ReSPECT: Study of Rezafungin Compared to Standard Antimicrobial Regimen for Prevention of Invasive Fungal Diseases in Adults Undergoing Allogeneic Blood and Marrow Transplantation
Study Details
Study Description
Brief Summary
The purpose of this pivotal study is to determine if intravenous Rezafungin is efficacious and safe in the prevention of invasive fungal diseases when compared to the standard antimicrobial regimen.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
A Phase 3, multicenter, prospective, randomized, double-blind, efficacy and safety study of Rezafungin for injection versus the standard antimicrobial regimen for the prevention of invasive fungal diseases in subjects undergoing allogeneic blood and marrow transplantation.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Group 1: Rezafungin for Injection Subjects in Rezafungin treatment group will receive a 400 mg loading dose in Week 1, followed by 200 mg once weekly, for a total of 13 weeks. Subjects will receive oral placebo for standard antimicrobial regimen (SAR) azole prophylaxis and oral placebo for SAR anti-PCP prophylaxis in accordance with the respective SAR dosing regimens for each. For subjects who are switched to a SAR IV regimen, oral placebo for SAR azole prophylaxis will be changed to IV placebo. |
Drug: Rezafungin for Injection
Intravenous antifungal therapy
Other Names:
Drug: Intravenous Placebo
Normal saline
Other Names:
Drug: Oral Placebo
Microcrystalline cellulose
Other Names:
|
| Active Comparator: Group 2: Oral Antifungal Subjects in SAR treatment group will receive 400 mg oral fluconazole once daily for 13 weeks. Fluconazole may be switched, due to acute clinically significant GVHD, to 300 mg oral posaconazole twice daily on the first day of the medication switch and 300 mg once daily, thereafter. However, subjects who are switched to posaconazole cannot be switched back to fluconazole. Azole-based antifungal therapy (fluconazole or posaconazole) can be switched from daily oral therapy to daily IV therapy at the discretion of the Investigator. In addition, subjects in the SAR group will receive anti-PCP prophylaxis with oral TMP/SMX (80 mg TMP/400 mg SMX) once daily. |
Drug: Posaconazole
Oral antifungal therapy
Other Names:
Drug: Fluconazole
Oral antifungal therapy
Other Names:
Drug: Trimethoprim-sulfamethoxazole (TMP/SMX)
Oral antibacterial therapy
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Noninferior Fungal-Free Survival (US FDA) [Day 90 (±7 days)]
The number of subjects in each treatment group who are fungal-free and survive.
- Noninferior Fungal-Free Survival (US FDA) [Day 90 (±7 days)]
The percentage of subjects in each treatment group who are fungal-free and survive.
- Superior Fungal-Free Survival (EMA) [Day 90 (±7 days)]
The number of subjects in each treatment group who are fungal-free and survive.
- Superior Fungal-Free Survival (EMA) [Day 90 (±7 days)]
The percentage of subjects in each treatment group who are fungal-free and survive.
Secondary Outcome Measures
- Compare Discontinuation for Toxicity or Intolerance [Day 90 (±7 days)]
The number of subjects that discontinued Rezafungin for Injection compared to the standard antimicrobial regimen (SAR) secondary to toxicity or intolerance.
- Compare Discontinuation for Toxicity or Intolerance [Day 90 (±7 days)]
The percentage of subjects that discontinued Rezafungin for Injection compared to the standard antimicrobial regimen (SAR) secondary to toxicity or intolerance.
- Compare Proven and Probable IFD [Day 90 (±7 days)]
The number of subjects in each treatment group who have proven and probable IFD including the number of invasive infections from Candida spp., Aspergillus spp., and Pneumocystis jirovecii.
- Compare Proven and Probable IFD [Day 90 (±7 days)]
The percentage of subjects in each treatment group who have proven and probable IFD including the number of invasive infections from Candida spp., Aspergillus spp., and Pneumocystis jirovecii.
- Compare Fungal-Free Survival with or without a Diagnosis of Clinically Significant GVHD [Day 90 (±7 days)]
The number of subjects in each treatment group who are fungal-free survival with or without a diagnosis of clinically significant GVHD.
