estimated Difference in Percent
	Estimated Value	-5.3
	Confidence Interval	(2-Sided) 95%; -11.6 to 1.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Participants Who Died Through Day 42 in the Full Analysis Set Population
Description	The percentage of participants who died with POS compared to VOR in the first line treatment of invasive aspergillosis (IA) in the Full Analysis Set (FAS) population through Day 42 was assessed.
Time Frame	Up to ~42 days

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who have been classified as having proven or probable IA (based upon independent adjudication assessment using the modified 2008 European Organization for Research and Treatment of Cancer/Mycoses study group [EORTC/MSG] definitions) and received at least one dose of study drug.

Arm/Group Title	Posaconazole	Voriconazole
Arm/Group Description	Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.	Participants received 6 mg/kg voriconazole (VOR) IV twice per day (BID) on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
Measure Participants	163	171
Number [Percentage of Participants]	19.0 6.6%	18.7 6.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Posaconazole, Voriconazole
	Comments
	Type of Statistical Test	Other
	Comments	Based on Miettinen and Nurminen's method stratified by the risk for mortality/poor outcome (high risk, not high risk) and using Cochran-Mantel-Haenszel weighting scheme.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Estimated Difference in Percent
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -8.2 to 8.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Participants Who Died Through Day 84 in the ITT Population
Description	The percentage of participants who died with POS compared to VOR in the first line treatment of invasive aspergillosis (IA) in the ITT population through Day 84 was assessed.
Time Frame	Up to ~84 days

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who received at least one dose of study treatment.

Arm/Group Title	Posaconazole	Voriconazole
Arm/Group Description	Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.	Participants received 6 mg/kg voriconazole (VOR) IV twice per day (BID) on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
Measure Participants	288	287
Number [Percentage of Participants]	28.1 9.8%	30.7 10.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Posaconazole, Voriconazole
	Comments
	Type of Statistical Test	Other
	Comments	Based on Miettinen and Nurminen's method stratified by the risk for mortality/poor outcome (high risk, not high risk) and using Cochran-Mantel-Haenszel weighting scheme.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Estimated Difference in Percent
	Estimated Value	-2.5
	Confidence Interval	(2-Sided) 95%; -9.9 to 4.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percentage of Participants Who Died Through Day 84 in the FAS Population
Description	The percentage of participants who died with POS compared to VOR in the first line treatment of invasive aspergillosis (IA) in the FAS population through Day 84 was assessed.
Time Frame	Up to ~ 84 days

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who have been classified as having proven or probable IA (based upon independent adjudication assessment using the modified 2008 European Organization for Research and Treatment of Cancer/Mycoses study group [EORTC/MSG] definitions) and received at least one dose of study drug.

Arm/Group Title	Posaconazole	Voriconazole
Arm/Group Description	Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.	Participants received 6 mg/kg voriconazole (VOR) IV twice per day (BID) on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
Measure Participants	163	171
Number [Percentage of Participants]	34.4 11.9%	31.0 10.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Posaconazole, Voriconazole
	Comments
	Type of Statistical Test	Other
	Comments	Based on Miettinen and Nurminen's method stratified by the risk for mortality/poor outcome (high risk, not high risk) and using Cochran-Mantel-Haenszel weighting scheme.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Estimated Difference in Percent
	Estimated Value	3.1
	Confidence Interval	(2-Sided) 95%; -6.9 to 13.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Percentage of Participants Achieving Global Clinical Response at Week 12 in the FAS Population
Description	The global clinical response of POS compared to VOR in the first line treatment of invasive aspergillosis (IA) was assessed. The percentage of participants achieving adjudicated global clinical response (complete or partial) at Week 12 was reported. Complete response was classified as survival with resolution of fungal disease evidence; Partial response was survival and improvement of fungal disease.
Time Frame	Up to 12 weeks (± 4 weeks)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who have been classified as having proven or probable IA (based upon independent adjudication assessment using the modified 2008 European Organization for Research and Treatment of Cancer/Mycoses study group [EORTC/MSG] definitions) and received at least one dose of study drug.

Arm/Group Title	Posaconazole	Voriconazole
Arm/Group Description	Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.	Participants received 6 mg/kg voriconazole (VOR) IV twice per day (BID) on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
Measure Participants	163	171
Number [Percentage of Participants]	42.3 14.7%	46.2 16.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Posaconazole, Voriconazole
	Comments
	Type of Statistical Test	Other
	Comments	Based on Miettinen and Nurminen's method stratified by the risk for mortality/poor outcome (high risk, not high risk) and using Cochran-Mantel-Haenszel weighting scheme.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Estimated Difference in Percent
	Estimated Value	-3.4
	Confidence Interval	(2-Sided) 95%; -13.9 to 7.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Percentage of Participants Achieving Global Clinical Response at Week 6 in the FAS Population
Description	The global clinical response of POS compared to VOR in the first line treatment of invasive aspergillosis (IA) was assessed. The percentage of participants achieving adjudicated global clinical response (complete or partial) at Week 6 was reported. Complete response was classified as survival with resolution of fungal disease evidence; Partial response was survival and improvement of fungal disease.
Time Frame	Up to 6 weeks (± 2 weeks)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who have been classified as having proven or probable IA (based upon independent adjudication assessment using the modified 2008 European Organization for Research and Treatment of Cancer/Mycoses study group [EORTC/MSG] definitions) and received at least one dose of study drug.

