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
Enrollment
107
Locations
2
Arms
72.7
Actual Duration (Months)
4.9
Patients Per Site
0.1
Patients Per Site Per Month

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 DiseaseIntervention/TreatmentPhase
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

ArmIntervention/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

    SiteCityStateCountryPostal Code
    1University of AlabamaBirminghamAlabamaUnited States35294-0006
    2University of California at San FranciscoSan FranciscoCaliforniaUnited States94143
    3University of Chicago, Division of Infectious DiseasesChicagoIllinoisUnited States60637
    4Indiana BMTSpringfieldIllinoisUnited States62703
    5Springfield Clinic LLPSpringfieldIllinoisUnited States62703
    6Infectious Disease of IndianaIndianapolisIndianaUnited States46280
    7Brigham & Womens HospitalBostonMassachusettsUnited States02115
    8WorcesterMassachusettsUnited States01655
    9Upstate Infectious Diseases Association LLPAlbanyNew YorkUnited States12208
    10Regional Infection Diseases Infusion Center Inc.LimaOhioUnited States45801
    11University of Texas MD Anderson Cancer CenterHoustonTexasUnited States77030
    12Buenos AiresArgentinaC1039AAO
    13Buenos AiresArgentinaC1157ADP
    14Buenos AiresArgentina
    15Capital FederalArgentinaC1180AAV
    16Capital FederalArgentinaC1405DCS
    17Hospital Italiano de Buenos AiresCiudad AutonomaArgentina1181
    18Instituto Medico Especializado Alexander FlemingCiudad AutonomaArgentina1426
    19PerthAustralia6000
    20Mater Medical CentreSouth BrisbaneAustralia4101
    21WoolloongabbaAustralia4102
    22AZ ST JanBruggeBelgium8000
    23Institut Jules BordetBrusselsBelgium1000
    24ULB Hospital ErasmeBruxellesBelgium1070
    25Universitair Ziekenhuis GentGentBelgium9000
    26Universitaire Ziekenhuizen LeuvenLeuvenBelgium3000
    27Felicio RochoBelo HorizonteBrazil30110-908
    28Santa Casa de Misericordia de Belo HorizonteBelo HorizonteBrazil30150-221
    29Hospital das Clinicas da UFPRCuritibaBrazil80060-150
    30Hospital de Clinicas da FMUSP - Ribeirao PretoRibeirão PretoBrazil14048-900
    31Hospital Universitario Clementino Fraga FilhoRio de JaneiroBrazil21941-913
    32The Ottawa Hospital - General CampusOttawaOntarioCanadaK1H 8L6
    33Hamilton Health Sciences - Henderson SiteHamiltonCanadaL8V 1C3
    34SantiagoChile
    35Hospital Dr. Hernan Henriquez AravenaTemucoChile4780000
    36ValdiviaChile5090000
    373rd Hospital, Peking UniversityBeijingChina100083
    38The 1st Hospital, Jilin UniversityChangchunChina130021
    39The Third Xiangya Hospital of Central South UniversityChangshaChina410013
    40West China Hospital of Sichuan UniversityChengduChina610041
    41The Affiliated Union Hospital of Fujian Medical UniversityFuzhouChina350001
    42The First Affiliated Hospital, Med. School, Zhejiang Uni.HangzhouChina310003
    43The First Affiliated Hospital of Nanjing Medical UniversityNanjingChina310009
    44The 1st Affiliated Hospital of Guangxi Medical UniversityNanningChina530021
    45Huashan Hospital, Insitute of AntibioticsShanghaiChina200040
    46No.6 Renmin Hosp. of Shanghai CityShanghaiChina200233
    47Chang Hai HospitalShanghaiChina200433
    48Wuhan Union HospitalWuhanChina430022
    49Alexandria University HospitalAlexandriaEgypt21131
    50National Cancer InstituteCairoEgypt11796
    51Nasser InstituteCairoEgypt12655
    52DijonFrance21079
    53Hotel DieuNantes Cedex 01France44093
    54CHU de Nantes - Hôpital Hôtel DieuNantes CedexFrance44035
    55Hôpital HautepierreStrasbourgFrance67098
    56Hôpital de brabois adultesVandoeuvre les NancyFrance54511
    57Universitaetsklinikum AachenAachenGermany52074
    58Charité Universitaetsmedizin Berlin- Campus Charité MitteBerlinGermany12200
    59Universitaet KoelnKölnGermany50937
    60Universitaetsklinik LeipzigLeipzigGermany04289
    61LuebeckGermany23538
    62Klinikum SchwabingMuenchenGermany81737
    63Medizinische klinik und Polyklinik IIWürzburgGermany97080
    64BudapestHungary1094
    65Petz Aladar Megyei Oktato KorhazGyörHungary9024
    66Szegedi TudomanyegyetemSzegedHungary6720
    67Apollo HospitalsHyderabadAndh PradIndia500033
