Candidemia, Fungal Infection, Fungemia, Invasive Candidiasis, Mycoses
Conditions
Keywords
mycoses
Brief summary
The purpose of this study is to determine if intravenous CD101 is safe and effective in the treatment of candidemia and/or invasive candidiasis when compared to caspofungin (followed by oral fluconazole).
Detailed description
This Bridging Extension is to determine if intravenous CD101 is safe \[Day 45- 52 for subjects with candidemia only, or Day 52- 59 for subjects with invasive candidiasis with or without candidemia\] and effective \[Day 14 (± 1 day)\] in the treatment of candidemia and/or invasive candidiasis when compared to caspofungin (followed by oral fluconazole).
Interventions
DRUGCD101
Intravenous antifungal therapy
DRUGCaspofungin
Intravenous antifungal therapy
DRUGFluconazole
oral antifungal therapy
DRUGintravenous placebo
normal saline
DRUGoral placebo
microcrystalline cellulose
Sponsors
Cidara Therapeutics Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* mycological diagnosis of candidemia and/or invasive candidiasis from a sample taken less than or equal to 96 hours before randomization (defined as: at least 1 blood culture positive for Candida or positive test for Candida from a sponsor approved rapid diagnostic test or positive gram stain for yeast or positive culture for Candida spp. from a specimen obtained from a normally sterile site) * willing to initiate or continue medical treatment to cure infections, including receipt of antibiotics and surgical procedures, if required. Patients receiving only medications and measures for comfort and not cure should not be enrolled. * female subjects of child bearing potential \<2 years post menopausal must agree to one barrier method and one highly effective method of birth control or sexual abstinence. * male subjects must be vasectomized, abstain from sexual intercourse, or agree to use barrier contraception (condom with spermicide), and also agree not to donate sperm from first dose of CD101 (Day 1) until 90 days following last administration of study drug. * 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 their behalf. * presence of one or more systemic signs attributable to candidemia and/or invasive candidiasis
Exclusion criteria
* Any of the following forms of IC: 1. Septic arthritis in a prosthetic joint (septic arthritis in a native joint is allowed) 2. Osteomyelitis 3. Endocarditis or myocarditis 4. Meningitis, endophthalmitis, or any central nervous system infection * neutropenia * alanine aminotransferase or aspartate aminotransferase levels \>10 fold the upper limit of normal * severe hepatic impairment in subjects with a history of chronic cirrhosis * greater than 48 hours systemic antifungal treatment at approved doses to treat candidemia * pregnant females * lactating females who are nursing * known hypersensitivity to CD101, caspofungin, any echinocandin, or to any of their excipients * previous participation in this or any previous CD101 study * recent use of an investigational medicinal product within 28 days of first dose of study drug or presence of an investigational device at the time of screening * Principal Investigator considers the subject should not participate * presence of indwelling vascular catheter or device that cannot be removed and is likely to be the source of candidemia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment Emergent Adverse Events [Safety and Tolerability] | From first dose of study drug through Days 45-52 for subjects with candidemia only or Days 52-59 for subjects with IC, with or without candidemia. | 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. |
| Resolution of Systemic Signs Attributable to Candidemia and/or Invasive Candidiasis and Mycological Eradication [Overall Success] | Day 14 (± 1 day) | Number of subjects with mycological eradication and complete resolution of all systemic signs of candidemia and/or invasive candidiasis which were present at baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Cure | Day 14 (±1 day) and FU (Days 45-52 for subjects with candidemia only or Days 52-59 for subjects with IC, with or without candidemia). | Evaluate clinical cure as assessed by the Investigator in the mITT population. Subjects must meet all of the following requirements: * Resolution of attributable systemic signs and symptoms of candidemia/IC that were present at baseline * No new systemic signs or symptoms attributable to candidemia/IC * No additional systemic antifungal therapy administered for candidemia/IC * The subject is alive |
| Mycological Eradication and Resolution of Systemic Signs | Day 5, and Follow-up (FU Days 45-52 for subjects with candidemia only or Days 52-59 for subjects with IC, with or without candidemia. | Evaluate overall success signs (mycological eradication and resolution of systemic signs attributable to candidemia and/or IC) in the mITT population. |
| Evaluate PK (Cmin) | Day 8, predose | Evaluate minimum plasma concentration (Cmin) (Part A only) |
| Evaluate PK (Cmax) | Day 1, 10 minutes before end of infusion (EOI) | Evaluate maximum plasma concentration (Cmax) (Part A only) |
| Mycological Eradication | Day 5, Day 14 (±1 day), and FU (Days 45-52 for subjects with candidemia only or Days 52-59 for subjects with IC, with or without candidemia) | Evaluate mycological success (eradication) in the mITT population. |
Countries
Belgium, Bulgaria, Canada, Greece, Hungary, Italy, Romania, Russia, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1 Subjects in the CD101 IV treatment group 1 (Part A Only - up to 30 mITT subjects) will receive CD101 IV 400 mg on Day 1 and Day 8, with an optional dose of 400 mg on Day 15 (for all subjects) and an optional dose of 400 mg on Day 22 (only for subjects with IC), if needed.
