Isavuconazole (BAL8557) for Primary Treatment of Invasive Aspergillosis

Sponsor
Astellas Pharma Inc (Industry)
Overall Status
Completed
CT.gov ID
NCT00412893
Collaborator
Basilea Pharmaceutica International Ltd (Industry)
527
107
2
72.7
4.9
0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to compare the efficacy and safety of isavuconazole versus voriconazole in the treatment of patients with invasive aspergillosis.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

Acute invasive fungal infections caused by aspergillus, zygomycetes and other filamentous fungi remain life threatening diseases. Early treatment with highly effective anti-fungals reduces mortality. This study investigates the efficacy and safety of isavuconazole in the treatment of invasive fungal diseases, caused by Aspergillus or other filamentous fungi.

Study Design

Study Type:
Interventional
Actual Enrollment :
527 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Phase III, Double Blind, Randomized Study to Evaluate Safety and Efficacy of BAL8557 Versus Voriconazole for Primary Treatment of Invasive Fungal Disease Caused by Aspergillus Species or Other Filamentous Fungi.
Actual Study Start Date :
Mar 7, 2007
Actual Primary Completion Date :
Mar 28, 2013
Actual Study Completion Date :
Mar 28, 2013

Arms and Interventions

Arm Intervention/Treatment
Experimental: Isavuconazole

Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days.

Drug: Isavuconazole
Loading doses were administered as IV infusion and maintenance doses were administered as IV infusion or oral (capsules).
Other Names:
  • ASP9766
  • BAL8557
  • Active Comparator: Voriconazole

    Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days.

    Drug: Voriconazole
    Loading doses were administered as IV infusion and maintenance doses were administered as IV infusion or oral (capsules).
    Other Names:
  • VFend
  • Outcome Measures

    Primary Outcome Measures

    1. All-cause Mortality Through Day 42 [Through Day 42]

      All-cause mortality is represented as the percentage of participants who died after first dose of study drug through Day 42 from any cause. Participants with unknown survival status through Day 42 were included as deaths in the calculation.

    Secondary Outcome Measures

    1. Percentage of Participants With an Overall Outcome of Success Evaluated by the Data Review Committee (DRC) [Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.]

      The DRC was an independent, blinded committee consisting of experts in the field of infectious disease who assessed patients' outcomes. The overall response was based on the DRC-assessed clinical, mycological and radiological responses. Success was defined as the resolution or partial resolution of all attributable clinical symptoms and physical findings, the eradication or presumed eradication of the original causative organism cultured or identified by histology/cytology at Baseline and a > 50% improvement in radiological response from Baseline (or improvement of at least 25% from Baseline for the Day 42 analysis or End of Treatment if it occurred prior to Day 42). End of treatment (EOT) is the last day of study drug administration. For the Day 42 and Day 84 analyses, any visits that the DRC assessed as Not Done were considered a failure for that visit. A death before Day 42 was also considered a failure, even if the DRC assessed the participant to be a success prior to death.

    2. All-cause Mortality Through Day 84 [Through Day 84]

      All-cause mortality is represented as the percentage of participants who died after first dose of study drug through Day 84 from any cause. Participants with unknown survival status through Day 84 were included as deaths in the calculation.

    3. Percentage of Participants With an Overall Outcome of Success Evaluated by Investigator [Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.]

      Overall response based on investigators' assessments was not derived as it was not deemed necessary because participants overall response status was determined by the DRC. All investigators' assessments of clinical, mycological and radiological responses are analyzed separately (see Outcome Measures 8-10).

    4. Percentage of Participants With a Clinical Response Assessed by the DRC [Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.]

      Blinded assessments of clinical symptoms and physical findings of invasive fungal disease were performed by the independent DRC. Clinical response is defined as the resolution or partial resolution of all attributable clinical symptoms and physical findings. Failure is defined as no resolution of any attributable clinical symptoms and physical findings and/or worsening. Participants with no attributable signs and symptoms present at Baseline and no symptoms attributable to invasive fungal disease (IFD) developed post-baseline were classified as "Not Applicable." End of treatment is the last day of study drug administration.

    5. Percentage of Participants With a Mycological Response Assessed by the DRC [Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.]

      Blinded mycological assessments of the participant's invasive fungal disease status were performed by the independent DRC using the results from fungal culture and isolation and/or histology/cytology of biopsy or biological fluid samples from the infected site. Mycological response is defined as eradication or presumed eradication of the original causative organism cultured or identified by histology/cytology at Baseline. Failure was defined as persistence or presumed persistence. Participants with no mycological evidence available at Baseline were classified as "Not Applicable". End of treatment is the last day of study drug administration.

    6. Percentage of Participants With a Radiological Response Assessed by the DRC [Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.]

      Independent reviews of radiology assessments were completed by radiology experts which were provided to the independent, blinded DRC. Blinded radiological assessments were performed by the DRC. Radiological response is defined as a ≥ 50% improvement from Baseline, or improvement of at least 25% from Baseline for the Day 42 analysis or if end of treatment occurred before Day 42. Participants without any radiology at Baseline were considered "Not Applicable." End of Treatment is the last day of study drug administration.

    7. Percentage of Participants With a Clinical Response Assessed by the Investigator [Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.]

      Assessment of clinical symptoms and physical findings of invasive fungal disease were performed by the investigator. Clinical response is defined as the resolution or partial resolution of all attributable clinical symptoms and physical findings. Failure is defined as no resolution of any attributable clinical symptoms and physical findings and/or worsening, or if results were unavailable or the participant was unevaluable. Participants with no attributable signs and symptoms present at Baseline were classified as "Not Applicable." End of treatment is the last day of study drug administration.

    8. Percentage of Participants With a Mycological Response Assessed by the Investigator [Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.]

      Mycological assessments of the participant's invasive fungal disease status were performed by the investigator using the results from fungal culture and isolation and/or histology/cytology of biopsy or biological fluid samples from the infected site. Mycological response is defined as eradication or presumed eradication of the original causative organism cultured or identified by histology/cytology at Baseline. Failure was defined as persistence or presumed persistence. Participants with no mycological evidence available at Baseline, or no mycological follow-up results available or indeterminate results were classified as "Not Applicable". End of treatment is the last day of study drug administration.

    9. Percentage of Participants With a Radiological Response Assessed by the Investigator [Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.]

      Radiological assessments were performed by the investigator. Radiological response is defined as a ≥ 50% improvement from Baseline, or improvement of at least 25% from Baseline for the Day 42 analysis or if end of treatment occurred before Day 42. Failure is defined as a < 25% improvement at any time or results not available. Participants with no signs on radiological images at Baseline were considered "Not Applicable." End of Treatment is the last day of study drug administration.

    10. Number of Participants With Adverse Events, Reported by System Organ Class [From the first study drug administration until 28 days after the last dose of study drug. The median duration of study drug administration was 45 days.]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Patients must have proven, probable or possible invasive fungal disease caused by Aspergillus species or other filamentous fungi

    • Female patients must be non-lactating and at no risk for pregnancy

    Exclusion Criteria:
    • Patients with invasive fungal infections other than Aspergillus species or other filamentous fungi

    • Evidence of hepatic dysfunction at Baseline or moderate to severe renal dysfunction

    • Patients with chronic aspergillosis, or aspergilloma or allergic bronchopulmonary aspergillosis

    • Patients who have received more than 4 days of systemic antifungal therapy other than fluconazole within the 7 days prior to the first administration of study medication

