Aspergillosis
Conditions
Brief summary
This study compares the effectiveness and safety of the combination of anidulafungin and voriconazole compared to that of voriconazole alone (which is generally considered the standard of care) for the treatment of Invasive Aspergillosis.
Interventions
DRUGvoriconazole
First week: Voriconazole 6 mg/kg IV bid for the first 24 hours, followed by 4 mg/kg IV BID plus anidulafungin placebo IV qd. Second week: Voriconazole 4 mg/kg IV bid or 300 mg PO bid plus anidulafungin placebo IV qd. Third and fourth weeks: Voriconazole 4 mg/kg IV bid OR 300 mg PO bid plus anidulafungin placebo IV qd, OR Voriconazole 4 mg/kg IV bid or 300 mg PO bid monotherapy. Fifth and sixth weeks: Voriconazole 4 mg/kg IV bid or 300 mg PO bid monotherapy.
DRUGanidulafungin
First week: Voriconazole 6 mg/kg IV bid for the first 24 hours, followed by 4 mg/kg IV bid plus anidulafungin 200 mg IV on day 1, followed by 100 mg IV qd thereafter. Second week: Voriconazole 4 mg/kg IV bid or 300 mg PO bid plus anidulafungin 100 mg IV qd. Third and fourth weeks: Voriconazole 4 mg/kg IV bid OR 300 mg PO bid plus anidulafungin 100 mg IV qd, OR Voriconazole 4 mg/kg IV bid or 300 mg PO bid monotherapy. Fifth and sixth weeks: Voriconazole 4 mg/kg IV bid or 300 mg PO bid monotherapy.
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Immunocompromised state due to either 1. receipt of hematopoeitic stem cell transplantation or 2. hematologic malignancy; * Diagnosis of possible, probable, or proven invasive aspergillosis.
Exclusion criteria
* Patients with aspergilloma or chronic aspergillosis * Receipt of 4 or more days of systemic antifungal treatment for the current episode of invasive aspergillosis * Anticipated survival of less than 5 days or Karnofsky score \<=20
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| All-cause Mortality at Week 6 in Participants With Proven or Probable Invasive Aspergillosis | Day 1 to Day 42 (Week 6) | Number of deaths measured 6 weeks after start of treatment. Time to death defined as date of death minus first treatment date + 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All-cause Mortality at Week 6 in Participants With Possible, Probable, or Proven Invasive Aspergillosis (IA) | Day 1 to Day 42 (Week 6) | Number of deaths due to any cause measured 6 weeks after start of treatment. Time to death defined as date of death minus first treatment date + 1. |
| All-cause Mortality at Week 12 in Participants With Probable or Proven Invasive Aspergillosis (IA) | Day 1 to Day 84 (Week 12) | Number of deaths due to any cause measured 12 weeks after start of treatment. Time to death defined as date of death minus first treatment date + 1. |
| Global Response at Week 6 | Baseline, Day 42 (Week 6) | Number of participants with a successful response (complete or partial global response). Complete response = resolution of all clinical signs and symptoms and \>90% of lesions due to IA that were visible on radiologic studies at baseline (BL); partial response = clinical improvement and \>50% improvement in radiological findings present at BL. |
| Time to Death: All-Cause Mortality | Day 1 to Day 84 (Week 12) | Survival time from start of treatment. Time to death defined as date of death due to any cause minus first treatment date + 1. |
| Time to Death Due to Invasive Aspergillosis (IA) | Day 1 to Day 84 (Week 12) | Survival time from start of treatment. Time to death defined as date of death due to IA minus first treatment date + 1. |
| Mortality Due to Invasive Aspergillosis (IA) at Week 6 in Participants With Probable or Proven IA | Day 1 to Day 42 (Week 6) | Number of deaths due to Invasive Aspergillosis measured 6 weeks after start of treatment. Time to death defined as date of death minus first treatment date + 1. |
Countries
Australia, Belgium, Brazil, Canada, Czechia, France, Germany, Greece, India, Italy, Netherlands, Peru, Poland, Portugal, Russia, Singapore, South Korea, Spain, Switzerland, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Pre-assignment details
Participants were stratified at study entry for host and transplant variables known to have an independent impact on the probablity of death due to invasive aspergillosis (IA) (allogenic hematopoietic stem cell transplant versus other, and pulmonary IA).