    68Sterling HospitalAhmedabadGujaratIndia380052
    69Kasturba Medical College and HospitalMangaloreKarnaIndia575001
    70Shirdi Sai Baba Cancer Hospital K. M. C. HospitalManipalKarnaIndia576104
    71Tata Memorial Hopital, Department of AnesthesiaMumbaiMaharaIndia400012
    72Deenanath Mangeshkar Hospital & Research CentrePuneMaharaIndia411004
    73Sahyadri HospitalPuneMaharaIndia411004
    74NoidaUttar PradIndia201301
    75Rambam Health Care CampusHaifaIsrael31096
    76Hadassah Universtiy Hospital - Ein KeremJerusalemIsrael91200
    77Rabin MCPetah TikvaIsrael49100
    78Chaim Sheba Medical CenterRamat-GanIsrael52621
    79Sourasky MC Ichilov Hospital Tel AvivTel AvivIsrael64239
    80Unità Funzionale di Ematologia; Azienda Ospedaliera Universitaria CareggiFirenzeItaly50134
    81Azienda Ospedaliera Ospedale Niguarda Ca' GrandaMilanoItaly20162
    82Gachon University Gil HospitalIncheonKorea, Republic of405-760
    83SeoulKorea, Republic of120-752
    84Samsung Medical CenterSeoulKorea, Republic of135-710
    85The Catholic University of Korea, St. Mary's HospitalSeoulKorea, Republic of137-701
    86Asan Medical CenterSeoulKorea, Republic of138-736
    87Kuala LumpurMalaysia59100
    88Kuala LumpurMalaysia68000
    89MexicoMexico06726
    90Hospital Universitario Dr Jose Eleuterio GonzalezMonterreyMexico64040
    91NijmegenNetherlands6525
    92Palmerston NorthNew Zealand4442
    93Samodzielny Publiczny Centralny Szpital KlinicznyWarszawaPoland02-097
    94State Institution "Hematology Research Center" RAMSMoscowRussian Federation125167
    95Republican Hospital named after V.A. BaranovPetrozavodskRussian Federation185019
    96Leningrad Regional HospitalSt. PetersburgRussian Federation194291
    97St-Petersburg MA Postgraduate EducationSt. PetersburgRussian Federation194291
    98St. PetersburgRussian Federation197089
    99SalamancaSpain37007
    100ZurichSwitzerland8091
    101Songklanagarind HospitalHat YaiThailand90110
    102Khon KaenThailand40002
    103Maharat Nakhon Ratchasima HospitalMuangThailand30000
    104Srinagarind HospitalMuangThailand40002
    105Maharaj Nakorn Chiang Mai HospitalMuangThailand50200
    106SongklaThailand90110
    107IstanbulTurkey34662

    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 DetailsConsenting 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 DetailParticipants 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 TitleIsavuconazoleVoriconazole
    Arm/Group DescriptionParticipants 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
    STARTED263264
    Received Treatment258258
    COMPLETED118120
    NOT COMPLETED145144

    Baseline Characteristics

    Arm/Group TitleIsavuconazoleVoriconazoleTotal
    Arm/Group DescriptionParticipants 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 Participants258258516
    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
    TitleAll-cause Mortality Through Day 42
    DescriptionAll-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 FrameThrough Day 42

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat population
    Arm/Group TitleIsavuconazoleVoriconazole
    Arm/Group DescriptionParticipants 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 Participants258258
    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 Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterAdjusted Treatment Difference
    Estimated Value-1.0
    Confidence Interval (2-Sided) 95%
    -7.759 to 5.683
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 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
    TitlePercentage of Participants With an Overall Outcome of Success Evaluated by the Data Review Committee (DRC)
    DescriptionThe 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 FrameDay 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 TitleIsavuconazoleVoriconazole
    Arm/Group DescriptionParticipants 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 Participants143129
    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 Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterAdjusted Treatment Difference
    Estimated Value1.6
    Confidence Interval (2-Sided) 95%
    -9.336 to 12.572