    • Patients previously enrolled in a Phase III study with isavuconazole

    • Patients with a body weight </= 40 kg

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of Alabama Birmingham Alabama United States 35294-0006
    2 University of California at San Francisco San Francisco California United States 94143
    3 University of Chicago, Division of Infectious Diseases Chicago Illinois United States 60637
    4 Indiana BMT Springfield Illinois United States 62703
    5 Springfield Clinic LLP Springfield Illinois United States 62703
    6 Infectious Disease of Indiana Indianapolis Indiana United States 46280
    7 Brigham & Womens Hospital Boston Massachusetts United States 02115
    8 Worcester Massachusetts United States 01655
    9 Upstate Infectious Diseases Association LLP Albany New York United States 12208
    10 Regional Infection Diseases Infusion Center Inc. Lima Ohio United States 45801
    11 University of Texas MD Anderson Cancer Center Houston Texas United States 77030
    12 Buenos Aires Argentina C1039AAO
    13 Buenos Aires Argentina C1157ADP
    14 Buenos Aires Argentina
    15 Capital Federal Argentina C1180AAV
    16 Capital Federal Argentina C1405DCS
    17 Hospital Italiano de Buenos Aires Ciudad Autonoma Argentina 1181
    18 Instituto Medico Especializado Alexander Fleming Ciudad Autonoma Argentina 1426
    19 Perth Australia 6000
    20 Mater Medical Centre South Brisbane Australia 4101
    21 Woolloongabba Australia 4102
    22 AZ ST Jan Brugge Belgium 8000
    23 Institut Jules Bordet Brussels Belgium 1000
    24 ULB Hospital Erasme Bruxelles Belgium 1070
    25 Universitair Ziekenhuis Gent Gent Belgium 9000
    26 Universitaire Ziekenhuizen Leuven Leuven Belgium 3000
    27 Felicio Rocho Belo Horizonte Brazil 30110-908
    28 Santa Casa de Misericordia de Belo Horizonte Belo Horizonte Brazil 30150-221
    29 Hospital das Clinicas da UFPR Curitiba Brazil 80060-150
    30 Hospital de Clinicas da FMUSP - Ribeirao Preto Ribeirão Preto Brazil 14048-900
    31 Hospital Universitario Clementino Fraga Filho Rio de Janeiro Brazil 21941-913
    32 The Ottawa Hospital - General Campus Ottawa Ontario Canada K1H 8L6
    33 Hamilton Health Sciences - Henderson Site Hamilton Canada L8V 1C3
    34 Santiago Chile
    35 Hospital Dr. Hernan Henriquez Aravena Temuco Chile 4780000
    36 Valdivia Chile 5090000
    37 3rd Hospital, Peking University Beijing China 100083
    38 The 1st Hospital, Jilin University Changchun China 130021
    39 The Third Xiangya Hospital of Central South University Changsha China 410013
    40 West China Hospital of Sichuan University Chengdu China 610041
    41 The Affiliated Union Hospital of Fujian Medical University Fuzhou China 350001
    42 The First Affiliated Hospital, Med. School, Zhejiang Uni. Hangzhou China 310003
    43 The First Affiliated Hospital of Nanjing Medical University Nanjing China 310009
    44 The 1st Affiliated Hospital of Guangxi Medical University Nanning China 530021
    45 Huashan Hospital, Insitute of Antibiotics Shanghai China 200040
    46 No.6 Renmin Hosp. of Shanghai City Shanghai China 200233
    47 Chang Hai Hospital Shanghai China 200433
    48 Wuhan Union Hospital Wuhan China 430022
    49 Alexandria University Hospital Alexandria Egypt 21131
    50 National Cancer Institute Cairo Egypt 11796
    51 Nasser Institute Cairo Egypt 12655
    52 Dijon France 21079
    53 Hotel Dieu Nantes Cedex 01 France 44093
    54 CHU de Nantes - Hôpital Hôtel Dieu Nantes Cedex France 44035
    55 Hôpital Hautepierre Strasbourg France 67098
    56 Hôpital de brabois adultes Vandoeuvre les Nancy France 54511
    57 Universitaetsklinikum Aachen Aachen Germany 52074
    58 Charité Universitaetsmedizin Berlin- Campus Charité Mitte Berlin Germany 12200
    59 Universitaet Koeln Köln Germany 50937
    60 Universitaetsklinik Leipzig Leipzig Germany 04289
    61 Luebeck Germany 23538
    62 Klinikum Schwabing Muenchen Germany 81737
    63 Medizinische klinik und Polyklinik II Würzburg Germany 97080
    64 Budapest Hungary 1094
    65 Petz Aladar Megyei Oktato Korhaz Györ Hungary 9024
    66 Szegedi Tudomanyegyetem Szeged Hungary 6720
    67 Apollo Hospitals Hyderabad Andh Prad India 500033
    68 Sterling Hospital Ahmedabad Gujarat India 380052
    69 Kasturba Medical College and Hospital Mangalore Karna India 575001
    70 Shirdi Sai Baba Cancer Hospital K. M. C. Hospital Manipal Karna India 576104
    71 Tata Memorial Hopital, Department of Anesthesia Mumbai Mahara India 400012
    72 Deenanath Mangeshkar Hospital & Research Centre Pune Mahara India 411004
    73 Sahyadri Hospital Pune Mahara India 411004
    74 Noida Uttar Prad India 201301
    75 Rambam Health Care Campus Haifa Israel 31096
    76 Hadassah Universtiy Hospital - Ein Kerem Jerusalem Israel 91200
    77 Rabin MC Petah Tikva Israel 49100
    78 Chaim Sheba Medical Center Ramat-Gan Israel 52621
    79 Sourasky MC Ichilov Hospital Tel Aviv Tel Aviv Israel 64239
    80 Unità Funzionale di Ematologia; Azienda Ospedaliera Universitaria Careggi Firenze Italy 50134
    81 Azienda Ospedaliera Ospedale Niguarda Ca' Granda Milano Italy 20162
    82 Gachon University Gil Hospital Incheon Korea, Republic of 405-760
    83 Seoul Korea, Republic of 120-752
    84 Samsung Medical Center Seoul Korea, Republic of 135-710
    85 The Catholic University of Korea, St. Mary's Hospital Seoul Korea, Republic of 137-701
    86 Asan Medical Center Seoul Korea, Republic of 138-736
    87 Kuala Lumpur Malaysia 59100
    88 Kuala Lumpur Malaysia 68000
    89 Mexico Mexico 06726
    90 Hospital Universitario Dr Jose Eleuterio Gonzalez Monterrey Mexico 64040
    91 Nijmegen Netherlands 6525
    92 Palmerston North New Zealand 4442
    93 Samodzielny Publiczny Centralny Szpital Kliniczny Warszawa Poland 02-097
    94 State Institution "Hematology Research Center" RAMS Moscow Russian Federation 125167
    95 Republican Hospital named after V.A. Baranov Petrozavodsk Russian Federation 185019
    96 Leningrad Regional Hospital St. Petersburg Russian Federation 194291
    97 St-Petersburg MA Postgraduate Education St. Petersburg Russian Federation 194291
    98 St. Petersburg Russian Federation 197089
    99 Salamanca Spain 37007
    100 Zurich Switzerland 8091
    101 Songklanagarind Hospital Hat Yai Thailand 90110
    102 Khon Kaen Thailand 40002
    103 Maharat Nakhon Ratchasima Hospital Muang Thailand 30000
    104 Srinagarind Hospital Muang Thailand 40002
    105 Maharaj Nakorn Chiang Mai Hospital Muang Thailand 50200
    106 Songkla Thailand 90110
    107 Istanbul Turkey 34662

    Sponsors and Collaborators

    • Astellas Pharma Inc
    • Basilea Pharmaceutica International Ltd

    Investigators

    • Study Director: Medical Director, Astellas Pharma Global Development

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Astellas Pharma Inc
    ClinicalTrials.gov Identifier:
    NCT00412893
    Other Study ID Numbers:
    • 9766-CL-0104
    • WSA-CS-004
    • 2006-003868-59
    First Posted:
    Dec 19, 2006
    Last Update Posted:
    Apr 5, 2019
    Last Verified:
    Mar 1, 2019
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Keywords provided by Astellas Pharma Inc
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details Consenting adult patients with proven, probable or possible invasive fungal disease (IFD) caused by Aspergillus species or other filamentous fungi, meeting the inclusion/exclusion criteria, were enrolled in the study.
    Pre-assignment Detail Participants were stratified by geographic location (North America; Western Europe plus Australia and New Zealand; and Other Regions), whether or not they underwent an allogeneic bone marrow transplant (BMT) and whether or not they had uncontrolled malignancy.
    Arm/Group Title Isavuconazole Voriconazole
    Arm/Group Description Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days.
    Period Title: Overall Study
    STARTED 263 264
    Received Treatment 258 258
    COMPLETED 118 120
    NOT COMPLETED 145 144

