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Safety and Pharmacokinetics of Rezafungin

Primary Purpose

Fungal Infection

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Placebo
Rezafungin
Rezafungin
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Fungal Infection focused on measuring Dose Escalation Study, Double-Blind, Healthy Adult Subjects, Phase 1, Rezafungin, Safety and Pharmacokinetic

Eligibility Criteria

18 Years - 45 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  1. Males and females aged 18 to 45 years, inclusive.
  2. Willing and able to provide written informed consent and authorization for use of protected health information.
  3. Willing and able to comply with protocol requirements, instructions, and protocol-stated restrictions (including confinement to the Clinical Research Unit) and is likely to complete the study as planned.
  4. Males must be vasectomized or agree to use barrier contraception (condom with spermicide) from first dose of study drug until at least 18 weeks following the last dose of study drug.
  5. Males must agree to refrain from sperm donation from first dose of investigational product (IP) through at least 18 weeks after last dose of IP.

  6. Females are eligible if they are of non-childbearing potential* or if they use a highly effective** method of contraception for 30 days prior to dosing and for a minimum of 30 days after dosing.

    *Non-childbearing potential is defined as: Pre-menopausal with documentation of irreversible surgical sterilization (i.e., hysterectomy, bilateral oophorectomy, or bilateral salpingectomy (but not tubal ligation alone); or, Post-menopausal defined as amenorrhea for at least 12 months following cessation of all exogenous hormonal treatments and with Follicle Stimulating Hormone (FSH) levels > / = 40 mIU/mL at Screening.

    **A highly effective contraceptive method is, defined by < 1 percent failure rate that is not affected by user adherence, include surgical sterilization and long-acting reversible contraception (LARC). LARC comes in three forms: progestin-releasing subdermal implants (Nexplanon and Implanon [Merck]); copper intrauterine devices (IUD) (ParaGard [Teva]); and levonorgestrel-releasing IUDs (Mirena [Bayer], Skyla [Bayer], and Liletta [Allergan/Medicines360]. Subjects must use one of these three methods.

  7. Subject is in good health as deemed by the Investigator*,**.

    • Good health is defined by the absence of any medical condition described in the exclusion criteria in a subject who undergoes a medical history, with a normal complete physical examination including resting vital signs, and screening safety laboratory testing.

      • If the subject has an active, ongoing medical condition, the condition cannot meet any of the following criteria: 1) first diagnosed within 3 months of enrollment; 2) is worsening in terms of clinical outcome in last 6 months; or 3) involves need for medication that may pose a risk to subject's safety or significantly impede assessment of adverse events if they participate in the study.
  8. Subjects with a body mass index (BMI) (weight in kg divided by height in m, squared) between 18.5 and/or 35.0 kg/m^2, inclusive, and a minimum weight of 50 kg.
  9. Subjects must refrain from strenuous physical activity that could cause muscle aches or injury, including contact sports, at any time from screening until completion of the trial.

  10. Subjects must refrain from over-the-counter and prescription medications* and nutritional supplements within 14 days before first study drug administration, and until after the final study visit.

    *Except for hormonal contraceptives, acetaminophen, or ibuprofen.

  11. Subject has adequate venous access for blood collection.

Exclusion Criteria:

  1. History of any hypersensitivity or allergic reaction to echinocandins or excipients (mannitol, polysorbate 80, histidine) of the rezafungin for injection and rezafungin for infusion formulations.

  2. Subjects presenting with a clinically significant condition*.

    *Subjects with any of the following must not be included into the study: clinically significant oncologic, infectious, cardiovascular, pulmonary, hepatic, gastrointestinal, hematologic, metabolic, endocrine, neurologic, immunologic, renal, psychiatric, or other condition that in the opinion of the Investigator would preclude the safe participation of the subject in the study or would prevent the subject from meeting the study requirements.

  3. Any condition that in the opinion of the Investigator could significantly impact drug absorption, distribution, or elimination.
  4. Symptoms of acute illness or chronic disease within 14 days of initial dosing.
  5. Positive screen for hepatitis B virus surface antigen, hepatitis C virus antibody, or Human Immunodeficiency Virus (HIV) antibody.

  6. Subjects with clinical laboratory values outside the site reference ranges* prior to initial dosing.

    *Clinical laboratory values outside the site reference ranges, if considered by the site investigator to be clinically insignificant, are acceptable if not exceeding Grade 1 severity. One repeat of lab testing is allowed to make this determination during screening.

  7. Abnormal Electrocardiograms (ECGs).

  8. Female subject of childbearing potential who is pregnant*, lactating, or planning to become pregnant during the study period or at least 30 days after the final dose of study product.

    *Having a positive serum pregnancy test at the Screening Visit or any other specified time point prior to the dose of study product.

  9. Received any prescription medications (except for hormonal contraceptives) within 14 days before first study drug administration.

  10. Received any non-prescription medications, vitamins, herbal or dietary supplements* within 14 days of initial dosing, unless prior approval is granted by both the Investigator and the Sponsor.

    *Excluded from this list is intermittent use of acetaminophen at doses of < / = 2 g/day or ibuprofen < / = 1200 mg/day. However, acetaminophen only is accepted to treat AEs for pain (ie. headaches) during in-clinic stay.

  11. Current smoker or tobacco* use within 90 days prior to screening or while a subject is enrolled in the study.

    *Tobacco use includes vaping, smoking tobacco, the use of snuff and chewing tobacco, and other nicotine or nicotine-containing products

  12. History of illicit/illegal drug use prior to dosing or while a subject is enrolled in the study* or reports an alcohol or substance abuse problem** within 6 months of dosing.

    *A urine drug test will be performed at screening and upon admission to the Clinical Research Unit (CRU). Drug screen includes amphetamines, barbiturates, cocaine, opiates, cannabinoids, phencyclidine, and benzodiazepines.

    **Inclusive of vaping of non-nicotine products.

  13. Consumed foods or beverages containing alcohol or xanthines/caffeine*,**:

    *Alcohol: < / = 48 hours before the first study drug administration, until discharge.

    **Xanthines/caffeine: < / = 24 hours before the first study drug administration, until discharge.

  14. Received any live or killed vaccines or immunoglobulins within 14 days of dosing.
  15. Donated blood or blood products or experienced significant blood loss within 60 days of dosing.
  16. Received a blood transfusion within 14 days of dosing.

  17. Previous participation in this trial, any other rezafungin trial, or any trial* within 28 days of dosing. Plans to enroll in another clinical trial**.

    *Includes trials that have a study intervention such as a drug, biologic, or device.

    **Includes trials that could interfere with safety assessment of the investigational product at any time during the study period.