Arm/Group Title	Posaconazole	Voriconazole
Arm/Group Description	Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.	Participants received 6 mg/kg voriconazole (VOR) IV twice per day (BID) on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
Measure Participants	163	171
Number [Percentage of Participants]	44.8 15.6%	45.6 15.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Posaconazole, Voriconazole
	Comments
	Type of Statistical Test	Other
	Comments	Based on Miettinen and Nurminen's method stratified by the risk for mortality/poor outcome (high risk, not high risk) and using Cochran-Mantel-Haenszel weighting scheme.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Percent
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -11.2 to 10.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Number of Participants Experiencing Mortality at Day 42, Day 84, and Day 114 in the FAS Population (Kaplan-Meier Time To Death Estimate)
Description	The number of participants experiencing mortality at Day 42, Day 84 and Day 114 in participants with proven or probable IA receiving POS versus VOR were assessed. The Kaplan-Meier estimate reports the number of participants who experienced death (all causes) through Day 114 or ~16 weeks. Participants who did not have any endpoint event until last visit or who were lost to follow-up and had no event were censored at the time of last available information (last study visit). For Day 42 and Day 84, missing or 'unable to determine' responses were considered as failures (dead).
Time Frame	Up to ~16 weeks (± 2 weeks)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who have been classified as having proven or probable IA (based upon independent adjudication assessment using the modified 2008 European Organization for Research and Treatment of Cancer/Mycoses study group [EORTC/MSG] definitions) and received at least one dose of study drug.

Arm/Group Title	Posaconazole	Voriconazole
Arm/Group Description	Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.	Participants received 6 mg/kg voriconazole (VOR) IV twice per day (BID) on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
Measure Participants	163	171
Day 42 (missing responses were included as dead)	31 10.8%	32 11.1%
Day 84 (missing responses were included as dead)	56 19.4%	53 18.5%
Day 114	64 22.2%	56 19.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Posaconazole, Voriconazole
	Comments	Analysis of Time to All-Cause Mortality Through Day 114: Posaconazole vs. Voriconazole
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2767
	Comments	Based on Stratified Log-Rank method stratified by the risk for mortality/poor outcome (high risk, not high risk).
	Method	Kaplan-Meier
	Comments	From product-limit (Kaplan-Meier) method for censored data.
Method of Estimation	Estimation Parameter	Survival Rate in Percent
	Estimated Value	60.7
	Confidence Interval	(2-Sided) 95%; 52.8 to 67.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Number of Participants Who Died Due to Invasive Aspergillosis Through Day 42 in the FAS Population
Description	The number of participants who died due to IA receiving POS versus VOR through Day 42 was assessed.
Time Frame	Up to 42 days

Outcome Measure Data

Analysis Population Description

All randomized participants who died by Day 42 and who have been classified as having proven or probable IA (based upon independent adjudication assessment using the modified 2008 European Organization for Research and Treatment of Cancer/Mycoses study group [EORTC/MSG] definitions), and received at least one dose of study drug.

Arm/Group Title	Posaconazole	Voriconazole
Arm/Group Description	Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.	Participants received 6 mg/kg voriconazole (VOR) IV twice per day (BID) on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
Measure Participants	163	171
Count of Participants [Participants]	16 5.6%	10 3.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Posaconazole, Voriconazole
	Comments
	Type of Statistical Test	Other
	Comments	Based on Miettinen and Nurminen's method.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Percent
	Estimated Value	20.4
	Confidence Interval	(2-Sided) 95%; -4.1 to 42.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Number of Participants Who Died Due to Invasive Aspergillosis Through Day 84 in the FAS Population
Description	The number of participants who died due to IA receiving POS versus VOR in the FAS population through Day 84 was assessed.
Time Frame	Up to 84 days

Outcome Measure Data

Analysis Population Description

All randomized participants who died by Day 84 and who have been classified as having proven or probable IA (based upon independent adjudication assessment using the modified 2008 European Organization for Research and Treatment of Cancer/Mycoses study group [EORTC/MSG] definitions), and received at least one dose of study drug.

Arm/Group Title	Posaconazole	Voriconazole
Arm/Group Description	Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.	Participants received 6 mg/kg voriconazole (VOR) IV twice per day (BID) on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
Measure Participants	163	171
Count of Participants [Participants]	22 7.6%	14 4.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Posaconazole, Voriconazole
	Comments
	Type of Statistical Test	Other
	Comments	Based on Miettinen and Nurminen's method.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Percent
	Estimated Value	11.3
	Confidence Interval	(2-Sided) 95%; -6.9 to 28.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Percentage of Participants With Tier 1 Treatment Emergent Adverse Events
Description	The percentage of participants with Tier 1 treatment-emergent adverse events (TEAEs) was determined. The Tier 1 TEAEs included hepatic safety (elevated aspartate serum transaminase [AST] or alanine serum transaminase [ALT] value ≥3x upper limit of normal (ULN) and an elevated total bilirubin value ≥2x ULN and, at the same time, an alkaline phosphatase value <2 ULN); central nervous system (CNS) and visual disturbances (eye disorders, nervous system disorders, psychiatric disorders), dermatologic reactions, and adrenal insufficiency or temporally associated TEAEs of hypotension.
Time Frame	Up to ~16 weeks (± 2 weeks)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all participants who received at least one dose of study treatment.

