Candidemia, Candidiasis, Invasive, Mycoses
Conditions
Keywords
Invasive Candida infections, BAL8557, ASP9766, Isavuconazole, Candidemia, Candidemia and other invasive candida infections, Phase III study
Brief summary
The purpose of the study is to compare the safety and efficacy of isavuconazole versus caspofungin followed by voriconazole in the treatment of candidemia and other invasive Candida infections.
Detailed description
Candida infections, representing approximately 80% of all major systemic fungal infections, are the fourth most common cause of nosocomial bloodstream infections, with a mortality rate of 40%. Isavuconazole is not yet approved for the treatment of fungal infections. This study investigates the efficacy and safety of intravenous and oral isavuconazole. Patients are randomized to isavuconazole and the reference regimen. Patients with a positive blood- or deep tissue culture of candida fungi can be included.
Interventions
DRUGIsavuconazole
Administered by intravenous infusion.
DRUGCaspofungin
Administered by intravenous infusion.
DRUGVoriconazole
Administered by intravenous infusion.
Sponsors
Basilea Pharmaceutica
Astellas Pharma Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with candidemia or with an invasive Candida infection * Presence of fever, hypothermia or other appropriate local sign of infection * Female patients must be non-lactating and at no risk of pregnancy
Exclusion criteria
* Patients with a sole diagnosis of mucocutaneous candidiasis, i.e. oropharyngeal, esophageal or genital candidiasis; or candidal lower urinary tract infection or Candida isolated solely from respiratory tract specimens * Patients with candidemia who failed a previous antifungal therapy for the same infection * Patients previously enrolled in a phase III study with isavuconazole * Patients with a body weight \<40kg
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Overall Response of Success at the End of Intravenous Therapy (EOIV) as Determined by the Data Review Committee (DRC) Based on the Assessments of Clinical and Mycological Responses as Well as Alternative Systemic AFT Use | End of Intravenous Treatment (EOIV) (Days 11-56) | A Data Review Committee (DRC) was established from independent experts in the field of fungal infections to determine diagnosis and outcomes independently of the investigators and sponsor. Success was defined as clinical response (complete or partial) and mycological response (eradication or presumed eradication) without the use of alternative systemic antifungal therapy (AFT) within 48 hours after the last dose of IV study medication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Overall Response of Success at EOT and Follow Up Visit 2 (FU2) as Determined by the DRC Based on the Assessments of Clinical and Mycological Responses as Well as Alternative Systemic AFT Use at EOT and FU2 | EOT (Day 56) and FU2 (6 weeks after end of treatment) | A data review committee (DRC) was established from independent experts in the field of fungal infections to determine diagnosis and outcomes independently of the investigators and sponsor. Success was defined as clinical response (complete or partial) and mycological response (eradication or presumed eradication), without the use of alternative systemic antifungal therapy AFT within 48 hours after the last dose of IV study medication (for EOT analysis) or for continued treatment of the primary infection, or for recurrent or emergent infection by FU2, with no recurrent or emergent infection by FU2 (for FU2 analysis). |
| Percentage of Participants With Clinical Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC) | EOIV (Days 11-56), EOT (Day 56), FU1 (2 weeks after end of treatment) and FU2 (6 weeks after end of treatment) | A data review committee (DRC) was established from independent experts in the field of fungal infections to determine diagnosis and outcomes independently of the investigators and sponsor. Success was defined as clinical response (complete or partial). |
| Percentage of Participants With Mycological Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC) | EOIV (Days 11-56), EOT (Day 56), FU1 (2 weeks after end of treatment) and FU2 (6 weeks after end of treatment) | A data review committee (DRC) was established from independent experts in the field of fungal infections to determine diagnosis and outcomes independently of the investigators and sponsor. Success was defined as mycological response (Eradication or Presumed Eradication). |
| Percentage of Participants With Overall Response of Success at Follow Up Visit 1 (FU1-2 Weeks After End of Treatment (EOT)) as Determined by the DRC Based on the Assessments of Clinical, Mycological Responses and Antifungal Therapy (AFT) | End of Treatment (EOT) (Day 56) and FU1 (2 weeks after end of treatment) | A data review committee (DRC) was established from independent experts in the field of fungal infections to determine diagnosis and outcomes independently of the investigators and sponsor. Success was defined as clinical response (complete or partial) and mycological response (eradication or presumed eradication), without the use of alternative systemic AFT within 48 hours after the last dose of IV study medication. |
| Percentage of Participants With Clinical Response of Success at Day 7 and EOT as Determined by The Investigator | Day 7 and EOT (Day 56) | Investigators defined clinical response as success if participants exhibited complete or partial clinical response after evaluation of clinical signs and symptoms. |
