Antifungal Prophylaxis of Invasive Fungal Infections
Conditions
Brief summary
Study is to compare antifungal prophylaxis of Voriconazole and Itraconazole in subjects who have had a Stem Cell Transplant. The success of the end point will be measured using evidence of Infection, drug compliance and survival.
Interventions
DRUGItraconazole
Prophylaxis
DRUGVfend - voriconazole
Prophylaxis
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Allogeneic HSCT for acute leukemia (AML, ALL or myelodysplastic syndrome) failed lymphoma therapy or transformation of CML * Male and Female over 12 years or greater
Exclusion criteria
* Possible, probable or proven IFI at study entry or at any time in 6 months prior to study entry, defined according to the 'consensus criteria' (Ascioglu et al 2002) * Previous history of zygomycosis * Anticipated survival less than one month
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Success at Day 180: Percent of Responders (Randomization Strata) | Day 180 (Visit 9) | Percent of responders (by randomization strata) with success of antifungal prophylaxis at 180 days after allogeneic hematopoietic stem cell transplant (HSCT). Success: alive at Day 180 (Visit 9), had not developed a breakthrough proven or probable invasive fungal infection (IFI) by Visit 9, and received full course of study drug prophylaxis without interruption of greater than 14 days in total during the prophylaxis period; defined as failure if these criteria were not met. Additionally, if subject withdrew from study completely before Visit 9, imputed as failure at Visit 9 (programmatically). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Breakthrough Invasive Fungal Infection (IFI) | Day 1 up to Day 180 (Visit 9) | Summary of time (in days) from start of prophylaxis to first recorded occurrence of breakthrough proven or probable IFI. |
| Percent of Subjects With Occurrence of Breakthrough IFI | Day 1 up to Day 100 (Visit 7) and Day 180 (Visit 9) | Percent of subjects with occurrence of breakthrough IFI (proven or probable). Included all subjects in the MITT population. |
| Survival: Percent of Subjects Who Died at or Before Day 180 | Day 1 up to Day 180 (Visit 9) | Percent of subjects who died at or before Day 180, derived from the crude death rate. All subjects in the MITT population included in this proportion. |
| Success at Day 100: Percent of Responders (Randomization Strata) | Day 100 (Visit 7) | Percent of responders (by randomization strata) with success of antifungal prophylaxis at 100 days after allogeneic HSCT. Success defined as: alive at Day 100 (Visit 7), had not developed a breakthrough proven or probable IFI by Visit 7, and received full course of study drug prophylaxis without an interruption of \>14 days in total during the prophylaxis period; defined as failure if these criteria were not met. Additionally, if subject withdrew from study completely before Visit 7, imputed as failure at Visit 7 (programmatically). |
| Survival: Percent of Subjects Who Died Within 1 Year | Day 1 up to 1 year (Day 365) | Percent of subjects who died within 1 year after transplant, derived from the crude death rate. All subjects in the MITT population included in this proportion. Only deaths up until and including 365 days after first dose of study medication included in the analysis. |
| Duration of Treatment | Day 1 up to Day 180 | Median duration in days of treatment. Treatment is defined as the total number of days on which subjects took medication. |
| Percent of Subjects With Use of Other Systemic Antifungal Agents as Empirical or Therapeutic Treatment | Day 1 up to Day 180 | Percent of subjects who used other systemic antifungal agents as empirical or therapeutic treatment, defined as either empirical: subject took a systemic antifungal agent at any time after the day of first dose of medication and did not develop a breakthrough proven or probable IFI during the study or therapeutic: subject developed a breakthrough proven or probable IFI. |
| Time to Discontinuation of Study Treatment | Day 1 up to Day 180 (Visit 9) | Time in days to discontinuation of study treatment defined as the number of days from first dose to last dose inclusive as recorded in the dosing log. |
Countries
Canada, Czechia, Egypt, France, Greece, Jordan, Portugal, Russia, Spain, Switzerland, Turkey (Türkiye), United Kingdom
Participant flow
Pre-assignment details
Subjects were stratified at the time of randomization by the following factors: conditioning regimen (myeloablative or non-myeloablative); relatedness of donor (matched/related or mismatched/unrelated).