Arm/Group Title	Posaconazole	Voriconazole
Arm/Group Description	Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.	Participants received 6 mg/kg voriconazole (VOR) IV twice per day (BID) on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
Measure Participants	288	287
Abnormal Hepatic Laboratory Value	3.8 1.3%	3.5 1.2%
CNS and Visual Disturbances	32.3 11.2%	35.9 12.5%
Dermatologic Reactions	16.3 5.7%	19.2 6.7%
Adrenal Insufficiency or Temporal Hypotension	8.0 2.8%	7.0 2.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Posaconazole, Voriconazole
	Comments	Abnormal Hepatic Laboratory Value
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8305
	Comments
	Method	Miettinen & Nurminen
	Comments
Method of Estimation	Estimation Parameter	Difference in Percent
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -2.9 to 3.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Posaconazole, Voriconazole
	Comments	CNS and Visual Disturbances
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3633
	Comments
	Method	Miettinen & Nurminen
	Comments
Method of Estimation	Estimation Parameter	Difference in Percent
	Estimated Value	-3.6
	Confidence Interval	(2-Sided) 95%; -11.3 to 4.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Posaconazole, Voriconazole
	Comments	Dermatologic Reactions
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3724
	Comments
	Method	Miettinen & Nurminen
	Comments
Method of Estimation	Estimation Parameter	Difference in Percent
	Estimated Value	-2.8
	Confidence Interval	(2-Sided) 95%; -9.1 to 3.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Posaconazole, Voriconazole
	Comments	Adrenal Insufficiency or Temporal Hypotension
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6431
	Comments
	Method	Miettinen & Nurminen
	Comments
Method of Estimation	Estimation Parameter	Difference in Percent
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 95%; -3.4 to 5.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Percentage of Participants With at Least One Adverse Event
Description	An adverse event (AE) was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product.
Time Frame	Up to ~16 weeks (± 2 weeks)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who received at least one dose of study treatment.

Arm/Group Title	Posaconazole	Voriconazole
Arm/Group Description	Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.	Participants received 6 mg/kg voriconazole (VOR) IV twice per day (BID) on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
Measure Participants	288	287
Number [Percentage of Participants]	97.6 33.9%	97.6 34%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Posaconazole, Voriconazole
	Comments
	Type of Statistical Test	Other
	Comments	Based on Miettinen & Nurminen
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Percent
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -2.8 to 2.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Percentage of Participants With at Least One Drug Related Adverse Event
Description	An adverse event (AE) was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product.
Time Frame	Up to ~16 weeks (± 2 weeks)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who received at least one dose of study treatment.

Arm/Group Title	Posaconazole	Voriconazole
Arm/Group Description	Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.	Participants received 6 mg/kg voriconazole (VOR) IV twice per day (BID) on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
Measure Participants	288	287
Number [Percentage of Participants]	29.9 10.4%	40.1 14%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Posaconazole, Voriconazole
	Comments
	Type of Statistical Test	Other
	Comments	Based on Miettinen & Nurminen method.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Percent
	Estimated Value	-10.2
	Confidence Interval	(2-Sided) 95%; -17.9 to -2.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Percentage of Participants With at Least One Serious Adverse Event
Description	A serious adverse event (SAE) was an AE that resulted in death, was life threatening, required or prolonged an existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, or was another important medical event deemed such by medical or scientific judgment.
Time Frame	Up to ~16 weeks (± 2 weeks)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who received at least one dose of study treatment.

Arm/Group Title	Posaconazole	Voriconazole
Arm/Group Description	Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.	Participants received 6 mg/kg voriconazole (VOR) IV twice per day (BID) on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
Measure Participants	288	287
Number [Percentage of Participants]	61.8 21.5%	59.9 20.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Posaconazole, Voriconazole
	Comments
	Type of Statistical Test	Other
	Comments	Based on Miettinen & Nurminen method.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Percent
	Estimated Value	1.9
	Confidence Interval	(2-Sided) 95%; -6.1 to 9.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Percentage of Participants With at Least One Serious Drug Related Adverse Event
Description	An SAE was an AE that resulted in death, was life threatening, required or prolonged an existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, or was another important medical event deemed such by medical or scientific judgment.
Time Frame	Up to ~16 weeks (± 2 weeks)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who received at least one dose of study treatment.

Arm/Group Title	Posaconazole	Voriconazole
Arm/Group Description	Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.	Participants received 6 mg/kg voriconazole (VOR) IV twice per day (BID) on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
Measure Participants	288	287
Number [Percentage of Participants]	5.6 1.9%	7.0 2.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Posaconazole, Voriconazole
	Comments
	Type of Statistical Test	Other
	Comments	Based on Miettinen & Nurminen method.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Percent
	Estimated Value	-1.4
	Confidence Interval	(2-Sided) 95%; -5.6 to 2.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Percentage of Participants Who Discontinued Study Treatment Due to an Adverse Event
Description	An AE was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product.
Time Frame	Up to ~12 weeks

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who received at least one dose of study treatment.

Arm/Group Title	Posaconazole	Voriconazole
Arm/Group Description	Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.	Participants received 6 mg/kg voriconazole (VOR) IV twice per day (BID) on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
Measure Participants	288	287
Number [Percentage of Participants]	32.3 11.2%	35.5 12.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Posaconazole, Voriconazole
	Comments
	Type of Statistical Test	Other
	Comments	Based on Miettinen & Nurminen method.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Percent
	Estimated Value	-3.2
	Confidence Interval	(2-Sided) 95%; -11.0 to 4.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Steady State Average Concentration (Cavg) of Posaconazole With Food Intake
Description	The characterization of the pharmacokinetics (PK) parameters of POS was determined from plasma samples taken at steady-state after receiving oral tablet of POS. Steady-state Cavg, where Cavg is defined as area under the concentration time-curve from 0 to 24 hours (AUC0-24hr) divided by the dosing interval. Data is presented in POS group column only. No evaluation of food intake on the VOR capsule was presented.
Time Frame	Baseline, and at pre-dose on Day 7, Week 2, Week 4, Week 6, and Week 12

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants in the POS group only who received at least one dose of study treatment. Per protocol, the VOR group was not included in the analysis population because the food intake evaluation was limited to the POS group.