| All-Cause Mortality (ACM) at Day 14 and Day 56 | Day 14 and Day 56 | All-cause mortality is represented as the percentage of participants who died on or before the analysis day. Participants who were lost to follow-up (i.e., unknown survival status) before the analysis day were counted as death. All-cause mortality was examined on Day 14 and Day 56. |
| Time to First Confirmed Negative Culture | Day 1 up to FU1 (2 weeks after EOT (Day 56)) | The first confirmed negative blood culture was defined as the first negative blood culture on or after first dose followed by a second negative blood culture at least 24 hours apart without any positive blood cultures in between. A participant without a confirmed negative blood culture was censored on the participant's last visit day. This endpoint was analyzed for mITT participants with candidemia only using the Kaplan-Meier method. Only participants with at least one positive blood culture on or prior to first dose and the culture not resolved prior to first dose were included in this analysis |
| Percentage of Participants With Mycological Response of Success at Day 7 and EOT as Determined by The Investigator | Day 7 and EOT (Day 56) | Success was defined as mycological response (eradication or presumed eradication). |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Chile, China, France, Germany, Hungary, India, Israel, Italy, Lebanon, Malaysia, Mexico, New Zealand, Philippines, Russia, Singapore, South Africa, Spain, Switzerland, Thailand, United States
Participant flow
Recruitment details
Consenting male and female participants ≥ 18 with candidemia or an invasive Candida infection who had a positive blood or tissue culture obtained within 96 hours prior to randomization and meeting the inclusion/exclusion criteria were enrolled in the study.
Pre-assignment details
Participants were stratified at randomization by geographical region and baseline neutropenic status.
Participants by arm
| Arm | Count |
|---|---|
| Isavuconazole (ISA) Participants received 3 intravenous (IV) loading doses of 200 mg of isavuconazole on days 1 and 2, followed by an IV maintenance dose of 200 mg once daily from day 3 to day 56. On day 11 at the discretion of the investigator, non-neutropenic patients could switch from IV to oral therapy. Oral therapy consisted of 200 mg isavuconazole twice daily. | 221 |
| Caspofungin (CAS)/Voriconazole Participants received 1 intravenous (IV) loading dose of 70 mg CAS on day 1, followed by an IV maintenance dose of 50 mg CAS from day 2 to day 56. Participants with body weight \> 80 kg received 70 mg CAS daily. On day 11 at the discretion of the investigator, non-neutropenic patients could switch from IV CAS to oral voriconazole comprising of a loading dose of 400 mg twice daily (BID) on the first day of oral therapy followed by standard dosing of 200 mg BID thereafter. | 219 |
| Total | 440 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Admin | 20 | 14 |
| Overall Study | Death | 57 | 56 |
| Overall Study | Lost to Follow-up | 14 | 17 |
| Overall Study | Missing | 1 | 0 |
| Overall Study | Randomized but didn't receive study drug | 2 | 8 |
| Overall Study | Withdrawal by Subject | 9 | 1 |
Baseline characteristics
| Characteristic | Isavuconazole (ISA) | Total | Caspofungin (CAS)/Voriconazole |
|---|---|---|---|
| Age, Continuous | 58.0 Years STANDARD_DEVIATION 17.54 | 58.0 Years STANDARD_DEVIATION 17.2 | 57.9 Years STANDARD_DEVIATION 16.88 |
| Geographical Region North America | 38 Participants | 71 Participants | 33 Participants |
| Geographical Region Other Regions | 129 Participants | 259 Participants | 130 Participants |
| Geographical Region Western Europe | 54 Participants | 110 Participants | 56 Participants |
| Neutropenic Status: Presence or Absence of Neutropenia Absence | 196 Participants | 391 Participants | 195 Participants |
| Neutropenic Status: Presence or Absence of Neutropenia Presence | 25 Participants | 49 Participants | 24 Participants |
| Race/Ethnicity, Customized Asian | 56 Participants | 120 Participants | 64 Participants |
| Race/Ethnicity, Customized Black or African American | 11 Participants | 18 Participants | 7 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 26 Participants | 45 Participants | 19 Participants |
| Race/Ethnicity, Customized Missing | 8 Participants | 13 Participants | 5 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 187 Participants | 382 Participants | 195 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 8 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 150 Participants | 294 Participants | 144 Participants |
| Sex: Female, Male Female | 78 Participants | 171 Participants | 93 Participants |
| Sex: Female, Male Male | 143 Participants | 269 Participants | 126 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 55 / 220 | 55 / 220 |
| other Total, other adverse events | 162 / 220 | 167 / 220 |
| serious Total, serious adverse events | 112 / 220 | 106 / 220 |
Outcome results
Primary
Percentage of Participants With Overall Response of Success at the End of Intravenous Therapy (EOIV) as Determined by the Data Review Committee (DRC) Based on the Assessments of Clinical and Mycological Responses as Well as Alternative Systemic AFT Use
A Data Review Committee (DRC) was established from independent experts in the field of fungal infections to determine diagnosis and outcomes independently of the investigators and sponsor. Success was defined as clinical response (complete or partial) and mycological response (eradication or presumed eradication) without the use of alternative systemic antifungal therapy (AFT) within 48 hours after the last dose of IV study medication.