- Compare Fungal-Free Survival with or without a Diagnosis of Clinically Significant GVHD [Day 90 (±7 days)]
The percentage of subjects in each treatment group who are fungal-free survival with or without a diagnosis of clinically significant GVHD.
- Compare Time to IFD, or Death [Day 90 (±7 days)]
Evaluate time to IFD (proven or probable IFD) or death in subjects randomized to Rezafungin for Injection compared to the standard antimicrobial regimen (SAR).
- Compare Mortality [Day 1 through follow-up visit (Day 120)]
Evaluate overall mortality and attributable mortality, with and without adjustment for patient comorbidity indices, in subjects randomized to Rezafungin for Injection compared to the SAR.
- Incidence of Treatment Emergent Adverse Events [Safety and Tolerability] [Day 1 through follow-up visit (Day 120)]
The number of subjects with incidence of treatment emergent adverse events based on clinical chemistry, hematology and urine analysis laboratory test, vital sign, physical exams and ECG abnormalities.
- Comparison of Fungal-Free [Day 14 (±1 day), Day 28 (±1 day), Day 60 (±5 days), and Day 120 (±7 days)]
The number of subjects in each treatment group who are fungal-free.
- Comparison of Fungal-Free [Day 14 (±1 day), Day 28 (±1 day), Day 60 (±5 days), and Day 120 (±7 days)]
The percentage of subjects in each treatment group who are fungal-free.
- Comparison of Presence and Severity of GHVD [Day 90 (±7 days)]
Evaluate the presence and severity of GVHD in subjects randomized to Rezafungin for Injection compared to the SAR.
- Comparison of Fungal-Free with AML [Day 90 (±7 days)]
The number of subjects in each treatment group who are fungal-free with an underlying diagnosis of acute myeloid leukemia (AML).
- Comparison of Fungal-Free with AML [Day 90 (±7 days)]
The percentage of subjects in each treatment group who are fungal-free with an underlying diagnosis of acute myeloid leukemia (AML).
- Compare Incidence of IFD [Day 14 (±1 day), Day 28 (±1 day), Day 60 (±5 days), Day 90 (±7 days), and Day 120 (±7 days)]
Evaluate the incidence of proven, probable, possible, and presumptive IFD in subjects randomized to Rezafungin for Injection compared to the SAR.
- Compare Relapse-Free Survival [Day 1 through follow-up visit (Day 120)]
Evaluate relapse-free survival, with and without adjustment for patient comorbidity indices, in subjects randomized to Rezafungin for Injection compared to the SAR.
- Evaluate PK (Cmax) [Day 0 (±2 days) within 10 minutes before end of infusion, and one sample between end of infusion and 12 hours after end of infusion; Days 1-4, one sample at any time; Day 7 (±1 day), Day 28 (±1 day), and Day 63 (±1 day) prior to dosing; and EOT visit]
Evaluate maximum plasma concentration (Cmax).
- Evaluate PK (Tmax) [Day 0 (±2 days) within 10 minutes before end of infusion, and one sample between end of infusion and 12 hours after end of infusion; Days 1-4, one sample at any time; Day 7 (±1 day), Day 28 (±1 day), and Day 63 (±1 day) prior to dosing; and EOT visit]
Evaluate time to Cmax.
- Evaluate PK (AUC) [Day 0 (±2 days) within 10 minutes before end of infusion, and one sample between end of infusion and 12 hours after end of infusion; Days 1-4, one sample at any time; Day 7 (±1 day), Day 28 (±1 day), and Day 63 (±1 day) prior to dosing; and EOT visit]
Evaluate area under the curve (AUC).
- Compare Post-Engraftment Cytopenias and Transfusion Requirements [Day 1 through follow-up visit (Day 120)]
Evaluate post-engraftment cytopenias and transfusion requirements of Rezafungin for Injection compared to the SAR.
- Compare Infections Caused by TMP/SMX-Sensitive Organisms [Day 14 (±1 day), Day 28 (±1 day), Day 60 (±5 days), Day 90 (±7 days), and Day 120 (±7 days)]
Evaluate infections caused by TMP/SMX-sensitive organisms (Toxoplasma gondii [T. gondii], Nocardia spp.) in Rezafungin for Injection compared to the SAR.