Arm/Group Title	Posaconazole
Arm/Group Description	Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
Measure Participants	288
Week 1	1625 (902.9)
Week 2	1992 (1190)
Week 4	1994 (956.3)
Week 6	2005 (1333)
Week 12	2169 (1255)

Adverse Events

Time Frame	Up to ~Week 16 (± 2 weeks)
Adverse Event Reporting Description	The analysis population was defined as all randomized participants who received at least one dose of study treatment. The analysis population for the all-cause mortality included all randomized participants.
Arm/Group Title	Posaconazole		Voriconazole
Arm/Group Description	Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.		Participants received 6 mg/kg voriconazole (VOR) IV twice per day (BID) on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
All Cause Mortality
	Posaconazole		Voriconazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	99/293 (33.8%)		99/292 (33.9%)
Serious Adverse Events
	Posaconazole		Voriconazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	178/288 (61.8%)		172/287 (59.9%)
Blood and lymphatic system disorders
Anaemia	2/288 (0.7%)	2	0/287 (0%)	0
Blood disorder	1/288 (0.3%)	1	0/287 (0%)	0
Bone marrow failure	3/288 (1%)	3	2/287 (0.7%)	3
Febrile neutropenia	24/288 (8.3%)	32	21/287 (7.3%)	26
Leukopenia	0/288 (0%)	0	1/287 (0.3%)	1
Neutropenia	2/288 (0.7%)	2	1/287 (0.3%)	1
Pancytopenia	0/288 (0%)	0	1/287 (0.3%)	1
Thrombocytopenia	1/288 (0.3%)	2	1/287 (0.3%)	1
Thrombotic thrombocytopenic purpura	1/288 (0.3%)	1	1/287 (0.3%)	1
Cardiac disorders
Accessory cardiac pathway	0/288 (0%)	0	1/287 (0.3%)	1
Acute coronary syndrome	1/288 (0.3%)	1	0/287 (0%)	0
Acute left ventricular failure	1/288 (0.3%)	1	0/287 (0%)	0
Angina pectoris	0/288 (0%)	0	1/287 (0.3%)	1
Arrhythmia	0/288 (0%)	0	1/287 (0.3%)	1
Atrial fibrillation	4/288 (1.4%)	4	2/287 (0.7%)	2
Cardiac arrest	1/288 (0.3%)	1	1/287 (0.3%)	1
Cardiac failure	2/288 (0.7%)	2	1/287 (0.3%)	1
Cardiac failure acute	0/288 (0%)	0	1/287 (0.3%)	1
Cardiac failure congestive	1/288 (0.3%)	2	1/287 (0.3%)	1
Left ventricular failure	1/288 (0.3%)	1	0/287 (0%)	0
Myocardial infarction	1/288 (0.3%)	1	0/287 (0%)	0
Ventricular extrasystoles	1/288 (0.3%)	1	0/287 (0%)	0
Ventricular fibrillation	0/288 (0%)	0	1/287 (0.3%)	1
Eye disorders
Vision blurred	0/288 (0%)	0	1/287 (0.3%)	1
Gastrointestinal disorders
Abdominal distension	0/288 (0%)	0	1/287 (0.3%)	1
Abdominal pain	2/288 (0.7%)	2	0/287 (0%)	0
Abdominal pain upper	0/288 (0%)	0	1/287 (0.3%)	1
Colitis	2/288 (0.7%)	2	0/287 (0%)	0
Diarrhoea	1/288 (0.3%)	1	2/287 (0.7%)	3
Duodenitis	1/288 (0.3%)	1	0/287 (0%)	0
Gastric varices haemorrhage	0/288 (0%)	0	1/287 (0.3%)	1
Gastritis	0/288 (0%)	0	1/287 (0.3%)	1
Gastrointestinal disorder	1/288 (0.3%)	1	0/287 (0%)	0
Gastrointestinal haemorrhage	0/288 (0%)	0	3/287 (1%)	3
Gastrointestinal hypomotility	0/288 (0%)	0	1/287 (0.3%)	1
Ileus	1/288 (0.3%)	1	0/287 (0%)	0
Inflammatory bowel disease	1/288 (0.3%)	1	0/287 (0%)	0
Intestinal obstruction	0/288 (0%)	0	1/287 (0.3%)	1
Melaena	1/288 (0.3%)	1	0/287 (0%)	0
Nausea	0/288 (0%)	0	2/287 (0.7%)	2
Neutropenic colitis	2/288 (0.7%)	2	1/287 (0.3%)	1
Oesophageal ulcer	0/288 (0%)	0	1/287 (0.3%)	1
Pancreatitis	0/288 (0%)	0	1/287 (0.3%)	1
Rectal haemorrhage	0/288 (0%)	0	1/287 (0.3%)	1
Small intestinal obstruction	0/288 (0%)	0	1/287 (0.3%)	1
Stomatitis	1/288 (0.3%)	1	0/287 (0%)	0
Upper gastrointestinal haemorrhage	1/288 (0.3%)	1	1/287 (0.3%)	1
Vomiting	0/288 (0%)	0	1/287 (0.3%)	1
General disorders
Asthenia	1/288 (0.3%)	1	1/287 (0.3%)	1
Death	2/288 (0.7%)	2	2/287 (0.7%)	2
General physical health deterioration	1/288 (0.3%)	1	1/287 (0.3%)	1