Time frame: End of Intravenous Treatment (EOIV) (Days 11-56)
Population: The ITT population consisted of all randomized participants who received at least one dose of study drug. The mITT population consisted of ITT participants who had documented invasive candidiasis or candidemia at baseline based on the assessment of the independent blinded DRC. Reporting arms included participants who switched to oral ISA and CAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Isavuconazole (ISA) | Percentage of Participants With Overall Response of Success at the End of Intravenous Therapy (EOIV) as Determined by the Data Review Committee (DRC) Based on the Assessments of Clinical and Mycological Responses as Well as Alternative Systemic AFT Use | 60.3 Percentage of Participants |
| Caspofungin (CAS)/Voriconazole | Percentage of Participants With Overall Response of Success at the End of Intravenous Therapy (EOIV) as Determined by the Data Review Committee (DRC) Based on the Assessments of Clinical and Mycological Responses as Well as Alternative Systemic AFT Use | 71.1 Percentage of Participants |
Comparison: The adjusted treatment difference (ISA-CAS) was calculated by a stratified Cochran-Mantel-Haenszel (CMH) method with the strata of geographical region and baseline neutropenic status.95% CI: [-19.9, -1.8]
Secondary
All-Cause Mortality (ACM) at Day 14 and Day 56
All-cause mortality is represented as the percentage of participants who died on or before the analysis day. Participants who were lost to follow-up (i.e., unknown survival status) before the analysis day were counted as death. All-cause mortality was examined on Day 14 and Day 56.
Time frame: Day 14 and Day 56
Population: The mITT was the primary efficacy population and it consisted of ITT participants who had documented invasive candidiasis or candidemia at baseline based on the assessment of the independent blinded DRC.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Isavuconazole (ISA) | All-Cause Mortality (ACM) at Day 14 and Day 56 | Day 14 All-cause Mortality | 14.6 Percentage of Participants |
| Isavuconazole (ISA) | All-Cause Mortality (ACM) at Day 14 and Day 56 | Day 56 All-cause Mortality | 30.7 Percentage of Participants |
| Caspofungin (CAS)/Voriconazole | All-Cause Mortality (ACM) at Day 14 and Day 56 | Day 14 All-cause Mortality | 12.4 Percentage of Participants |
| Caspofungin (CAS)/Voriconazole | All-Cause Mortality (ACM) at Day 14 and Day 56 | Day 56 All-cause Mortality | 29.9 Percentage of Participants |
Comparison: Statistical analysis of all-cause mortality on Day 14. Adjusted treatment difference (Isavuconazole-Caspofungin) is calculated by a stratified CMH method with the strata of geographical regions, and baseline neutropenic status.95% CI: [-3.8, 8.9]
Comparison: Statistical analysis of all-cause mortality on Day 56. Adjusted treatment difference (Isavuconazole-Caspofungin) is calculated by a stratified CMH method with the strata of geographical regions, and baseline neutropenic status.95% CI: [-7.1, 10]
Secondary
Percentage of Participants With Clinical Response of Success at Day 7 and EOT as Determined by The Investigator
Investigators defined clinical response as success if participants exhibited complete or partial clinical response after evaluation of clinical signs and symptoms.