    Baseline Characteristics

    Arm/Group Title Isavuconazole Voriconazole Total
    Arm/Group Description Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days. Total of all reporting groups
    Overall Participants 258 258 516
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    51.1
    (16.15)
    51.2
    (15.85)
    51.1
    (15.98)
    Sex: Female, Male (Count of Participants)
    Female
    113
    43.8%
    95
    36.8%
    208
    40.3%
    Male
    145
    56.2%
    163
    63.2%
    308
    59.7%
    Race/Ethnicity, Customized (participants) [Number]
    White
    211
    81.8%
    191
    74%
    402
    77.9%
    Black or African American
    1
    0.4%
    1
    0.4%
    2
    0.4%
    Asian
    45
    17.4%
    64
    24.8%
    109
    21.1%
    Other
    1
    0.4%
    1
    0.4%
    2
    0.4%
    Missing
    0
    0%
    1
    0.4%
    1
    0.2%
    Race/Ethnicity, Customized (participants) [Number]
    Hispanic or Latino
    22
    8.5%
    9
    3.5%
    31
    6%
    Not Hispanic or Latino
    236
    91.5%
    248
    96.1%
    484
    93.8%
    Missing
    0
    0%
    1
    0.4%
    1
    0.2%
    Hematologic Malignancy Status (participants) [Number]
    Yes
    211
    81.8%
    222
    86%
    433
    83.9%
    No
    47
    18.2%
    36
    14%
    83
    16.1%
    Prior Allogeneic Bone Marrow Transplant (BMT) (participants) [Number]
    Yes
    54
    20.9%
    51
    19.8%
    105
    20.3%
    No
    204
    79.1%
    207
    80.2%
    411
    79.7%
    Uncontrolled Malignancy Status (participants) [Number]
    Yes
    173
    67.1%
    187
    72.5%
    360
    69.8%
    No
    85
    32.9%
    71
    27.5%
    156
    30.2%
    Neutropenic Status (participants) [Number]
    Yes
    163
    63.2%
    175
    67.8%
    338
    65.5%
    No
    95
    36.8%
    83
    32.2%
    178
    34.5%

    Outcome Measures

    1. Primary Outcome
    Title All-cause Mortality Through Day 42
    Description All-cause mortality is represented as the percentage of participants who died after first dose of study drug through Day 42 from any cause. Participants with unknown survival status through Day 42 were included as deaths in the calculation.
    Time Frame Through Day 42

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat population
    Arm/Group Title Isavuconazole Voriconazole
    Arm/Group Description Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days.
    Measure Participants 258 258
    Number [percentage of participants]
    18.6
    7.2%
    20.2
    7.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Isavuconazole, Voriconazole
    Comments Approximately 255 patients per group were to be enrolled to ensure at least 80% power to demonstrate that the upper bound of the 95% confidence interval (CI) for a treatment difference in favor of the comparator was no larger than 10%.
    Type of Statistical Test Non-Inferiority or Equivalence
    Comments The upper bound of the 95% CI for the treatment difference was compared to the protocol prespecified non-inferiority margin of 10%. If the upper bound was smaller than 10%, isavuconazole was declared as non-inferior to voriconazole with respect to the primary outcome measure.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted Treatment Difference
    Estimated Value -1.0
    Confidence Interval (2-Sided) 95%
    -7.759 to 5.683
    Parameter Dispersion Type:
    Value:
    Estimation Comments The treatment difference (isavuconazole minus voriconazole) was calculated using a stratified Cochran-Mantel-Haenszel (CMH) method. The strata included Geographical Regions, Allogeneic BMT Status and Uncontrolled Malignancy Status.
    2. Secondary Outcome
    Title Percentage of Participants With an Overall Outcome of Success Evaluated by the Data Review Committee (DRC)
    Description The DRC was an independent, blinded committee consisting of experts in the field of infectious disease who assessed patients' outcomes. The overall response was based on the DRC-assessed clinical, mycological and radiological responses. Success was defined as the resolution or partial resolution of all attributable clinical symptoms and physical findings, the eradication or presumed eradication of the original causative organism cultured or identified by histology/cytology at Baseline and a > 50% improvement in radiological response from Baseline (or improvement of at least 25% from Baseline for the Day 42 analysis or End of Treatment if it occurred prior to Day 42). End of treatment (EOT) is the last day of study drug administration. For the Day 42 and Day 84 analyses, any visits that the DRC assessed as Not Done were considered a failure for that visit. A death before Day 42 was also considered a failure, even if the DRC assessed the participant to be a success prior to death.
    Time Frame Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.

    Outcome Measure Data

    Analysis Population Description
    Modified Intent-to-treat (mITT) population consisted of ITT participants who had proven or probable IFD as determined by the DRC.
    Arm/Group Title Isavuconazole Voriconazole
    Arm/Group Description Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days.
    Measure Participants 143 129
    Day 42
    35.7
    13.8%
    35.7
    13.8%
    Day 84
    25.2
    9.8%
    32.6
    12.6%
    End of Treatment
    35.0
    13.6%
    36.4
    14.1%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Isavuconazole, Voriconazole
    Comments End of Treatment comparison
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted Treatment Difference
    Estimated Value 1.6
    Confidence Interval (2-Sided) 95%
    -9.336 to 12.572
    Parameter Dispersion Type:
    Value:
    Estimation Comments The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Isavuconazole, Voriconazole
    Comments Day 42 comparison
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted Treatment Difference
    Estimated Value -0.5
    Confidence Interval (2-Sided) 95%
    -11.277 to 10.329
    Parameter Dispersion Type:
    Value:
    Estimation Comments The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Isavuconazole, Voriconazole
    Comments Day 84 comparison
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted Treatment Difference
    Estimated Value 8.2
    Confidence Interval (2-Sided) 95%
    -1.993 to 18.379
    Parameter Dispersion Type:
    Value:
    Estimation Comments The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status.
    3. Secondary Outcome
    Title All-cause Mortality Through Day 84
    Description All-cause mortality is represented as the percentage of participants who died after first dose of study drug through Day 84 from any cause. Participants with unknown survival status through Day 84 were included as deaths in the calculation.
    Time Frame Through Day 84

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat population
    Arm/Group Title Isavuconazole Voriconazole
    Arm/Group Description Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days.
    Measure Participants 258 258
    Number [percentage of participants]
    29.1
    11.3%
    31.0
    12%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Isavuconazole, Voriconazole
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted Treatment Difference
    Estimated Value -1.4
    Confidence Interval (2-Sided) 95%
    -9.150 to 6.340
    Parameter Dispersion Type:
    Value:
    Estimation Comments The treatment difference (isavuconazole minus voriconazole) was calculated using a stratified Cochran-Mantel-Haenszel (CMH) method. The strata included Geographical Regions, Allogeneic BMT Status and Uncontrolled Malignancy Status.
    4. Secondary Outcome
    Title Percentage of Participants With an Overall Outcome of Success Evaluated by Investigator
    Description Overall response based on investigators' assessments was not derived as it was not deemed necessary because participants overall response status was determined by the DRC. All investigators' assessments of clinical, mycological and radiological responses are analyzed separately (see Outcome Measures 8-10).
    Time Frame Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Isavuconazole Voriconazole
    Arm/Group Description Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days.
    Measure Participants 0 0
    5. Secondary Outcome
    Title Percentage of Participants With a Clinical Response Assessed by the DRC
    Description Blinded assessments of clinical symptoms and physical findings of invasive fungal disease were performed by the independent DRC. Clinical response is defined as the resolution or partial resolution of all attributable clinical symptoms and physical findings. Failure is defined as no resolution of any attributable clinical symptoms and physical findings and/or worsening. Participants with no attributable signs and symptoms present at Baseline and no symptoms attributable to invasive fungal disease (IFD) developed post-baseline were classified as "Not Applicable." End of treatment is the last day of study drug administration.
    Time Frame Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.