Daily intravenous placebo infusion when not administered CD101. Daily oral placebo as step down.
CD101: Intravenous antifungal therapy
intravenous placebo: normal saline
oral placebo: microcrystalline cellulose | 81 |
| Group 2 Subjects in the CD101 IV treatment group 2 (Part B Only - up to 30 mITT subjects) will receive CD101 IV 400 mg on Day 1 and Day 8, with an optional dose of 200 mg on Day 15 (for all subjects) and an optional dose of 200 mg on Day 22 (only for subjects with IC), if needed.
Daily intravenous placebo infusion when not administered CD101. Daily oral placebo as step down.
CD101: Intravenous antifungal therapy
intravenous placebo: normal saline
oral placebo: microcrystalline cellulose | 57 |
| Group 3 Subjects in the caspofungin group will receive IV caspofungin (a single 70 mg loading dose on Day 1 followed by 50 mg once daily) for ≥3 days up to a maximum of 21 days for subjects with candidemia only and up to a maximum of 28 days for subjects with IC (with or without candidemia).
After ≥3 days of IV therapy, subjects in the caspofungin group can be switched to oral step-down therapy of fluconazole (a loading dose of 800 mg \[4 capsules\] on the first day followed by 400 mg \[2 capsules\]/day thereafter). 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.
Caspofungin: Intravenous antifungal therapy
Fluconazole: oral antifungal therapy
intravenous placebo: normal saline | 69 |
| Total | 207 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part A | Adverse Event | 2 | 0 | 1 |
| Part A | Death | 3 | 4 | 6 |
| Part A | Lost to Follow-up | 2 | 1 | 1 |
| Part A | Noncompliance | 1 | 1 | 0 |
| Part A | Other | 1 | 1 | 3 |
| Part A | Physician Decision | 2 | 0 | 1 |
| Part A | Withdrawal by Subject | 1 | 1 | 2 |
| Part B | Death | 8 | 3 | 5 |
| Part B | Lost to Follow-up | 2 | 2 | 0 |
| Part B | Other | 0 | 1 | 0 |
| Part B | Withdrawal by Subject | 3 | 1 | 0 |
Baseline characteristics
| Characteristic | Group 1 | Total | Group 3 | Group 2 |
|---|---|---|---|---|
| Acute Physiology and Chronic Health Evaluation (APACHE) II Category 0-9 | 23 Participants | 55 Participants | 17 Participants | 15 Participants |
| Acute Physiology and Chronic Health Evaluation (APACHE) II Category 10-19 | 39 Participants | 102 Participants | 37 Participants | 26 Participants |
| Acute Physiology and Chronic Health Evaluation (APACHE) II Category ≥20 | 17 Participants | 40 Participants | 9 Participants | 14 Participants |
| Acute Physiology and Chronic Health Evaluation (APACHE) II Category Missing | 2 Participants | 10 Participants | 6 Participants | 2 Participants |
| Acute Physiology and Chronic Health Evaluation (APACHE) II Score | 13.4 units on a scale STANDARD_DEVIATION 7.13 | 13.8 units on a scale STANDARD_DEVIATION 7.07 | 14.0 units on a scale STANDARD_DEVIATION 7.39 | 14.1 units on a scale STANDARD_DEVIATION 6.72 |
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 32 Participants | 86 Participants | 29 Participants | 25 Participants |
| Age, Categorical Between 18 and 65 years | 49 Participants | 121 Participants | 40 Participants | 32 Participants |
| Age, Continuous | 61.0 years | 62.0 years | 59.4 Years STANDARD_DEVIATION 15.85 | 63.0 years |
| Diagnosis Candidemia | 62 Participants | 164 Participants | 56 Participants | 46 Participants |
| Diagnosis Invasive Candidiasis | 19 Participants | 43 Participants | 13 Participants | 11 Participants |
| Estimated Normalized Creatinine Clearance | 81.8 mL/min/1.73m^2 | 74.8 mL/min/1.73m^2 | 74.4 mL/min/1.73m^2 | 57.7 mL/min/1.73m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 24 Participants | 7 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 73 Participants | 178 Participants | 59 Participants | 46 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 5 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 4 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 19 Participants | 4 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 12 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) White | 69 Participants | 172 Participants | 59 Participants | 44 Participants |