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 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 Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterAdjusted Treatment Difference
    Estimated Value-0.5
    Confidence Interval (2-Sided) 95%
    -11.277 to 10.329
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 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 Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterAdjusted Treatment Difference
    Estimated Value8.2
    Confidence Interval (2-Sided) 95%
    -1.993 to 18.379
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 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
    TitleAll-cause Mortality Through Day 84
    DescriptionAll-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 FrameThrough Day 84

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat population
    Arm/Group TitleIsavuconazoleVoriconazole
    Arm/Group DescriptionParticipants 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 Participants258258
    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 Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterAdjusted Treatment Difference
    Estimated Value-1.4
    Confidence Interval (2-Sided) 95%
    -9.150 to 6.340
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 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
    TitlePercentage of Participants With an Overall Outcome of Success Evaluated by Investigator
    DescriptionOverall 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 FrameDay 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 TitleIsavuconazoleVoriconazole
    Arm/Group DescriptionParticipants 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 Participants00
    5. Secondary Outcome
    TitlePercentage of Participants With a Clinical Response Assessed by the DRC
    DescriptionBlinded 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 FrameDay 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 TitleIsavuconazoleVoriconazole
    Arm/Group DescriptionParticipants 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 Participants143129
    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 Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterAdjusted Treatment Difference
    Estimated Value0.4
    Confidence Interval (2-Sided) 95%
    -10.640 to 11.531
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 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 Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterAdjusted Treatment Difference
    Estimated Value-5.8
    Confidence Interval (2-Sided) 95%
    -17.368 to 5.802
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 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 Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterAdjusted Treatment Difference
    Estimated Value0.3
    Confidence Interval (2-Sided) 95%
    -11.116 to 11.758
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 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
    TitlePercentage of Participants With a Mycological Response Assessed by the DRC
    DescriptionBlinded 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 FrameDay 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 TitleIsavuconazoleVoriconazole
    Arm/Group DescriptionParticipants 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 Participants143129
    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 Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterAdjusted Treatment Difference
    Estimated Value3.8
    Confidence Interval (2-Sided) 95%
    -7.429 to 15.087
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 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 Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterAdjusted Treatment Difference
    Estimated Value-0.7
    Confidence Interval (2-Sided) 95%
    -11.917 to 10.586
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 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 Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterAdjusted Treatment Difference
    Estimated Value9.1
    Confidence Interval (2-Sided) 95%
    -1.624 to 19.830
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 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