- Compare Antifungal Prophylaxis [Day 14 (±1 day), Day 28 (±1 day), Day 60 (±5 days), Day 90 (±7 days), and Day 120 (±7 days)]
Evaluate interruption and discontinuation of antifungal prophylaxis due to suspected IFDs of Rezafungin for Injection compared to the SAR.
- Compare the health economics outcome research (HEOR) variable of "Days in Hospital" [Once weekly for outpatient, or twice weekly for inpatient, at completion of study drug therapy [Day 90 (±7 days)] and for 30 days [Day 120 (±7 days)]]
Evaluate the number of hospital days for subjects randomized to Rezafungin for Injection compared to the SAR.
- Compare the health economics outcome research (HEOR) variable of "Days in Intensive Care Unit (ICU)" [Once weekly for outpatient, or twice weekly for inpatient, at completion of study drug therapy [Day 90 (±7 days)] and for 30 days [Day 120 (±7 days)]]
Evaluate the number of days in ICU for subjects randomized to Rezafungin for Injection compared to the SAR.
- Compare the health economics outcome research (HEOR) variable of "Readmission due to Infectious Disease Diagnosis" [Once weekly for outpatient, or twice weekly for inpatient, at completion of study drug therapy [Day 90 (±7 days)] and for 30 days [Day 120 (±7 days)]]
Evaluate readmission(s) due to infectious disease diagnosis for subjects randomized to Rezafungin for Injection compared to the SAR.
- Compare the health economics outcome research (HEOR) variable of "Readmission due to Invasive Fungal Disease Diagnosis" [Once weekly for outpatient, or twice weekly for inpatient, at completion of study drug therapy [Day 90 (±7 days)] and for 30 days [Day 120 (±7 days)]]
Evaluate readmission(s) due to invasive fungal disease diagnosis for subjects randomized to Rezafungin for Injection compared to the SAR.
- Compare the health economics outcome research (HEOR) variable of "Alternative Antifungal Therapy" [Once weekly for outpatient, or twice weekly for inpatient, at completion of study drug therapy [Day 90 (±7 days)] and for 30 days [Day 120 (±7 days)]]
Evaluate the incidence of alternative antifungal therapy compared to Rezafungin for Injection and the SAR.
- Compare the health economics outcome research (HEOR) variable of "Antibiotic Therapy" [Once weekly for outpatient, or twice weekly for inpatient, at completion of study drug therapy [Day 90 (±7 days)] and for 30 days [Day 120 (±7 days)]]
Evaluate the incidence of antibiotic therapy compared to Rezafungin for Injection and the SAR.
Eligibility Criteria
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:
-
Acute myeloid leukemia (AML), with or without a history of myelodysplastic syndrome, in first or second complete remission.
-
Acute lymphoblastic leukemia, in first or second complete remission.
-
Acute undifferentiated leukemia in first or second remission.
-
Acute biphenotypic leukemia in first or second complete remission.
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Chronic myelogenous leukemia in either chronic or accelerated phase.
-
One of the following myelodysplastic syndrome(s) defined by the following:
- Refractory anemia.
-
Refractory anemia with ringed sideroblasts.
-
Refractory cytopenia with multilineage dysplasia.
-
Refractory cytopenia with multilineage dysplasia and ringed sideroblasts.
-
Refractory anemia with excess blasts - 1 (5-10% blasts).
-
Refractory anemia with excess blasts - 2 (10-20% blasts).
-
Myelodysplastic syndrome, unclassified.
-
Myelodysplastic syndrome associated with isolated del (5q).
-
Chronic myelomonocytic leukemia.
-
Lymphoma (including Hodgkin's) with chemosensitive disease (i.e., response to chemotherapy) and receiving a related donor transplant.
-
Aplastic anemia.
-
Primary or secondary myelofibrosis.
-
Receiving myeloablative or reduced-intensity conditioning regimens.
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Adequate renal and hepatic function, within 6 weeks of initiation of conditioning, as measured by:
-
Hepatic (within 72 hours of Day 0): alanine aminotransferase
-
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.
