Phase 3 Randomized Study of Rezafungin Acetate vs. Standard Antimicrobial Regimen for Preventing Invasive Fungal Diseases in Allogeneic BMT Recipients
- Trial ID
- 2024-514471-18-00
- Protocol
- CD101.IV.3.08
- Sponsor
- Mundipharma Research Limited
Trial statistics
Objectives
The primary objective of this Phase 3, multicenter, randomized, double-blind study is to demonstrate the **non-inferiority** of Rezafungin for Injection compared to the standard antimicrobial regimen (SAR) in achieving fungal-free survival at Day 90 (±7 days) in adults undergoing allogeneic blood and marrow transplantation. This is clinically relevant as it aims to establish Rezafungin as an effective alternative for preventing invasive fungal diseases, which are significant complications in this patient population. Additionally, the study seeks to assess the superiority of Rezafungin over SAR for fungal-free survival at the same time point.
Secondary objectives include:
- Evaluating the discontinuation of Rezafungin due to toxicity or intolerance compared to SAR at Day 90 (±7 days).
- Assessing the cumulative incidence of proven and probable invasive fungal disease (IFD), including infections from **Candida spp.**, **Aspergillus spp.**, and **Pneumocystis jirovecii**.
- Evaluating fungal-free survival in subjects with and without clinically significant graft-versus-host disease (GVHD).
- Assessing the time to IFD or death.
- Evaluating overall mortality and mortality attributable to IFD, with and without adjustment for patient comorbidity indices (Sorror Score).
- Assessing the safety and tolerability of Rezafungin compared to SAR.
- Evaluating the cumulative incidence of invasive-candidiasis-free survival.
Participants
The clinical trial involves a total of **210 participants** diagnosed with **Invasive Fungal Diseases** in adults undergoing allogeneic blood and marrow transplantation (BMT). The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their receipt of a human leukocyte antigen (HLA) matched allogeneic peripheral BMT from various donor types, including family, unrelated, or haploidentical donors. The trial includes individuals with underlying conditions such as acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, and other specified hematological disorders. Participants are required to have adequate renal and hepatic function prior to the initiation of the conditioning regimen. The trial population is characterized by a vulnerable group due to their medical conditions and treatment requirements. Lifestyle considerations such as diet and physical activity are not specified, but participants must comply with specific contraceptive measures if applicable. The selection criteria ensure that participants have no known glucose-6-phosphate dehydrogenase (G6PD) deficiency and have baseline serological assessments completed prior to randomization.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, controlled study designed to evaluate the efficacy and safety of **Rezafungin** for injection compared to a standard antimicrobial regimen in preventing **invasive fungal diseases** in adults undergoing allogeneic blood and marrow transplantation. The trial aims to demonstrate non-inferiority and assess the superiority of Rezafungin over the standard regimen for fungal-free survival at Day 90. The study is expected to run from May 2020 to February 2025, with participant involvement lasting up to 90 days post-transplantation.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, medical history, and baseline laboratory tests. Following randomization, participants will receive either Rezafungin or the standard regimen. Study visits will include regular follow-ups to monitor safety, efficacy, and any adverse events. The end-of-study visit will occur at Day 90, where the primary endpoint of fungal-free survival will be evaluated. Participants may be withdrawn from the study early due to adverse events, withdrawal of consent, or non-compliance with study procedures.
The trial includes several key elements of research methodology, such as the use of a placebo and comparator groups, ensuring blinding of both participants and investigators to treatment allocation. The primary efficacy endpoint is defined as survival without proven or probable invasive fungal disease and without the need for non-study systemic antifungal therapy for more than 10 days. Secondary endpoints include study drug withdrawal due to toxicities, incidence of proven and probable invasive fungal disease, time to invasive fungal disease or death, and all-cause mortality. The trial's design and procedures are structured to ensure rigorous assessment of the investigational product's safety and efficacy in the specified patient population.
