| 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 (BMT) |
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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 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 to IFD, with and without adjustment for patient comorbidity indices (Sorror Score), in subjects randomized to Rezafungin for Injection versus the SAR
•Evaluate the safety and tolerability of Rezafungin versus the SAR
|
|
| 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 allogenic peripheral blood or marrow transplant (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).
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.
j. Chronic myelomonocytic leukemia.
k. Chronic lymphocytic leukemia.
l. Drepanocytosis (sickle cell anemia)
m. Red blood cell aplasia
n. Myeloproliferative disorder, unclassified
o. Multiple myeloma (plasma cell myeloma)
5. Receiving myeloablative or reduced-intensity conditioning regimens.
6. Adequate renal and hepatic function prior to initiation of conditioning regimen, therefore between 40 days prior and 10 days prior to BMT, documented as follows:
a. Hepatic: alanine aminotransferase ≤2.5 × upper limit of normal (ULN) and total serum bilirubin ≤1.5 × ULN (excluding Gilbert’s Syndrome).
b. Renal: serum creatinine ≤2 mg/dL and with creatinine clearance (CrCl) ≥30 mL/min without a history of renal transplant, or undergoing weekly dialysis within 4 weeks of the BMT.
7. Baseline blood samples drawn for Platelia galactomannan enzyme immunoassay (GM EIA) and β-D-glucan levels within 14 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 any time prior to randomization.
10. Female subjects of child-bearing potential <2 years post-menopausal (unless surgically sterile)must agree to and comply with using one 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 (only possible if it corresponds to the subject's usual lifestyle) while participating in this study, and for 30 days after the last dose of study drug. Male subjects must be vasectomized, abstain from sexual intercourse, or agree to use barrier contraception (condom with spermicide), and agree not to donate sperm while participating in the study and for 120 days from the last IV dose of study drug.
Definitions:
• Woman of childbearing potential: fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
• A postmenopausal state: no menses for 12 months without an alternative medical cause.
• Abstinence: refraining from heterosexual intercourse. |
|
| E.4 | Principal exclusion criteria |
1. Diagnosis of AML not in morphological remission.
2. Diagnosis of chemotherapy-resistant lymphoma: a first relapse can occur provided that a second complete remission has been achieved.
3. Suspected or diagnosed invasive fungal disease (IFD) within 4 weeks of screening.
4. Diagnosed symptomatic heart failure or with left ventricular ejection fraction (LVEF) at rest ≤50%, or shortening fraction ≤26%.
5. Personal or family history of Long QT interval on ECG (QT) syndrome or a prolonged QT interval corrected for heart rate by Fridericia’s formula (QTcF) (>470 msec in males and >480 msec in females); or concurrent administration of terfenadine, cisapride, astemizole, erythromycin, pimozide, quinidine, or halofantrine (Appendix 6A).
6. Diagnosed reduced lung function with either diffusion capacity (corrected for hemoglobin) or forced expiratory volume in 1 second (FEV1) ≤70% of predicted value, or O2 saturation ≤82% on room air.
7. Suspected or documented PCP within 2 years of screening.
8. Positive baseline serum Platelia GM EIA (≥ 0.5) and/or β-D-glucan assay (Fungitell ≥80 pg/mL or Fujifilm Wako >11 pg/mL) within 14 days of transplant.
9. Receipt of previous allogeneic BMT.
10. Planned receipt of cord blood for transplantation.
11. Planned peripheral blood or marrow autograft.
12. Not applicable for protocol Amendment 6.
13. Grade 2 or higher ataxia, tremor, motor neuropathy, or sensory neuropathy, per NCI CTCAE version 5.0.
14. History of severe (Grade ≥3) ataxia, neuropathy or tremors; or a diagnosis of multiple sclerosis or a movement disorder (including Parkinson’s disease or Huntington’s disease).
15. a. Planned or ongoing intake at screening of a known severe neurotoxic medication (see Appendix 5) or with a known moderate neurotoxic medication (see Appendix 5) in a patient with ataxia, tremor, motor neuropathy, or sensory neuropathy of CTCAE version 5.0 Grade 1 or higher.
b. Any contraindication or a medication or supplement known to severely interact with the standard antimicrobial regimen (SAR) as detailed in the US Prescribing Information (USPI) or Summary of Product Characteristics (SmPC) of fluconazole, posaconazole, or TMP/SMX (see Appendix 6B, Appendix 6C, or Appendix 6D, respectively).
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, including but not limited to anaphylaxis, exfoliative skin disorders, or acute porphyria.
18. Recent use of an investigational medicinal product within 28 days or greater to assure more than 5 half-lives have passed to prevent overlapping toxicities when this study’s investigational product is dosed, or presence of an investigational device at the time of screening.
19. Known infection with HIV. Subjects with unknown HIV status should be tested for HIV antibodies per standard of care.
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).
23. Known liver cirrhosis, diagnosed according to country or Medical Society specific guidelines and documented in the medical records prior to initiating conditioning regimen.
24. Body weight >130 kg at screening. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is fungal-free survival at Day 90 (±7 days), as defined by:
• Survival,
• Absence of proven or probable IFD. Proven and probable IFD are defined per the modified 2020 European Organization for Research and Treatment of Cancer Mycoses Study Group Education and Research Consortium (EORTC-MSGERC) criteria (see Appendix 4 for complete IFD definitions)
• Absence of receipt of non-study drug systemic antifungal therapy (including anti-PCP drugs) for a cumulative exposure >10 days. Anti-PCP drugs include TMP-SMX, dapsone, atovaquone, pentamidine (IV or inhaled), and combined clindamycin and primaquine. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
To evaluate secondary efficacy objectives, secondary efficacy endpoints include:
• Study drug withdrawal due to toxicities or intolerance
• 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). Subjects who do not have an event will be censored at the date last known to be IFD-free or alive. Subjects who are lost to follow-up will be censored at the date of last contact.
• All-cause mortality
• Attributable mortality associated with IFD |
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| E.5.2.1 | 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.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 | Yes |
| 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 | 4 |
| 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 |
| Switzerland |
| Canada |
| Turkey |
| United Kingdom |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Spain |
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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
|
|
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 8 |
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