Participants by arm
| Arm | Count |
|---|---|
| Voriconazole Voriconazole (tablet or powder for oral suspension) loading dose regimen IV for first 24 hours: 6 mg/kg of body weight every 12 hours; maintenance dose (after first 24 hours) 4 mg/kg of body weight (IV) BID or 200 mg tablet or powder for oral suspension PO BID (subjects ≥ 40 kg body weight) or 100 mg tablet or powder for oral suspension twice daily (subjects \< 40 kg body weight). | 234 |
| Itraconazole Itraconazole (Sporanox™ Liquid) oral solution 200 mg PO BID. Loading dose as IV formulation on Days 0 and 1. | 255 |
| Total | 489 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 15 | 13 |
| Overall Study | Death | 35 | 38 |
| Overall Study | Failure of prophylaxis | 1 | 1 |
| Overall Study | Fungal breakthrough infection | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Other | 5 | 14 |
| Overall Study | Withdrawal by Subject | 2 | 12 |
Baseline characteristics
| Characteristic | Total | Itraconazole | Voriconazole |
|---|---|---|---|
| Age, Continuous | 43.0 years STANDARD_DEVIATION 14.5 | 42.7 years STANDARD_DEVIATION 14.6 | 43.3 years STANDARD_DEVIATION 14.4 |
| Age, Customized <18 years | 20 participants | 11 participants | 9 participants |
| Age, Customized >=65 years | 25 participants | 10 participants | 15 participants |
| Age, Customized Between 18 and 44 years | 225 participants | 119 participants | 106 participants |
| Age, Customized Between 45 and 64 years | 219 participants | 115 participants | 104 participants |
| Sex: Female, Male Female | 196 Participants | 100 Participants | 96 Participants |
| Sex: Female, Male Male | 293 Participants | 155 Participants | 138 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 228 / 234 | 252 / 255 |
| serious Total, serious adverse events | 111 / 234 | 95 / 255 |
Outcome results
Primary
Success at Day 180: Percent of Responders (Randomization Strata)
Percent of responders (by randomization strata) with success of antifungal prophylaxis at 180 days after allogeneic hematopoietic stem cell transplant (HSCT). Success: alive at Day 180 (Visit 9), had not developed a breakthrough proven or probable invasive fungal infection (IFI) by Visit 9, and received full course of study drug prophylaxis without interruption of greater than 14 days in total during the prophylaxis period; defined as failure if these criteria were not met. Additionally, if subject withdrew from study completely before Visit 9, imputed as failure at Visit 9 (programmatically).
Time frame: Day 180 (Visit 9)
Population: Modified Intent to Treat (MITT): primary analysis population; all randomized subjects: received at least 1 dose of randomized study drug and had allogeneic HSCT; data from 1 site excluded due to Good Clinical Practice (GCP) deviations; (n)=number of subjects with analyzable data at observation for voriconazole and itraconazole, respectively.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Voriconazole | Success at Day 180: Percent of Responders (Randomization Strata) | Myeloablative/matched related (n=66, 85) | 59.1 percent of participants |
| Voriconazole | Success at Day 180: Percent of Responders (Randomization Strata) | Non-myeloablative/matched related (n=58, 57) | 34.5 percent of participants |
| Voriconazole | Success at Day 180: Percent of Responders (Randomization Strata) | Myeloablative/mismatched unrelated (n=59, 58) | 52.5 percent of participants |
| Voriconazole | Success at Day 180: Percent of Responders (Randomization Strata) | Non-myeloablative/mismatched unrelated (n=41, 41) | 46.3 percent of participants |
| Itraconazole | Success at Day 180: Percent of Responders (Randomization Strata) | Non-myeloablative/mismatched unrelated (n=41, 41) | 26.8 percent of participants |
| Itraconazole | Success at Day 180: Percent of Responders (Randomization Strata) | Myeloablative/matched related (n=66, 85) | 44.7 percent of participants |
| Itraconazole | Success at Day 180: Percent of Responders (Randomization Strata) | Myeloablative/mismatched unrelated (n=59, 58) | 25.9 percent of participants |
| Itraconazole | Success at Day 180: Percent of Responders (Randomization Strata) | Non-myeloablative/matched related (n=58, 57) | 28.1 percent of participants |
Comparison: Non-inferiority inferred if lower limit of the 2-sided 95 percent (%) confidence interval (CI) for the difference between the voriconazole and itraconazole treatment groups in the adjusted proportion of subjects classified as Success at Day 180 after transplant is above -10%. Superiority achieved if 2-sided 95% CI for difference between these treatment groups in the adjusted proportion of subjects classified as Success at Day 180 after transplant does not include zero and is positive.95% CI: [7.7, 25.1]Difference in adjusted responder rates
Secondary
Duration of Treatment
Median duration in days of treatment. Treatment is defined as the total number of days on which subjects took medication.