Participants by arm
| Arm | Count |
|---|---|
| Voriconazole/Anidulafungin Week 1: Voriconazole 6 mg/kg intravenously (IV) twice a day (bid) for 24 hours, followed by voriconazole 4 milligrams per kilogram (mg/kg) IV BID plus anidulafungin 200 mg IV on day 1, followed by 100 mg IV once a day (QD); Week 2: Voriconazole 4 mg/kg IV BID or 300 mg orally (PO) BID plus anidulafungin 100 mg IV QD; Weeks 3 and 4: voriconazole 4 mg/kg IV BID or 300 mg PO BID plus anidulafungin 100 mg IV QD or voriconazole 4 mg/kg IV BID or 300 mg PO BID monotherapy; Weeks 5 and 6: voriconazole 4 mg/kg IV BID or 300 mg PO BID monotherapy. | 228 |
| Voriconazole / Placebo Week 1: Voriconazole 6 mg/kg IV BID for 24 hours, followed by voriconazole 4 mg/kg IV BID plus anidulafungin placebo IV QD; Week 2: voriconazole 4 mg/kg IV BID or voriconazole 300 mg PO BID plus anidulafungin placebo IV QD through Day 14; Weeks 3 and 4: voriconazole 4 mg/kg IV BID or 300 mg PO BID plus anidulafungin placebo; Weeks 5 and 6: voriconazole 4 mg/kg IV BID or 300 mg PO BID monotherapy. | 226 |
| Total | 454 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 68 | 71 |
| Overall Study | Did not receive treatment | 2 | 3 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Other | 0 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 6 |
Baseline characteristics
| Characteristic | Voriconazole/Anidulafungin | Voriconazole / Placebo | Total |
|---|---|---|---|
| Age Continuous | 52.0 years STANDARD_DEVIATION 15.4 | 51.0 years STANDARD_DEVIATION 15.9 | 51.5 years STANDARD_DEVIATION 15.7 |
| Sex: Female, Male Female | 94 Participants | 95 Participants | 189 Participants |
| Sex: Female, Male Male | 134 Participants | 131 Participants | 265 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 194 / 228 | 192 / 226 |
| serious Total, serious adverse events | 115 / 228 | 104 / 226 |
Outcome results
Primary
All-cause Mortality at Week 6 in Participants With Proven or Probable Invasive Aspergillosis
Number of deaths measured 6 weeks after start of treatment. Time to death defined as date of death minus first treatment date + 1.
Time frame: Day 1 to Day 42 (Week 6)
Population: Modified intent-to-treat (MITT) population: all randomized participants with proven or probable IA confirmed by Day 7 following enrollment who received at least 1 dose of study medication. N=number of participants in MITT population at Week 6. Participants not known to have died were censored at last study visit (Day 84).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Voriconazole/Anidulafungin | All-cause Mortality at Week 6 in Participants With Proven or Probable Invasive Aspergillosis | 26 participants |
| Voriconazole / Placebo | All-cause Mortality at Week 6 in Participants With Proven or Probable Invasive Aspergillosis | 39 participants |
Comparison: All-cause mortality calculated using the Kaplan-Meier (KM) product limit estimator on Day 42 (Week 6) within each stratum and weighted by the harmonic mean of the sample sizes in the strata. Treatment difference (stratified) based on a weighted difference in proportions. Stratification variables were site of infection and host factors.p-value: 0.043495% CI: [-18.99, 1.51]Z test for difference in proportions
Secondary
All-cause Mortality at Week 12 in Participants With Probable or Proven Invasive Aspergillosis (IA)
Number of deaths due to any cause measured 12 weeks after start of treatment. Time to death defined as date of death minus first treatment date + 1.
Time frame: Day 1 to Day 84 (Week 12)
Population: MITT; N=number of participants in MITT population at Week 12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Voriconazole/Anidulafungin | All-cause Mortality at Week 12 in Participants With Probable or Proven Invasive Aspergillosis (IA) | 39 participants |
| Voriconazole / Placebo | All-cause Mortality at Week 12 in Participants With Probable or Proven Invasive Aspergillosis (IA) | 55 participants |
Comparison: Treatment difference (stratified) based on a weighted difference in proportions. Stratification variables: site of infection and host factors.p-value: 0.038395% CI: [-21.44, 1.09]Z test for difference in proportions
Secondary
All-cause Mortality at Week 6 in Participants With Possible, Probable, or Proven Invasive Aspergillosis (IA)
Number of deaths due to any cause measured 6 weeks after start of treatment. Time to death defined as date of death minus first treatment date + 1.