Time frame: Day 7 and EOT (Day 56)
Population: The mITT was the primary efficacy population and it consisted of ITT participants who had documented invasive candidiasis or candidemia at baseline based on the assessment of the independent blinded DRC. The isavuconazole and caspofungin group included participants who switched to oral isavuconazol and voriconazole
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Isavuconazole (ISA) | Percentage of Participants With Clinical Response of Success at Day 7 and EOT as Determined by The Investigator | Day 7 | 54.3 Percentage of Participants |
| Isavuconazole (ISA) | Percentage of Participants With Clinical Response of Success at Day 7 and EOT as Determined by The Investigator | EOT | 70.9 Percentage of Participants |
| Caspofungin (CAS)/Voriconazole | Percentage of Participants With Clinical Response of Success at Day 7 and EOT as Determined by The Investigator | Day 7 | 64.7 Percentage of Participants |
| Caspofungin (CAS)/Voriconazole | Percentage of Participants With Clinical Response of Success at Day 7 and EOT as Determined by The Investigator | EOT | 78.6 Percentage of Participants |
Comparison: Statistical analysis of adjusted treatment difference (ISA-CAS) at Day 7. The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status.95% CI: [-20.3, -1.9]
Comparison: Statistical analysis of adjusted treatment difference (ISA-CAS) at EOT (Day 56). The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status.95% CI: [-16.3, 0.1]
Secondary
Percentage of Participants With Clinical Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC)
A data review committee (DRC) was established from independent experts in the field of fungal infections to determine diagnosis and outcomes independently of the investigators and sponsor. Success was defined as clinical response (complete or partial).
Time frame: EOIV (Days 11-56), EOT (Day 56), FU1 (2 weeks after end of treatment) and FU2 (6 weeks after end of treatment)
Population: The mITT was the primary efficacy population and it consisted of ITT participants who had documented invasive candidiasis or candidemia at baseline based on the assessment of the independent blinded DRC. The isavuconazole and caspofungin group included participants who switched to oral isavuconazol and voriconazole.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Isavuconazole (ISA) | Percentage of Participants With Clinical Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC) | Success- End of Intravenous Treatment (EOIV) | 76.4 Percentage of Participants |
| Isavuconazole (ISA) | Percentage of Participants With Clinical Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC) | Success- End of Treatment (EOT) | 76.4 Percentage of Participants |
| Isavuconazole (ISA) | Percentage of Participants With Clinical Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC) | Success- Follow-up Visit 1 (FU1) | 67.8 Percentage of Participants |
| Isavuconazole (ISA) | Percentage of Participants With Clinical Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC) | Success- Follow-up Visit 2 (FU2) | 52.8 Percentage of Participants |
| Caspofungin (CAS)/Voriconazole | Percentage of Participants With Clinical Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC) | Success- Follow-up Visit 2 (FU2) | 58.2 Percentage of Participants |
| Caspofungin (CAS)/Voriconazole | Percentage of Participants With Clinical Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC) | Success- End of Intravenous Treatment (EOIV) | 84.1 Percentage of Participants |
| Caspofungin (CAS)/Voriconazole | Percentage of Participants With Clinical Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC) | Success- Follow-up Visit 1 (FU1) | 67.7 Percentage of Participants |
| Caspofungin (CAS)/Voriconazole | Percentage of Participants With Clinical Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC) | Success- End of Treatment (EOT) | 84.6 Percentage of Participants |
Comparison: Statistical analysis of adjusted treatment difference (ISA-CAS) at EOIV (Days 11-56).The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status.95% CI: [-15.4, -0.9]
Comparison: Statistical analysis of adjusted treatment difference (ISA-CAS) at EOT (Day 56). The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status.95% CI: [-15.8, -1.5]
Comparison: Statistical analysis of adjusted treatment difference (ISA-CAS) at FU1 (2 weeks after end of treatment). The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status.95% CI: [-9.1, 8.3]
Comparison: Statistical analysis of adjusted treatment difference (ISA-CAS) at FU2 (6 weeks after end of treatment).The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status.95% CI: [-15.3, 3.6]
Secondary
Percentage of Participants With Mycological Response of Success at Day 7 and EOT as Determined by The Investigator
Success was defined as mycological response (eradication or presumed eradication).
