Aspergillosis, Invasive Fungal Infection
Conditions
Keywords
Invasive fungal disease, BAL8557, Isavuconazole, ASP9766, Filamentous fungi, Phase III, Aspergillus species
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.
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.
Interventions
DRUGIsavuconazole
Loading doses were administered as IV infusion and maintenance doses were administered as IV infusion or oral (capsules).
DRUGVoriconazole
Loading doses were administered as IV infusion and maintenance doses were administered as IV infusion or oral (capsules).
Sponsors
Basilea Pharmaceutica International Ltd
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 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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). |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. | — |
| 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. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Chile, China, Egypt, France, Germany, Hungary, India, Israel, Italy, Malaysia, Mexico, Netherlands, New Zealand, Poland, Russia, South Korea, Spain, Switzerland, Thailand, Turkey (Türkiye), United States
Participant flow
Recruitment details
Consenting adult patients with proven, probable or possible invasive fungal disease (IFD) caused by Aspergillus species or other filamentous fungi, meeting the inclusion/exclusion criteria, were enrolled in the study.
Pre-assignment details
Participants were stratified by geographic location (North America; Western Europe plus Australia and New Zealand; and Other Regions), whether or not they underwent an allogeneic bone marrow transplant (BMT) and whether or not they had uncontrolled malignancy.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 258 |
| 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. | 258 |
| Total | 516 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative Reason | 12 | 15 |
| Overall Study | Adverse Event | 31 | 53 |
| Overall Study | Death | 17 | 21 |
| Overall Study | Did Not Cooperate | 12 | 9 |
| Overall Study | Insufficient Therapeutic Response | 39 | 23 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Other Protocol Violation | 10 | 6 |
| Overall Study | Randomized but Never Received Study Drug | 5 | 6 |
| Overall Study | Violation of Selection at Entry | 17 | 10 |
Baseline characteristics
| Characteristic | Voriconazole | Isavuconazole | Total |
|---|---|---|---|
| Age, Continuous | 51.2 years STANDARD_DEVIATION 15.85 | 51.1 years STANDARD_DEVIATION 16.15 | 51.1 years STANDARD_DEVIATION 15.98 |
| Hematologic Malignancy Status No | 36 participants | 47 participants | 83 participants |
| Hematologic Malignancy Status Yes | 222 participants | 211 participants | 433 participants |
| Neutropenic Status No | 83 participants | 95 participants | 178 participants |
| Neutropenic Status Yes | 175 participants | 163 participants | 338 participants |
| Prior Allogeneic Bone Marrow Transplant (BMT) No | 207 participants | 204 participants | 411 participants |
| Prior Allogeneic Bone Marrow Transplant (BMT) Yes | 51 participants | 54 participants | 105 participants |
| Race/Ethnicity, Customized Asian | 64 participants | 45 participants | 109 participants |
| Race/Ethnicity, Customized Black or African American | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 9 participants | 22 participants | 31 participants |
| Race/Ethnicity, Customized Missing | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 248 participants | 236 participants | 484 participants |
| Race/Ethnicity, Customized Other | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized White | 191 participants | 211 participants | 402 participants |
| Sex: Female, Male Female | 95 Participants | 113 Participants | 208 Participants |
| Sex: Female, Male Male | 163 Participants | 145 Participants | 308 Participants |
| Uncontrolled Malignancy Status No | 71 participants | 85 participants | 156 participants |
| Uncontrolled Malignancy Status Yes | 187 participants | 173 participants | 360 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 227 / 257 | 228 / 259 |
| serious Total, serious adverse events | 134 / 257 | 149 / 259 |
Outcome results
Primary
All-cause Mortality 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.
Time frame: Through Day 42
Population: Intent-to-treat population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Isavuconazole | All-cause Mortality Through Day 42 | 18.6 percentage of participants |
| Voriconazole | All-cause Mortality Through Day 42 | 20.2 percentage of participants |
Comparison: 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%.95% CI: [-7.759, 5.683]
Secondary
All-cause Mortality 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.