-
Baseline blood samples drawn for serum Platelia galactomannan enzyme immunoassay (GM EIA) and β-D glucan levels within 14 days before randomization, with results available prior to randomization.
-
Baseline Toxoplasma serologies available within 6 weeks prior to randomization.
-
Baseline glucose-6-phosphate dehydrogenase (G6PD) deficiency testing with no evidence of G6PD deficiency performed within 6 weeks prior to randomization.
-
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.
Exclusion Criteria:
-
Diagnosis of AML not in morphological remission.
-
Diagnosis of chemotherapy-resistant lymphoma.
-
Suspected or diagnosed invasive fungal disease (IFD) within 4 weeks of screening.
-
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%.
-
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.
-
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.
-
Suspected or documented PCP within 2 years of screening.
-
Positive baseline serum Platelia GM EIA (≥ 0.5) and/or β-D glucan assay (≥80 pg/mL).
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Receipt of previous allogeneic BMT.
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Planned receipt of cord blood for transplantation.
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Planned peripheral blood or marrow autograft.
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Underlying diagnosis of multiple myeloma.
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Grade 2 or higher ataxia, tremor, motor neuropathy, or sensory neuropathy, per NCI CTCAE version 5.0.
-
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).
-
Planned or ongoing therapy at screening with a known neurotoxic medication for a complete list of prohibited neurotoxic medications).
-
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.
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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.
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Known infection with HIV.
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Pregnant or lactating females.
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The Principal Investigator (PI) determines that the subject should not participate in the study.
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Considered unlikely to follow up for 90 days after receipt of the BMT due to logistic concerns (i.e., location relative to transplant center).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | AZ Sint-Jan | Brugge | West Vlaanderen | Belgium | 8000 |
| 2 | University Hospitals Leuven, Campus Gasthuisberg - UZ Leuven | Leuven | Belgium | 3000 | |
| 3 | Hamilton Health Sciences' Juravinski Hospital | Hamilton | Ontario | Canada | L8V1C3 |
| 4 | McGill University Health Center | Montréal | Canada | H4A3J1 | |
| 5 | Jean Minjoz Hospital | Besançon | France | 25030 | |
| 6 | Henri Mondor Hospital | Créteil | France | 94000 | |
| 7 | Grenoble Alpes University Hospital Center | Grenoble | France | 3803 | |
| 8 | University Hospital of Limoges | Limoges | France | 87000 | |
| 9 | University Hospital of Nantes | Nantes | France | 44000 | |
| 10 | University Hospital of Bordeaux | Pessac | France | 33604 | |
| 11 | Lyon-Sud Hospital Center | Pierre-Bénite | France | 69495 | |
| 12 | University Hospital Carl Gustav Carus Dresden | Dresden | Germany | 01307 | |
| 13 | Essen University Hospital | Essen | Germany | 45147 | |
| 14 | University Hospital of Cologne | Köln | Germany | 50931 | |
| 15 | Johannes Gutenberg University Medical Center | Mainz | Germany | 55131 | |
| 16 | San Martino Polyclinic Hospital | Genova | Italy | 16132 | |
| 17 | Agostino Gemelli University Policlinic | Rome | Italy | 00135 | |
| 18 | Hospital Clinic of Barcelona | Barcelona | Spain | 08036 | |
| 19 | Hospital de la Princesa | Madrid | Spain | 28006 | |
| 20 | University Hospital Ramon y Cajal | Madrid | Spain | 28034 | |
| 21 | Puerta de Hierro Majadahonda University Hospital | Majadahonda | Spain | 28220 | |
| 22 | University Hospital of Salamanca | Salamanca | Spain | 37007 | |
| 23 | University Hospital of Valencia | Valencia | Spain | 46010 | |
| 24 | La Fe University and Polytechnic Hospital | Valencia | Spain | 46026 | |
| 25 | Kings College Hospital NHS Foundation Trust | London | United Kingdom |
Sponsors and Collaborators
- Cidara Therapeutics Inc.
Investigators
- Study Director: Taylor Sandison, MD, MPH, Cidara Therapeutics Inc.
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CD101.IV.3.08