    TitlePercentage of Participants With a Radiological Response Assessed by the DRC
    DescriptionIndependent 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 FrameDay 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 TitleIsavuconazoleVoriconazole
    Arm/Group DescriptionParticipants 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 Participants143129
    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 Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterAdjusted Treatment Difference
    Estimated Value5.7
    Confidence Interval (2-Sided) 95%
    -4.936 to 16.268
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 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 Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterAdjusted Treatment Difference
    Estimated Value5.3
    Confidence Interval (2-Sided) 95%
    -5.338 to 16.032
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 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 Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterAdjusted Treatment Difference
    Estimated Value9.0
    Confidence Interval (2-Sided) 95%
    -1.231 to 19.186
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 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
    TitlePercentage of Participants With a Clinical Response Assessed by the Investigator
    DescriptionAssessment 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 FrameDay 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 TitleIsavuconazoleVoriconazole
    Arm/Group DescriptionParticipants 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 Participants143129
    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 Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterAdjusted Treatment Difference
    Estimated Value5.0
    Confidence Interval (2-Sided) 95%
    -6.043 to 16.026
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 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 Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterAdjusted treatment Difference
    Estimated Value0.2
    Confidence Interval (2-Sided) 95%
    -10.873 to 11.220
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 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 Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterAdjusted treatment Difference
    Estimated Value4.7
    Confidence Interval (2-Sided) 95%
    -6.533 to 15.939
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 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
    TitlePercentage of Participants With a Mycological Response Assessed by the Investigator
    DescriptionMycological 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 FrameDay 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 TitleIsavuconazoleVoriconazole
    Arm/Group DescriptionParticipants 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 Participants143129
    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 Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterAdjusted Treatment Difference
    Estimated Value4.4
    Confidence Interval (2-Sided) 95%
    -8.429 to 17.218
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 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 Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterAdjusted Treatment Difference
    Estimated Value-2.5
    Confidence Interval (2-Sided) 95%
    -15.071 to 10.073
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 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 Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterAdjusted Treatment Difference
    Estimated Value2.9
    Confidence Interval (2-Sided) 95%
    -8.633 to 14.499
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 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
    TitlePercentage of Participants With a Radiological Response Assessed by the Investigator
    DescriptionRadiological 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 FrameDay 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 TitleIsavuconazoleVoriconazole
    Arm/Group DescriptionParticipants 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 Participants143129