Hypothermia	0/288 (0%)	0	1/287 (0.3%)	1
Mucosal inflammation	1/288 (0.3%)	1	0/287 (0%)	0
Multiple organ dysfunction syndrome	0/288 (0%)	0	3/287 (1%)	3
Oedema	0/288 (0%)	0	1/287 (0.3%)	1
Pain	0/288 (0%)	0	1/287 (0.3%)	1
Pyrexia	7/288 (2.4%)	9	5/287 (1.7%)	5
Hepatobiliary disorders
Cholangitis	1/288 (0.3%)	1	0/287 (0%)	0
Cholecystitis	1/288 (0.3%)	1	0/287 (0%)	0
Cholecystitis acute	0/288 (0%)	0	2/287 (0.7%)	2
Hepatic cirrhosis	1/288 (0.3%)	1	0/287 (0%)	0
Hepatic function abnormal	3/288 (1%)	3	1/287 (0.3%)	1
Hepatocellular injury	0/288 (0%)	0	1/287 (0.3%)	1
Hepatotoxicity	0/288 (0%)	0	2/287 (0.7%)	2
Hydrocholecystis	1/288 (0.3%)	1	0/287 (0%)	0
Hyperbilirubinaemia	2/288 (0.7%)	2	1/287 (0.3%)	1
Immune system disorders
Acute graft versus host disease	1/288 (0.3%)	1	0/287 (0%)	0
Acute graft versus host disease in skin	0/288 (0%)	0	1/287 (0.3%)	1
Engraftment syndrome	1/288 (0.3%)	1	0/287 (0%)	0
Graft versus host disease in gastrointestinal tract	2/288 (0.7%)	2	2/287 (0.7%)	2
Graft versus host disease in liver	0/288 (0%)	0	1/287 (0.3%)	1
Haemophagocytic lymphohistiocytosis	1/288 (0.3%)	1	0/287 (0%)	0
Immune reconstitution inflammatory syndrome	1/288 (0.3%)	1	0/287 (0%)	0
Kidney transplant rejection	0/288 (0%)	0	1/287 (0.3%)	1
Infections and infestations
Abdominal abscess	0/288 (0%)	0	1/287 (0.3%)	1
Abdominal sepsis	0/288 (0%)	0	1/287 (0.3%)	1
Anal infection	0/288 (0%)	0	1/287 (0.3%)	1
Appendicitis	1/288 (0.3%)	1	0/287 (0%)	0
Aspergillus infection	0/288 (0%)	0	2/287 (0.7%)	2
Atypical pneumonia	1/288 (0.3%)	1	0/287 (0%)	0
Bacteraemia	5/288 (1.7%)	5	3/287 (1%)	3
Bacterial pericarditis	0/288 (0%)	0	1/287 (0.3%)	1
Bacterial sepsis	0/288 (0%)	0	1/287 (0.3%)	1
Brain abscess	0/288 (0%)	0	1/287 (0.3%)	1
Bronchopulmonary aspergillosis	6/288 (2.1%)	6	6/287 (2.1%)	6
Candida sepsis	0/288 (0%)	0	1/287 (0.3%)	1
Cellulitis	1/288 (0.3%)	1	0/287 (0%)	0
Cellulitis pharyngeal	0/288 (0%)	0	1/287 (0.3%)	1
Cerebral aspergillosis	0/288 (0%)	0	1/287 (0.3%)	1
Citrobacter sepsis	1/288 (0.3%)	1	0/287 (0%)	0
Clostridial infection	1/288 (0.3%)	1	0/287 (0%)	0
Clostridium difficile colitis	0/288 (0%)	0	2/287 (0.7%)	2
Clostridium difficile infection	2/288 (0.7%)	2	1/287 (0.3%)	1
Corona virus infection	1/288 (0.3%)	1	0/287 (0%)	0
Cystitis viral	0/288 (0%)	0	1/287 (0.3%)	1
Cytomegalovirus infection	2/288 (0.7%)	2	2/287 (0.7%)	2
Cytomegalovirus viraemia	0/288 (0%)	0	1/287 (0.3%)	1
Device related infection	1/288 (0.3%)	1	0/287 (0%)	0
Device related sepsis	1/288 (0.3%)	1	1/287 (0.3%)	1
Disseminated cytomegaloviral infection	0/288 (0%)	0	1/287 (0.3%)	1
Diverticulitis	1/288 (0.3%)	1	0/287 (0%)	0
Emphysematous cholecystitis	1/288 (0.3%)	1	0/287 (0%)	0
Endocarditis	0/288 (0%)	0	1/287 (0.3%)	1
Endocarditis bacterial	0/288 (0%)	0	1/287 (0.3%)	1
Enteritis infectious	0/288 (0%)	0	1/287 (0.3%)	1
Enterobacter pneumonia	0/288 (0%)	0	2/287 (0.7%)	2
Enterobacter sepsis	1/288 (0.3%)	1	0/287 (0%)	0
Enterococcal bacteraemia	1/288 (0.3%)	1	1/287 (0.3%)	1
Enterococcal sepsis	1/288 (0.3%)	1	0/287 (0%)	0
Escherichia bacteraemia	3/288 (1%)	4	2/287 (0.7%)	2
Escherichia sepsis	0/288 (0%)	0	2/287 (0.7%)	2
Febrile infection	2/288 (0.7%)	2	1/287 (0.3%)	1
Fungal infection	1/288 (0.3%)	1	0/287 (0%)	0
Gastroenteritis norovirus	0/288 (0%)	0	1/287 (0.3%)	1
Hepatosplenic candidiasis	0/288 (0%)	0	1/287 (0.3%)	1
Herpes zoster	0/288 (0%)	0	1/287 (0.3%)	1
Infection	0/288 (0%)	0	1/287 (0.3%)	1
Infectious pleural effusion	1/288 (0.3%)	1	0/287 (0%)	0
Influenza	3/288 (1%)	3	1/287 (0.3%)	1
Intervertebral discitis	1/288 (0.3%)	1	0/287 (0%)	0
Klebsiella bacteraemia	0/288 (0%)	0	3/287 (1%)	3