Time frame: Through Day 84
Population: Intent-to-treat population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Isavuconazole | All-cause Mortality Through Day 84 | 29.1 percentage of participants |
| Voriconazole | All-cause Mortality Through Day 84 | 31.0 percentage of participants |
95% CI: [-9.15, 6.34]
Secondary
Number of Participants With Adverse Events, Reported by System Organ Class
Time frame: From the first study drug administration until 28 days after the last dose of study drug. The median duration of study drug administration was 45 days.
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Infections and Infestations | 152 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Renal and Urinary Disorders | 55 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Skin and Subcutaneous Tissue Disorders | 86 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Cardiac Disorders | 43 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Respiratory, Thoracic and Mediastinal Disorders | 143 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Eye Disorders | 39 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Investigations | 85 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Injury, Poisoning and Procedural Complications | 33 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Gastrointestinal Disorders | 174 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Hepatobiliary Disorders | 23 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Blood and Lymphatic System Disorders | 77 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Immune System Disorders | 20 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Metabolism and Nutrition Disorders | 108 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Neoplasms benign, malignant and unspecified | 19 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Psychiatric Disorders | 70 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Ear and Labyrinth Disorders | 14 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | General Disorders / Administration Site Conditions | 148 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Reproductive System and Breast Disorders | 8 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Musculoskeletal and Connective Tissue Disorders | 69 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Endocrine Disorders | 5 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Nervous System Disorders | 95 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Congenital, Familial and Genetic Disorders | 3 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Vascular Disorders | 67 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Social Circumstances | 0 participants |
| Isavuconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Patients with ≥ 1 TEAE | 247 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Social Circumstances | 1 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Patients with ≥ 1 TEAE | 255 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Gastrointestinal Disorders | 180 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Infections and Infestations | 158 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | General Disorders / Administration Site Conditions | 144 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Respiratory, Thoracic and Mediastinal Disorders | 147 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Metabolism and Nutrition Disorders | 121 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Nervous System Disorders | 89 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Skin and Subcutaneous Tissue Disorders | 110 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Investigations | 96 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Blood and Lymphatic System Disorders | 82 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Psychiatric Disorders | 86 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Musculoskeletal and Connective Tissue Disorders | 77 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Vascular Disorders | 77 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Renal and Urinary Disorders | 58 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Cardiac Disorders | 57 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Eye Disorders | 69 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Injury, Poisoning and Procedural Complications | 39 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Hepatobiliary Disorders | 42 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Immune System Disorders | 25 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Neoplasms benign, malignant and unspecified | 31 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Ear and Labyrinth Disorders | 13 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Reproductive System and Breast Disorders | 13 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Endocrine Disorders | 3 participants |
| Voriconazole | Number of Participants With Adverse Events, Reported by System Organ Class | Congenital, Familial and Genetic Disorders | 2 participants |
Secondary
Percentage of Participants With a Clinical Response Assessed by the DRC
Blinded assessments of clinical symptoms and physical findings of invasive fungal disease were performed by the independent DRC. Clinical response is defined as the resolution or partial resolution of all attributable clinical symptoms and physical findings. Failure is defined as no resolution of any attributable clinical symptoms and physical findings and/or worsening. Participants with no attributable signs and symptoms present at Baseline and no symptoms attributable to invasive fungal disease (IFD) developed post-baseline were classified as Not Applicable. End of treatment is the last day of study drug administration.