    Outcome Measure Data

    Analysis Population Description
    Modified intent-to-treat population. Any visits the DRC assessed as not done were considered as missing and included as a failure; participants with a Not Applicable assessment were excluded. The number of participants included in the analysis at each time point in indicated by "n".
    Arm/Group Title Isavuconazole Voriconazole
    Arm/Group Description Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days.
    Measure Participants 143 129
    Day 42 (n=139, 120)
    64.0
    24.8%
    57.5
    22.3%
    Day 84 (n=141, 124)
    46.1
    17.9%
    44.4
    17.2%
    End of Treatment (n=137, 121)
    62.0
    24%
    60.3
    23.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Isavuconazole, Voriconazole
    Comments End of Treatment Comparison
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted Treatment Difference
    Estimated Value 0.4
    Confidence Interval (2-Sided) 95%
    -10.640 to 11.531
    Parameter Dispersion Type:
    Value:
    Estimation Comments The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Isavuconazole, Voriconazole
    Comments Day 42 comparison
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted Treatment Difference
    Estimated Value -5.8
    Confidence Interval (2-Sided) 95%
    -17.368 to 5.802
    Parameter Dispersion Type:
    Value:
    Estimation Comments The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Isavuconazole, Voriconazole
    Comments Day 84 comparison
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted Treatment Difference
    Estimated Value 0.3
    Confidence Interval (2-Sided) 95%
    -11.116 to 11.758
    Parameter Dispersion Type:
    Value:
    Estimation Comments The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status.
    6. Secondary Outcome
    Title Percentage of Participants With a Mycological Response Assessed by the DRC
    Description Blinded mycological assessments of the participant's invasive fungal disease status were performed by the independent DRC using the results from fungal culture and isolation and/or histology/cytology of biopsy or biological fluid samples from the infected site. Mycological response is defined as eradication or presumed eradication of the original causative organism cultured or identified by histology/cytology at Baseline. Failure was defined as persistence or presumed persistence. Participants with no mycological evidence available at Baseline were classified as "Not Applicable". End of treatment is the last day of study drug administration.
    Time Frame Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.

    Outcome Measure Data

    Analysis Population Description
    Modified intent-to-treat population. Any visits the DRC assessed as not done were considered as missing and included as a failure; participants with a Not Applicable assessment were excluded.
    Arm/Group Title Isavuconazole Voriconazole
    Arm/Group Description Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days.
    Measure Participants 143 129
    Day 42
    39.9
    15.5%
    39.5
    15.3%
    Day 84
    28.0
    10.9%
    36.4
    14.1%
    End of Treatment
    37.8
    14.7%
    41.1
    15.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Isavuconazole, Voriconazole
    Comments End of Treatment comparison
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted Treatment Difference
    Estimated Value 3.8
    Confidence Interval (2-Sided) 95%
    -7.429 to 15.087
    Parameter Dispersion Type:
    Value:
    Estimation Comments The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Isavuconazole, Voriconazole
    Comments Day 42 Comparison
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted Treatment Difference
    Estimated Value -0.7
    Confidence Interval (2-Sided) 95%
    -11.917 to 10.586
    Parameter Dispersion Type:
    Value:
    Estimation Comments The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Isavuconazole, Voriconazole
    Comments Day 84 Comparison
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted Treatment Difference
    Estimated Value 9.1
    Confidence Interval (2-Sided) 95%
    -1.624 to 19.830
    Parameter Dispersion Type:
    Value:
    Estimation Comments The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status.
    7. Secondary Outcome
    Title Percentage of Participants With a Radiological Response Assessed by the DRC
    Description Independent reviews of radiology assessments were completed by radiology experts which were provided to the independent, blinded DRC. Blinded radiological assessments were performed by the DRC. Radiological response is defined as a ≥ 50% improvement from Baseline, or improvement of at least 25% from Baseline for the Day 42 analysis or if end of treatment occurred before Day 42. Participants without any radiology at Baseline were considered "Not Applicable." End of Treatment is the last day of study drug administration.
    Time Frame Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.

    Outcome Measure Data

    Analysis Population Description
    Modified intent-to-treat population. A participant with no post-baseline radiology data with evidence of radiologic disease at Baseline was considered a failure. Participants with a Not Applicable assessment were excluded. The number of participants included in the analysis at each time point is indicated by "n".
    Arm/Group Title Isavuconazole Voriconazole
    Arm/Group Description Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days.
    Measure Participants 143 129
    Day 42 (n=141, 128)
    28.4
    11%
    34.4
    13.3%
    Day 84 (n=141, 128)
    22.0
    8.5%
    29.7
    11.5%
    End of Treatment (n=141, 127)
    29.1
    11.3%
    33.1
    12.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Isavuconazole, Voriconazole
    Comments End of Treatment comparison
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted Treatment Difference
    Estimated Value 5.7
    Confidence Interval (2-Sided) 95%
    -4.936 to 16.268
    Parameter Dispersion Type:
    Value:
    Estimation Comments The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Isavuconazole, Voriconazole
    Comments Day 42 comparison
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted Treatment Difference
    Estimated Value 5.3
    Confidence Interval (2-Sided) 95%
    -5.338 to 16.032
    Parameter Dispersion Type:
    Value:
    Estimation Comments The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Isavuconazole, Voriconazole
    Comments Day 84 comparison
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted Treatment Difference
    Estimated Value 9.0
    Confidence Interval (2-Sided) 95%
    -1.231 to 19.186
    Parameter Dispersion Type:
    Value:
    Estimation Comments The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status.
    8. Secondary Outcome
    Title Percentage of Participants With a Clinical Response Assessed by the Investigator
    Description Assessment of clinical symptoms and physical findings of invasive fungal disease were performed by the investigator. Clinical response is defined as the resolution or partial resolution of all attributable clinical symptoms and physical findings. Failure is defined as no resolution of any attributable clinical symptoms and physical findings and/or worsening, or if results were unavailable or the participant was unevaluable. Participants with no attributable signs and symptoms present at Baseline were classified as "Not Applicable." End of treatment is the last day of study drug administration.
    Time Frame Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.

    Outcome Measure Data

    Analysis Population Description
    Modified intent-to-treat population. Missing data for any participant at any visit was included as a failure; participants with a Not Applicable assessment were excluded. The number of participants included in the analysis at each time point in indicated by "n".
    Arm/Group Title Isavuconazole Voriconazole
    Arm/Group Description Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days.
    Measure Participants 143 129
    Day 42 (n=137, 120)
    64.2
    24.9%
    61.7
    23.9%
    Day 84 (n=140, 122)
    41.4
    16%
    44.3
    17.2%
    End of Treatment (n=137, 121)
    62.0
    24%
    64.5
    25%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Isavuconazole, Voriconazole
    Comments End of Treatment comparison
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted Treatment Difference
    Estimated Value 5.0
    Confidence Interval (2-Sided) 95%
    -6.043 to 16.026
    Parameter Dispersion Type:
    Value:
    Estimation Comments The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Isavuconazole
    Comments Day 42 comparison
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted treatment Difference
    Estimated Value 0.2
    Confidence Interval (2-Sided) 95%
    -10.873 to 11.220
    Parameter Dispersion Type:
    Value:
    Estimation Comments The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Isavuconazole, Voriconazole
    Comments Day 84 comparison
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted treatment Difference
    Estimated Value 4.7
    Confidence Interval (2-Sided) 95%
    -6.533 to 15.939
    Parameter Dispersion Type:
    Value:
    Estimation Comments The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status.
    9. Secondary Outcome
    Title Percentage of Participants With a Mycological Response Assessed by the Investigator
    Description Mycological assessments of the participant's invasive fungal disease status were performed by the investigator using the results from fungal culture and isolation and/or histology/cytology of biopsy or biological fluid samples from the infected site. Mycological response is defined as eradication or presumed eradication of the original causative organism cultured or identified by histology/cytology at Baseline. Failure was defined as persistence or presumed persistence. Participants with no mycological evidence available at Baseline, or no mycological follow-up results available or indeterminate results were classified as "Not Applicable". End of treatment is the last day of study drug administration.
    Time Frame Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.