  18. The PI considers that the subject should not participate in the trial.

Sites / Locations

  • ICON Early Phase Services Clinical Research Unit

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm 10

Arm 11

Arm 12

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

BA1

BA2

MAD1

MAD2

MAD3

MAD4

SAD1

SAD2

SAD3

SAD4

SAD5

SAD6

Arm Description

100 mg (1 injection of 1.0 ml) or maximum tolerated dose (MTD) determined in SAD of Rezafungin administered subcutaneously into the abdomen on Day 1, and 100 mg (250 ml) or MTD of Rezafungin administered via intravenous infusion on Day 22 in an open label manner. n=5.

100 mg (250 ml) or maximum tolerated dose (MTD) determined in SAD of Rezafungin administered via intravenous infusion on Day 1, and 100 mg (1 injection of 1.0 ml) or MTD of Rezafungin administered subcutaneously into the abdomen on Day 22 in an open label manner. n=5.

30 mg (1 injection of 0.3 ml) of Rezafungin administered subcutaneously into the abdomen as three doses, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Days 1, 8, and 15 in a double-blind manner.

60 mg (1 injection of 0.6 ml) of Rezafungin administered subcutaneously into the abdomen as three doses, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Days 1, 8, and 15 in a double-blind manner.

100 mg (1 injection of 1.0 ml) of Rezafungin administered subcutaneously into alternating abdominal quadrants as three doses, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Days 1, 8, and 15 in a double-blind manner.

200 mg (2 injections of 1.0 ml) of Rezafungin administered subcutaneously into alternating abdominal quadrants as three doses, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Days 1, 8, and 15 in a double-blind manner.

1 mg (1 injection of 0.1 ml diluted 1:10 in 5% Dextrose Injection, USP) of Rezafungin administered subcutaneously into the abdomen as a single dose, n=3 (no sentinel dosing), or matching placebo, n=1 (no sentinel dosing), on Day 1 in a double-blind manner.

10 mg (1 injection of 0.1 ml) of Rezafungin administered subcutaneously into the abdomen as a single dose, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Day 1 in a double-blind manner.

30 mg (1 injection of 0.3 ml) of Rezafungin administered subcutaneously into the abdomen as a single dose, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Day 1 in a double-blind manner.

60 mg (1 injection of 0.6 ml) of Rezafungin administered subcutaneously into the abdomen as a single dose, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Day 1 in a double-blind manner.

100 mg (1 injection of 1.0 ml) of Rezafungin administered subcutaneously into alternating abdominal quadrants as a single dose, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Day 1 in a double-blind manner.

200 mg (2 injections of 1.0 ml) of Rezafungin administered subcutaneously into alternating abdominal quadrants as a single dose, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Day 1 in a double-blind manner.