Time frame: Day 1 to Day 42 (Week 6)
Population: Intent-to-treat (ITT) population: participants in MITT analysis set plus participants with possible IA who could not be upgraded to probable or proven IA within 7 days and had received at least 1 dose of study medication. N=number of participants in ITT population at Week 6.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Voriconazole/Anidulafungin | All-cause Mortality at Week 6 in Participants With Possible, Probable, or Proven Invasive Aspergillosis (IA) | 44 participants |
| Voriconazole / Placebo | All-cause Mortality at Week 6 in Participants With Possible, Probable, or Proven Invasive Aspergillosis (IA) | 47 participants |
Comparison: Treatment difference (stratified) based on a weighted difference in proportions. Stratification variables: site of infection and host factors.p-value: 0.261195% CI: [-10.77, 5.56]Z test for difference in proportions
Secondary
Global Response at Week 6
Number of participants with a successful response (complete or partial global response). Complete response = resolution of all clinical signs and symptoms and \>90% of lesions due to IA that were visible on radiologic studies at baseline (BL); partial response = clinical improvement and \>50% improvement in radiological findings present at BL.
Time frame: Baseline, Day 42 (Week 6)
Population: MITT; N = number of participants in MITT population at Week 6. Missing data and participants who died at Week 6 were treated as failure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Voriconazole/Anidulafungin | Global Response at Week 6 | 44 participants |
| Voriconazole / Placebo | Global Response at Week 6 | 61 participants |
Comparison: Treatment difference (stratified) based on a weighted difference in proportions. Stratification variables: site of infection and host factors.95% CI: [-21.6, 1.15]
Secondary
Mortality Due to Invasive Aspergillosis (IA) at Week 6 in Participants With Probable or Proven IA
Number of deaths due to Invasive Aspergillosis measured 6 weeks after start of treatment. Time to death defined as date of death minus first treatment date + 1.
Time frame: Day 1 to Day 42 (Week 6)
Population: MITT; N = number of participants in MITT population at Week 6. Participants who died due to causes other than IA before Week 6 were censored at their time of death in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Voriconazole/Anidulafungin | Mortality Due to Invasive Aspergillosis (IA) at Week 6 in Participants With Probable or Proven IA | 23 participants |
| Voriconazole / Placebo | Mortality Due to Invasive Aspergillosis (IA) at Week 6 in Participants With Probable or Proven IA | 33 participants |
Comparison: Treatment difference (stratified) based on a weighted difference in proportions. Stratification variables: site of infection and host factors.p-value: 0.102995% CI: [-15.9, 3.42]Z test for difference in proportions
Secondary
Time to Death: All-Cause Mortality
Survival time from start of treatment. Time to death defined as date of death due to any cause minus first treatment date + 1.
Time frame: Day 1 to Day 84 (Week 12)
Population: MITT; N = number of participants in MITT population at time of assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Voriconazole/Anidulafungin | Time to Death: All-Cause Mortality | 30.0 days |
| Voriconazole / Placebo | Time to Death: All-Cause Mortality | 30.0 days |
Comparison: Hazard Ratio: hazard of death in the Voriconazole/Anidulafungin arm relative to the Voriconazole/Placebo arm, adjusted for host factor status and site of infection. Participants who died beyond Day 84 were censored.p-value: 0.08395% CI: [0.46, 1.04]Cox proportional hazards model
Secondary
Time to Death Due to Invasive Aspergillosis (IA)
Survival time from start of treatment. Time to death defined as date of death due to IA minus first treatment date + 1.
Time frame: Day 1 to Day 84 (Week 12)
Population: MITT; N = number of participants in MITT population at time of assessment. Participants who died due to causes other than IA were defined as censored at time of death.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Voriconazole/Anidulafungin | Time to Death Due to Invasive Aspergillosis (IA) | 14.0 days |
| Voriconazole / Placebo | Time to Death Due to Invasive Aspergillosis (IA) | 18.5 days |
Comparison: Analysis based on Cox proportional hazards model. Participants who died beyond day 84 were censored.p-value: 0.16495% CI: [0.4, 1.16]Cox proportional hazards model