Study of Rezafungin Compared to Standard Antimicrobial Regimen for Prevention of Invasive Fungal Diseases in Adults Undergoing Allogeneic Blood and Marrow Transplantation (ReSPECT)
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| ClinicalTrials.gov Identifier: NCT04368559 |
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Recruitment Status :
Recruiting
First Posted : April 30, 2020
Last Update Posted : April 27, 2023
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Sponsor:
Cidara Therapeutics Inc.
Information provided by (Responsible Party):
Cidara Therapeutics Inc.
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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 |
|---|---|---|
| Candidemia Mycoses Fungal Infection Fungemia Invasive Candidiasis Pneumocystis Mold Infection Invasive Fungal Disease Prophylaxis of Invasive Fungal Infections Aspergillus | Drug: Rezafungin for Injection Drug: Posaconazole Drug: Fluconazole Drug: Trimethoprim-sulfamethoxazole (TMP/SMX) Drug: Intravenous Placebo Drug: Oral Placebo | Phase 3 |
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 462 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Primary Purpose: | Prevention |
| Official Title: | A Phase 3, Multicenter, Randomized, Double-Blind Study of the Efficacy and Safety of Rezafungin for Injection Versus the Standard Antimicrobial Regimen to Prevent Invasive Fungal Diseases in Adults Undergoing Allogeneic Blood and Marrow Transplantation (The ReSPECT Study) |
| Actual Study Start Date : | May 11, 2020 |
| Estimated Primary Completion Date : | August 2024 |
| Estimated Study Completion Date : | August 2024 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
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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-Pneumocystis pneumonia (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. There is no IV option for SAR anti-PCP prophylaxis.
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Drug: Rezafungin for Injection
Intravenous antifungal therapy
Other Name: Intravenous antifungal therapy Drug: Intravenous Placebo Normal saline
Other Name: Placebo Infusion Drug: Oral Placebo Microcrystalline cellulose
Other Name: encapsulated cellulose |
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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 graft versus-host disease (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. There is no IV option for SAR anti-PCP prophylaxis.
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Drug: Posaconazole
Oral antifungal therapy
Other Name: Noxafil Drug: Fluconazole Oral antifungal therapy
Other Name: Generic Fluconazole Drug: Trimethoprim-sulfamethoxazole (TMP/SMX) Oral antibacterial therapy
Other Names:
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Primary Outcome Measures :
- Noninferior Fungal-Free Survival (US FDA) [ Time Frame: Day 90 (±7 days) ]The number of subjects in each treatment group who are fungal-free and survive.
- Noninferior Fungal-Free Survival (US FDA) [ Time Frame: Day 90 (±7 days) ]The percentage of subjects in each treatment group who are fungal-free and survive.
- Superior Fungal-Free Survival (EMA) [ Time Frame: Day 90 (±7 days) ]The number of subjects in each treatment group who are fungal-free and survive.
- Superior Fungal-Free Survival (EMA) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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] [ Time Frame: 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.
Other Outcome Measures:
- Comparison of Fungal-Free [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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" [ Time Frame: 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)" [ Time Frame: 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" [ Time Frame: 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" [ Time Frame: 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" [ Time Frame: 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" [ Time Frame: 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.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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.
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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.
- Chronic myelogenous leukemia in either chronic or accelerated phase.
- 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).
- Receiving myeloablative or reduced-intensity conditioning regimens.
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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:
- Hepatic: alanine aminotransferase less than or equal to (≤) 2.5 × upper limit of normal (ULN) and total serum bilirubin ≤1.5 × ULN (excluding Gilbert's Syndrome).
- Renal: serum creatinine ≤2 milligrams (mg)/deciliter (dL) and with creatinine clearance (CrCl) greater than or equal to (≥) 30 milliliters (mL)/minute (min) without a history of renal transplant, or undergoing weekly dialysis within 4 weeks of the BMT.
- 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.
- 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 any time prior to randomization.
- Female subjects of child-bearing potential <2 years post-menopausal (unless surgically sterile) 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 (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.
- Diagnosis of chemotherapy-resistant lymphoma: a first relapse can occur provided that a second complete remission has occurred.
- Suspected or diagnosed invasive fungal disease (IFD) within 4 weeks of screening.
- Diagnosed symptomatic heart failure with left ventricular ejection fraction (LVEF) at rest ≤50%, or shortening fraction ≤26%.
- Personal or family history of Long QT interval on electrocardiogram (ECG) (QT) syndrome or a prolonged QT interval corrected for heart rate by Fridericia's formula (QTcF) (>470 milliseconds [msec] in males and >480 msec in females); or concurrent administration of terfenadine, cisapride, astemizole, erythromycin, pimozide, quinidine, or halofantrine.
- 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.
- 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 picograms [pg]/mL or Fujifilm Wako >11 pg/mL) within 14 days of transplant.
- Receipt of previous allogeneic BMT.
- Planned receipt of cord blood for transplantation.
- Planned peripheral blood or marrow autograft.
- Not applicable to 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.
- 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).
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- 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.
- 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.
- 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.
- 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.
- Known infection with HIV. Subjects with unknown HIV status should be tested for HIV antibodies per standard of care.
- 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.
- Body weight >130 kilograms (kg) at screening.
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04368559
Contacts
| Contact: Head of Clinical Operations | 858-888-7868 | clinicaltrialinfo@cidara.com |
Locations
Show 37 study locations
Sponsors and Collaborators
Cidara Therapeutics Inc.
Investigators
| Study Director: | Taylor Sandison, MD, MPH | Cidara Therapeutics Inc. |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Cidara Therapeutics Inc. |
| ClinicalTrials.gov Identifier: | NCT04368559 |
| Other Study ID Numbers: |
CD101.IV.3.08 2017-004981-85 ( EudraCT Number ) |
| First Posted: | April 30, 2020 Key Record Dates |
| Last Update Posted: | April 27, 2023 |
| Last Verified: | April 2023 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
| Product Manufactured in and Exported from the U.S.: | Yes |
Keywords provided by Cidara Therapeutics Inc.:
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Mycoses Prophylaxis of Invasive Fungal Infections Aspergillus Candidiasis Candidemia Candidiasis, Invasive Fungemia Sepsis Blood and Marrow Transplant (BMT) Infection Invasive Fungal Infections Systemic Inflammatory Response Syndrome Inflammation Pathologic Processes Fluconazole |
Posaconazole Caspofungin Trimethoprim-sulfamethoxazole (TMP/SMX) Echinocandins Antifungal Agents 14-alpha Demethylase Inhibitors Cytochrome P-450 Enzyme Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Steroid Synthesis Inhibitors Physiological Effects of Drugs Cytochrome P-450 CYP2C9 Inhibitors Cytochrome P-450 CYP2C19 Inhibitors Pneumocystis Mold Infection |
Additional relevant MeSH terms:
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Infections Communicable Diseases Mycoses Candidiasis Pneumonia, Pneumocystis Invasive Fungal Infections Candidemia Candidiasis, Invasive Fungemia Disease Attributes Pathologic Processes Bacterial Infections and Mycoses Lung Diseases, Fungal Pneumocystis Infections Respiratory Tract Infections |
Pneumonia Lung Diseases Respiratory Tract Diseases Sepsis Systemic Inflammatory Response Syndrome Inflammation Fluconazole Posaconazole Rezafungin Trimethoprim Sulfamethoxazole Trimethoprim, Sulfamethoxazole Drug Combination Antifungal Agents Anti-Infective Agents 14-alpha Demethylase Inhibitors |