    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 Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterAdjusted Treatment Difference
    Estimated Value6.3
    Confidence Interval (2-Sided) 95%
    -5.145 to 17.696
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 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 Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterAdjusted Treatment Difference
    Estimated Value8.0
    Confidence Interval (2-Sided) 95%
    -3.335 to 19.356
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 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 Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterAdjusted Treatment Difference
    Estimated Value5.1
    Confidence Interval (2-Sided) 95%
    -6.187 to 16.332
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 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
    TitleNumber of Participants With Adverse Events, Reported by System Organ Class
    Description
    Time FrameFrom 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 TitleIsavuconazoleVoriconazole
    Arm/Group DescriptionParticipants 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 Participants257259
    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 FrameFrom 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 TitleIsavuconazoleVoriconazole
    Arm/Group DescriptionParticipants 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
    IsavuconazoleVoriconazole
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total/ (NaN) / (NaN)
    Serious Adverse Events
    IsavuconazoleVoriconazole
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total134/257 (52.1%) 149/259 (57.5%)
    Blood and lymphatic system disorders
    Agranulocytosis2/257 (0.8%) 0/259 (0%)
    Anaemia1/257 (0.4%) 2/259 (0.8%)
    Febrile neutropenia14/257 (5.4%) 5/259 (1.9%)
    Haemorrhagic anaemia0/257 (0%) 1/259 (0.4%)
    Haemorrhagic disorder1/257 (0.4%) 0/259 (0%)
    Leukocytosis1/257 (0.4%) 0/259 (0%)
    Microangiopathic haemolytic anaemia0/257 (0%) 1/259 (0.4%)
    Neutropenia4/257 (1.6%) 3/259 (1.2%)
    Pancytopenia4/257 (1.6%) 3/259 (1.2%)
    Splenic infarction1/257 (0.4%) 0/259 (0%)
    Thrombocytopenia3/257 (1.2%) 4/259 (1.5%)
    Thrombocytopenic purpura0/257 (0%) 1/259 (0.4%)
    Cardiac disorders
    Acute myocardial infarction1/257 (0.4%) 1/259 (0.4%)
    Angina pectoris0/257 (0%) 1/259 (0.4%)
    Arrhythmia1/257 (0.4%) 0/259 (0%)
    Atrial fibrillation1/257 (0.4%) 1/259 (0.4%)
    Cardiac arrest1/257 (0.4%) 5/259 (1.9%)
    Cardio-respiratory arrest2/257 (0.8%) 2/259 (0.8%)
    Cardiogenic shock1/257 (0.4%) 0/259 (0%)
    Congestive cardiomyopathy1/257 (0.4%) 0/259 (0%)
    Pericarditis1/257 (0.4%) 0/259 (0%)
    Sinus bradycardia1/257 (0.4%) 0/259 (0%)
    Supraventricular tachycardia1/257 (0.4%) 0/259 (0%)
    Ventricular tachycardia0/257 (0%) 2/259 (0.8%)
    Eye disorders
    Blindness unilateral1/257 (0.4%) 0/259 (0%)
    Eyelid oedema0/257 (0%) 1/259 (0.4%)
    Optic neuropathy1/257 (0.4%) 0/259 (0%)
    Gastrointestinal disorders
    Abdominal pain1/257 (0.4%) 0/259 (0%)
    Colitis1/257 (0.4%) 0/259 (0%)
    Constipation1/257 (0.4%) 0/259 (0%)
    Diarrhoea2/257 (0.8%) 1/259 (0.4%)
    Food poisoning0/257 (0%) 1/259 (0.4%)
    Gastric perforation1/257 (0.4%) 0/259 (0%)
    Gastrointestinal haemorrhage0/257 (0%) 3/259 (1.2%)
    Gastrointestinal inflammation0/257 (0%) 1/259 (0.4%)
    Ileus paralytic0/257 (0%) 1/259 (0.4%)
    Intestinal haemorrhage1/257 (0.4%) 1/259 (0.4%)
    Nausea1/257 (0.4%) 1/259 (0.4%)
    Oesophageal ulcer1/257 (0.4%) 0/259 (0%)
    Peritonitis1/257 (0.4%) 1/259 (0.4%)
    Proctalgia0/257 (0%) 1/259 (0.4%)
    Rectal haemorrhage0/257 (0%) 1/259 (0.4%)
    Small intestinal obstruction2/257 (0.8%) 0/259 (0%)
    General disorders
    Asthenia1/257 (0.4%) 0/259 (0%)
    Chest pain1/257 (0.4%) 0/259 (0%)
    Chills1/257 (0.4%) 1/259 (0.4%)
    Death1/257 (0.4%) 1/259 (0.4%)
    General physical health deterioration1/257 (0.4%) 0/259 (0%)
    Multi-organ failure1/257 (0.4%) 7/259 (2.7%)
    Pyrexia8/257 (3.1%) 10/259 (3.9%)
    Sudden cardiac death0/257 (0%) 1/259 (0.4%)
    Hepatobiliary disorders
    Cholecystitis1/257 (0.4%) 0/259 (0%)
    Cholecystitis acute0/257 (0%) 1/259 (0.4%)