Outcomes

Primary Outcome Measures

Number of Participants With Abnormal Chemistry Laboratory Toxicity Results for Single Ascending Dose (SAD) on Day 2
Laboratory parameters and associated thresholds include albumin <=3.4 g/dL, glucose <= 69 mg/dL or >=106 mg/dL, blood urea nitrogen (BUN) >= 21 mg/dL, potassium >=5.2 mEq/L or <=3.4 mEq/L, calcium < 8.7 mg/dL or >=10.3 mg/dL, sodium <=132 mEq/L or >=144 mEq/L, total protein <=5.9 g/dL, creatinine >=1.3 mg/dL (male) or >= 1.0 mg/dL (female), creatine phosphokinase >= 309 U/L, phosphorus <=2.4 mg/dL, alkaline phosphatase >= 131 IU/L (males) or >= 106 IU/L (female), aspartate aminotransferase >= 40 U/L (male) or >= 32 U/L (female), alanine aminotransferase >=41 U/L (male) or >= 33 U/L (female), and total bilirubin >=106 mg/dL. If a clinical chemistry laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Chemistry Laboratory Toxicity Results for Single Ascending Dose (SAD) on Day 7
Laboratory parameters and associated thresholds include albumin <=3.4 g/dL, glucose <= 69 mg/dL or >=106 mg/dL, blood urea nitrogen (BUN) >= 21 mg/dL, potassium >=5.2 mEq/L or <=3.4 mEq/L, calcium < 8.7 mg/dL or >=10.3 mg/dL, sodium <=132 mEq/L or >=144 mEq/L, total protein <=5.9 g/dL, creatinine >=1.3 mg/dL (male) or >= 1.0 mg/dL (female), creatine phosphokinase >= 309 U/L, phosphorus <=2.4 mg/dL, alkaline phosphatase >= 131 IU/L (males) or >= 106 IU/L (female), aspartate aminotransferase >= 40 U/L (male) or >= 32 U/L (female), alanine aminotransferase >=41 U/L (male) or >= 33 U/L (female), and total bilirubin >=106 mg/dL. If a clinical chemistry laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Chemistry Laboratory Toxicity Results for Single Ascending Dose (SAD) on Day 30
Laboratory parameters and associated thresholds include albumin <=3.4 g/dL, glucose <= 69 mg/dL or >=106 mg/dL, blood urea nitrogen (BUN) >= 21 mg/dL, potassium >=5.2 mEq/L or <=3.4 mEq/L, calcium < 8.7 mg/dL or >=10.3 mg/dL, sodium <=132 mEq/L or >=144 mEq/L, total protein <=5.9 g/dL, creatinine >=1.3 mg/dL (male) or >= 1.0 mg/dL (female), creatine phosphokinase >= 309 U/L, phosphorus <=2.4 mg/dL, alkaline phosphatase >= 131 IU/L (males) or >= 106 IU/L (female), aspartate aminotransferase >= 40 U/L (male) or >= 32 U/L (female), alanine aminotransferase >=41 U/L (male) or >= 33 U/L (female), and total bilirubin >=106 mg/dL. If a clinical chemistry laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Chemistry Laboratory Toxicity Results for Multiple Ascending Dose (MAD)
Laboratory parameters and associated thresholds include albumin <=3.4 g/dL, glucose <= 69 mg/dL or >=106 mg/dL, blood urea nitrogen (BUN) >= 21 mg/dL, potassium >=5.2 mEq/L or <=3.4 mEq/L, calcium < 8.7 mg/dL or >=10.3 mg/dL, sodium <=132 mEq/L or >=144 mEq/L, total protein <=5.9 g/dL, creatinine >=1.3 mg/dL (male) or >= 1.0 mg/dL (female), creatine phosphokinase >= 309 U/L, phosphorus <=2.4 mg/dL, alkaline phosphatase >= 131 IU/L (males) or >= 106 IU/L (female), aspartate aminotransferase >= 40 U/L (male) or >= 32 U/L (female), alanine aminotransferase >=41 U/L (male) or >= 33 U/L (female), and total bilirubin >=106 mg/dL. If a clinical chemistry laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Hematology Laboratory Toxicity Results for Single Ascending Dose (SAD) on Day 2
Laboratory parameters and associated thresholds for adverse events include hemoglobin <= 12.2 g/dL (male) or <= 10.8 g/dL (female), hematocrit <= 36.1 % (male) or <= 32.6 % (female), red blood cell (RBC) count <= 4.1 x 10^6/uL (male) or <= 3.7 x 10^6/uL (female), white blood cell (WBC) count >= 9,001 cell/mm3 or <= 2,499 cell/mm3 (African American Males) or >= 11,001 cell/mm3 or <= 2,499 cell/mm3 (African American Females) or >= 10,001 cell/mm3 or <= 3,999 cell/mm3 (all others), neutrophil count <= 1,299 cell/mm3 (African Americans) or <= 1,699 cell/mm3 (all others), lymphocyte count <= 799 cell/mm3, monocyte count >= 1001 cell/mm3, eosinophil count >= 871 cell/mm3, basophil count >= 101 cell/mm3, and platelet count <= 149 x 10^3/mm3. If a result met the threshold for an AE at baseline, subsequent results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Hematology Laboratory Toxicity Results for Single Ascending Dose (SAD) on Day 7
Laboratory parameters and associated thresholds for adverse events include hemoglobin <= 12.2 g/dL (male) or <= 10.8 g/dL (female), hematocrit <= 36.1 % (male) or <= 32.6 % (female), red blood cell (RBC) count <= 4.1 x 10^6/uL (male) or <= 3.7 x 10^6/uL (female), white blood cell (WBC) count >= 9,001 cell/mm3 or <= 2,499 cell/mm3 (African American Males) or >= 11,001 cell/mm3 or <= 2,499 cell/mm3 (African American Females) or >= 10,001 cell/mm3 or <= 3,999 cell/mm3 (all others), neutrophil count <= 1,299 cell/mm3 (African Americans) or <= 1,699 cell/mm3 (all others), lymphocyte count <= 799 cell/mm3, monocyte count >= 1001 cell/mm3, eosinophil count >= 871 cell/mm3, basophil count >= 101 cell/mm3, and platelet count <= 149 x 10^3/mm3. If a result met the threshold for an AE at baseline, subsequent results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Hematology Laboratory Toxicity Results for Single Ascending Dose (SAD) on Day 30
Laboratory parameters and associated thresholds for adverse events include hemoglobin <= 12.2 g/dL (male) or <= 10.8 g/dL (female), hematocrit <= 36.1 % (male) or <= 32.6 % (female), red blood cell (RBC) count <= 4.1 x 10^6/uL (male) or <= 3.7 x 10^6/uL (female), white blood cell (WBC) count >= 9,001 cell/mm3 or <= 2,499 cell/mm3 (African American Males) or >= 11,001 cell/mm3 or <= 2,499 cell/mm3 (African American Females) or >= 10,001 cell/mm3 or <= 3,999 cell/mm3 (all others), neutrophil count <= 1,299 cell/mm3 (African Americans) or <= 1,699 cell/mm3 (all others), lymphocyte count <= 799 cell/mm3, monocyte count >= 1001 cell/mm3, eosinophil count >= 871 cell/mm3, basophil count >= 101 cell/mm3, and platelet count <= 149 x 10^3/mm3. If a result met the threshold for an AE at baseline, subsequent results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Hematology Laboratory Toxicity Results for Multiple Ascending Dose (MAD)
Laboratory parameters and associated thresholds for adverse events include hemoglobin <= 12.2 g/dL (male) or <= 10.8 g/dL (female), hematocrit <= 36.1 % (male) or <= 32.6 % (female), red blood cell (RBC) count <= 4.1 x 10^6/uL (male) or <= 3.7 x 10^6/uL (female), white blood cell (WBC) count >= 9,001 cell/mm3 or <= 2,499 cell/mm3 (African American Males) or >= 11,001 cell/mm3 or <= 2,499 cell/mm3 (African American Females) or >= 10,001 cell/mm3 or <= 3,999 cell/mm3 (all others), neutrophil count <= 1,299 cell/mm3 (African Americans) or <= 1,699 cell/mm3 (all others), lymphocyte count <= 799 cell/mm3, monocyte count >= 1001 cell/mm3, eosinophil count >= 871 cell/mm3, basophil count >= 101 cell/mm3, and platelet count <= 149 x 10^3/mm3. If a result met the threshold for an AE at baseline, subsequent results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Coagulation Laboratory Toxicity Results for Single Ascending Dose (SAD), Day 2