Time frame: Day 7 and EOT (Day 56)
Population: The mITT was the primary efficacy population and it consisted of ITT participants who had documented invasive candidiasis or candidemia at baseline based on the assessment of the independent blinded DRC. The isavuconazole and caspofungin group included participants who switched to oral isavuconazol and voriconazole.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Isavuconazole (ISA) | Percentage of Participants With Mycological Response of Success at Day 7 and EOT as Determined by The Investigator | Day 7 | 61.3 Percentage of Participants |
| Isavuconazole (ISA) | Percentage of Participants With Mycological Response of Success at Day 7 and EOT as Determined by The Investigator | EOT | 72.9 Percentage of Participants |
| Caspofungin (CAS)/Voriconazole | Percentage of Participants With Mycological Response of Success at Day 7 and EOT as Determined by The Investigator | Day 7 | 72.1 Percentage of Participants |
| Caspofungin (CAS)/Voriconazole | Percentage of Participants With Mycological Response of Success at Day 7 and EOT as Determined by The Investigator | EOT | 81.1 Percentage of Participants |
Comparison: Statistical analysis of adjusted treatment difference (ISA-CAS) at Day 7. The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status.95% CI: [-20.4, -2.5]
Comparison: Statistical analysis of adjusted treatment difference (ISA-CAS) at EOT (Day 56). The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status.95% CI: [-16.5, -0.4]
Secondary
Percentage of Participants With Mycological Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC)
A data review committee (DRC) was established from independent experts in the field of fungal infections to determine diagnosis and outcomes independently of the investigators and sponsor. Success was defined as mycological response (Eradication or Presumed Eradication).
Time frame: EOIV (Days 11-56), EOT (Day 56), FU1 (2 weeks after end of treatment) and FU2 (6 weeks after end of treatment)
Population: The mITT was the primary efficacy population and it consisted of ITT participants who had documented invasive candidiasis or candidemia at baseline based on the assessment of the independent blinded DRC. The isavuconazole and caspofungin group included participants who switched to oral isavuconazol and voriconazole.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Isavuconazole (ISA) | Percentage of Participants With Mycological Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC) | Success-EOIV | 70.9 Percentage of Participants |
| Isavuconazole (ISA) | Percentage of Participants With Mycological Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC) | Success-EOT | 71.9 Percentage of Participants |
| Isavuconazole (ISA) | Percentage of Participants With Mycological Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC) | Success-FU1 | 66.8 Percentage of Participants |
| Isavuconazole (ISA) | Percentage of Participants With Mycological Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC) | Success-FU2 | 51.8 Percentage of Participants |
| Caspofungin (CAS)/Voriconazole | Percentage of Participants With Mycological Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC) | Success-FU2 | 56.7 Percentage of Participants |
| Caspofungin (CAS)/Voriconazole | Percentage of Participants With Mycological Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC) | Success-EOIV | 85.6 Percentage of Participants |
| Caspofungin (CAS)/Voriconazole | Percentage of Participants With Mycological Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC) | Success-FU1 | 65.7 Percentage of Participants |
| Caspofungin (CAS)/Voriconazole | Percentage of Participants With Mycological Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC) | Success-EOT | 87.6 Percentage of Participants |
Comparison: Statistical analysis of adjusted treatment difference (ISA-CAS) at EOIV (Days 11-56). The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status.95% CI: [-22.7, -7]
Comparison: Statistical analysis of adjusted treatment difference (ISA-CAS) at EOT (Day 56). The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status.95% CI: [-23.5, -8.4]
Comparison: Statistical analysis of adjusted treatment difference (ISA-CAS) at FU1 (2 weeks after end of treatment).The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status.95% CI: [-8.1, 9.6]
Comparison: Statistical analysis of adjusted treatment difference (ISA-CAS) at FU2 (6 weeks after end of treatment).The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status.95% CI: [-14.7, 4.3]
Secondary
Percentage of Participants With Overall Response of Success at EOT and Follow Up Visit 2 (FU2) as Determined by the DRC Based on the Assessments of Clinical and Mycological Responses as Well as Alternative Systemic AFT Use at EOT and FU2
A data review committee (DRC) was established from independent experts in the field of fungal infections to determine diagnosis and outcomes independently of the investigators and sponsor. Success was defined as clinical response (complete or partial) and mycological response (eradication or presumed eradication), without the use of alternative systemic antifungal therapy AFT within 48 hours after the last dose of IV study medication (for EOT analysis) or for continued treatment of the primary infection, or for recurrent or emergent infection by FU2, with no recurrent or emergent infection by FU2 (for FU2 analysis).
