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Study of Rezafungin Compared to Caspofungin in Subjects With Candidemia and/or Invasive Candidiasis (ReSTORE)

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ClinicalTrials.gov Identifier: NCT03667690
Recruitment Status : Recruiting
First Posted : September 12, 2018
Last Update Posted : August 7, 2020
Sponsor:
Information provided by (Responsible Party):
Cidara Therapeutics Inc.

Brief Summary:
The purpose of this pivotal study is to determine if intravenous Rezafungin is efficacious and safe in the treatment of candidemia and/or invasive candidiasis when compared to caspofungin (followed by optional oral fluconazole).

Condition or disease Intervention/treatment Phase
Candidemia Mycoses Fungal Infection Invasive Candidiases Drug: Rezafungin for Injection Drug: Caspofungin Drug: Fluconazole Drug: intravenous placebo Drug: oral placebo Phase 3

Detailed Description:
A Phase 3, multicenter, prospective, randomized, double-blind, efficacy and safety study of Rezafungin for Injection versus an active comparator regimen of caspofungin followed by optional oral fluconazole step-down therapy in subjects with candidemia and/or invasive candidiasis.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 218 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 3, Multicenter, Randomized, Double-blind Study of the Efficacy and Safety of Rezafungin for Injection vs. Intravenous Caspofungin Followed by Oral Fluconazole Step Down in the Treatment of Subjects With Candidemia and/or Invasive Candidiasis
Actual Study Start Date : October 12, 2018
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : September 2020


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 2 to 4 doses.

Daily intravenous placebo infusions, when not administered Rezafungin and a daily placebo for oral step-down therapy (first eligibility on Day 4 or later as advised by a site's national/regional/local guidelines) administered every day.

Drug: Rezafungin for Injection
Intravenous antifungal therapy

Drug: oral placebo
Microcrystalline cellulose
Other Name: encapsulated cellulose

Active Comparator: Group 2: Caspofungin

Subjects in caspofungin arm will receive a total treatment of ≥14 days beginning with a single caspofungin 70 mg IV loading dose on Day 1 followed by 50 mg IV once daily up to 28 days. After ≥3 days of caspofungin treatment(or the minimum duration of IV therapy advised by the site's national/regional/local guidelines, whichever is greater), subjects may be switched to oral fluconazole if specific parameters are met.

If the subject qualifies, then oral step-down therapy of fluconazole (6 mg/kg to the nearest 200 mg) is administered. After switch to oral step down before Day 8, subjects in the caspofungin group will receive IV placebo on Day 8 to preserve the study blind.

Drug: Caspofungin
Intravenous antifungal therapy
Other Name: Cancidas

Drug: Fluconazole
Oral antifungal therapy
Other Name: generic fluconazole

Drug: intravenous placebo
Normal saline
Other Name: placebo infusion




Primary Outcome Measures :
  1. All cause mortality (US FDA only) [ Time Frame: Day 30 (-2 days) ]
    The number of subjects in each treatment group who are alive and deceased (or with missing data) in the mITT population.

  2. All cause mortality (US FDA only) [ Time Frame: Day 30 (-2 days) ]
    The percentage of subjects in each treatment group who are alive and deceased (or with missing data) in the mITT population.

  3. Global Cure (EU only) [ Time Frame: Day 14 (±1 day) ]
    The number of subjects in each treatment group who have a global response of cure (clinical cure as assessed by the Investigator, radiological cure [for qualifying invasive candidiasis subjects at baseline], and mycological eradication, as confirmed by the DRC), failure and indeterminate in the modified Intent to Treat (mITT2) population.

  4. Global Cure (EU only) [ Time Frame: Day 14 (±1 day) ]
    The percentage of subjects in each treatment group who have a global response of cure (clinical cure as assessed by the Investigator, radiological cure [for qualifying invasive candidiasis subjects], and mycological eradication, as confirmed by the DRC), failure and indeterminate in the modified Intent to Treat (mITT) population.


Secondary Outcome Measures :
  1. Global Cure [ Time Frame: Day 14 (±1 day) ]
    The number of subjects in each treatment group who have a global response of cure (clinical cure as assessed by the Investigator, radiological cure [for qualifying invasive candidiasis subjects at baseline], and mycological eradication, as confirmed by the DRC), failure and indeterminate in the mITT population.

  2. Global Cure [ Time Frame: Day 5, Day 30 (-2 days), EOT (≤2 days of last dose) and Follow-up (Days 52-59) ]
    The number of subjects in each treatment group who have a global response of cure (clinical cure as assessed by the Investigator, radiological cure [for qualifying invasive candidiasis subjects at baseline], and mycological eradication, as confirmed by the DRC), failure and indeterminate in the mITT population.