| Region of Enrollment Belgium | 9 participants | 30 participants | 12 participants | 9 participants |
| Region of Enrollment Bulgaria | 4 participants | 7 participants | 2 participants | 1 participants |
| Region of Enrollment Canada | 1 participants | 5 participants | 3 participants | 1 participants |
| Region of Enrollment Greece | 6 participants | 20 participants | 8 participants | 6 participants |
| Region of Enrollment Hungary | 2 participants | 2 participants | 0 participants | 0 participants |
| Region of Enrollment Italy | 7 participants | 14 participants | 5 participants | 2 participants |
| Region of Enrollment Romania | 2 participants | 5 participants | 3 participants | 0 participants |
| Region of Enrollment Russia | 2 participants | 3 participants | 0 participants | 1 participants |
| Region of Enrollment Spain | 22 participants | 50 participants | 13 participants | 15 participants |
| Region of Enrollment United States | 26 participants | 71 participants | 23 participants | 22 participants |
| Sex: Female, Male Female | 37 Participants | 89 Participants | 31 Participants | 21 Participants |
| Sex: Female, Male Male | 44 Participants | 118 Participants | 38 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 14 / 81 | 7 / 57 | 13 / 69 |
| other Total, other adverse events | 70 / 81 | 49 / 53 | 53 / 68 |
| serious Total, serious adverse events | 35 / 81 | 28 / 53 | 29 / 68 |
Outcome results
Primary
Incidence of Treatment Emergent Adverse Events [Safety and Tolerability]
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.
Time frame: From first dose of study drug through Days 45-52 for subjects with candidemia only or Days 52-59 for subjects with IC, with or without candidemia.
Population: Safety Population includes all subjects randomized to treatment and who received any amount of study drug. A total of 202 subjects were included in the Safety Population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1 | Incidence of Treatment Emergent Adverse Events [Safety and Tolerability] | 71 Participants |
| Group 2 | Incidence of Treatment Emergent Adverse Events [Safety and Tolerability] | 49 Participants |
| Group 3 | Incidence of Treatment Emergent Adverse Events [Safety and Tolerability] | 55 Participants |
Primary
Resolution of Systemic Signs Attributable to Candidemia and/or Invasive Candidiasis and Mycological Eradication [Overall Success]
Number of subjects with mycological eradication and complete resolution of all systemic signs of candidemia and/or invasive candidiasis which were present at baseline
Time frame: Day 14 (± 1 day)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1 | Resolution of Systemic Signs Attributable to Candidemia and/or Invasive Candidiasis and Mycological Eradication [Overall Success] | 46 Participants |
| Group 2 | Resolution of Systemic Signs Attributable to Candidemia and/or Invasive Candidiasis and Mycological Eradication [Overall Success] | 35 Participants |
| Group 3 | Resolution of Systemic Signs Attributable to Candidemia and/or Invasive Candidiasis and Mycological Eradication [Overall Success] | 41 Participants |
Secondary
Clinical Cure
Evaluate clinical cure as assessed by the Investigator in the mITT population. Subjects must meet all of the following requirements: * Resolution of attributable systemic signs and symptoms of candidemia/IC that were present at baseline * No new systemic signs or symptoms attributable to candidemia/IC * No additional systemic antifungal therapy administered for candidemia/IC * The subject is alive