    Outcome Measure Data

    Analysis Population Description
    Modified intent-to-treat population. Missing data for any participant at any visit was included as a failure; participants with a Not Applicable assessment were excluded. The number of participants included in the analysis at each time point in indicated by "n".
    Arm/Group Title Isavuconazole Voriconazole
    Arm/Group Description Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days.
    Measure Participants 143 129
    Day 42 (n=109, 100)
    52.3
    20.3%
    50.0
    19.4%
    Day 84 (n=126, 117)
    35.7
    13.8%
    37.6
    14.6%
    End of Treatment (n=107, 100)
    50.5
    19.6%
    55.0
    21.3%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Isavuconazole, Voriconazole
    Comments End of Treatment comparison
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted Treatment Difference
    Estimated Value 4.4
    Confidence Interval (2-Sided) 95%
    -8.429 to 17.218
    Parameter Dispersion Type:
    Value:
    Estimation Comments The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Isavuconazole, Voriconazole
    Comments Day 42 comparison
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted Treatment Difference
    Estimated Value -2.5
    Confidence Interval (2-Sided) 95%
    -15.071 to 10.073
    Parameter Dispersion Type:
    Value:
    Estimation Comments The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Isavuconazole, Voriconazole
    Comments Day 84 comparison
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted Treatment Difference
    Estimated Value 2.9
    Confidence Interval (2-Sided) 95%
    -8.633 to 14.499
    Parameter Dispersion Type:
    Value:
    Estimation Comments The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status.
    10. Secondary Outcome
    Title Percentage of Participants With a Radiological Response Assessed by the Investigator
    Description Radiological assessments were performed by the investigator. Radiological response is defined as a ≥ 50% improvement from Baseline, or improvement of at least 25% from Baseline for the Day 42 analysis or if end of treatment occurred before Day 42. Failure is defined as a < 25% improvement at any time or results not available. Participants with no signs on radiological images at Baseline were considered "Not Applicable." End of Treatment is the last day of study drug administration.
    Time Frame Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.

    Outcome Measure Data

    Analysis Population Description
    Modified intent-to-treat population. Missing data for any participant at any visit was included as a failure. Participants with a Not Applicable assessment were excluded. The number of participants included in the analysis at each time point is indicated by "n".
    Arm/Group Title Isavuconazole Voriconazole
    Arm/Group Description Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days.
    Measure Participants 143 129
    Day 42 (n=142, 128)
    45.1
    17.5%
    51.6
    20%
    Day 84 (n=141, 128)
    38.3
    14.8%
    41.4
    16%
    End of Treatment (n=141, 128)
    43.3
    16.8%
    47.7
    18.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Isavuconazole, Voriconazole
    Comments End of Treatment comparison
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted Treatment Difference
    Estimated Value 6.3
    Confidence Interval (2-Sided) 95%
    -5.145 to 17.696
    Parameter Dispersion Type:
    Value:
    Estimation Comments The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Isavuconazole, Voriconazole
    Comments Day 42 comparison
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted Treatment Difference
    Estimated Value 8.0
    Confidence Interval (2-Sided) 95%
    -3.335 to 19.356
    Parameter Dispersion Type:
    Value:
    Estimation Comments The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Isavuconazole, Voriconazole
    Comments Day 84 comparison
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Adjusted Treatment Difference
    Estimated Value 5.1
    Confidence Interval (2-Sided) 95%
    -6.187 to 16.332
    Parameter Dispersion Type:
    Value:
    Estimation Comments The adjusted treatment difference (Voriconazole-Isavuconazole) was calculated by a stratified CMH method with the strata of Geographical Region, Allogeneic BMT Status and Uncontrolled Malignancy Status.
    11. Secondary Outcome
    Title Number of Participants With Adverse Events, Reported by System Organ Class
    Description
    Time Frame From the first study drug administration until 28 days after the last dose of study drug. The median duration of study drug administration was 45 days.

    Outcome Measure Data

    Analysis Population Description
    The safety analysis set consists of all randomized patients who received at least one dose of study drug according to the study drug that the participant actually received as the first dose. One participant was randomized to isavuconazole but received voriconazole treatment for the first 7 days and is included in the voriconazole arm for safety.
    Arm/Group Title Isavuconazole Voriconazole
    Arm/Group Description Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days.
    Measure Participants 257 259
    Patients with ≥ 1 TEAE
    247
    95.7%
    255
    98.8%
    Gastrointestinal Disorders
    174
    67.4%
    180
    69.8%
    Infections and Infestations
    152
    58.9%
    158
    61.2%
    General Disorders / Administration Site Conditions
    148
    57.4%
    144
    55.8%
    Respiratory, Thoracic and Mediastinal Disorders
    143
    55.4%
    147
    57%
    Metabolism and Nutrition Disorders
    108
    41.9%
    121
    46.9%
    Nervous System Disorders
    95
    36.8%
    89
    34.5%
    Skin and Subcutaneous Tissue Disorders
    86
    33.3%
    110
    42.6%
    Investigations
    85
    32.9%
    96
    37.2%
    Blood and Lymphatic System Disorders
    77
    29.8%
    82
    31.8%
    Psychiatric Disorders
    70
    27.1%
    86
    33.3%
    Musculoskeletal and Connective Tissue Disorders
    69
    26.7%
    77
    29.8%
    Vascular Disorders
    67
    26%
    77
    29.8%
    Renal and Urinary Disorders
    55
    21.3%
    58
    22.5%
    Cardiac Disorders
    43
    16.7%
    57
    22.1%
    Eye Disorders
    39
    15.1%
    69
    26.7%
    Injury, Poisoning and Procedural Complications
    33
    12.8%
    39
    15.1%
    Hepatobiliary Disorders
    23
    8.9%
    42
    16.3%
    Immune System Disorders
    20
    7.8%
    25
    9.7%
    Neoplasms benign, malignant and unspecified
    19
    7.4%
    31
    12%
    Ear and Labyrinth Disorders
    14
    5.4%
    13
    5%
    Reproductive System and Breast Disorders
    8
    3.1%
    13
    5%
    Endocrine Disorders
    5
    1.9%
    3
    1.2%
    Congenital, Familial and Genetic Disorders
    3
    1.2%
    2
    0.8%
    Social Circumstances
    0
    0%
    1
    0.4%