Time frame: Day 1 up to Day 180
Population: MITT; data from 1 site excluded due to GCP deviations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Voriconazole | Duration of Treatment | 96.0 days |
| Itraconazole | Duration of Treatment | 68.0 days |
Secondary
Percent of Subjects With Occurrence of Breakthrough IFI
Percent of subjects with occurrence of breakthrough IFI (proven or probable). Included all subjects in the MITT population.
Time frame: Day 1 up to Day 100 (Visit 7) and Day 180 (Visit 9)
Population: MITT; data from 1 site excluded due to GCP deviations. Analysis excludes additional data on IFIs that were only captured on EORTC/MSG worksheets (not on Case Report Forms or in the database).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Voriconazole | Percent of Subjects With Occurrence of Breakthrough IFI | Day 100 | 0.9 percent of participants |
| Voriconazole | Percent of Subjects With Occurrence of Breakthrough IFI | Day 180 | 1.3 percent of participants |
| Itraconazole | Percent of Subjects With Occurrence of Breakthrough IFI | Day 100 | 1.2 percent of participants |
| Itraconazole | Percent of Subjects With Occurrence of Breakthrough IFI | Day 180 | 1.7 percent of participants |
Comparison: Day 100; difference in proportions (expressed as percentages), voriconazole relative to itraconazole.p-value: 0.711495% CI: [-2.2, 1.5]Difference in proportions
Comparison: Day 180; difference in proportions (expressed as percentages), voriconazole relative to itraconazole.p-value: 0.775995% CI: [-2.5, 1.9]Difference in proportions
Secondary
Percent of Subjects With Use of Other Systemic Antifungal Agents as Empirical or Therapeutic Treatment
Percent of subjects who used other systemic antifungal agents as empirical or therapeutic treatment, defined as either empirical: subject took a systemic antifungal agent at any time after the day of first dose of medication and did not develop a breakthrough proven or probable IFI during the study or therapeutic: subject developed a breakthrough proven or probable IFI.
Time frame: Day 1 up to Day 180
Population: MITT; data from 1 site excluded due to GCP deviations. Subjects who developed a breakthrough proven or probable IFI were identified only from the study database, not the EORTC/MSG worksheet. In addition, all agents identified to be antifungals were considered to be systemic.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Voriconazole | Percent of Subjects With Use of Other Systemic Antifungal Agents as Empirical or Therapeutic Treatment | 40.6 percent of participants |
| Itraconazole | Percent of Subjects With Use of Other Systemic Antifungal Agents as Empirical or Therapeutic Treatment | 49.4 percent of participants |
Comparison: Difference in proportions (expressed as a percentage), voriconazole relative to itraconazole.p-value: 0.05795% CI: [-17.8, 0.3]Difference in proportions
Secondary
Success at Day 100: Percent of Responders (Randomization Strata)
Percent of responders (by randomization strata) with success of antifungal prophylaxis at 100 days after allogeneic HSCT. Success defined as: alive at Day 100 (Visit 7), had not developed a breakthrough proven or probable IFI by Visit 7, and received full course of study drug prophylaxis without an interruption of \>14 days in total during the prophylaxis period; defined as failure if these criteria were not met. Additionally, if subject withdrew from study completely before Visit 7, imputed as failure at Visit 7 (programmatically).