    Hepatic failure0/257 (0%) 2/259 (0.8%)
    Hepatic function abnormal0/257 (0%) 2/259 (0.8%)
    Hepatitis1/257 (0.4%) 0/259 (0%)
    Hepatitis acute1/257 (0.4%) 0/259 (0%)
    Hyperbilirubinaemia0/257 (0%) 2/259 (0.8%)
    Immune system disorders
    Acute graft versus host disease1/257 (0.4%) 1/259 (0.4%)
    Acute graft versus host disease in intestine1/257 (0.4%) 2/259 (0.8%)
    Acute graft versus host disease in liver0/257 (0%) 1/259 (0.4%)
    Anaphylactic reaction0/257 (0%) 2/259 (0.8%)
    Anaphylactic shock1/257 (0.4%) 0/259 (0%)
    Hypersensitivity1/257 (0.4%) 0/259 (0%)
    Infections and infestations
    Acinetobacter bacteraemia1/257 (0.4%) 0/259 (0%)
    Aspergillosis4/257 (1.6%) 3/259 (1.2%)
    Bacteraemia0/257 (0%) 2/259 (0.8%)
    Bacterial sepsis0/257 (0%) 4/259 (1.5%)
    Bronchitis pneumococcal1/257 (0.4%) 0/259 (0%)
    Bronchopneumonia1/257 (0.4%) 0/259 (0%)
    Bronchopulmonary aspergillosis2/257 (0.8%) 1/259 (0.4%)
    Campylobacter gastroenteritis0/257 (0%) 1/259 (0.4%)
    Catheter related infection0/257 (0%) 1/259 (0.4%)
    Cellulitis1/257 (0.4%) 1/259 (0.4%)
    Cerebral aspergillosis1/257 (0.4%) 0/259 (0%)
    Clostridium bacteraemia0/257 (0%) 2/259 (0.8%)
    Clostridium difficile colitis1/257 (0.4%) 0/259 (0%)
    Cytomegalovirus infection2/257 (0.8%) 2/259 (0.8%)
    Cytomegalovirus viraemia1/257 (0.4%) 0/259 (0%)
    Diarrhoea infectious0/257 (0%) 1/259 (0.4%)
    Empyema0/257 (0%) 1/259 (0.4%)
    Encephalitis herpes1/257 (0.4%) 0/259 (0%)
    Endocarditis1/257 (0.4%) 0/259 (0%)
    Enterococcal bacteraemia1/257 (0.4%) 0/259 (0%)
    Escherichia sepsis1/257 (0.4%) 1/259 (0.4%)
    Fungal infection3/257 (1.2%) 3/259 (1.2%)
    Fusarium infection1/257 (0.4%) 0/259 (0%)
    Gastric ulcer helicobacter0/257 (0%) 1/259 (0.4%)
    Herpes simplex0/257 (0%) 1/259 (0.4%)
    Herpes zoster0/257 (0%) 1/259 (0.4%)
    Infection1/257 (0.4%) 0/259 (0%)
    Infusion site infection1/257 (0.4%) 0/259 (0%)
    Klebsiella bacteraemia1/257 (0.4%) 1/259 (0.4%)
    Klebsiella sepsis1/257 (0.4%) 1/259 (0.4%)
    Lung abscess0/257 (0%) 1/259 (0.4%)
    Meningitis0/257 (0%) 2/259 (0.8%)
    Mucormycosis1/257 (0.4%) 0/259 (0%)
    Muscle abscess1/257 (0.4%) 0/259 (0%)
    Necrotising fasciitis0/257 (0%) 1/259 (0.4%)
    Pneumonia5/257 (1.9%) 10/259 (3.9%)
    Pneumonia bacterial0/257 (0%) 1/259 (0.4%)
    Pneumonia moraxella1/257 (0.4%) 0/259 (0%)
    Pneumonia pneumococcal0/257 (0%) 1/259 (0.4%)
    Pneumonia staphylococcal0/257 (0%) 1/259 (0.4%)
    Pseudomonal bacteraemia0/257 (0%) 1/259 (0.4%)
    Pseudomonal sepsis1/257 (0.4%) 1/259 (0.4%)
    Pseudomonas infection0/257 (0%) 1/259 (0.4%)
    Pyothorax0/257 (0%) 1/259 (0.4%)
    Respiratory tract infection1/257 (0.4%) 0/259 (0%)
    Sepsis7/257 (2.7%) 8/259 (3.1%)
    Sepsis syndrome1/257 (0.4%) 0/259 (0%)
    Septic shock14/257 (5.4%) 10/259 (3.9%)
    Skin infection1/257 (0.4%) 0/259 (0%)
    Staphylococcal bacteraemia0/257 (0%) 3/259 (1.2%)
    Staphylococcal infection1/257 (0.4%) 0/259 (0%)
    Staphylococcal sepsis0/257 (0%) 2/259 (0.8%)
    Stenotrophomonas sepsis0/257 (0%) 1/259 (0.4%)
    Systemic candida0/257 (0%) 1/259 (0.4%)
    Toxoplasmosis0/257 (0%) 1/259 (0.4%)
    Tuberculosis0/257 (0%) 1/259 (0.4%)
    Urinary tract infection1/257 (0.4%) 1/259 (0.4%)
    Urinary tract infection bacterial0/257 (0%) 1/259 (0.4%)
    Injury, poisoning and procedural complications
    Accident at home0/257 (0%) 1/259 (0.4%)
    Drug toxicity2/257 (0.8%) 0/259 (0%)
    Fall1/257 (0.4%) 0/259 (0%)
    Femoral neck fracture0/257 (0%) 1/259 (0.4%)
    Radius fracture0/257 (0%) 1/259 (0.4%)
    Investigations
    Alanine aminotransferase increased0/257 (0%) 1/259 (0.4%)
    Aspartate aminotransferase increased0/257 (0%) 1/259 (0.4%)
    Blood alkaline phosphatase increased0/257 (0%) 1/259 (0.4%)
    Blood bilirubin increased0/257 (0%) 1/259 (0.4%)
    Blood sodium decreased1/257 (0.4%) 0/259 (0%)
    Electrocardiogram QT prolonged0/257 (0%) 1/259 (0.4%)
    Haemoglobin decreased1/257 (0.4%) 0/259 (0%)
    Hepatic enzyme increased0/257 (0%) 1/259 (0.4%)
    Liver function test abnormal1/257 (0.4%) 1/259 (0.4%)
    Metabolism and nutrition disorders
    Dehydration0/257 (0%) 2/259 (0.8%)