Time frame: Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Isavuconazole | Percentage of Participants With a Clinical Response Assessed by the DRC | Day 42 (n=139, 120) | 64.0 percentage of participants |
| Isavuconazole | Percentage of Participants With a Clinical Response Assessed by the DRC | Day 84 (n=141, 124) | 46.1 percentage of participants |
| Isavuconazole | Percentage of Participants With a Clinical Response Assessed by the DRC | End of Treatment (n=137, 121) | 62.0 percentage of participants |
| Voriconazole | Percentage of Participants With a Clinical Response Assessed by the DRC | Day 42 (n=139, 120) | 57.5 percentage of participants |
| Voriconazole | Percentage of Participants With a Clinical Response Assessed by the DRC | Day 84 (n=141, 124) | 44.4 percentage of participants |
| Voriconazole | Percentage of Participants With a Clinical Response Assessed by the DRC | End of Treatment (n=137, 121) | 60.3 percentage of participants |
Comparison: Day 84 comparison95% CI: [-11.116, 11.758]
Comparison: End of Treatment Comparison95% CI: [-10.64, 11.531]
Comparison: Day 42 comparison95% CI: [-17.368, 5.802]
Secondary
Percentage of Participants With a Clinical Response Assessed by the Investigator
Assessment of clinical symptoms and physical findings of invasive fungal disease were performed by the investigator. Clinical response is defined as the resolution or partial resolution of all attributable clinical symptoms and physical findings. Failure is defined as no resolution of any attributable clinical symptoms and physical findings and/or worsening, or if results were unavailable or the participant was unevaluable. Participants with no attributable signs and symptoms present at Baseline were classified as Not Applicable. End of treatment is the last day of study drug administration.
Time frame: Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Isavuconazole | Percentage of Participants With a Clinical Response Assessed by the Investigator | Day 42 (n=137, 120) | 64.2 percentage of participants |
| Isavuconazole | Percentage of Participants With a Clinical Response Assessed by the Investigator | Day 84 (n=140, 122) | 41.4 percentage of participants |
| Isavuconazole | Percentage of Participants With a Clinical Response Assessed by the Investigator | End of Treatment (n=137, 121) | 62.0 percentage of participants |
| Voriconazole | Percentage of Participants With a Clinical Response Assessed by the Investigator | Day 42 (n=137, 120) | 61.7 percentage of participants |
| Voriconazole | Percentage of Participants With a Clinical Response Assessed by the Investigator | Day 84 (n=140, 122) | 44.3 percentage of participants |
| Voriconazole | Percentage of Participants With a Clinical Response Assessed by the Investigator | End of Treatment (n=137, 121) | 64.5 percentage of participants |
Comparison: End of Treatment comparison95% CI: [-6.043, 16.026]
Comparison: Day 42 comparison95% CI: [-10.873, 11.22]
Comparison: Day 84 comparison95% CI: [-6.533, 15.939]
Secondary
Percentage of Participants With a Mycological Response Assessed by the DRC
Blinded mycological assessments of the participant's invasive fungal disease status were performed by the independent DRC using the results from fungal culture and isolation and/or histology/cytology of biopsy or biological fluid samples from the infected site. Mycological response is defined as eradication or presumed eradication of the original causative organism cultured or identified by histology/cytology at Baseline. Failure was defined as persistence or presumed persistence. Participants with no mycological evidence available at Baseline were classified as Not Applicable. End of treatment is the last day of study drug administration.
Time frame: Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Isavuconazole | Percentage of Participants With a Mycological Response Assessed by the DRC | Day 42 | 39.9 percentage of participants |
| Isavuconazole | Percentage of Participants With a Mycological Response Assessed by the DRC | Day 84 | 28.0 percentage of participants |
| Isavuconazole | Percentage of Participants With a Mycological Response Assessed by the DRC | End of Treatment | 37.8 percentage of participants |
| Voriconazole | Percentage of Participants With a Mycological Response Assessed by the DRC | Day 42 | 39.5 percentage of participants |
| Voriconazole | Percentage of Participants With a Mycological Response Assessed by the DRC | Day 84 | 36.4 percentage of participants |
| Voriconazole | Percentage of Participants With a Mycological Response Assessed by the DRC | End of Treatment | 41.1 percentage of participants |
Comparison: End of Treatment comparison95% CI: [-7.429, 15.087]
Comparison: Day 42 Comparison95% CI: [-11.917, 10.586]
Comparison: Day 84 Comparison95% CI: [-1.624, 19.83]
Secondary
Percentage of Participants With a Mycological Response Assessed by the Investigator
Mycological assessments of the participant's invasive fungal disease status were performed by the investigator using the results from fungal culture and isolation and/or histology/cytology of biopsy or biological fluid samples from the infected site. Mycological response is defined as eradication or presumed eradication of the original causative organism cultured or identified by histology/cytology at Baseline. Failure was defined as persistence or presumed persistence. Participants with no mycological evidence available at Baseline, or no mycological follow-up results available or indeterminate results were classified as Not Applicable. End of treatment is the last day of study drug administration.