    Adverse Events

    Time Frame From the first study drug administration until 28 days after the last dose of study drug. The median duration of study drug administration was 45 days.
    Adverse Event Reporting Description The safety analysis set consists of all randomized patients who received at least one dose of study drug according to the study drug that the participant actually received as the first dose. One participant was randomized to isavuconazole but received voriconazole treatment for the first 7 days and is included in the voriconazole arm for safety.
    Arm/Group Title Isavuconazole Voriconazole
    Arm/Group Description Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days. Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days.
    All Cause Mortality
    Isavuconazole Voriconazole
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Isavuconazole Voriconazole
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 134/257 (52.1%) 149/259 (57.5%)
    Blood and lymphatic system disorders
    Agranulocytosis 2/257 (0.8%) 0/259 (0%)
    Anaemia 1/257 (0.4%) 2/259 (0.8%)
    Febrile neutropenia 14/257 (5.4%) 5/259 (1.9%)
    Haemorrhagic anaemia 0/257 (0%) 1/259 (0.4%)
    Haemorrhagic disorder 1/257 (0.4%) 0/259 (0%)
    Leukocytosis 1/257 (0.4%) 0/259 (0%)
    Microangiopathic haemolytic anaemia 0/257 (0%) 1/259 (0.4%)
    Neutropenia 4/257 (1.6%) 3/259 (1.2%)
    Pancytopenia 4/257 (1.6%) 3/259 (1.2%)
    Splenic infarction 1/257 (0.4%) 0/259 (0%)
    Thrombocytopenia 3/257 (1.2%) 4/259 (1.5%)
    Thrombocytopenic purpura 0/257 (0%) 1/259 (0.4%)
    Cardiac disorders
    Acute myocardial infarction 1/257 (0.4%) 1/259 (0.4%)
    Angina pectoris 0/257 (0%) 1/259 (0.4%)
    Arrhythmia 1/257 (0.4%) 0/259 (0%)
    Atrial fibrillation 1/257 (0.4%) 1/259 (0.4%)
    Cardiac arrest 1/257 (0.4%) 5/259 (1.9%)
    Cardio-respiratory arrest 2/257 (0.8%) 2/259 (0.8%)
    Cardiogenic shock 1/257 (0.4%) 0/259 (0%)
    Congestive cardiomyopathy 1/257 (0.4%) 0/259 (0%)
    Pericarditis 1/257 (0.4%) 0/259 (0%)
    Sinus bradycardia 1/257 (0.4%) 0/259 (0%)
    Supraventricular tachycardia 1/257 (0.4%) 0/259 (0%)
    Ventricular tachycardia 0/257 (0%) 2/259 (0.8%)
    Eye disorders
    Blindness unilateral 1/257 (0.4%) 0/259 (0%)
    Eyelid oedema 0/257 (0%) 1/259 (0.4%)
    Optic neuropathy 1/257 (0.4%) 0/259 (0%)
    Gastrointestinal disorders
    Abdominal pain 1/257 (0.4%) 0/259 (0%)
    Colitis 1/257 (0.4%) 0/259 (0%)
    Constipation 1/257 (0.4%) 0/259 (0%)
    Diarrhoea 2/257 (0.8%) 1/259 (0.4%)
    Food poisoning 0/257 (0%) 1/259 (0.4%)
    Gastric perforation 1/257 (0.4%) 0/259 (0%)
    Gastrointestinal haemorrhage 0/257 (0%) 3/259 (1.2%)
    Gastrointestinal inflammation 0/257 (0%) 1/259 (0.4%)
    Ileus paralytic 0/257 (0%) 1/259 (0.4%)
    Intestinal haemorrhage 1/257 (0.4%) 1/259 (0.4%)
    Nausea 1/257 (0.4%) 1/259 (0.4%)
    Oesophageal ulcer 1/257 (0.4%) 0/259 (0%)
    Peritonitis 1/257 (0.4%) 1/259 (0.4%)
    Proctalgia 0/257 (0%) 1/259 (0.4%)
    Rectal haemorrhage 0/257 (0%) 1/259 (0.4%)
    Small intestinal obstruction 2/257 (0.8%) 0/259 (0%)
    General disorders
    Asthenia 1/257 (0.4%) 0/259 (0%)
    Chest pain 1/257 (0.4%) 0/259 (0%)
    Chills 1/257 (0.4%) 1/259 (0.4%)
    Death 1/257 (0.4%) 1/259 (0.4%)
    General physical health deterioration 1/257 (0.4%) 0/259 (0%)
    Multi-organ failure 1/257 (0.4%) 7/259 (2.7%)
    Pyrexia 8/257 (3.1%) 10/259 (3.9%)
    Sudden cardiac death 0/257 (0%) 1/259 (0.4%)
    Hepatobiliary disorders
    Cholecystitis 1/257 (0.4%) 0/259 (0%)
    Cholecystitis acute 0/257 (0%) 1/259 (0.4%)
    Hepatic failure 0/257 (0%) 2/259 (0.8%)
    Hepatic function abnormal 0/257 (0%) 2/259 (0.8%)
    Hepatitis 1/257 (0.4%) 0/259 (0%)
    Hepatitis acute 1/257 (0.4%) 0/259 (0%)
    Hyperbilirubinaemia 0/257 (0%) 2/259 (0.8%)
    Immune system disorders
    Acute graft versus host disease 1/257 (0.4%) 1/259 (0.4%)
    Acute graft versus host disease in intestine 1/257 (0.4%) 2/259 (0.8%)
    Acute graft versus host disease in liver 0/257 (0%) 1/259 (0.4%)
    Anaphylactic reaction 0/257 (0%) 2/259 (0.8%)
    Anaphylactic shock 1/257 (0.4%) 0/259 (0%)
    Hypersensitivity 1/257 (0.4%) 0/259 (0%)
    Infections and infestations
    Acinetobacter bacteraemia 1/257 (0.4%) 0/259 (0%)
    Aspergillosis 4/257 (1.6%) 3/259 (1.2%)
    Bacteraemia 0/257 (0%) 2/259 (0.8%)
    Bacterial sepsis 0/257 (0%) 4/259 (1.5%)
    Bronchitis pneumococcal 1/257 (0.4%) 0/259 (0%)
    Bronchopneumonia 1/257 (0.4%) 0/259 (0%)
    Bronchopulmonary aspergillosis 2/257 (0.8%) 1/259 (0.4%)
    Campylobacter gastroenteritis 0/257 (0%) 1/259 (0.4%)
    Catheter related infection 0/257 (0%) 1/259 (0.4%)
    Cellulitis 1/257 (0.4%) 1/259 (0.4%)
    Cerebral aspergillosis 1/257 (0.4%) 0/259 (0%)
    Clostridium bacteraemia 0/257 (0%) 2/259 (0.8%)
    Clostridium difficile colitis 1/257 (0.4%) 0/259 (0%)
    Cytomegalovirus infection 2/257 (0.8%) 2/259 (0.8%)
    Cytomegalovirus viraemia 1/257 (0.4%) 0/259 (0%)
    Diarrhoea infectious 0/257 (0%) 1/259 (0.4%)
    Empyema 0/257 (0%) 1/259 (0.4%)
    Encephalitis herpes 1/257 (0.4%) 0/259 (0%)
    Endocarditis 1/257 (0.4%) 0/259 (0%)
    Enterococcal bacteraemia 1/257 (0.4%) 0/259 (0%)
    Escherichia sepsis 1/257 (0.4%) 1/259 (0.4%)
    Fungal infection 3/257 (1.2%) 3/259 (1.2%)
    Fusarium infection 1/257 (0.4%) 0/259 (0%)
    Gastric ulcer helicobacter 0/257 (0%) 1/259 (0.4%)
    Herpes simplex 0/257 (0%) 1/259 (0.4%)
    Herpes zoster 0/257 (0%) 1/259 (0.4%)
    Infection 1/257 (0.4%) 0/259 (0%)
    Infusion site infection 1/257 (0.4%) 0/259 (0%)
    Klebsiella bacteraemia 1/257 (0.4%) 1/259 (0.4%)
    Klebsiella sepsis 1/257 (0.4%) 1/259 (0.4%)
    Lung abscess 0/257 (0%) 1/259 (0.4%)
    Meningitis 0/257 (0%) 2/259 (0.8%)