Treatment
The clinical trial involves several treatments, including both experimental and non-experimental medications. **REZZAYO 200 mg powder for concentrate for solution for infusion** is the primary experimental medication. It contains the active substance **rezafungin acetate** and is administered intravenously. The pharmaceutical form is a powder for concentrate for solution for infusion. The maximum daily dose is 400 mg, with a total maximum dose of 2800 mg over a treatment period of 13 weeks. This medication is not a paediatric formulation and is classified as a chemical substance.
**Posaconazol HEXAL 100 mg** is a comparator treatment in the study. It is a gastro-resistant tablet containing the active substance **posaconazole**. The medication is administered orally, with a maximum daily dose of 600 mg and a total maximum dose of 23400 mg over a 77-day treatment period. This formulation is also not intended for paediatric use and is classified as a chemical substance.
**DIFLUCAN INJECTION** is another comparator treatment, containing the active substance **fluconazole**. It is provided as a solution for injection and administered intravenously. The maximum daily dose is 400 mg, with a total maximum dose of 36000 mg over a 90-day treatment period. This medication is not a paediatric formulation and is classified as a chemical substance.
**NOXAFIL® (posaconazole) Injection** is also used as a comparator. It contains **posaconazole** and is administered intravenously. The maximum daily dose is 600 mg, with a total maximum dose of 23400 mg over a 77-day treatment period. This formulation is not intended for paediatric use and is classified as a chemical substance.
**Bactrim Tablets** serve as a comparator treatment, containing the active substances **sulfamethoxazole** and **trimethoprim**. These tablets are administered orally, with a maximum daily dose of 480 mg and a total maximum dose of 36960 mg over a 77-day treatment period. This medication is not a paediatric formulation and is classified as a chemical substance.
**NOXAFIL® (posaconazole) Delayed-Release Tablets** are another comparator treatment, containing **posaconazole**. These tablets are administered orally, with a maximum daily dose of 600 mg and a total maximum dose of 23400 mg over a 77-day treatment period. This formulation is not intended for paediatric use and is classified as a chemical substance.
**Diflucan 200mg Hard Capsules** are used as a comparator, containing **fluconazole**. These capsules are administered orally, with a maximum daily dose of 400 mg and a total maximum dose of 36000 mg over a 90-day treatment period. This medication is not a paediatric formulation and is classified as a chemical substance.
**Saline solution** is used as a non-experimental treatment in the study. It serves as a standard-of-care therapy and is not associated with any specific pharmaceutical form, dosage, or route of administration in the context of this trial.
**Placebo to bactrim, diflucan 200 mg - microcrystalline cellulose capsules** and **PLACEBO to Posaconazol hexal** are used as placebo treatments in the study. These do not contain active substances and are not associated with any specific pharmaceutical form, dosage, or route of administration in the context of this trial.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the endpoint of fungal-free survival at Day 90 (±7 days). This primary efficacy endpoint is defined by three parameters: survival, absence of proven or probable **Invasive Fungal Disease (IFD)**, and absence of receipt of non-study drug systemic antifungal therapy for a cumulative exposure of more than 10 days. Proven and probable IFD are determined according to the modified 2020 European Organization for Research and Treatment of Cancer Mycoses Study Group Education and Research Consortium (EORTC-MSGERC) criteria.
Secondary efficacy endpoints include the evaluation of study drug withdrawal due to toxicities or intolerance, cumulative incidence of proven and probable IFD, time to IFD or death, all-cause mortality, and attributable mortality associated with IFD. The time to IFD or death is calculated from the first dose of the study drug to the date of proven or probable IFD or death from any cause. Subjects without an event will be censored at the last known date they were IFD-free or alive, and those lost to follow-up will be censored at the date of last contact.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Willing and able to provide written informed consent.
- Males or females ≥18 years of age.
- 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.
- 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 or unrelated 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)
- Receiving myeloablative or reduced-intensity conditioning regimens.
- 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.
- Baseline blood samples drawn for serum Platelia galactomannan enzyme immunoassay (GM EIA) and β-D-glucan levels within 15 days before randomization, with results available prior to randomization.
- Baseline Toxoplasma serologies available within 6 weeks prior to randomization. Subjects with a positive Toxoplasma IgG serology at any time prior to randomization do not need to repeat the Toxoplasma serologies (IgG and IgM) and will be considered to have a prior history of toxoplasmosis.