Laboratory parameters include prothrombin time (PT), activated partial prothrombin time (PTT), and prothrombin international normalized ratio (INR). Thresholds for adverse events were considered as PT >= 11.1 s (before 23DEC2019) or >= 11.6 s (on or after 23DEC2019), PTT >= 34.1 s (before 23DEC2019) or >= 30.1 (on or after 23DEC2019), INR >= 1.2. If a coagulation laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Coagulation Laboratory Toxicity Results for Single Ascending Dose (SAD), Day 7
Laboratory parameters include prothrombin time (PT), activated partial prothrombin time (PTT), and prothrombin international normalized ratio (INR). Thresholds for adverse events were considered as PT >= 11.1 s (before 23DEC2019) or >= 11.6 s (on or after 23DEC2019), PTT >= 34.1 s (before 23DEC2019) or >= 30.1 (on or after 23DEC2019), INR >= 1.2. If a coagulation laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Coagulation Laboratory Toxicity Results for Single Ascending Dose (SAD), Day 30
Laboratory parameters include prothrombin time (PT), activated partial prothrombin time (PTT), and prothrombin international normalized ratio (INR). Thresholds for adverse events were considered as PT >= 11.1 s (before 23DEC2019) or >= 11.6 s (on or after 23DEC2019), PTT >= 34.1 s (before 23DEC2019) or >= 30.1 (on or after 23DEC2019), INR >= 1.2. If a coagulation laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Coagulation Laboratory Toxicity Results for Multiple Ascending Dose (MAD)
Laboratory parameters include prothrombin time (PT), activated partial prothrombin time (PTT), and prothrombin international normalized ratio (INR). Thresholds for adverse events were considered as PT >= 11.1 s (before 23DEC2019) or >= 11.6 s (on or after 23DEC2019), PTT >= 34.1 s (before 23DEC2019) or >= 30.1 (on or after 23DEC2019), INR >= 1.2. If a coagulation laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Urinalysis Laboratory Toxicity Results for Single Ascending Dose (SAD), Day 2
Laboratory parameters include protein, glucose, and occult blood. Thresholds for adverse events were considered as protein >= 1+, glucose >= 1+, and occult blood >= 5 (before 23DEC2019) or >=3 (on or after 23DEC2019). If a urinalysis laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Urinalysis Laboratory Toxicity Results for Single Ascending Dose (SAD), Day 7
Laboratory parameters include protein, glucose, and occult blood. Thresholds for adverse events were considered as protein >= 1+, glucose >= 1+, and occult blood >= 5 (before 23DEC2019) or >=3 (on or after 23DEC2019). If a urinalysis laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Urinalysis Laboratory Toxicity Results for Single Ascending Dose (SAD), Day 30
Laboratory parameters include protein, glucose, and occult blood. Thresholds for adverse events were considered as protein >= 1+, glucose >= 1+, and occult blood >= 5 (before 23DEC2019) or >=3 (on or after 23DEC2019). If a urinalysis laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Urinalysis Laboratory Toxicity Results for Multiple Ascending Dose (MAD)
Each subject is only counted once per toxicity grade for the worst severity recorded. Laboratory parameters include protein, glucose, and occult blood. Thresholds for adverse events were considered as protein >= 1+, glucose >= 1+, and occult blood >= 5 (before 23DEC2019) or >=3 (on or after 23DEC2019). If a urinalysis laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal ECG Toxicity Results for Single Ascending Dose (SAD), Day 1
Each subject is only counted once per toxicity grade for the worst severity recorded. ECG parameters include PR interval and QTcF interval. Thresholds for adverse events were considered as PR interval >= 0.21 sec, a type II 2nd degree AV block, or ventricular pause >3 sec and QTcF interval >= 450 msec or >= 30 msec above baseline. If an ECG value met the threshold for an AE at baseline, subsequent safety ECG results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal ECG Toxicity Results for Single Ascending Dose (SAD), Day 7
Each subject is only counted once per toxicity grade for the worst severity recorded. ECG parameters include PR interval and QTcF interval. Thresholds for adverse events were considered as PR interval >= 0.21 sec, a type II 2nd degree AV block, or ventricular pause >3 sec and QTcF interval >= 450 msec or >= 30 msec above baseline. If an ECG value met the threshold for an AE at baseline, subsequent safety ECG results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal ECG Toxicity Results for Single Ascending Dose (SAD), Day 30
Each subject is only counted once per toxicity grade for the worst severity recorded. ECG parameters include PR interval and QTcF interval. Thresholds for adverse events were considered as PR interval >= 0.21 sec, a type II 2nd degree AV block, or ventricular pause >3 sec and QTcF interval >= 450 msec or >= 30 msec above baseline. If an ECG value met the threshold for an AE at baseline, subsequent safety ECG results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal ECG Toxicity Results for Multiple Ascending Doses (MAD)
This table includes the maximum severity experienced over all post-baseline time points. ECG parameters include PR interval and QTcF interval. Thresholds for adverse events were considered as PR interval >= 0.21 sec, a type II 2nd degree AV block, or ventricular pause >3 sec and QTcF interval >= 450 msec or >= 30 msec above baseline. If an ECG value met the threshold for an AE at baseline, subsequent safety ECG results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Physical Exams for Single Ascending Dose (SAD), Day 1
Physical examination includes general appearance; head, eyes, nose and throat; neck; chest and lungs; cardiovascular system, abdomen, musculoskeletal system, lymph nodes, extremities/skin, and neurological system.
Number of Participants With Abnormal Physical Exams for Single Ascending Dose (SAD), Day 2
Physical examination includes general appearance; head, eyes, nose and throat; neck; chest and lungs; cardiovascular system, abdomen, musculoskeletal system, lymph nodes, extremities/skin, and neurological system.
Number of Participants With Abnormal Physical Exams for Single Ascending Dose (SAD), Day 4
Physical examination includes general appearance; head, eyes, nose and throat; neck; chest and lungs; cardiovascular system, abdomen, musculoskeletal system, lymph nodes, extremities/skin, and neurological system.
Number of Participants With Abnormal Physical Exams for Single Ascending Dose (SAD), Day 7