Time frame: Day 14 (±1 day) and FU (Days 45-52 for subjects with candidemia only or Days 52-59 for subjects with IC, with or without candidemia).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1 | Clinical Cure | Day 14 | 53 Participants |
| Group 1 | Clinical Cure | Follow-up | 42 Participants |
| Group 2 | Clinical Cure | Day 14 | 37 Participants |
| Group 2 | Clinical Cure | Follow-up | 32 Participants |
| Group 3 | Clinical Cure | Day 14 | 43 Participants |
| Group 3 | Clinical Cure | Follow-up | 38 Participants |
Secondary
Evaluate PK (Cmax)
Evaluate maximum plasma concentration (Cmax) (Part A only)
Time frame: Day 1, 10 minutes before end of infusion (EOI)
Population: PK Population: all rezafungin-treated subjects from Part A with at least 1 plasma sample obtained for PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 | Evaluate PK (Cmax) | 15.258 μg/mL | Standard Deviation 5.543 |
| Group 2 | Evaluate PK (Cmax) | 14.743 μg/mL | Standard Deviation 5.645 |
Secondary
Evaluate PK (Cmin)
Evaluate minimum plasma concentration (Cmin) (Part A only)
Time frame: Day 8, predose
Population: PK Population: all rezafungin-treated subjects from Part A with at least 1 plasma sample obtained for PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 | Evaluate PK (Cmin) | 2.050 μg/mL | Standard Deviation 0.9767 |
| Group 2 | Evaluate PK (Cmin) | 2.313 μg/mL | Standard Deviation 1.2165 |
Secondary
Evaluate PK (Cmin)
Evaluate minimum plasma concentration (Cmin) (Part A only)
Time frame: Day 15, predose
Population: PK Population: all rezafungin-treated subjects from Part A with at least 1 plasma sample obtained for PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 | Evaluate PK (Cmin) | 3.068 μg/mL | Standard Deviation 1.4565 |
| Group 2 | Evaluate PK (Cmin) | 2.131 μg/mL | Standard Deviation 0.8506 |
Secondary
Mycological Eradication
Evaluate mycological success (eradication) in the mITT population.
Time frame: Day 5, Day 14 (±1 day), and FU (Days 45-52 for subjects with candidemia only or Days 52-59 for subjects with IC, with or without candidemia)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1 | Mycological Eradication | Day 14 | 50 Participants |
| Group 1 | Mycological Eradication | Day 5 | 50 Participants |
| Group 1 | Mycological Eradication | Follow-up | 39 Participants |
| Group 2 | Mycological Eradication | Day 14 | 35 Participants |
| Group 2 | Mycological Eradication | Day 5 | 35 Participants |
| Group 2 | Mycological Eradication | Follow-up | 30 Participants |
| Group 3 | Mycological Eradication | Day 5 | 38 Participants |
| Group 3 | Mycological Eradication | Follow-up | 36 Participants |
| Group 3 | Mycological Eradication | Day 14 | 42 Participants |
Secondary
Mycological Eradication and Resolution of Systemic Signs
Evaluate overall success signs (mycological eradication and resolution of systemic signs attributable to candidemia and/or IC) in the mITT population.
Time frame: Day 5, and Follow-up (FU Days 45-52 for subjects with candidemia only or Days 52-59 for subjects with IC, with or without candidemia.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1 | Mycological Eradication and Resolution of Systemic Signs | Day 5 | 42 Participants |
| Group 1 | Mycological Eradication and Resolution of Systemic Signs | Follow-up | 36 Participants |
| Group 2 | Mycological Eradication and Resolution of Systemic Signs | Day 5 | 34 Participants |
| Group 2 | Mycological Eradication and Resolution of Systemic Signs | Follow-up | 30 Participants |
| Group 3 | Mycological Eradication and Resolution of Systemic Signs | Day 5 | 34 Participants |
| Group 3 | Mycological Eradication and Resolution of Systemic Signs | Follow-up | 36 Participants |