  3. Global Cure [ Time Frame: Day 14 (±1 day) ]
    The percentage of subjects in each treatment group who have a global response of cure (clinical cure as assessed by the Investigator, radiological cure [for qualifying invasive candidiasis subjects at baseline], and mycological eradication, as confirmed by the DRC), failure and indeterminate in the mITT population.

  4. Global Cure [ Time Frame: Day 5, Day 30 (-2 days), EOT (≤2 days of last dose) and Follow-up (Days 52-59) ]
    The percentage of subjects in each treatment group who have a global response of cure (clinical cure as assessed by the Investigator, radiological cure [for qualifying invasive candidiasis subjects at baseline], and mycological eradication, as confirmed by the DRC), failure and indeterminate in the mITT population.

  5. All cause mortality (EU only) [ Time Frame: Day 30 (-2 days) ]
    The number of subjects in each treatment group who are alive and deceased (or with missing data) in the mITT population.

  6. All cause mortality (EU only) [ Time Frame: Day 30 (-2 days) ]
    The percentage of subjects in each treatment group who are alive and deceased (or with missing data) in the mITT population.

  7. Comparison of Global Response (as confirmed by the DRC) [ Time Frame: Day 5, Day 30 (-2 days), End Of Treatment (≤2 days of last dose) and Follow-up (Days 52-59). ]
    The number of subjects with a global response of cure, failure, or indeterminate will be presented by treatment group in the mITT population

  8. Comparison of Global Response (as confirmed by the DRC) [ Time Frame: Day 5, Day 30 (-2 days), End Of Treatment (≤2 days of last dose) and Follow-up (Days 52-59). ]
    The percentage of subjects with a global response of cure, failure, or indeterminate will be presented by treatment group in the mITT population

  9. Comparison of Mycological Response [ Time Frame: Day 5, Day 14 (±1 day), Day 30 (-2 days), End Of Treatment (≤2 days of last dose), and Follow-up (Days 52-59). ]
    The number of subjects with a mycological response of eradication, failure, or indeterminate, by treatment group, in the mITT population

  10. Comparison of Mycological Response [ Time Frame: Day 5, Day 14 (±1 day), Day 30 (-2 days), End Of Treatment (≤2 days of last dose), and Follow-up (Days 52-59). ]
    The percentage of subjects with a mycological response of eradication, failure, or indeterminate, by treatment group, in the mITT population

  11. Comparison of Clinical Cure [ Time Frame: Day 5, Day 14 (±1 day), Day 30 (-2 days), End Of Treatment (≤2 days of last dose), and Follow-up (Days 52-59). ]
    The number of subjects with a clinical response of cure, failure, or indeterminate, presented by treatment group, in the mITT population

  12. Comparison of Clinical Cure [ Time Frame: Day 5, Day 14 (±1 day), Day 30 (-2 days), End Of Treatment (≤2 days of last dose), and Follow-up (Days 52-59). ]
    The percentage of subjects with a clinical response of cure, failure, or indeterminate, presented by treatment group, in the mITT population

  13. Incidence of treatment emergent adverse events [Safety and Tolerability] [ Time Frame: Day 1 through Follow-up visit (Days 52-59) ]
    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.

  14. Evaluate Pharmacokinetics (Cmax) [ Time Frame: Day 1; Days 2, 3, 4, or 5 (one sample on one day only); Day 8; Day 14 (for subjects not receiving a Day 15 dose); Day 15 (if applicable) and Day 22 (if applicable) ]
    Evaluate maximum plasma concentration (Cmax)

  15. Evaluate Pharmacokinetics (Time to Cmax [Tmax]) [ Time Frame: Day 1; Days 2, 3, 4, or 5 (one sample on one day only); Day 8; Day 14 (for subjects not receiving a Day 15 dose); Day 15 (if applicable) and Day 22 (if applicable) ]
    Evaluate Tmax (time to Cmax)

  16. Evaluate Pharmacokinetics (AUC) [ Time Frame: Day 1; Days 2, 3, 4, or 5 (one sample on one day only); Day 8; Day 14 (for subjects not receiving a Day 15 dose); Day 15 (if applicable) and Day 22 (if applicable) ]
    Evaluate area under the curve (AUC)

  17. Comparison of Radiological Cure [ Time Frame: Day 5, Day 14 (±1 day), Day 30 (-2 days), EOT (≤2 days of last dose), and Follow-up (Days 52-59) ]
    The number of invasive candidiasis subjects with radiological cure, failure, or indeterminate, presented by treatment group, in the mITT population.