Physical examination includes general appearance; head, eyes, nose and throat; neck; chest and lungs; cardiovascular system, abdomen, musculoskeletal system, lymph nodes, extremities/skin, and neurological system.
Number of Participants With Abnormal Physical Exams for Single Ascending Dose (SAD), Day 30
Physical examination includes general appearance; head, eyes, nose and throat; neck; chest and lungs; cardiovascular system, abdomen, musculoskeletal system, lymph nodes, extremities/skin, and neurological system.
Number of Participants With Abnormal Physical Exams for Multiple Ascending Dose (MAD)
Physical examination includes general appearance; head, eyes, nose and throat; neck; chest and lungs; cardiovascular system, abdomen, musculoskeletal system, lymph nodes, extremities/skin, and neurological system.
Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 1, 15 Minutes Post-dose
Each subject is only counted once per toxicity grade for the worst severity recorded. Vital sign parameters include systolic blood pressure (BP), diastolic BP, heart rate, respiratory rate, and temperature. Thresholds for abnormal vital signs were considered as systolic BP >= 141 mmHg or <= 89 mmHg, diastolic BP >= 91 mmHg, heart rate <= 54 bpm (baseline >= 60 bpm) or <=50 (baseline < 60 bpm) or >= 101 bpm, respiratory rate >= 23 breaths per minute, and temperature >= 38.0 degrees Celsius. If a vital sign result met the threshold for an AE at baseline, subsequent vital sign results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 1, 1 Hour Post-dose
Each subject is only counted once per toxicity grade for the worst severity recorded. Vital sign parameters include systolic blood pressure (BP), diastolic BP, heart rate, respiratory rate, and temperature. Thresholds for abnormal vital signs were considered as systolic BP >= 141 mmHg or <= 89 mmHg, diastolic BP >= 91 mmHg, heart rate <= 54 bpm (baseline >= 60 bpm) or <=50 (baseline < 60 bpm) or >= 101 bpm, respiratory rate >= 23 breaths per minute, and temperature >= 38.0 degrees Celsius. If a vital sign result met the threshold for an AE at baseline, subsequent vital sign results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 1, 2 Hours Post-dose
Each subject is only counted once per toxicity grade for the worst severity recorded. Vital sign parameters include systolic blood pressure (BP), diastolic BP, heart rate, respiratory rate, and temperature. Thresholds for abnormal vital signs were considered as systolic BP >= 141 mmHg or <= 89 mmHg, diastolic BP >= 91 mmHg, heart rate <= 54 bpm (baseline >= 60 bpm) or <=50 (baseline < 60 bpm) or >= 101 bpm, respiratory rate >= 23 breaths per minute, and temperature >= 38.0 degrees Celsius. If a vital sign result met the threshold for an AE at baseline, subsequent vital sign results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 2
Each subject is only counted once per toxicity grade for the worst severity recorded. Vital sign parameters include systolic blood pressure (BP), diastolic BP, heart rate, respiratory rate, and temperature. Thresholds for abnormal vital signs were considered as systolic BP >= 141 mmHg or <= 89 mmHg, diastolic BP >= 91 mmHg, heart rate <= 54 bpm (baseline >= 60 bpm) or <=50 (baseline < 60 bpm) or >= 101 bpm, respiratory rate >= 23 breaths per minute, and temperature >= 38.0 degrees Celsius. If a vital sign result met the threshold for an AE at baseline, subsequent vital sign results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 4
Each subject is only counted once per toxicity grade for the worst severity recorded. Vital sign parameters include systolic blood pressure (BP), diastolic BP, heart rate, respiratory rate, and temperature. Thresholds for abnormal vital signs were considered as systolic BP >= 141 mmHg or <= 89 mmHg, diastolic BP >= 91 mmHg, heart rate <= 54 bpm (baseline >= 60 bpm) or <=50 (baseline < 60 bpm) or >= 101 bpm, respiratory rate >= 23 breaths per minute, and temperature >= 38.0 degrees Celsius. If a vital sign result met the threshold for an AE at baseline, subsequent vital sign results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 7
Each subject is only counted once per toxicity grade for the worst severity recorded. Vital sign parameters include systolic blood pressure (BP), diastolic BP, heart rate, respiratory rate, and temperature. Thresholds for abnormal vital signs were considered as systolic BP >= 141 mmHg or <= 89 mmHg, diastolic BP >= 91 mmHg, heart rate <= 54 bpm (baseline >= 60 bpm) or <=50 (baseline < 60 bpm) or >= 101 bpm, respiratory rate >= 23 breaths per minute, and temperature >= 38.0 degrees Celsius. If a vital sign result met the threshold for an AE at baseline, subsequent vital sign results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 14
Each subject is only counted once per toxicity grade for the worst severity recorded. Vital sign parameters include systolic blood pressure (BP), diastolic BP, heart rate, respiratory rate, and temperature. Thresholds for abnormal vital signs were considered as systolic BP >= 141 mmHg or <= 89 mmHg, diastolic BP >= 91 mmHg, heart rate <= 54 bpm (baseline >= 60 bpm) or <=50 (baseline < 60 bpm) or >= 101 bpm, respiratory rate >= 23 breaths per minute, and temperature >= 38.0 degrees Celsius. If a vital sign result met the threshold for an AE at baseline, subsequent vital sign results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 30
Each subject is only counted once per toxicity grade for the worst severity recorded. Vital sign parameters include systolic blood pressure (BP), diastolic BP, heart rate, respiratory rate, and temperature. Thresholds for abnormal vital signs were considered as systolic BP >= 141 mmHg or <= 89 mmHg, diastolic BP >= 91 mmHg, heart rate <= 54 bpm (baseline >= 60 bpm) or <=50 (baseline < 60 bpm) or >= 101 bpm, respiratory rate >= 23 breaths per minute, and temperature >= 38.0 degrees Celsius. If a vital sign result met the threshold for an AE at baseline, subsequent vital sign results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Abnormal Vital Signs for Multiple Ascending Dose (MAD)
Each subject is only counted once per toxicity grade for the worst severity recorded. Vital sign parameters include systolic blood pressure (BP), diastolic BP, heart rate, respiratory rate, and temperature. Thresholds for abnormal vital signs were considered as systolic BP >= 141 mmHg or <= 89 mmHg, diastolic BP >= 91 mmHg, heart rate <= 54 bpm (baseline >= 60 bpm) or <=50 (baseline < 60 bpm) or >= 101 bpm, respiratory rate >= 23 breaths per minute, and temperature >= 38.0 degrees Celsius. If a vital sign result met the threshold for an AE at baseline, subsequent vital sign results were only considered to be an AE if the grading worsened in severity.
Number of Participants With Unsolicited Adverse Events (AEs) for Single Ascending Dose (SAD)