    Mucormycosis 1/257 (0.4%) 0/259 (0%)
    Muscle abscess 1/257 (0.4%) 0/259 (0%)
    Necrotising fasciitis 0/257 (0%) 1/259 (0.4%)
    Pneumonia 5/257 (1.9%) 10/259 (3.9%)
    Pneumonia bacterial 0/257 (0%) 1/259 (0.4%)
    Pneumonia moraxella 1/257 (0.4%) 0/259 (0%)
    Pneumonia pneumococcal 0/257 (0%) 1/259 (0.4%)
    Pneumonia staphylococcal 0/257 (0%) 1/259 (0.4%)
    Pseudomonal bacteraemia 0/257 (0%) 1/259 (0.4%)
    Pseudomonal sepsis 1/257 (0.4%) 1/259 (0.4%)
    Pseudomonas infection 0/257 (0%) 1/259 (0.4%)
    Pyothorax 0/257 (0%) 1/259 (0.4%)
    Respiratory tract infection 1/257 (0.4%) 0/259 (0%)
    Sepsis 7/257 (2.7%) 8/259 (3.1%)
    Sepsis syndrome 1/257 (0.4%) 0/259 (0%)
    Septic shock 14/257 (5.4%) 10/259 (3.9%)
    Skin infection 1/257 (0.4%) 0/259 (0%)
    Staphylococcal bacteraemia 0/257 (0%) 3/259 (1.2%)
    Staphylococcal infection 1/257 (0.4%) 0/259 (0%)
    Staphylococcal sepsis 0/257 (0%) 2/259 (0.8%)
    Stenotrophomonas sepsis 0/257 (0%) 1/259 (0.4%)
    Systemic candida 0/257 (0%) 1/259 (0.4%)
    Toxoplasmosis 0/257 (0%) 1/259 (0.4%)
    Tuberculosis 0/257 (0%) 1/259 (0.4%)
    Urinary tract infection 1/257 (0.4%) 1/259 (0.4%)
    Urinary tract infection bacterial 0/257 (0%) 1/259 (0.4%)
    Injury, poisoning and procedural complications
    Accident at home 0/257 (0%) 1/259 (0.4%)
    Drug toxicity 2/257 (0.8%) 0/259 (0%)
    Fall 1/257 (0.4%) 0/259 (0%)
    Femoral neck fracture 0/257 (0%) 1/259 (0.4%)
    Radius fracture 0/257 (0%) 1/259 (0.4%)
    Investigations
    Alanine aminotransferase increased 0/257 (0%) 1/259 (0.4%)
    Aspartate aminotransferase increased 0/257 (0%) 1/259 (0.4%)
    Blood alkaline phosphatase increased 0/257 (0%) 1/259 (0.4%)
    Blood bilirubin increased 0/257 (0%) 1/259 (0.4%)
    Blood sodium decreased 1/257 (0.4%) 0/259 (0%)
    Electrocardiogram QT prolonged 0/257 (0%) 1/259 (0.4%)
    Haemoglobin decreased 1/257 (0.4%) 0/259 (0%)
    Hepatic enzyme increased 0/257 (0%) 1/259 (0.4%)
    Liver function test abnormal 1/257 (0.4%) 1/259 (0.4%)
    Metabolism and nutrition disorders
    Dehydration 0/257 (0%) 2/259 (0.8%)
    Diabetes mellitus inadequate control 1/257 (0.4%) 0/259 (0%)
    Failure to thrive 1/257 (0.4%) 0/259 (0%)
    Hypernatraemia 0/257 (0%) 1/259 (0.4%)
    Hypoglycaemia 0/257 (0%) 1/259 (0.4%)
    Hypokalaemia 0/257 (0%) 1/259 (0.4%)
    Hypophagia 0/257 (0%) 1/259 (0.4%)
    Metabolic acidosis 0/257 (0%) 2/259 (0.8%)
    Musculoskeletal and connective tissue disorders
    Muscle haemorrhage 1/257 (0.4%) 0/259 (0%)
    Musculoskeletal chest pain 1/257 (0.4%) 0/259 (0%)
    Myositis 1/257 (0.4%) 0/259 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute leukaemia 0/257 (0%) 1/259 (0.4%)
    Acute lymphocytic leukaemia 0/257 (0%) 1/259 (0.4%)
    Acute lymphocytic leukaemia recurrent 1/257 (0.4%) 1/259 (0.4%)
    Acute myeloid leukaemia 3/257 (1.2%) 8/259 (3.1%)
    Acute myeloid leukaemia recurrent 0/257 (0%) 5/259 (1.9%)
    B-cell lymphoma 0/257 (0%) 1/259 (0.4%)
    B-cell lymphoma recurrent 0/257 (0%) 1/259 (0.4%)
    Blast cell crisis 1/257 (0.4%) 1/259 (0.4%)
    Burkitt's leukaemia 0/257 (0%) 1/259 (0.4%)
    Chronic lymphocytic leukaemia 0/257 (0%) 2/259 (0.8%)
    Chronic lymphocytic leukaemia recurrent 1/257 (0.4%) 0/259 (0%)
    Endometrial cancer 1/257 (0.4%) 0/259 (0%)
    Epstein-Barr virus associated lymphoproliferative disorder 0/257 (0%) 1/259 (0.4%)
    Leukaemia 0/257 (0%) 1/259 (0.4%)
    Lung neoplasm malignant 0/257 (0%) 1/259 (0.4%)
    Lymphoma 2/257 (0.8%) 1/259 (0.4%)
    Malignant neoplasm progression 1/257 (0.4%) 1/259 (0.4%)
    Metastases to bone 0/257 (0%) 1/259 (0.4%)
    Metastases to meninges 1/257 (0.4%) 0/259 (0%)
    Metastatic pain 0/257 (0%) 1/259 (0.4%)
    Multiple myeloma 2/257 (0.8%) 0/259 (0%)
    Myelodysplastic syndrome 1/257 (0.4%) 0/259 (0%)
    Myeloid leukaemia 1/257 (0.4%) 1/259 (0.4%)
    Neoplasm progression 1/257 (0.4%) 1/259 (0.4%)
    Non-Hodgkin's lymphoma 1/257 (0.4%) 0/259 (0%)
    Primary effusion lymphoma 1/257 (0.4%) 0/259 (0%)
    Nervous system disorders
    Aphasia 0/257 (0%) 1/259 (0.4%)
    Brain stem stroke 1/257 (0.4%) 0/259 (0%)
    Central nervous system lesion 1/257 (0.4%) 1/259 (0.4%)
    Cerebral haemorrhage 0/257 (0%) 1/259 (0.4%)
    Cerebral ischaemia 1/257 (0.4%) 0/259 (0%)
    Convulsion 3/257 (1.2%) 1/259 (0.4%)
    Dizziness 0/257 (0%) 1/259 (0.4%)
    Encephalitis 0/257 (0%) 1/259 (0.4%)
    Encephalopathy 1/257 (0.4%) 1/259 (0.4%)
    Epilepsy 2/257 (0.8%) 1/259 (0.4%)
    Febrile convulsion 1/257 (0.4%) 0/259 (0%)
    Grand mal convulsion 0/257 (0%) 1/259 (0.4%)
    Haemorrhage intracranial 2/257 (0.8%) 3/259 (1.2%)
    Headache 1/257 (0.4%) 0/259 (0%)
    Hemiplegia 0/257 (0%) 1/259 (0.4%)
    Ischaemic stroke 1/257 (0.4%) 1/259 (0.4%)
    Neurotoxicity 1/257 (0.4%) 0/259 (0%)
    Paraplegia 1/257 (0.4%) 1/259 (0.4%)
    Polyneuropathy 2/257 (0.8%) 0/259 (0%)
    Stupor 0/257 (0%) 1/259 (0.4%)
    Subarachnoid haemorrhage 0/257 (0%) 1/259 (0.4%)
    Tremor 0/257 (0%) 1/259 (0.4%)
    VIIth nerve paralysis 0/257 (0%) 1/259 (0.4%)
    Psychiatric disorders
    Confusional state 0/257 (0%) 1/259 (0.4%)
    Depressed mood 0/257 (0%) 1/259 (0.4%)
    Depression 1/257 (0.4%) 0/259 (0%)
    Hallucination 0/257 (0%) 1/259 (0.4%)
    Hallucination, visual 0/257 (0%) 2/259 (0.8%)
    Mental status changes 0/257 (0%) 2/259 (0.8%)
    Suicide attempt 0/257 (0%) 1/259 (0.4%)
    Renal and urinary disorders
    Haematuria 1/257 (0.4%) 0/259 (0%)
    Renal failure 3/257 (1.2%) 2/259 (0.8%)
    Renal failure acute 6/257 (2.3%) 8/259 (3.1%)
    Respiratory, thoracic and mediastinal disorders
    Acute lung injury 0/257 (0%) 1/259 (0.4%)
    Acute respiratory distress syndrome 0/257 (0%) 2/259 (0.8%)