Time frame: Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Isavuconazole | Percentage of Participants With a Mycological Response Assessed by the Investigator | Day 42 (n=109, 100) | 52.3 percentage of participants |
| Isavuconazole | Percentage of Participants With a Mycological Response Assessed by the Investigator | Day 84 (n=126, 117) | 35.7 percentage of participants |
| Isavuconazole | Percentage of Participants With a Mycological Response Assessed by the Investigator | End of Treatment (n=107, 100) | 50.5 percentage of participants |
| Voriconazole | Percentage of Participants With a Mycological Response Assessed by the Investigator | Day 42 (n=109, 100) | 50.0 percentage of participants |
| Voriconazole | Percentage of Participants With a Mycological Response Assessed by the Investigator | Day 84 (n=126, 117) | 37.6 percentage of participants |
| Voriconazole | Percentage of Participants With a Mycological Response Assessed by the Investigator | End of Treatment (n=107, 100) | 55.0 percentage of participants |
Comparison: End of Treatment comparison95% CI: [-8.429, 17.218]
Comparison: Day 42 comparison95% CI: [-15.071, 10.073]
Comparison: Day 84 comparison95% CI: [-8.633, 14.499]
Secondary
Percentage of Participants With an Overall Outcome of Success Evaluated by Investigator
Overall response based on investigators' assessments was not derived as it was not deemed necessary because participants overall response status was determined by the DRC. All investigators' assessments of clinical, mycological and radiological responses are analyzed separately (see Outcome Measures 8-10).
Time frame: Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.
Secondary
Percentage of Participants With an Overall Outcome of Success Evaluated by the Data Review Committee (DRC)
The DRC was an independent, blinded committee consisting of experts in the field of infectious disease who assessed patients' outcomes. The overall response was based on the DRC-assessed clinical, mycological and radiological responses. Success was defined as the resolution or partial resolution of all attributable clinical symptoms and physical findings, the eradication or presumed eradication of the original causative organism cultured or identified by histology/cytology at Baseline and a \> 50% improvement in radiological response from Baseline (or improvement of at least 25% from Baseline for the Day 42 analysis or End of Treatment if it occurred prior to Day 42). End of treatment (EOT) is the last day of study drug administration. For the Day 42 and Day 84 analyses, any visits that the DRC assessed as Not Done were considered a failure for that visit. A death before Day 42 was also considered a failure, even if the DRC assessed the participant to be a success prior to death.
Time frame: Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.