Klebsiella sepsis	1/288 (0.3%)	1	0/287 (0%)	0
Lower respiratory tract infection bacterial	1/288 (0.3%)	1	0/287 (0%)	0
Lower respiratory tract infection viral	1/288 (0.3%)	1	0/287 (0%)	0
Meningitis	0/288 (0%)	0	1/287 (0.3%)	1
Mucormycosis	0/288 (0%)	0	1/287 (0.3%)	1
Muscle abscess	1/288 (0.3%)	1	0/287 (0%)	0
Neutropenic sepsis	0/288 (0%)	0	1/287 (0.3%)	1
Nocardiosis	0/288 (0%)	0	1/287 (0.3%)	1
Peritonitis	1/288 (0.3%)	1	0/287 (0%)	0
Pneumocystis jirovecii pneumonia	1/288 (0.3%)	1	1/287 (0.3%)	1
Pneumonia	23/288 (8%)	27	12/287 (4.2%)	12
Pneumonia bacterial	1/288 (0.3%)	1	1/287 (0.3%)	1
Pneumonia cytomegaloviral	2/288 (0.7%)	2	1/287 (0.3%)	1
Pneumonia fungal	1/288 (0.3%)	1	2/287 (0.7%)	2
Pneumonia klebsiella	0/288 (0%)	0	2/287 (0.7%)	2
Pneumonia pseudomonal	1/288 (0.3%)	1	1/287 (0.3%)	1
Pneumonia respiratory syncytial viral	0/288 (0%)	0	1/287 (0.3%)	1
Pneumonia viral	0/288 (0%)	0	1/287 (0.3%)	1
Pseudomembranous colitis	2/288 (0.7%)	2	0/287 (0%)	0
Pseudomonal bacteraemia	1/288 (0.3%)	1	1/287 (0.3%)	1
Pseudomonal sepsis	1/288 (0.3%)	1	1/287 (0.3%)	1
Pulmonary mycosis	1/288 (0.3%)	1	1/287 (0.3%)	1
Pulmonary sepsis	0/288 (0%)	0	1/287 (0.3%)	1
Pulmonary tuberculosis	0/288 (0%)	0	1/287 (0.3%)	1
Pyelonephritis	1/288 (0.3%)	1	0/287 (0%)	0
Relapsing fever	1/288 (0.3%)	1	0/287 (0%)	0
Renal graft infection	0/288 (0%)	0	1/287 (0.3%)	1
Respiratory tract infection fungal	0/288 (0%)	0	1/287 (0.3%)	1
Sepsis	10/288 (3.5%)	10	7/287 (2.4%)	7
Sepsis syndrome	1/288 (0.3%)	1	0/287 (0%)	0
Septic shock	16/288 (5.6%)	16	16/287 (5.6%)	16
Sinusitis	1/288 (0.3%)	1	1/287 (0.3%)	1
Sinusitis fungal	0/288 (0%)	0	1/287 (0.3%)	1
Staphylococcal bacteraemia	1/288 (0.3%)	1	0/287 (0%)	0
Staphylococcal sepsis	0/288 (0%)	0	2/287 (0.7%)	2
Subcutaneous abscess	0/288 (0%)	0	1/287 (0.3%)	1
Systemic candida	2/288 (0.7%)	2	1/287 (0.3%)	1
Urinary tract infection	2/288 (0.7%)	2	0/287 (0%)	0
Urinary tract infection enterococcal	0/288 (0%)	0	1/287 (0.3%)	1
Varicella zoster virus infection	1/288 (0.3%)	1	0/287 (0%)	0
Viral upper respiratory tract infection	0/288 (0%)	0	1/287 (0.3%)	1
Injury, poisoning and procedural complications
Concussion	0/288 (0%)	0	1/287 (0.3%)	1
Hip fracture	1/288 (0.3%)	1	0/287 (0%)	0
Procedural pneumothorax	1/288 (0.3%)	1	0/287 (0%)	0
Spinal compression fracture	0/288 (0%)	0	1/287 (0.3%)	1
Subdural haematoma	0/288 (0%)	0	1/287 (0.3%)	1
Thoracic vertebral fracture	0/288 (0%)	0	1/287 (0.3%)	1
Investigations
Alanine aminotransferase increased	3/288 (1%)	3	3/287 (1%)	3
Aspartate aminotransferase increased	2/288 (0.7%)	2	2/287 (0.7%)	2
Blood alkaline phosphatase increased	0/288 (0%)	0	1/287 (0.3%)	1
Blood creatinine increased	1/288 (0.3%)	1	0/287 (0%)	0
Blood lactate dehydrogenase increased	0/288 (0%)	0	1/287 (0.3%)	1
Cytomegalovirus test positive	1/288 (0.3%)	1	0/287 (0%)	0
Gamma-glutamyltransferase increased	2/288 (0.7%)	2	0/287 (0%)	0
Liver function test increased	0/288 (0%)	0	1/287 (0.3%)	1
Neutrophil count decreased	0/288 (0%)	0	1/287 (0.3%)	1
Transaminases increased	0/288 (0%)	0	1/287 (0.3%)	1
Metabolism and nutrition disorders
Cachexia	0/288 (0%)	0	1/287 (0.3%)	1
Dehydration	1/288 (0.3%)	1	0/287 (0%)	0
Diabetes mellitus	1/288 (0.3%)	1	0/287 (0%)	0
Hyperkalaemia	2/288 (0.7%)	2	1/287 (0.3%)	1
Hypokalaemia	4/288 (1.4%)	4	0/287 (0%)	0
Metabolic acidosis	0/288 (0%)	0	1/287 (0.3%)	1
Tumour lysis syndrome	1/288 (0.3%)	1	0/287 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/288 (0.3%)	1	0/287 (0%)	0
Back pain	1/288 (0.3%)	1	0/287 (0%)	0
Muscle twitching	0/288 (0%)	0	1/287 (0.3%)	1
