Study of Rezafungin Compared to Standard Antimicrobial Regimen for Prevention of Invasive Fungal Diseases in Adults Undergoing Allogeneic Blood and Marrow Transplantation

Fungal Infection Clinical Trial

— ReSPECT  

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04368559
• Other study ID #: CD101.IV.3.08
• Secondary ID: 2017-004981-85
• Status: Recruiting
• Phase: Phase 3
• Start date: May 11, 2020
• Est. completion date: August 2024

Study information

• Verified date: June 2024
• Source: Cidara Therapeutics Inc.
• Contact: Head of Clinical Operations
• Phone: 858-888-7868
• Email: clinicaltrialinfo[@]cidara.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 462
• Est. completion date: August 2024
• Est. primary completion date: August 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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:

1. Acute myeloid leukemia (AML), with or without a history of myelodysplastic syndrome, in first or second complete remission.

2. Acute lymphoblastic leukemia, in first or second complete remission.

3. Acute undifferentiated leukemia in first or second remission.

4. Acute biphenotypic leukemia in first or second complete remission.

5. Chronic myelogenous leukemia in either chronic or accelerated phase.

6. 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:

1. 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).

2. 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.

7. Baseline blood samples drawn for Platelia galactomannan enzyme immunoassay (GM EIA) and ß-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 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:

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 occurred.

3. Suspected or diagnosed invasive fungal disease (IFD) within 4 weeks of screening.

4. Diagnosed symptomatic heart failure with left ventricular ejection fraction (LVEF) at rest =50%, or shortening fraction =26%.

5. 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.

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 ß-D glucan assay (Fungitell =80 picograms [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 to protocol Amendment 6.

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 (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. . .

1. 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.

2. 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.

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 kilograms (kg) at screening.

Related Conditions & MeSH terms

• Aspergillus
• Candidemia
• Candidiasis
• Candidiasis, Invasive
• Communicable Diseases
• Fungal Infection
• Fungemia
• Infections
• Invasive Candidiasis
• Invasive Fungal Disease
• Invasive Fungal Infections
• Mold Infection
• Mycoses
• Pneumocystis
• Pneumonia, Pneumocystis
• Prophylaxis of Invasive Fungal Infections

Intervention

Drug:
• Rezafungin for Injection
Intravenous antifungal therapy
• Posaconazole
Oral antifungal therapy
• Fluconazole
Oral antifungal therapy
• Trimethoprim-sulfamethoxazole (TMP/SMX)
Oral antibacterial therapy
• Intravenous Placebo
Normal saline
• Oral Placebo
Microcrystalline cellulose

Locations

Country	Name	City	State
Belgium	AZ Sint-Jan	Brugge	West Vlaanderen
Belgium	University Hospitals Leuven, Campus Gasthuisberg - UZ Leuven	Leuven
Canada	Hamilton Health Sciences' Juravinski Hospital	Hamilton
Canada	McGill University Health Center	Montréal
France	Jean Minjoz Hospital	Besançon
France	Henri Mondor Hospital	Créteil
France	Grenoble Alpes University Hospital Center	Grenoble
France	University Hospital of Limoges	Limoges
France	University Hospital of Nantes	Nantes
France	Hospital Saint Antoine Ap-Hp	Paris
France	University Hospital of Bordeaux	Pessac
France	Lyon-Sud Hospital Center	Pierre-Bénite
Germany	University Hospital Carl Gustav Carus Dresden	Dresden
Germany	Essen University Hospital	Essen
Germany	University Hospital of Cologne	Köln
Germany	Johannes Gutenberg University Medical Center	Mainz
Germany	University Hospital Münster	Münster
Italy	San Martino Polyclinic Hospital	Genova
Italy	IEO Istituto Europeo di Oncologia	Milan
Italy	Agostino Gemelli University Policlinic	Rome
Italy	Humanitas Cancer Center	Rozzano
Spain	Hospital Clinic of Barcelona	Barcelona
Spain	University Hospital Vall d'Hebron	Barcelona
Spain	Hospital de la Princesa	Madrid
Spain	University Hospital Ramon y Cajal	Madrid
Spain	Puerta de Hierro Majadahonda University Hospital	Majadahonda
Spain	University Hospital of Salamanca	Salamanca
Spain	La Fe University and Polytechnic Hospital	Valencia
Spain	University Hospital of Valencia	Valencia
Switzerland	University Hospitals Geneva	Geneva
Turkey	Ankara University School of Medicine	Ankara
Turkey	Hacettepe University School of Medicine	Ankara
United Kingdom	Kings College Hospital NHS Foundation Trust	London
United States	Augusta University Medical Center	Augusta	Georgia
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Chicago	Chicago	Illinois
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	UCLA Center for Health Sciences	Los Angeles	California
United States	The University of Oklahoma College of Medicine	Oklahoma City	Oklahoma
United States	Mayo Clinic	Rochester	Minnesota
United States	Fred Hutchinson Cancer Center	Seattle	Washington
United States	Stony Brook University Hospital	Stony Brook	New York

Sponsors (1)

Lead Sponsor	Collaborator
Cidara Therapeutics Inc.