Time frame: EOT (Day 56) and FU2 (6 weeks after end of treatment)
Population: The mITT was the primary efficacy population and it consisted of ITT participants who had documented invasive candidiasis or candidemia at baseline based on the assessment of the independent blinded DRC. The isavuconazole and caspofungin group included participants who switched to oral isavuconazol and voriconazole.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Isavuconazole (ISA) | Percentage of Participants With Overall Response of Success at EOT and Follow Up Visit 2 (FU2) as Determined by the DRC Based on the Assessments of Clinical and Mycological Responses as Well as Alternative Systemic AFT Use at EOT and FU2 | EOT (Day 56) | 61.3 Percentage of Participants |
| Isavuconazole (ISA) | Percentage of Participants With Overall Response of Success at EOT and Follow Up Visit 2 (FU2) as Determined by the DRC Based on the Assessments of Clinical and Mycological Responses as Well as Alternative Systemic AFT Use at EOT and FU2 | FU2 (6 weeks after end of treatment) | 43.2 Percentage of Participants |
| Caspofungin (CAS)/Voriconazole | Percentage of Participants With Overall Response of Success at EOT and Follow Up Visit 2 (FU2) as Determined by the DRC Based on the Assessments of Clinical and Mycological Responses as Well as Alternative Systemic AFT Use at EOT and FU2 | EOT (Day 56) | 72.1 Percentage of Participants |
| Caspofungin (CAS)/Voriconazole | Percentage of Participants With Overall Response of Success at EOT and Follow Up Visit 2 (FU2) as Determined by the DRC Based on the Assessments of Clinical and Mycological Responses as Well as Alternative Systemic AFT Use at EOT and FU2 | FU2 (6 weeks after end of treatment) | 48.3 Percentage of Participants |
Comparison: Statistical analysis of adjusted treatment difference (ISA-CAS) at EOT (Day 56). The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status.95% CI: [-19.9, -1.9]
Comparison: Statistical analysis of adjusted treatment difference (ISA-CAS) at FU2 (6 weeks after end of treatment). The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status.95% CI: [-15, 4.2]
Secondary
Percentage of Participants With Overall Response of Success at Follow Up Visit 1 (FU1-2 Weeks After End of Treatment (EOT)) as Determined by the DRC Based on the Assessments of Clinical, Mycological Responses and Antifungal Therapy (AFT)
A data review committee (DRC) was established from independent experts in the field of fungal infections to determine diagnosis and outcomes independently of the investigators and sponsor. Success was defined as clinical response (complete or partial) and mycological response (eradication or presumed eradication), without the use of alternative systemic AFT within 48 hours after the last dose of IV study medication.
Time frame: End of Treatment (EOT) (Day 56) and FU1 (2 weeks after end of treatment)
Population: The mITT was the primary efficacy population and it consisted of ITT participants who had documented invasive candidiasis or candidemia at baseline based on the assessment of the independent blinded DRC. The isavuconazole and caspofungin group included participants who switched to oral isavuconazol and voriconazole.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Isavuconazole (ISA) | Percentage of Participants With Overall Response of Success at Follow Up Visit 1 (FU1-2 Weeks After End of Treatment (EOT)) as Determined by the DRC Based on the Assessments of Clinical, Mycological Responses and Antifungal Therapy (AFT) | 54.8 Percentage of Participants |
| Caspofungin (CAS)/Voriconazole | Percentage of Participants With Overall Response of Success at Follow Up Visit 1 (FU1-2 Weeks After End of Treatment (EOT)) as Determined by the DRC Based on the Assessments of Clinical, Mycological Responses and Antifungal Therapy (AFT) | 57.2 Percentage of Participants |
Comparison: The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status.95% CI: [-12.2, 6.8]
Secondary
Time to First Confirmed Negative Culture
The first confirmed negative blood culture was defined as the first negative blood culture on or after first dose followed by a second negative blood culture at least 24 hours apart without any positive blood cultures in between. A participant without a confirmed negative blood culture was censored on the participant's last visit day. This endpoint was analyzed for mITT participants with candidemia only using the Kaplan-Meier method. Only participants with at least one positive blood culture on or prior to first dose and the culture not resolved prior to first dose were included in this analysis
Time frame: Day 1 up to FU1 (2 weeks after EOT (Day 56))
Population: The mITT was the primary efficacy population and it consisted of ITT participants who had documented invasive candidiasis or candidemia at baseline based on the assessment of the independent blinded DRC.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Isavuconazole (ISA) | Time to First Confirmed Negative Culture | 4.0 Days |
| Caspofungin (CAS)/Voriconazole | Time to First Confirmed Negative Culture | 3.0 Days |