Number of participants with an AE are summarized by MedDRA System Organ Class (SOC) and severity. If a condition was present at screening it was not considered an AE unless the severity worsened.
Number of Participants With Unsolicited Adverse Events (AEs) for Multiple Ascending Dose (MAD)
Number of participants with an AE are summarized by MedDRA System Organ Class (SOC). Each subject was counted once per SOC. If a condition was present at screening, it was not considered an AE unless the severity worsened.
Number of Unsolicited Adverse Events Reported for Single Ascending Dose (SAD)
The total number of unsolicited AE events reported summarized by MedDRA System Organ Class (SOC). If a condition was present at screening it was not considered an AE unless the severity worsened.
Number of Unsolicited Adverse Events Reported for Multiple Ascending Dose (MAD)
The total number of unsolicited AE events reported summarized by MedDRA System Organ Class (SOC). If a condition was present at screening it was not considered an AE unless the severity worsened.
Number of Participants With at Least One Severe Adverse Event (SAE) for Single Ascending Dose (SAD)
The number of participants who reported at least one SAE. SAEs include any AE that resulted in death, a life-threatening event, an inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or, or a congenital anomaly/birth defect.
Number of Participants With at Least One Severe Adverse Event (SAE) for Multiple Ascending Dose (MAD)
The number of participants who reported at least one SAE. SAEs include any AE that resulted in death, a life-threatening event, an inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or, or a congenital anomaly/birth defect.
Number of Participants With Solicited Local Reactogenicity Symptom(s) for Single Ascending Dose (SAD)
The number of participants who experienced solicited local reactogenicity events (injection site evaluation), summarized by symptom. Specified solicited events include pain, tenderness, pruritus, ecchymosis, erythema, induration, nodule, ulcer, healed, and scar. Thresholds for measurement grades of solicited local reactogenicity events were considered as ecchymosis >= 25 mm, erythema >=25 mm, induration >=25 mm, nodule >=25 mm, ulcer >=1 mm. For functional grades of solicited local reactogenicity events, the threshold for tenderness was considered as discomfort only to the touch or worse. For ecchymosis, erythema, induration, nodule, or ulcer thresholds for functional grade was interference with daily activity or worse, or any measurement over 1mm.
Number of Participants With Solicited Local Reactogenicity Symptom(s) for Multiple Ascending Dose (MAD)
The number of participants who experienced solicited local reactogenicity events (injection site evaluation), summarized by symptom. Specified solicited events include pain, tenderness, pruritus, ecchymosis, erythema, induration, nodule, ulcer, healed, and scar. Thresholds for measurement grades of solicited local reactogenicity events were considered as ecchymosis >= 25 mm, erythema >=25 mm, induration >=25 mm, nodule >=25 mm, ulcer >=1 mm. For functional grades of solicited local reactogenicity events, the threshold for tenderness was considered as discomfort only to the touch or worse. For ecchymosis, erythema, induration, nodule, or ulcer thresholds for functional grade was interference with daily activity or worse, or any measurement over 1mm.
Rezafungin Concentrations in Plasma, SAD 10 mg Dose Group Concentrations of Rezafungin in Plasma Samples
Mean and standard deviation of rezafungin concentrations in plasma from the SAD 10 mg Dose Group by nominal time point (0 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, 96 h, 144 h, 312 h, 696 h (post-dose)).
Rezafungin PK Parameter (Cmax) in Plasma, SAD 10 mg Dose Group
Mean and standard deviation (SD) of the Cmax (ng/mL) PK parameter estimated from the rezafungin plasma concentration-time data.
Rezafungin PK Parameters (Tmax and t 1/2) in Plasma, SAD 10 mg Dose Group
Mean and standard deviation (SD) of the Tmax (h) and t 1/2 (h) PK parameters were estimated from the rezafungin plasma concentration-time data using Phoenix WinNonlin Non-compartmental Analysis with the following Lambda Z Acceptance Criteria: rsq_adjusted (adjusted r squared) >= 0.90, span >= 3.0 half-lives, and includes at least 3 timepoints after tmax.
Rezafungin PK Parameters (AUC 0-last and AUC 0-inf ) in Plasma, SAD 10 mg Dose Group
Mean and standard deviation (SD) of the AUC 0-last (h*ng/mL) and AUC 0-inf (h*ng/mL) PK parameters were estimated from the rezafungin plasma concentration-time data using Phoenix WinNonlin Non-compartmental Analysis with the following Lambda Z Acceptance Criteria: rsq_adjusted (adjusted r squared) >= 0.90, span >= 3.0 half-lives, and includes at least 3 timepoints after tmax.
Rezafungin PK Parameter (Lambda z) in Plasma, SAD 10 mg Dose Group
Mean and standard deviation (SD) of the lambda z (1/h) PK parameter was estimated from the rezafungin plasma concentration-time data using Phoenix WinNonlin Non-compartmental Analysis with the following Lambda Z Acceptance Criteria: rsq_adjusted (adjusted r squared) >= 0.90, span >= 3.0 half-lives, and includes at least 3 timepoints after tmax.
Rezafungin PK Parameter (CL/F) in Plasma, SAD 10 mg Dose Group
Mean and standard deviation (SD) of the CL/F (L/h) PK parameter was estimated from the rezafungin plasma concentration-time data using Phoenix WinNonlin Non-compartmental Analysis with the following Lambda Z Acceptance Criteria: rsq_adjusted (adjusted r squared) >= 0.90, span >= 3.0 half-lives, and includes at least 3 timepoints after tmax.
Rezafungin PK Parameter (Vz/F) in Plasma, SAD 10 mg Dose Group
Mean and standard deviation (SD) of the Vz/F (L) PK parameter was estimated from the rezafungin plasma concentration-time data using Phoenix WinNonlin Non-compartmental Analysis with the following Lambda Z Acceptance Criteria: rsq_adjusted (adjusted r squared) >= 0.90, span >= 3.0 half-lives, and includes at least 3 timepoints after tmax.
Rezafungin Concentrations in Plasma Samples, Multiple Ascending Dose (MAD)
Mean and standard deviation of rezafungin concentrations in plasma from the SAD 10 mg Dose Group by nominal time point (0 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 12 h on Days 1 and 15, 24 h post-dose on Days 2 and 16, 48 h post-dose on Days 3 and 17; at 1 h and 4 h post-dose on Day 8; at 72 h post-dose on Days 4, 11, and 18; at 96 hours post-dose on Days 5, 12, and 19; at 120 h post-dose on Days 6, 13, and 20; at 144 h post-dose on Days 7, 14, and 21; on Days 30 and 45 post-dose)
Rezafungin PK Parameters in Plasma, Multiple Ascending Dose (MAD)
Mean and standard deviation (SD) of PK parameters estimated from the rezafungin plasma concentration-time data. PK Parameters include Cmax (ng/nL), Tmax (h), AUC 0-last (h*ng/mL), AUC 0-inf (h*ng/mL), lambda z (1/h), t 1/2 (h), CL/F (L/h), Vz/F (L).