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  France,  Germany,  Italy,  Spain,  Switzerland,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Comparison of Fungal-Free	The number of subjects in each treatment group who are fungal-free.	Day 14 (±1 day), Day 28 (±1 day), Day 60 (±5 days), and Day 120 (±7 days)
Other	Comparison of Fungal-Free	The percentage of subjects in each treatment group who are fungal-free.	Day 14 (±1 day), Day 28 (±1 day), Day 60 (±5 days), and Day 120 (±7 days)
Other	Comparison of Presence and Severity of GHVD	Evaluate the presence and severity of GVHD in subjects randomized to Rezafungin for Injection compared to the SAR.	Day 90 (±7 days)
Other	Comparison of Fungal-Free with AML	The number of subjects in each treatment group who are fungal-free with an underlying diagnosis of acute myeloid leukemia (AML).	Day 90 (±7 days)
Other	Comparison of Fungal-Free with AML	The percentage of subjects in each treatment group who are fungal-free with an underlying diagnosis of acute myeloid leukemia (AML).	Day 90 (±7 days)
Other	Compare Incidence of IFD	Evaluate the incidence of proven, probable, possible, and presumptive IFD in subjects randomized to Rezafungin for Injection compared to the SAR.	Day 14 (±1 day), Day 28 (±1 day), Day 60 (±5 days), Day 90 (±7 days), and Day 120 (±7 days)
Other	Compare Relapse-Free Survival	Evaluate relapse-free survival, with and without adjustment for patient comorbidity indices, in subjects randomized to Rezafungin for Injection compared to the SAR.	Day 1 through follow-up visit (Day 120)
Other	Evaluate PK (Cmax)	Evaluate maximum plasma concentration (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
Other	Evaluate PK (Tmax)	Evaluate time to 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
Other	Evaluate PK (AUC)	Evaluate area under the curve (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
Other	Compare Post-Engraftment Cytopenias and Transfusion Requirements	Evaluate post-engraftment cytopenias and transfusion requirements of Rezafungin for Injection compared to the SAR.	Day 1 through follow-up visit (Day 120)
Other	Compare Infections Caused by TMP/SMX-Sensitive Organisms	Evaluate infections caused by TMP/SMX-sensitive organisms (Toxoplasma gondii [T. gondii], Nocardia spp.) in Rezafungin for Injection compared to the SAR.	Day 14 (±1 day), Day 28 (±1 day), Day 60 (±5 days), Day 90 (±7 days), and Day 120 (±7 days)
Other	Compare Antifungal Prophylaxis	Evaluate interruption and discontinuation of antifungal prophylaxis due to suspected IFDs of Rezafungin for Injection compared to the SAR.	Day 14 (±1 day), Day 28 (±1 day), Day 60 (±5 days), Day 90 (±7 days), and Day 120 (±7 days)
Other	Compare the health economics outcome research (HEOR) variable of "Days in Hospital"	Evaluate the number of hospital days for subjects randomized to Rezafungin for Injection compared to the SAR.	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)]
Other	Compare the health economics outcome research (HEOR) variable of "Days in Intensive Care Unit (ICU)"	Evaluate the number of days in ICU for subjects randomized to Rezafungin for Injection compared to the SAR.	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)]
Other	Compare the health economics outcome research (HEOR) variable of "Readmission due to Infectious Disease Diagnosis"	Evaluate readmission(s) due to infectious disease diagnosis for subjects randomized to Rezafungin for Injection compared to the SAR.	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)]
Other	Compare the health economics outcome research (HEOR) variable of "Readmission due to Invasive Fungal Disease Diagnosis"	Evaluate readmission(s) due to invasive fungal disease diagnosis for subjects randomized to Rezafungin for Injection compared to the SAR.	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)]
Other	Compare the health economics outcome research (HEOR) variable of "Alternative Antifungal Therapy"	Evaluate the incidence of alternative antifungal therapy compared to Rezafungin for Injection and the SAR.	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)]
Other	Compare the health economics outcome research (HEOR) variable of "Antibiotic Therapy"	Evaluate the incidence of antibiotic therapy compared to Rezafungin for Injection and the SAR.	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)]
Primary	Noninferior Fungal-Free Survival (US FDA)	The number of subjects in each treatment group who are fungal-free and survive.	Day 90 (±7 days)
Primary	Noninferior Fungal-Free Survival (US FDA)	The percentage of subjects in each treatment group who are fungal-free and survive.	Day 90 (±7 days)
Primary	Superior Fungal-Free Survival (EMA)	The number of subjects in each treatment group who are fungal-free and survive.	Day 90 (±7 days)
Primary	Superior Fungal-Free Survival (EMA)	The percentage of subjects in each treatment group who are fungal-free and survive.	Day 90 (±7 days)
Secondary	Compare Discontinuation for Toxicity or Intolerance	The number of subjects that discontinued Rezafungin for Injection compared to the standard antimicrobial regimen (SAR) secondary to toxicity or intolerance.	Day 90 (±7 days)
Secondary	Compare Discontinuation for Toxicity or Intolerance	The percentage of subjects that discontinued Rezafungin for Injection compared to the standard antimicrobial regimen (SAR) secondary to toxicity or intolerance.	Day 90 (±7 days)
Secondary	Compare Proven and Probable IFD	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.	Day 90 (±7 days)
Secondary	Compare Proven and Probable IFD	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.	Day 90 (±7 days)
Secondary	Compare Fungal-Free Survival with or without a Diagnosis of Clinically Significant GVHD	The number of subjects in each treatment group who are fungal-free survival with or without a diagnosis of clinically significant GVHD.	Day 90 (±7 days)
Secondary	Compare Fungal-Free Survival with or without a Diagnosis of Clinically Significant GVHD	The percentage of subjects in each treatment group who are fungal-free survival with or without a diagnosis of clinically significant GVHD.	Day 90 (±7 days)
Secondary	Compare Time to IFD, or Death	Evaluate time to IFD (proven or probable IFD) or death in subjects randomized to Rezafungin for Injection compared to the standard antimicrobial regimen (SAR).	Day 90 (±7 days)
Secondary	Compare Mortality	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.	Day 1 through follow-up visit (Day 120)
Secondary	Incidence of Treatment Emergent Adverse Events [Safety and Tolerability]	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.	Day 1 through follow-up visit (Day 120)