E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Invasive Fungal Diseases in Adults undergoing Allogeneic Blood and Marrow Transplantation |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10017528 |
E.1.2 | Term | Fungal infectious disorders |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
-To demonstrate noninferiority in subjects who received an allogeneic BMT for subjects randomized to Rezafungin for Injection compared to subjects randomized to the standard antimicrobial regimen (SAR) for fungal-free survival at Day 90 (±7 days)
-To demonstrate superiority in subjects who received an allogeneic BMT randomized to Rezafungin for Injection compared to subjects randomized to the SAR for fungal-free survival at Day 90 (±7 days) |
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E.2.2 | Secondary objectives of the trial |
•Evaluate discontinuation of Rezafungin for Injection compared to the SAR secondary to toxicity or intolerance at Day 90 (±7 days)
•Evaluate cumulative incidence of proven and probable invasive fungal disease (IFD) including the number of invasive infections from Candida spp., Aspergillus spp., and Pneumocystis jirovecii in subjects randomized to Rezafungin for Injection compared to the SAR through Day 90 (±7 days)
•Evaluate fungal-free survival in subjects with and without a diagnosis of clinically significant graft-versus-host disease (GVHD) who are randomized to Rezafungin for Injection compared to the SAR through Day 90 (±7 days)
•Evaluate time to IFD or death in subjects randomized to Rezafungin for Injection versus the SAR
•Evaluate overall mortality and attributable mortality, with and without adjustment for patient comorbidity indices, in subjects randomized to Rezafungin for Injection versus the SAR
•Evaluate the safety and tolerability of Rezafungin versus the SAR
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Willing and able to provide written informed consent.
2. Males or females ≥18 years of age.
3.Receiving a human leukocyte antigen (HLA) matched allogeneic peripheral BMT from a family or unrelated donor, HLA-mismatched related or unrelated donor, or haploidentical donor.
4. Diagnosed with 1 of the following underlying diseases:
a. Acute myeloid leukemia (AML), with or without a history of myelodysplastic syndrome, in first or second complete remission.
b. Acute lymphoblastic leukemia, in first or second complete remission.
c. Acute undifferentiated leukemia in first or second remission.
d. Acute biphenotypic leukemia in first or second complete remission.
e. Chronic myelogenous leukemia in either chronic or accelerated phase.
f. One of the following myelodysplastic syndrome(s) defined by the following:
i. Refractory anemia.
ii. Refractory anemia with ringed sideroblasts.
iii. Refractory cytopenia with multilineage dysplasia.
iv. Refractory cytopenia with multilineage dysplasia and ringed sideroblasts.
v. Refractory anemia with excess blasts – 1 (5–10% blasts).
vi. Refractory anemia with excess blasts – 2 (10–20% blasts).
vii. Myelodysplastic syndrome, unclassified.
viii. Myelodysplastic syndrome associated with isolated del (5q).
ix. Chronic myelomonocytic leukemia.
g. Lymphoma (including Hodgkin’s) with chemosensitive disease (i.e., response to chemotherapy) and receiving a related donor transplant.
h. Aplastic anemia.
i. Primary or secondary myelofibrosis.
5. Receiving myeloablative or reduced-intensity conditioning regimens.
6. Adequate renal and hepatic function, within 6 weeks of initiation of conditioning, as measured by:
a. Hepatic (within 72 hours of Day 0): alanine aminotransferase <5× upper limit of normal (ULN)
and total serum bilirubin <2.5 mg/dL.
b. Renal (within 72 hours of Day 0): Serum creatinine within normal range for age or if serum
creatinine above ULN range for age, a creatinine clearance [CrCl]) ≥60 mL/min.
7. Baseline blood samples drawn for serum Platelia galactomannan enzyme immunoassay (GM EIA) and β-D glucan levels within 10 days before randomization, with results available prior to randomization.
8. Baseline Toxoplasma serologies available within 6 weeks prior to randomization.
9. Baseline glucose-6-phosphate dehydrogenase (G6PD) deficiency testing with no evidence of G6PD deficiency performed within 6 weeks prior to randomization.