Time frame: Day 100 (Visit 7)
Population: MITT; data from 1 site excluded due to GCP deviations; (n)=number of subjects with analyzable data at observation for voriconazole and itraconazole, respectively.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Voriconazole | Success at Day 100: Percent of Responders (Randomization Strata) | Myeloablative/matched related (n=66, 85) | 65.2 percent of participants |
| Voriconazole | Success at Day 100: Percent of Responders (Randomization Strata) | Myeloablative/mismatched unrelated (n=59, 58) | 55.9 percent of participants |
| Voriconazole | Success at Day 100: Percent of Responders (Randomization Strata) | Non-myeloablative/matched related (n=58, 57) | 43.1 percent of participants |
| Voriconazole | Success at Day 100: Percent of Responders (Randomization Strata) | Non-myeloablative/mismatched unrelated (n=41, 41) | 48.8 percent of participants |
| Itraconazole | Success at Day 100: Percent of Responders (Randomization Strata) | Non-myeloablative/mismatched unrelated (n=41, 41) | 36.6 percent of participants |
| Itraconazole | Success at Day 100: Percent of Responders (Randomization Strata) | Myeloablative/matched related (n=66, 85) | 50.6 percent of participants |
| Itraconazole | Success at Day 100: Percent of Responders (Randomization Strata) | Non-myeloablative/matched related (n=58, 57) | 38.6 percent of participants |
| Itraconazole | Success at Day 100: Percent of Responders (Randomization Strata) | Myeloablative/mismatched unrelated (n=59, 58) | 27.6 percent of participants |
95% CI: [6.6, 24.2]Difference in adjusted responder rates
Secondary
Survival: Percent of Subjects Who Died at or Before Day 180
Percent of subjects who died at or before Day 180, derived from the crude death rate. All subjects in the MITT population included in this proportion.
Time frame: Day 1 up to Day 180 (Visit 9)
Population: MITT; data from 1 site excluded due to GCP deviations. Analysis does not include any deaths recorded in the long-term follow-up data (not available at time of analysis).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Voriconazole | Survival: Percent of Subjects Who Died at or Before Day 180 | 15.6 percent of participants |
| Itraconazole | Survival: Percent of Subjects Who Died at or Before Day 180 | 15.4 percent of participants |
Comparison: Day 180; difference in proportions (expressed as a percentage), voriconazole relative to itraconazole.95% CI: [-6.3, 6.9]Difference in proportions
Secondary
Survival: Percent of Subjects Who Died Within 1 Year
Percent of subjects who died within 1 year after transplant, derived from the crude death rate. All subjects in the MITT population included in this proportion. Only deaths up until and including 365 days after first dose of study medication included in the analysis.
Time frame: Day 1 up to 1 year (Day 365)
Population: MITT; data from 1 site excluded due to GCP deviations. Typically, subjects received first dose study treatment on the day of their transplant; however, some subjects started treatment up to 48 hours after transplant. Data summarized with first day of study medication defined as Day 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Voriconazole | Survival: Percent of Subjects Who Died Within 1 Year | 25.9 percent of participants |
| Itraconazole | Survival: Percent of Subjects Who Died Within 1 Year | 30.7 percent of participants |
Comparison: Day 365; difference in proportions (expressed as a percentage), voriconazole relative to itraconazole.p-value: 0.248795% CI: [-13, 3.4]Difference in proportions
Secondary
Time to Breakthrough Invasive Fungal Infection (IFI)
Summary of time (in days) from start of prophylaxis to first recorded occurrence of breakthrough proven or probable IFI.
Time frame: Day 1 up to Day 180 (Visit 9)
Population: MITT; data from 1 site excluded due to GCP deviations. Analysis excludes additional data on IFIs that were only captured on European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) worksheets (not on Case Report Forms or in the database). Times were summarized only for subjects who experienced a breakthrough IFI.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Voriconazole | Time to Breakthrough Invasive Fungal Infection (IFI) | 119.0 days | 95% Confidence Interval 28.58 |
| Itraconazole | Time to Breakthrough Invasive Fungal Infection (IFI) | 77.0 days | 95% Confidence Interval 77.08 |
Secondary
Time to Discontinuation of Study Treatment
Time in days to discontinuation of study treatment defined as the number of days from first dose to last dose inclusive as recorded in the dosing log.
Time frame: Day 1 up to Day 180 (Visit 9)
Population: MITT; data from 1 site excluded due to GCP deviations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Voriconazole | Time to Discontinuation of Study Treatment | 88.7 days | 95% Confidence Interval 61.41 |
| Itraconazole | Time to Discontinuation of Study Treatment | 71.5 days | 95% Confidence Interval 52.21 |
Comparison: Mann-Whitney test used to investigate the null hypothesis that the times to discontinuation of study medication in each treatment group come from the same distribution.p-value: 0.0026Wilcoxon (Mann-Whitney)