Musculoskeletal pain	0/288 (0%)	0	1/287 (0.3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute lymphocytic leukaemia	3/288 (1%)	3	1/287 (0.3%)	1
Acute lymphocytic leukaemia recurrent	3/288 (1%)	3	3/287 (1%)	3
Acute myeloid leukaemia	7/288 (2.4%)	7	12/287 (4.2%)	12
Acute myeloid leukaemia recurrent	2/288 (0.7%)	2	0/287 (0%)	0
B-cell lymphoma recurrent	0/288 (0%)	0	1/287 (0.3%)	1
B-cell type acute leukaemia	0/288 (0%)	0	1/287 (0.3%)	1
Blast crisis in myelogenous leukaemia	0/288 (0%)	0	1/287 (0.3%)	1
Chronic lymphocytic leukaemia	0/288 (0%)	0	2/287 (0.7%)	2
Diffuse large B-cell lymphoma	1/288 (0.3%)	1	0/287 (0%)	0
Diffuse large B-cell lymphoma refractory	1/288 (0.3%)	1	0/287 (0%)	0
Hepatic cancer	1/288 (0.3%)	1	0/287 (0%)	0
Leukaemia recurrent	1/288 (0.3%)	1	0/287 (0%)	0
Lymphocytic leukaemia	0/288 (0%)	0	1/287 (0.3%)	1
Lymphoma	2/288 (0.7%)	2	0/287 (0%)	0
Malignant neoplasm progression	0/288 (0%)	0	1/287 (0.3%)	1
Myelodysplastic syndrome	1/288 (0.3%)	1	0/287 (0%)	0
Neuroendocrine tumour of the lung	1/288 (0.3%)	1	0/287 (0%)	0
Non-Hodgkin's lymphoma	0/288 (0%)	0	2/287 (0.7%)	2
Plasma cell myeloma	2/288 (0.7%)	2	1/287 (0.3%)	1
Precursor T-lymphoblastic lymphoma/leukaemia refractory	1/288 (0.3%)	1	0/287 (0%)	0
Primary mediastinal large B-cell lymphoma	1/288 (0.3%)	1	0/287 (0%)	0
Prostate cancer	1/288 (0.3%)	1	0/287 (0%)	0
Tumour associated fever	1/288 (0.3%)	1	0/287 (0%)	0
Nervous system disorders
Brain oedema	0/288 (0%)	0	2/287 (0.7%)	2
Cerebral disorder	0/288 (0%)	0	1/287 (0.3%)	1
Cerebral haemorrhage	2/288 (0.7%)	2	2/287 (0.7%)	2
Cerebral infarction	0/288 (0%)	0	1/287 (0.3%)	1
Cerebrovascular accident	0/288 (0%)	0	1/287 (0.3%)	1
Dizziness	1/288 (0.3%)	1	0/287 (0%)	0
Encephalopathy	3/288 (1%)	3	5/287 (1.7%)	5
Haemorrhage intracranial	1/288 (0.3%)	1	1/287 (0.3%)	1
Headache	1/288 (0.3%)	1	1/287 (0.3%)	1
Hypoaesthesia	0/288 (0%)	0	1/287 (0.3%)	1
Paraesthesia	0/288 (0%)	0	1/287 (0.3%)	1
Seizure	1/288 (0.3%)	1	2/287 (0.7%)	2
Status epilepticus	1/288 (0.3%)	1	0/287 (0%)	0
Syncope	2/288 (0.7%)	2	1/287 (0.3%)	1
Transient ischaemic attack	1/288 (0.3%)	1	1/287 (0.3%)	1
Wernicke's encephalopathy	0/288 (0%)	0	1/287 (0.3%)	1
Psychiatric disorders
Bipolar I disorder	0/288 (0%)	0	1/287 (0.3%)	1
Confusional state	2/288 (0.7%)	2	0/287 (0%)	0
Hallucination	2/288 (0.7%)	2	1/287 (0.3%)	1
Mental status changes	0/288 (0%)	0	1/287 (0.3%)	1
Suicide attempt	0/288 (0%)	0	1/287 (0.3%)	1
Renal and urinary disorders
Acute kidney injury	9/288 (3.1%)	9	5/287 (1.7%)	5
Cystitis haemorrhagic	0/288 (0%)	0	1/287 (0.3%)	1
Haematuria	1/288 (0.3%)	1	0/287 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	1/288 (0.3%)	1	0/287 (0%)	0
Acute respiratory distress syndrome	3/288 (1%)	3	2/287 (0.7%)	2
Acute respiratory failure	1/288 (0.3%)	1	3/287 (1%)	3
Aspiration	1/288 (0.3%)	1	0/287 (0%)	0
Chronic obstructive pulmonary disease	1/288 (0.3%)	1	0/287 (0%)	0
Dyspnoea	1/288 (0.3%)	1	0/287 (0%)	0
Epistaxis	2/288 (0.7%)	2	0/287 (0%)	0
Haemoptysis	4/288 (1.4%)	4	0/287 (0%)	0
Hypoxia	3/288 (1%)	3	1/287 (0.3%)	1
Interstitial lung disease	1/288 (0.3%)	1	0/287 (0%)	0
Lung disorder	0/288 (0%)	0	1/287 (0.3%)	1
Lung infiltration	0/288 (0%)	0	1/287 (0.3%)	1
Pneumonia aspiration	2/288 (0.7%)	2	0/287 (0%)	0
Pneumonitis	1/288 (0.3%)	1	0/287 (0%)	0
Pneumothorax	2/288 (0.7%)	2	1/287 (0.3%)	1
Pulmonary alveolar haemorrhage	2/288 (0.7%)	2	1/287 (0.3%)	1
Pulmonary artery thrombosis	1/288 (0.3%)	1	0/287 (0%)	0
Pulmonary cavitation	0/288 (0%)	0	2/287 (0.7%)	2
Pulmonary congestion	1/288 (0.3%)	1	0/287 (0%)	0
Pulmonary embolism	2/288 (0.7%)	2	2/287 (0.7%)	2
Pulmonary haemorrhage	0/288 (0%)	0	3/287 (1%)	3