    Acute respiratory failure 5/257 (1.9%) 5/259 (1.9%)
    Bronchopleural fistula 1/257 (0.4%) 0/259 (0%)
    Bronchospasm 1/257 (0.4%) 0/259 (0%)
    Chronic obstructive pulmonary disease 0/257 (0%) 1/259 (0.4%)
    Cough 0/257 (0%) 1/259 (0.4%)
    Dyspnoea 5/257 (1.9%) 1/259 (0.4%)
    Epistaxis 0/257 (0%) 4/259 (1.5%)
    Haemoptysis 2/257 (0.8%) 2/259 (0.8%)
    Haemothorax 0/257 (0%) 1/259 (0.4%)
    Hydropneumothorax 1/257 (0.4%) 0/259 (0%)
    Hypoxia 2/257 (0.8%) 1/259 (0.4%)
    Lung disorder 1/257 (0.4%) 1/259 (0.4%)
    Lung infiltration 0/257 (0%) 3/259 (1.2%)
    Pleural effusion 1/257 (0.4%) 1/259 (0.4%)
    Pleuritic pain 1/257 (0.4%) 0/259 (0%)
    Pneumonia aspiration 1/257 (0.4%) 0/259 (0%)
    Pneumothorax 0/257 (0%) 1/259 (0.4%)
    Productive cough 0/257 (0%) 1/259 (0.4%)
    Pulmonary embolism 0/257 (0%) 3/259 (1.2%)
    Pulmonary haemorrhage 2/257 (0.8%) 1/259 (0.4%)
    Pulmonary hypertension 0/257 (0%) 1/259 (0.4%)
    Pulmonary oedema 1/257 (0.4%) 1/259 (0.4%)
    Respiratory acidosis 1/257 (0.4%) 0/259 (0%)
    Respiratory arrest 0/257 (0%) 1/259 (0.4%)
    Respiratory depression 1/257 (0.4%) 1/259 (0.4%)
    Respiratory distress 4/257 (1.6%) 3/259 (1.2%)
    Respiratory failure 14/257 (5.4%) 12/259 (4.6%)
    Tachypnoea 1/257 (0.4%) 0/259 (0%)
    Skin and subcutaneous tissue disorders
    Decubitus ulcer 1/257 (0.4%) 0/259 (0%)
    Dermatitis 1/257 (0.4%) 0/259 (0%)
    Panniculitis 1/257 (0.4%) 0/259 (0%)
    Rash 0/257 (0%) 2/259 (0.8%)
    Vascular disorders
    Deep vein thrombosis 0/257 (0%) 1/259 (0.4%)
    Haemorrhage 1/257 (0.4%) 1/259 (0.4%)
    Hypotension 1/257 (0.4%) 2/259 (0.8%)
    Hypovolaemic shock 1/257 (0.4%) 1/259 (0.4%)
    Shock 0/257 (0%) 1/259 (0.4%)
    Vasculitis 1/257 (0.4%) 0/259 (0%)
    Other (Not Including Serious) Adverse Events
    Isavuconazole Voriconazole
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 227/257 (88.3%) 228/259 (88%)
    Blood and lymphatic system disorders
    Anaemia 11/257 (4.3%) 22/259 (8.5%)
    Febrile neutropenia 19/257 (7.4%) 34/259 (13.1%)
    Thrombocytopenia 10/257 (3.9%) 22/259 (8.5%)
    Cardiac disorders
    Tachycardia 12/257 (4.7%) 21/259 (8.1%)
    Eye disorders
    Visual impairment 4/257 (1.6%) 19/259 (7.3%)
    Gastrointestinal disorders
    Abdominal pain 24/257 (9.3%) 36/259 (13.9%)
    Abdominal pain upper 15/257 (5.8%) 25/259 (9.7%)
    Constipation 35/257 (13.6%) 54/259 (20.8%)
    Diarrhoea 59/257 (23%) 59/259 (22.8%)
    Dyspepsia 15/257 (5.8%) 13/259 (5%)
    Nausea 70/257 (27.2%) 78/259 (30.1%)
    Vomiting 64/257 (24.9%) 73/259 (28.2%)
    General disorders
    Asthenia 15/257 (5.8%) 20/259 (7.7%)
    Chills 27/257 (10.5%) 22/259 (8.5%)
    Fatigue 27/257 (10.5%) 18/259 (6.9%)
    Mucosal inflammation 23/257 (8.9%) 14/259 (5.4%)
    Oedema 13/257 (5.1%) 18/259 (6.9%)
    Oedema peripheral 26/257 (10.1%) 31/259 (12%)
    Pyrexia 53/257 (20.6%) 72/259 (27.8%)
    Infections and infestations
    Cytomegalovirus infection 15/257 (5.8%) 21/259 (8.1%)
    Oral herpes 13/257 (5.1%) 14/259 (5.4%)
    Investigations
    Alanine aminotransferase increased 13/257 (5.1%) 17/259 (6.6%)
    Aspartate aminotransferase increased 11/257 (4.3%) 14/259 (5.4%)
    Blood alkaline phosphatase increased 12/257 (4.7%) 14/259 (5.4%)
    Gamma-glutamyltransferase increased 16/257 (6.2%) 22/259 (8.5%)
    Metabolism and nutrition disorders
    Decreased appetite 22/257 (8.6%) 28/259 (10.8%)
    Hyperglycaemia 10/257 (3.9%) 13/259 (5%)
    Hypokalaemia 45/257 (17.5%) 55/259 (21.2%)
    Hypomagnesaemia 14/257 (5.4%) 27/259 (10.4%)
    Musculoskeletal and connective tissue disorders
    Back pain 26/257 (10.1%) 19/259 (7.3%)
    Pain in extremity 11/257 (4.3%) 15/259 (5.8%)
    Nervous system disorders
    Dizziness 10/257 (3.9%) 14/259 (5.4%)
    Headache 40/257 (15.6%) 38/259 (14.7%)
    Psychiatric disorders
    Anxiety 20/257 (7.8%) 17/259 (6.6%)
    Confusional state 16/257 (6.2%) 19/259 (7.3%)
    Insomnia 23/257 (8.9%) 24/259 (9.3%)
    Respiratory, thoracic and mediastinal disorders
    Cough 33/257 (12.8%) 34/259 (13.1%)
    Dyspnoea 30/257 (11.7%) 28/259 (10.8%)
    Epistaxis 21/257 (8.2%) 25/259 (9.7%)
    Haemoptysis 14/257 (5.4%) 16/259 (6.2%)
    Oropharyngeal pain 14/257 (5.4%) 14/259 (5.4%)
    Rales 5/257 (1.9%) 14/259 (5.4%)
    Skin and subcutaneous tissue disorders
    Erythema 9/257 (3.5%) 15/259 (5.8%)
    Pruritus 19/257 (7.4%) 15/259 (5.8%)
    Rash 17/257 (6.6%) 26/259 (10%)
    Vascular disorders
    Hypertension 25/257 (9.7%) 31/259 (12%)
    Hypotension 20/257 (7.8%) 26/259 (10%)

    Limitations/Caveats

    Company makes no warranties or representations of any kind as to the posting, expressed or implied, including warranties of merchantability and fitness for a particular purpose, and shall not be liable for any damages.

    More Information

    Certain Agreements

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

    Institute and/or Principal Investigator may publish trial data generated at their specific study site after Sponsor publication of the multi-center data. Sponsor must receive a site's manuscript at least 30 days prior to publication for review and comment. Sponsor may delay the publication for up to 60 days to seek patent protection.

    Results Point of Contact

    Name/Title Medical Head Immunology, Transplant and Infectious Disease Therapeutic Area
    Organization Astellas Pharma Global Development, Inc.
    Phone
    Email resultsdisclosure@astellas.com
    Responsible Party:
    Astellas Pharma Inc
    ClinicalTrials.gov Identifier:
    NCT00412893
    Other Study ID Numbers:
    • 9766-CL-0104
    • WSA-CS-004
    • 2006-003868-59
    First Posted:
    Dec 19, 2006
    Last Update Posted:
    Apr 5, 2019
    Last Verified:
    Mar 1, 2019