Secondary Outcome Measures

Bioavailability (BA) of Rezafungin in BA Cohorts
BA is calculated as the ratio of the area under the curve (AUC) for the subcutaneous (SC) injection to the AUC for the intravenous (IV) infusion, where AUC is assessed by plasma Rezafungin levels. Plasma rezafungin determined by LC-MS/MS methods.

Full Information

First Posted
September 12, 2019
Last Updated
June 25, 2021
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT04117607
Brief Title
Safety and Pharmacokinetics of Rezafungin
Official Title
A Phase 1, Three-Part, Randomized, Double-Blind, Single and Multiple Subcutaneous Dose Escalation Study to Determine the Safety, Tolerability, and Pharmacokinetics of Rezafungin in Healthy Adult Subjects
Study Type
Interventional

2. Study Status

Record Verification Date
June 18, 2020
Overall Recruitment Status
Terminated
Why Stopped
Stopped due to the formation of injection site skin nodules.
Study Start Date
December 4, 2019 (Actual)
Primary Completion Date
May 11, 2020 (Actual)
Study Completion Date
May 11, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

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.
No

5. Study Description

Brief Summary
This is a Phase 1, double-blind, placebo-controlled trial in three parts. A single ascending dose (SAD) study in six cohorts receiving a single subcutaneous (SC) dose of 1, 10, 30, 60, 100, or 200 mg of rezafungin; a multiple ascending dose (MAD) study in four cohorts receiving 30 mg x 3 doses, 60 mg x 3 doses, 100 mg x 3 doses, or 200 mg x 3 doses of rezafungin SC with dosing frequency of once every 7 days; and a two-period cross-over bioavailability (BA) study receiving 100 mg of rezafungin. The two period cross-over BA study will be assessed unblinded in two sequences (10 subjects, 100 mg or maximum tolerated dose (MTD) of rezafungin in Part 1); 5 subjects will receive an SC injection of rezafungin in Period 1 followed by an intravenous (IV) infusion of rezafungin in Period 2, and 5 subjects will receive an IV infusion of rezafungin in Period 1 followed by an SC injection of rezafungin in Period 2. Each SAD (except cohort 1) and MAD cohort will contain 8 subjects (6 subjects will receive a SC injection of rezafungin and 2 subjects will receive placebo). Each SAD (except cohort 1) and MAD cohort will be conducted with sentinel dosing. SAD cohort 1 will be comprised of 4 subjects (3:1 rezafungin to placebo) with no sentinel dosing. Parts 2 and 3 of the study will only be conducted after FDA review for safety data and PK data from all subjects participating in Part 1; Part 3 may be run in parallel with the first cohort (Cohort 7) of Part 2. Individuals in the SAD cohorts will participate for approximately 58 days, including up to 28 days for screening and 30 days for dosing and follow-up (FU). Individuals in the MAD cohorts will participate for approximately 73 days, including up to 28 days for screening and 45 days for dosing and FU. Individuals in the BA cohorts will participate for approximately 80 days, including up to 28 days for screening and 52 days for dosing and FU. The study will have a duration of approximately 30 months. The primary objectives are to determine the: 1) safety and tolerability of single ascending SC doses (SAD) of rezafungin; 2) safety and tolerability of multiple ascending SC doses (MAD) of rezafungin; and 3) pharmacokinetic (PK) profile in plasma of rezafungin in healthy adult subjects.
Detailed Description
This is a Phase 1, double-blind, placebo-controlled trial in three parts. A single ascending dose (SAD) study in six cohorts receiving a single subcutaneous (SC) dose of 1, 10, 30, 60, 100, or 200 mg of rezafungin; a multiple ascending dose (MAD) study in four cohorts receiving 30 mg x 3 doses, 60 mg x 3 doses, 100 mg x 3 doses, or 200 mg x 3 doses of rezafungin SC with dosing frequency of once every 7 days; and a two-period cross-over bioavailability (BA) study receiving 100 mg of rezafungin. The two period cross-over BA study will be assessed unblinded in two sequences (10 subjects, 100 mg or maximum tolerated dose (MTD) of rezafungin in Part 1); 5 subjects will receive an SC injection of rezafungin in Period 1 followed by an intravenous (IV) infusion of rezafungin in Period 2, and 5 subjects will receive an IV infusion of rezafungin in Period 1 followed by an SC injection of rezafungin in Period 2. Each SAD (except cohort 1) and MAD cohort will contain 8 subjects (6 subjects will receive a SC injection of rezafungin and 2 subjects will receive placebo). Each SAD (except cohort 1) and MAD cohort will be conducted with sentinel dosing. SAD cohort 1 will be comprised of 4 subjects (3:1 rezafungin to placebo) with no sentinel dosing. Parts 2 and 3 of the study will only be conducted after FDA review for safety data and PK data from all subjects participating in Part 1; Part 3 may be run in parallel with the first cohort (Cohort 7) of Part 2. Individuals in the SAD cohorts will participate for approximately 58 days, including up to 28 days for screening and 30 days for dosing and follow-up (FU). Individuals in the MAD cohorts will participate for approximately 73 days, including up to 28 days for screening and 45 days for dosing and FU. Individuals in the BA cohorts will participate for approximately 80 days, including up to 28 days for screening and 52 days for dosing and FU. The study will have a duration of approximately 30 months. The primary objectives are to determine the: 1) safety and tolerability of single ascending SC doses (SAD) of rezafungin; 2) safety and tolerability of multiple ascending SC doses (MAD) of rezafungin; and 3) pharmacokinetic (PK) profile in plasma of rezafungin in healthy adult subjects. The secondary objective is to evaluate the BA of rezafungin when administered by SC injection relative to IV infusion in healthy adult subjects.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Fungal Infection
Keywords
Dose Escalation Study, Double-Blind, Healthy Adult Subjects, Phase 1, Rezafungin, Safety and Pharmacokinetic

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
14 (Actual)