Pulmonary oedema	1/288 (0.3%)	1	4/287 (1.4%)	4
Respiratory disorder	1/288 (0.3%)	1	0/287 (0%)	0
Respiratory distress	1/288 (0.3%)	1	0/287 (0%)	0
Respiratory failure	10/288 (3.5%)	10	7/287 (2.4%)	8
Skin and subcutaneous tissue disorders
Dermatitis exfoliative generalised	1/288 (0.3%)	1	0/287 (0%)	0
Rash maculo-papular	0/288 (0%)	0	1/287 (0.3%)	1
Toxic skin eruption	0/288 (0%)	0	1/287 (0.3%)	1
Vascular disorders
Aortic aneurysm	1/288 (0.3%)	1	0/287 (0%)	0
Deep vein thrombosis	1/288 (0.3%)	1	1/287 (0.3%)	1
Hypotension	3/288 (1%)	3	0/287 (0%)	0
Shock	1/288 (0.3%)	1	0/287 (0%)	0
Other (Not Including Serious) Adverse Events
	Posaconazole		Voriconazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	232/288 (80.6%)		225/287 (78.4%)
Blood and lymphatic system disorders
Anaemia	23/288 (8%)	41	29/287 (10.1%)	46
Febrile neutropenia	21/288 (7.3%)	24	18/287 (6.3%)	22
Thrombocytopenia	22/288 (7.6%)	28	17/287 (5.9%)	23
Cardiac disorders
Tachycardia	11/288 (3.8%)	14	18/287 (6.3%)	23
Gastrointestinal disorders
Abdominal pain	27/288 (9.4%)	31	24/287 (8.4%)	24
Constipation	32/288 (11.1%)	36	23/287 (8%)	26
Diarrhoea	52/288 (18.1%)	66	50/287 (17.4%)	57
Nausea	65/288 (22.6%)	83	50/287 (17.4%)	63
Vomiting	52/288 (18.1%)	64	38/287 (13.2%)	57
General disorders
Chest pain	18/288 (6.3%)	19	11/287 (3.8%)	11
Chills	15/288 (5.2%)	19	8/287 (2.8%)	8
Fatigue	19/288 (6.6%)	20	7/287 (2.4%)	8
Oedema peripheral	32/288 (11.1%)	35	24/287 (8.4%)	27
Pyrexia	75/288 (26%)	122	69/287 (24%)	127
Infections and infestations
Cytomegalovirus infection	15/288 (5.2%)	17	14/287 (4.9%)	16
Pneumonia	14/288 (4.9%)	14	15/287 (5.2%)	15
Investigations
Alanine aminotransferase increased	39/288 (13.5%)	49	34/287 (11.8%)	46
Aspartate aminotransferase increased	36/288 (12.5%)	46	34/287 (11.8%)	41
Blood alkaline phosphatase increased	21/288 (7.3%)	23	28/287 (9.8%)	33
Blood bilirubin increased	24/288 (8.3%)	38	20/287 (7%)	24
Blood lactate dehydrogenase increased	13/288 (4.5%)	17	17/287 (5.9%)	20
Gamma-glutamyltransferase increased	13/288 (4.5%)	15	15/287 (5.2%)	21
Platelet count decreased	15/288 (5.2%)	21	11/287 (3.8%)	18
Metabolism and nutrition disorders
Decreased appetite	25/288 (8.7%)	25	14/287 (4.9%)	15
Hypocalcaemia	15/288 (5.2%)	25	13/287 (4.5%)	27
Hypokalaemia	78/288 (27.1%)	133	49/287 (17.1%)	72
Hypomagnesaemia	29/288 (10.1%)	48	18/287 (6.3%)	20
Hyponatraemia	12/288 (4.2%)	19	19/287 (6.6%)	26
Hypophosphataemia	22/288 (7.6%)	24	9/287 (3.1%)	11
Musculoskeletal and connective tissue disorders
Arthralgia	17/288 (5.9%)	21	9/287 (3.1%)	10
Pain in extremity	19/288 (6.6%)	20	13/287 (4.5%)	15
Nervous system disorders
Dizziness	21/288 (7.3%)	22	12/287 (4.2%)	12
Headache	34/288 (11.8%)	45	24/287 (8.4%)	29
Psychiatric disorders
Confusional state	8/288 (2.8%)	9	16/287 (5.6%)	16
Insomnia	18/288 (6.3%)	19	16/287 (5.6%)	17
Respiratory, thoracic and mediastinal disorders
Cough	30/288 (10.4%)	32	24/287 (8.4%)	24
Dyspnoea	27/288 (9.4%)	28	24/287 (8.4%)	28
Epistaxis	31/288 (10.8%)	34	17/287 (5.9%)	17
Skin and subcutaneous tissue disorders
Rash	19/288 (6.6%)	22	22/287 (7.7%)	32
Vascular disorders
Hypertension	28/288 (9.7%)	33	23/287 (8%)	25
Hypotension	17/288 (5.9%)	20	19/287 (6.6%)	25

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The investigator agrees to provide to the sponsor 45 days prior to submission for publication or presentation, review copies of abstracts or manuscripts for publication (including, without limitation, slides and texts of oral or other public presentations and texts of any transmission through any electronic media) that report any results of the trial.