    Diabetes mellitus inadequate control1/257 (0.4%) 0/259 (0%)
    Failure to thrive1/257 (0.4%) 0/259 (0%)
    Hypernatraemia0/257 (0%) 1/259 (0.4%)
    Hypoglycaemia0/257 (0%) 1/259 (0.4%)
    Hypokalaemia0/257 (0%) 1/259 (0.4%)
    Hypophagia0/257 (0%) 1/259 (0.4%)
    Metabolic acidosis0/257 (0%) 2/259 (0.8%)
    Musculoskeletal and connective tissue disorders
    Muscle haemorrhage1/257 (0.4%) 0/259 (0%)
    Musculoskeletal chest pain1/257 (0.4%) 0/259 (0%)
    Myositis1/257 (0.4%) 0/259 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute leukaemia0/257 (0%) 1/259 (0.4%)
    Acute lymphocytic leukaemia0/257 (0%) 1/259 (0.4%)
    Acute lymphocytic leukaemia recurrent1/257 (0.4%) 1/259 (0.4%)
    Acute myeloid leukaemia3/257 (1.2%) 8/259 (3.1%)
    Acute myeloid leukaemia recurrent0/257 (0%) 5/259 (1.9%)
    B-cell lymphoma0/257 (0%) 1/259 (0.4%)
    B-cell lymphoma recurrent0/257 (0%) 1/259 (0.4%)
    Blast cell crisis1/257 (0.4%) 1/259 (0.4%)
    Burkitt's leukaemia0/257 (0%) 1/259 (0.4%)
    Chronic lymphocytic leukaemia0/257 (0%) 2/259 (0.8%)
    Chronic lymphocytic leukaemia recurrent1/257 (0.4%) 0/259 (0%)
    Endometrial cancer1/257 (0.4%) 0/259 (0%)
    Epstein-Barr virus associated lymphoproliferative disorder0/257 (0%) 1/259 (0.4%)
    Leukaemia0/257 (0%) 1/259 (0.4%)
    Lung neoplasm malignant0/257 (0%) 1/259 (0.4%)
    Lymphoma2/257 (0.8%) 1/259 (0.4%)
    Malignant neoplasm progression1/257 (0.4%) 1/259 (0.4%)
    Metastases to bone0/257 (0%) 1/259 (0.4%)
    Metastases to meninges1/257 (0.4%) 0/259 (0%)
    Metastatic pain0/257 (0%) 1/259 (0.4%)
    Multiple myeloma2/257 (0.8%) 0/259 (0%)
    Myelodysplastic syndrome1/257 (0.4%) 0/259 (0%)
    Myeloid leukaemia1/257 (0.4%) 1/259 (0.4%)
    Neoplasm progression1/257 (0.4%) 1/259 (0.4%)
    Non-Hodgkin's lymphoma1/257 (0.4%) 0/259 (0%)
    Primary effusion lymphoma1/257 (0.4%) 0/259 (0%)
    Nervous system disorders
    Aphasia0/257 (0%) 1/259 (0.4%)
    Brain stem stroke1/257 (0.4%) 0/259 (0%)
    Central nervous system lesion1/257 (0.4%) 1/259 (0.4%)
    Cerebral haemorrhage0/257 (0%) 1/259 (0.4%)
    Cerebral ischaemia1/257 (0.4%) 0/259 (0%)
    Convulsion3/257 (1.2%) 1/259 (0.4%)
    Dizziness0/257 (0%) 1/259 (0.4%)
    Encephalitis0/257 (0%) 1/259 (0.4%)
    Encephalopathy1/257 (0.4%) 1/259 (0.4%)
    Epilepsy2/257 (0.8%) 1/259 (0.4%)
    Febrile convulsion1/257 (0.4%) 0/259 (0%)
    Grand mal convulsion0/257 (0%) 1/259 (0.4%)
    Haemorrhage intracranial2/257 (0.8%) 3/259 (1.2%)
    Headache1/257 (0.4%) 0/259 (0%)
    Hemiplegia0/257 (0%) 1/259 (0.4%)
    Ischaemic stroke1/257 (0.4%) 1/259 (0.4%)
    Neurotoxicity1/257 (0.4%) 0/259 (0%)
    Paraplegia1/257 (0.4%) 1/259 (0.4%)
    Polyneuropathy2/257 (0.8%) 0/259 (0%)
    Stupor0/257 (0%) 1/259 (0.4%)
    Subarachnoid haemorrhage0/257 (0%) 1/259 (0.4%)
    Tremor0/257 (0%) 1/259 (0.4%)
    VIIth nerve paralysis0/257 (0%) 1/259 (0.4%)
    Psychiatric disorders
    Confusional state0/257 (0%) 1/259 (0.4%)
    Depressed mood0/257 (0%) 1/259 (0.4%)
    Depression1/257 (0.4%) 0/259 (0%)
    Hallucination0/257 (0%) 1/259 (0.4%)
    Hallucination, visual0/257 (0%) 2/259 (0.8%)
    Mental status changes0/257 (0%) 2/259 (0.8%)
    Suicide attempt0/257 (0%) 1/259 (0.4%)
    Renal and urinary disorders
    Haematuria1/257 (0.4%) 0/259 (0%)
    Renal failure3/257 (1.2%) 2/259 (0.8%)
    Renal failure acute6/257 (2.3%) 8/259 (3.1%)
    Respiratory, thoracic and mediastinal disorders
    Acute lung injury0/257 (0%) 1/259 (0.4%)
    Acute respiratory distress syndrome0/257 (0%) 2/259 (0.8%)
    Acute respiratory failure5/257 (1.9%) 5/259 (1.9%)
    Bronchopleural fistula1/257 (0.4%) 0/259 (0%)
    Bronchospasm1/257 (0.4%) 0/259 (0%)
    Chronic obstructive pulmonary disease0/257 (0%) 1/259 (0.4%)
    Cough0/257 (0%) 1/259 (0.4%)
    Dyspnoea5/257 (1.9%) 1/259 (0.4%)
    Epistaxis0/257 (0%) 4/259 (1.5%)
    Haemoptysis2/257 (0.8%) 2/259 (0.8%)
    Haemothorax0/257 (0%) 1/259 (0.4%)
    Hydropneumothorax1/257 (0.4%) 0/259 (0%)
    Hypoxia2/257 (0.8%) 1/259 (0.4%)
    Lung disorder1/257 (0.4%) 1/259 (0.4%)
    Lung infiltration0/257 (0%) 3/259 (1.2%)
    Pleural effusion1/257 (0.4%) 1/259 (0.4%)
    Pleuritic pain1/257 (0.4%) 0/259 (0%)