10. Female subjects of child-bearing potential <2 years post-menopausal must agree to and comply with using 1 barrier method (e.g., female condom with spermicide) plus one other highly effective method of birth control (e.g., oral contraceptive, implant, injectable, indwelling intrauterine device, vasectomized partner), or sexual abstinence while participating in this study. Male subjects must be vasectomized, abstain from sexual intercourse, agree to use barrier contraception (condom with spermicide), and also agree not to donate sperm while participating in the study and for 120 days from the last IV dose of study drug. |
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E.4 | Principal exclusion criteria |
1. Diagnosis of AML not in morphological remission.
2. Diagnosis of chemotherapy-resistant lymphoma.
3. Suspected or diagnosed IFD within 4 weeks of screening.
4. Diagnosed symptomatic heart failure with left ventricular ejection fraction (LVEF) at rest ≤40%, LVEF >40% but fails to improve with exercise, or shortening fraction ≤26%.
5. Personal or family history of Long QT interval on ECG (QT) syndrome or a prolonged QT interval corrected (QTc) interval (>470 msec in males and >480 msec in females); or concurrent administration of terfenadine, cisapride, astemizole, erythromycin, pimozide, or quinidine
6. Diagnosed reduced lung function with either diffusion capacity (corrected for hemoglobin), forced expiratory volume 1, forced vital capacity ≤45% of predicted value, or O2 saturation ≤85% on room air.
7. Suspected or documented Pneumocystis pneumonia (PCP) within 2 years of screening.
8. Positive baseline serum Platelia GM EIA (≥ 0.5) and/or β-D glucan assay (≥80 pg/mL).
9. Receipt of previous allogeneic BMT.
10. Planned receipt of cord blood for transplantation.
11. Planned peripheral blood or marrow autograft.
12. Underlying diagnosis of multiple myeloma.
13. Grade 2 or higher ataxia, tremor, motor neuropathy, or sensory neuropathy, per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
14. History of severe ataxia, neuropathy, or tremors; or a diagnosis of multiple sclerosis or a movement disorder (including Parkinson’s disease or Huntington’s disease).
15. Planned or ongoing therapy at screening with a known neurotoxic medication.
16. Known hypersensitivity to Rezafungin for Injection, any echinocandin, fluconazole, posaconazole, other azole antifungal, or to any of their excipients.
17. Known hypersensitivity or inability to receive TMP/SMX or any of its excipients.
18. Recent use of an investigational medicinal product within 28 days of the first dose of prophylactic study drug or presence of an investigational device at the time of screening.
19. Known infection with human immunodeficiency virus (HIV).
20. Pregnant or lactating females.
21. The Principal Investigator (PI) determines that the subject should not participate in the study.
22. Considered unlikely to follow up for 90 days after receipt of the BMT due to logistic concerns (i.e., location relative to transplant center). |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is fungal-free survival as defined by:
Survival and absence of proven or probable IFD in subjects who tolerate study drug (i.e., do not withdraw from study drug due to toxicities or intolerance) and survive through Day 90 (±7 days).
Proven Candida infection documented by clinical criteria plus positive culture
or gram stain from a normally sterile site; probable Candida infection
documented by clinical criteria plus a positive β-D glucan assay
– Proven mold infection documented by clinical criteria plus culture from
a normally sterile site and/or histopathologic evidence of mold; probable mold
infection documented by clinical criteria plus GM antigen positivity and/or
positive culture from non-sterile site, or positive β-D glucan assay
– Proven PCP documented by clinical criteria plus histopathology plus microbial
evidence of disease by antigen from BAL fluid; Probable PCP documented by
clinical criteria plus microbial evidence provided by antigen from sputum, or two
positive β-D glucan assays |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Day 14 (±1 day), Day 28 (±1 day), Day 60 (±5 days), Day 90 (±7 days), and Day 120 (±7 days). |
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E.5.2 | Secondary end point(s) |
Study drug withdrawal due to toxicities or intolerance (I)
Cumulative incidence of proven and probable IFD including numbers of invasive infection from Candida spp., Aspergillus spp., and Pneumocystis jirovecii
Time to IFD or death, defined as the number days from the first dose of study drug to the date of proven or probable IFD or death
All-cause mortality
Attributable mortality associated with IFD
The secondary efficacy endpoint is fungal-free survival at Day 90 (±7 days) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Time to IFD or death, defined as the number days from the first dose of study drug to the date of proven or probable IFD or death (all-cause).
- All-cause mortality
- Attributable mortality associated with IFD
- through all protocol and Day 90 (±7 days) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 27 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Belgium |
Canada |
France |
Germany |
Italy |
Netherlands |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 10 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 10 |