- Baseline glucose-6-phosphate dehydrogenase (G6PD) deficiency determination by the investigator prior to randomization with no evidence of known G6PD deficiency performed any time prior to randomization. If the Investigator assesses the subject as G6PD sufficient, the G6PD test result does not need to be entered into the Electronic Data Capture (EDC) system.
- 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.
Exclusion Criteria
- Diagnosis of AML not in morphological remission.
- Recent use of an investigational medicinal product within 28 days or 5 half-lives of the investigational medicinal product, whichever is greater to prevent overlapping toxicities when this study’s investigational product is dosed, or presence of an investigational device at the time of screening.
- Known infection with human immunodeficiency virus (HIV). Subjects with unknown HIV status should be tested for HIV antibodies per standard of care.
- Receipt of previous allogeneic BMT.
- Pregnant or lactating females.
- The Principal Investigator (PI) determines that the subject should not participate in the study.
- Considered unlikely to follow up for 90 days after receipt of the BMT due to logistic concerns (i.e., location relative to transplant center).
- Known liver cirrhosis, diagnosed according to country or Medical Society specific guidelines and documented in the medical records prior to initiating conditioning regimen.
- Planned peripheral blood or marrow autograft.
- Not applicable for protocol Amendment 6.
- 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.
- Suspected or diagnosed IFD within 4 weeks of randomization.
- 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).
- a. Planned or ongoing intake at screening of a known severe neurotoxic medication or with a known moderate neurotoxic medication 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.
- Planned receipt of cord blood for transplantation.
- Diagnosis of chemotherapy-resistant lymphoma; a first relapse can occur provided that a second complete remission has been achieved.
- Diagnosed symptomatic heart failure or with left ventricular ejection fraction (LVEF) at rest ≤50%, or shortening fraction ≤26%.
- 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.
- Reduced lung function, that would significantly impact on clinical outcomes, based on routine clinical practice and assessments conducted at the Investigator site. If any of the following tests are conducted, the criteria for reduced lung function are as follows: a. Diffusion capacity (corrected for hemoglobin) or forced expiratory volume in 1 second (FEV1) ≤65% of predicted value b. O2 saturation ≤82% on room air.
- Suspected or documented PCP within 2 years of screening.
- 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 15 days prior to transplant.
- Known hypersensitivity to Rezafungin for Injection, any echinocandin, fluconazole, posaconazole, other azole antifungal, or to any of their excipients.
- 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.
- Toxoplasma IgM positive serology in the 6 weeks prior to randomisation.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 11 May 2020 | 120 |
 France | Not Recruiting | 11 May 2020 | 70 |
 Germany | Not Recruiting | 11 May 2020 | 70 |
 Italy | Not Recruiting | 11 May 2020 | 70 |
 Spain | Not Recruiting | 11 May 2020 | 90 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Diflucan 200mg Hard Capsules | Comparator | HARD CAPSULES | ORAL | 400 | 90 | PRD11332657 |
PLACEBO to Posaconazol hexal | Placebo | N/A | — | — | — | N/A |
Posaconazol HEXAL 100 mg | Comparator | GASTRO-RESISTANT TABLET | ORAL | 600 | 77 | PRD7723537 |
NOXAFIL® (posaconazole) Injection | Comparator | INJECTION | INTRAVENOUS | 600 | 77 | PRD11582452 |
Placebo to bactrim, diflucan 200 mg - microcrystalline cellulose capsules | Placebo | N/A | — | — | — | N/A |
DIFLUCAN INJECTION | Comparator | SOLUTION FOR INJECTION | INTRAVENOUS USE | 400 | 90 | PRD11581912 |
REZZAYO 200 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 400 | 13 | PRD9931889 |
Saline solution | Placebo | N/A | — | — | — | N/A |
REZZAYO 200 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 400 | 13 | PRD11067940 |
Bactrim Tablets | Comparator | TABLET | ORAL USE | 480 | 77 | PRD11581969 |