  18. Comparison of Radiological Cure [ Time Frame: Day 5, Day 14 (±1 day), Day 30 (-2 days), EOT (≤2 days of last dose), and Follow-up (Days 52-59) ]
    The percentage of invasive candidiasis subjects with radiological cure, failure, or indeterminate, presented by treatment group, in the mITT population.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  1. Willing and able to provide written informed consent. If the subject is unable to consent for himself/herself, a legally acceptable representative must provide informed consent on his/her behalf.
  2. Males or females ≥18 years of age.
  3. Established mycological diagnosis of candidemia and/or invasive candidiasis from a sample taken ≤4 days (96 hours) before randomization defined as

    • ≥1 blood culture positive for yeast or Candida OR
    • Positive test for Candida from a Sponsor-approved rapid IVD OR
    • Positive gram stain (or other method of direct microscopy) for yeast or positive culture for Candida spp. from a specimen obtained from a normally sterile site.
  4. Presence of one or more systemic signs attributable to candidemia or invasive candidiasis appearing from ≤12 hours prior to the qualifying positive culture through time of randomization.
  5. Willing to initiate or continue medical treatment to cure infections, including receipt of antibiotics and surgical procedures, if required.
  6. Female subjects of childbearing potential (all female subjects between 18 years <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, or sexual abstinence while participating in this study. Male subjects must be vasectomized, abstain from sexual intercourse, or agree to use barrier contraception, and also agree not to donate sperm while participating in the study and for 90 days thereafter (and at least 120 days from the last dose of study drug).
  7. For Candidemia only subjects, drawing of a set of blood cultures within 12 hours prior to randomization in the study. The result of these blood cultures is not required for inclusion in the study.

Exclusion Criteria:

  1. Any of the following forms of invasive candidiasis at baseline:

    1. Septic arthritis in a prosthetic joint (septic arthritis in a native joint is allowed)
    2. Osteomyelitis
    3. Endocarditis or myocarditis
    4. Meningitis, endophthalmitis, chorioretinitis, or any central nervous system infection
    5. Chronic disseminated candidiasis
    6. Urinary tract candidiasis due to ascending Candida infection secondary to obstruction or surgical instrumentation of the urinary tract
  2. Received systemic treatment with an antifungal agent at approved doses for treatment of candidemia for >48 hours (e.g., >2 doses of a once daily antifungal agent or >4 doses of a twice daily antifungal agent) ≤4 days (96 hours) before randomization

    a. Exception: Receipt of antifungal therapy to which any Candida spp. isolated in culture is not susceptible

  3. Alanine aminotransferase or aspartate aminotransferase levels >10-fold the upper limit of normal
  4. Severe hepatic impairment in subjects with a history of chronic cirrhosis (Child-Pugh score >9)
  5. Presence of an indwelling vascular catheter or device that cannot be removed or an abscess that cannot be drained and is likely to be the source of candidemia or invasive candidiasis
  6. Known hypersensitivity to Rezafungin for Injection, caspofungin, any echinocandin, or to any of their excipients
  7. Meets National Cancer Institute Common Terminology Criteria for Adverse Events, version 5, criteria for ataxia, tremor, motor neuropathy, or sensory neuropathy of Grade 2 or higher
  8. History of severe ataxia, tremor, or neuropathy or a diagnosis of multiple sclerosis or a movement disorder (including Parkinson's Disease or Huntington's Disease)
  9. Planned or ongoing therapy at Screening with a known neurotoxic medication
  10. Previous participation in this or any previous rezafungin study
  11. Current participation in another interventional treatment trial with an investigational agent
  12. Recent use of an investigational medicinal product within 28 days of the first dose of study drug or presence of an investigational device at the time of screening.
  13. Pregnant or lactating females
  14. The Principal Investigator (PI) is of the opinion the subject should not participate in the study

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): NCT03667690


Contacts
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Contact: Karen Mena 858-888-7868 clinicaltrialinfo@cidara.com

Locations
Show Show 78 study locations
Sponsors and Collaborators
Cidara Therapeutics Inc.
Investigators
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Study Director: Taylor Sandison, MD, MPH Cidara Therapeutics Inc.
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Responsible Party: Cidara Therapeutics Inc.
ClinicalTrials.gov Identifier: NCT03667690    
Other Study ID Numbers: CD101.IV.3.05
First Posted: September 12, 2018    Key Record Dates
Last Update Posted: August 7, 2020
Last Verified: August 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Cidara Therapeutics Inc.:
Candidemia
Mycoses
Candidiasis
Candidiasis, Invasive
Fungemia
Sepsis
Invasive Fungal Infections
Systemic Inflammatory Response Syndrome
Pathologic Processes
Fluconazole
Caspofungin
Echinocandins
Antifungal Agents
Anti-infective 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
Additional relevant MeSH terms:
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Candidemia
Mycoses
Candidiasis
Candidiasis, Invasive
Infection
Fungemia
Sepsis
Invasive Fungal Infections
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Fluconazole
Caspofungin
Rezafungin
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 CYP2C9 Inhibitors
Cytochrome P-450 CYP2C19 Inhibitors