    Pneumonia aspiration1/257 (0.4%) 0/259 (0%)
    Pneumothorax0/257 (0%) 1/259 (0.4%)
    Productive cough0/257 (0%) 1/259 (0.4%)
    Pulmonary embolism0/257 (0%) 3/259 (1.2%)
    Pulmonary haemorrhage2/257 (0.8%) 1/259 (0.4%)
    Pulmonary hypertension0/257 (0%) 1/259 (0.4%)
    Pulmonary oedema1/257 (0.4%) 1/259 (0.4%)
    Respiratory acidosis1/257 (0.4%) 0/259 (0%)
    Respiratory arrest0/257 (0%) 1/259 (0.4%)
    Respiratory depression1/257 (0.4%) 1/259 (0.4%)
    Respiratory distress4/257 (1.6%) 3/259 (1.2%)
    Respiratory failure14/257 (5.4%) 12/259 (4.6%)
    Tachypnoea1/257 (0.4%) 0/259 (0%)
    Skin and subcutaneous tissue disorders
    Decubitus ulcer1/257 (0.4%) 0/259 (0%)
    Dermatitis1/257 (0.4%) 0/259 (0%)
    Panniculitis1/257 (0.4%) 0/259 (0%)
    Rash0/257 (0%) 2/259 (0.8%)
    Vascular disorders
    Deep vein thrombosis0/257 (0%) 1/259 (0.4%)
    Haemorrhage1/257 (0.4%) 1/259 (0.4%)
    Hypotension1/257 (0.4%) 2/259 (0.8%)
    Hypovolaemic shock1/257 (0.4%) 1/259 (0.4%)
    Shock0/257 (0%) 1/259 (0.4%)
    Vasculitis1/257 (0.4%) 0/259 (0%)
    Other (Not Including Serious) Adverse Events
    IsavuconazoleVoriconazole
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total227/257 (88.3%) 228/259 (88%)
    Blood and lymphatic system disorders
    Anaemia11/257 (4.3%) 22/259 (8.5%)
    Febrile neutropenia19/257 (7.4%) 34/259 (13.1%)
    Thrombocytopenia10/257 (3.9%) 22/259 (8.5%)
    Cardiac disorders
    Tachycardia12/257 (4.7%) 21/259 (8.1%)
    Eye disorders
    Visual impairment4/257 (1.6%) 19/259 (7.3%)
    Gastrointestinal disorders
    Abdominal pain24/257 (9.3%) 36/259 (13.9%)
    Abdominal pain upper15/257 (5.8%) 25/259 (9.7%)
    Constipation35/257 (13.6%) 54/259 (20.8%)
    Diarrhoea59/257 (23%) 59/259 (22.8%)
    Dyspepsia15/257 (5.8%) 13/259 (5%)
    Nausea70/257 (27.2%) 78/259 (30.1%)
    Vomiting64/257 (24.9%) 73/259 (28.2%)
    General disorders
    Asthenia15/257 (5.8%) 20/259 (7.7%)
    Chills27/257 (10.5%) 22/259 (8.5%)
    Fatigue27/257 (10.5%) 18/259 (6.9%)
    Mucosal inflammation23/257 (8.9%) 14/259 (5.4%)
    Oedema13/257 (5.1%) 18/259 (6.9%)
    Oedema peripheral26/257 (10.1%) 31/259 (12%)
    Pyrexia53/257 (20.6%) 72/259 (27.8%)
    Infections and infestations
    Cytomegalovirus infection15/257 (5.8%) 21/259 (8.1%)
    Oral herpes13/257 (5.1%) 14/259 (5.4%)
    Investigations
    Alanine aminotransferase increased13/257 (5.1%) 17/259 (6.6%)
    Aspartate aminotransferase increased11/257 (4.3%) 14/259 (5.4%)
    Blood alkaline phosphatase increased12/257 (4.7%) 14/259 (5.4%)
    Gamma-glutamyltransferase increased16/257 (6.2%) 22/259 (8.5%)
    Metabolism and nutrition disorders
    Decreased appetite22/257 (8.6%) 28/259 (10.8%)
    Hyperglycaemia10/257 (3.9%) 13/259 (5%)
    Hypokalaemia45/257 (17.5%) 55/259 (21.2%)
    Hypomagnesaemia14/257 (5.4%) 27/259 (10.4%)
    Musculoskeletal and connective tissue disorders
    Back pain26/257 (10.1%) 19/259 (7.3%)
    Pain in extremity11/257 (4.3%) 15/259 (5.8%)
    Nervous system disorders
    Dizziness10/257 (3.9%) 14/259 (5.4%)
    Headache40/257 (15.6%) 38/259 (14.7%)
    Psychiatric disorders
    Anxiety20/257 (7.8%) 17/259 (6.6%)
    Confusional state16/257 (6.2%) 19/259 (7.3%)
    Insomnia23/257 (8.9%) 24/259 (9.3%)
    Respiratory, thoracic and mediastinal disorders
    Cough33/257 (12.8%) 34/259 (13.1%)
    Dyspnoea30/257 (11.7%) 28/259 (10.8%)
    Epistaxis21/257 (8.2%) 25/259 (9.7%)
    Haemoptysis14/257 (5.4%) 16/259 (6.2%)
    Oropharyngeal pain14/257 (5.4%) 14/259 (5.4%)
    Rales5/257 (1.9%) 14/259 (5.4%)
    Skin and subcutaneous tissue disorders
    Erythema9/257 (3.5%) 15/259 (5.8%)
    Pruritus19/257 (7.4%) 15/259 (5.8%)
    Rash17/257 (6.6%) 26/259 (10%)
    Vascular disorders
    Hypertension25/257 (9.7%) 31/259 (12%)
    Hypotension20/257 (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.

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    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/TitleMedical Head Immunology, Transplant and Infectious Disease Therapeutic Area
    OrganizationAstellas Pharma Global Development, Inc.
    Phone
    Emailresultsdisclosure@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