Population: Modified Intent-to-treat (mITT) population consisted of ITT participants who had proven or probable IFD as determined by the DRC.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Isavuconazole | Percentage of Participants With an Overall Outcome of Success Evaluated by the Data Review Committee (DRC) | Day 42 | 35.7 percentage of participants |
| Isavuconazole | Percentage of Participants With an Overall Outcome of Success Evaluated by the Data Review Committee (DRC) | Day 84 | 25.2 percentage of participants |
| Isavuconazole | Percentage of Participants With an Overall Outcome of Success Evaluated by the Data Review Committee (DRC) | End of Treatment | 35.0 percentage of participants |
| Voriconazole | Percentage of Participants With an Overall Outcome of Success Evaluated by the Data Review Committee (DRC) | Day 42 | 35.7 percentage of participants |
| Voriconazole | Percentage of Participants With an Overall Outcome of Success Evaluated by the Data Review Committee (DRC) | Day 84 | 32.6 percentage of participants |
| Voriconazole | Percentage of Participants With an Overall Outcome of Success Evaluated by the Data Review Committee (DRC) | End of Treatment | 36.4 percentage of participants |
Comparison: End of Treatment comparison95% CI: [-9.336, 12.572]
Comparison: Day 42 comparison95% CI: [-11.277, 10.329]
Comparison: Day 84 comparison95% CI: [-1.993, 18.379]
Secondary
Percentage of Participants With a Radiological Response Assessed by the DRC
Independent reviews of radiology assessments were completed by radiology experts which were provided to the independent, blinded DRC. Blinded radiological assessments were performed by the DRC. Radiological response is defined as a ≥ 50% improvement from Baseline, or improvement of at least 25% from Baseline for the Day 42 analysis or if end of treatment occurred before Day 42. Participants without any radiology at Baseline were considered Not Applicable. End of Treatment is the last day of study drug administration.
Time frame: Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Isavuconazole | Percentage of Participants With a Radiological Response Assessed by the DRC | Day 42 (n=141, 128) | 28.4 percentage of participants |
| Isavuconazole | Percentage of Participants With a Radiological Response Assessed by the DRC | Day 84 (n=141, 128) | 22.0 percentage of participants |
| Isavuconazole | Percentage of Participants With a Radiological Response Assessed by the DRC | End of Treatment (n=141, 127) | 29.1 percentage of participants |
| Voriconazole | Percentage of Participants With a Radiological Response Assessed by the DRC | Day 42 (n=141, 128) | 34.4 percentage of participants |
| Voriconazole | Percentage of Participants With a Radiological Response Assessed by the DRC | Day 84 (n=141, 128) | 29.7 percentage of participants |
| Voriconazole | Percentage of Participants With a Radiological Response Assessed by the DRC | End of Treatment (n=141, 127) | 33.1 percentage of participants |
Comparison: End of Treatment comparison95% CI: [-4.936, 16.268]
Comparison: Day 42 comparison95% CI: [-5.338, 16.032]
Comparison: Day 84 comparison95% CI: [-1.231, 19.186]
Secondary
Percentage of Participants With a Radiological Response Assessed by the Investigator
Radiological assessments were performed by the investigator. Radiological response is defined as a ≥ 50% improvement from Baseline, or improvement of at least 25% from Baseline for the Day 42 analysis or if end of treatment occurred before Day 42. Failure is defined as a \< 25% improvement at any time or results not available. Participants with no signs on radiological images at Baseline were considered Not Applicable. End of Treatment is the last day of study drug administration.
Time frame: Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Isavuconazole | Percentage of Participants With a Radiological Response Assessed by the Investigator | Day 42 (n=142, 128) | 45.1 percentage of participants |
| Isavuconazole | Percentage of Participants With a Radiological Response Assessed by the Investigator | Day 84 (n=141, 128) | 38.3 percentage of participants |
| Isavuconazole | Percentage of Participants With a Radiological Response Assessed by the Investigator | End of Treatment (n=141, 128) | 43.3 percentage of participants |
| Voriconazole | Percentage of Participants With a Radiological Response Assessed by the Investigator | Day 42 (n=142, 128) | 51.6 percentage of participants |
| Voriconazole | Percentage of Participants With a Radiological Response Assessed by the Investigator | Day 84 (n=141, 128) | 41.4 percentage of participants |
| Voriconazole | Percentage of Participants With a Radiological Response Assessed by the Investigator | End of Treatment (n=141, 128) | 47.7 percentage of participants |
Comparison: End of Treatment comparison95% CI: [-5.145, 17.696]
Comparison: Day 42 comparison95% CI: [-3.335, 19.356]
Comparison: Day 84 comparison95% CI: [-6.187, 16.332]