8. Arms, Groups, and Interventions

Arm Title
BA1
Arm Type
Experimental
Arm Description
100 mg (1 injection of 1.0 ml) or maximum tolerated dose (MTD) determined in SAD of Rezafungin administered subcutaneously into the abdomen on Day 1, and 100 mg (250 ml) or MTD of Rezafungin administered via intravenous infusion on Day 22 in an open label manner. n=5.
Arm Title
BA2
Arm Type
Experimental
Arm Description
100 mg (250 ml) or maximum tolerated dose (MTD) determined in SAD of Rezafungin administered via intravenous infusion on Day 1, and 100 mg (1 injection of 1.0 ml) or MTD of Rezafungin administered subcutaneously into the abdomen on Day 22 in an open label manner. n=5.
Arm Title
MAD1
Arm Type
Experimental
Arm Description
30 mg (1 injection of 0.3 ml) of Rezafungin administered subcutaneously into the abdomen as three doses, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Days 1, 8, and 15 in a double-blind manner.
Arm Title
MAD2
Arm Type
Experimental
Arm Description
60 mg (1 injection of 0.6 ml) of Rezafungin administered subcutaneously into the abdomen as three doses, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Days 1, 8, and 15 in a double-blind manner.
Arm Title
MAD3
Arm Type
Experimental
Arm Description
100 mg (1 injection of 1.0 ml) of Rezafungin administered subcutaneously into alternating abdominal quadrants as three doses, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Days 1, 8, and 15 in a double-blind manner.
Arm Title
MAD4
Arm Type
Experimental
Arm Description
200 mg (2 injections of 1.0 ml) of Rezafungin administered subcutaneously into alternating abdominal quadrants as three doses, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Days 1, 8, and 15 in a double-blind manner.
Arm Title
SAD1
Arm Type
Experimental
Arm Description
1 mg (1 injection of 0.1 ml diluted 1:10 in 5% Dextrose Injection, USP) of Rezafungin administered subcutaneously into the abdomen as a single dose, n=3 (no sentinel dosing), or matching placebo, n=1 (no sentinel dosing), on Day 1 in a double-blind manner.
Arm Title
SAD2
Arm Type
Experimental
Arm Description
10 mg (1 injection of 0.1 ml) of Rezafungin administered subcutaneously into the abdomen as a single dose, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Day 1 in a double-blind manner.
Arm Title
SAD3
Arm Type
Experimental
Arm Description
30 mg (1 injection of 0.3 ml) of Rezafungin administered subcutaneously into the abdomen as a single dose, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Day 1 in a double-blind manner.
Arm Title
SAD4
Arm Type
Experimental
Arm Description
60 mg (1 injection of 0.6 ml) of Rezafungin administered subcutaneously into the abdomen as a single dose, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Day 1 in a double-blind manner.
Arm Title
SAD5
Arm Type
Experimental
Arm Description
100 mg (1 injection of 1.0 ml) of Rezafungin administered subcutaneously into alternating abdominal quadrants as a single dose, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Day 1 in a double-blind manner.
Arm Title
SAD6
Arm Type
Experimental
Arm Description
200 mg (2 injections of 1.0 ml) of Rezafungin administered subcutaneously into alternating abdominal quadrants as a single dose, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Day 1 in a double-blind manner.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
5% Dextrose Injection, USP, a sterile, nonpyrogenic solution of dextrose in water for injection. The solution has the osmolarity of 252 mOsmol/L, which is slightly hypotonic. This solution contains no bacteriostat, antimicrobial agent or added buffer.
Intervention Type
Drug
Intervention Name(s)
Rezafungin
Intervention Description
Rezafungin, 100 mg/mL, is a sterile liquid product supplied in single-dose vials containing 1.0 mL of extractable volume. The active pharmaceutical ingredient is rezafungin acetate, a water-soluble amorphous acetate salt. The inactive ingredient is mannitol.
Intervention Type
Drug
Intervention Name(s)
Rezafungin
Intervention Description
Rezafungin, 200 mg/vial, is a sterile product supplied as a white to pale yellow lyophilized powder in single-dose glass vials for reconstitution with Sterile Water for Injection, United States Pharmacopeia (USP). The reconstituted product is diluted in 0.9% Sodium Chloride Injection, USP for IV infusion. The active pharmaceutical ingredient is rezafungin acetate, a water-soluble amorphous acetate salt. The inactive ingredients include excipients of mannitol, polysorbate 80, and histidine.
Primary Outcome Measure Information:
Title
Number of Participants With Abnormal Chemistry Laboratory Toxicity Results for Single Ascending Dose (SAD) on Day 2
Description
Laboratory parameters and associated thresholds include albumin <=3.4 g/dL, glucose <= 69 mg/dL or >=106 mg/dL, blood urea nitrogen (BUN) >= 21 mg/dL, potassium >=5.2 mEq/L or <=3.4 mEq/L, calcium < 8.7 mg/dL or >=10.3 mg/dL, sodium <=132 mEq/L or >=144 mEq/L, total protein <=5.9 g/dL, creatinine >=1.3 mg/dL (male) or >= 1.0 mg/dL (female), creatine phosphokinase >= 309 U/L, phosphorus <=2.4 mg/dL, alkaline phosphatase >= 131 IU/L (males) or >= 106 IU/L (female), aspartate aminotransferase >= 40 U/L (male) or >= 32 U/L (female), alanine aminotransferase >=41 U/L (male) or >= 33 U/L (female), and total bilirubin >=106 mg/dL. If a clinical chemistry laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 2
Title
Number of Participants With Abnormal Chemistry Laboratory Toxicity Results for Single Ascending Dose (SAD) on Day 7
Description
Laboratory parameters and associated thresholds include albumin <=3.4 g/dL, glucose <= 69 mg/dL or >=106 mg/dL, blood urea nitrogen (BUN) >= 21 mg/dL, potassium >=5.2 mEq/L or <=3.4 mEq/L, calcium < 8.7 mg/dL or >=10.3 mg/dL, sodium <=132 mEq/L or >=144 mEq/L, total protein <=5.9 g/dL, creatinine >=1.3 mg/dL (male) or >= 1.0 mg/dL (female), creatine phosphokinase >= 309 U/L, phosphorus <=2.4 mg/dL, alkaline phosphatase >= 131 IU/L (males) or >= 106 IU/L (female), aspartate aminotransferase >= 40 U/L (male) or >= 32 U/L (female), alanine aminotransferase >=41 U/L (male) or >= 33 U/L (female), and total bilirubin >=106 mg/dL. If a clinical chemistry laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 7
Title
Number of Participants With Abnormal Chemistry Laboratory Toxicity Results for Single Ascending Dose (SAD) on Day 30
Description
Laboratory parameters and associated thresholds include albumin <=3.4 g/dL, glucose <= 69 mg/dL or >=106 mg/dL, blood urea nitrogen (BUN) >= 21 mg/dL, potassium >=5.2 mEq/L or <=3.4 mEq/L, calcium < 8.7 mg/dL or >=10.3 mg/dL, sodium <=132 mEq/L or >=144 mEq/L, total protein <=5.9 g/dL, creatinine >=1.3 mg/dL (male) or >= 1.0 mg/dL (female), creatine phosphokinase >= 309 U/L, phosphorus <=2.4 mg/dL, alkaline phosphatase >= 131 IU/L (males) or >= 106 IU/L (female), aspartate aminotransferase >= 40 U/L (male) or >= 32 U/L (female), alanine aminotransferase >=41 U/L (male) or >= 33 U/L (female), and total bilirubin >=106 mg/dL. If a clinical chemistry laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 30
Title
Number of Participants With Abnormal Chemistry Laboratory Toxicity Results for Multiple Ascending Dose (MAD)
Description
Laboratory parameters and associated thresholds include albumin <=3.4 g/dL, glucose <= 69 mg/dL or >=106 mg/dL, blood urea nitrogen (BUN) >= 21 mg/dL, potassium >=5.2 mEq/L or <=3.4 mEq/L, calcium < 8.7 mg/dL or >=10.3 mg/dL, sodium <=132 mEq/L or >=144 mEq/L, total protein <=5.9 g/dL, creatinine >=1.3 mg/dL (male) or >= 1.0 mg/dL (female), creatine phosphokinase >= 309 U/L, phosphorus <=2.4 mg/dL, alkaline phosphatase >= 131 IU/L (males) or >= 106 IU/L (female), aspartate aminotransferase >= 40 U/L (male) or >= 32 U/L (female), alanine aminotransferase >=41 U/L (male) or >= 33 U/L (female), and total bilirubin >=106 mg/dL. If a clinical chemistry laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 2 through Day 45
Title
Number of Participants With Abnormal Hematology Laboratory Toxicity Results for Single Ascending Dose (SAD) on Day 2
Description
Laboratory parameters and associated thresholds for adverse events include hemoglobin <= 12.2 g/dL (male) or <= 10.8 g/dL (female), hematocrit <= 36.1 % (male) or <= 32.6 % (female), red blood cell (RBC) count <= 4.1 x 10^6/uL (male) or <= 3.7 x 10^6/uL (female), white blood cell (WBC) count >= 9,001 cell/mm3 or <= 2,499 cell/mm3 (African American Males) or >= 11,001 cell/mm3 or <= 2,499 cell/mm3 (African American Females) or >= 10,001 cell/mm3 or <= 3,999 cell/mm3 (all others), neutrophil count <= 1,299 cell/mm3 (African Americans) or <= 1,699 cell/mm3 (all others), lymphocyte count <= 799 cell/mm3, monocyte count >= 1001 cell/mm3, eosinophil count >= 871 cell/mm3, basophil count >= 101 cell/mm3, and platelet count <= 149 x 10^3/mm3. If a result met the threshold for an AE at baseline, subsequent results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 2
Title
Number of Participants With Abnormal Hematology Laboratory Toxicity Results for Single Ascending Dose (SAD) on Day 7
Description
Laboratory parameters and associated thresholds for adverse events include hemoglobin <= 12.2 g/dL (male) or <= 10.8 g/dL (female), hematocrit <= 36.1 % (male) or <= 32.6 % (female), red blood cell (RBC) count <= 4.1 x 10^6/uL (male) or <= 3.7 x 10^6/uL (female), white blood cell (WBC) count >= 9,001 cell/mm3 or <= 2,499 cell/mm3 (African American Males) or >= 11,001 cell/mm3 or <= 2,499 cell/mm3 (African American Females) or >= 10,001 cell/mm3 or <= 3,999 cell/mm3 (all others), neutrophil count <= 1,299 cell/mm3 (African Americans) or <= 1,699 cell/mm3 (all others), lymphocyte count <= 799 cell/mm3, monocyte count >= 1001 cell/mm3, eosinophil count >= 871 cell/mm3, basophil count >= 101 cell/mm3, and platelet count <= 149 x 10^3/mm3. If a result met the threshold for an AE at baseline, subsequent results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 7
Title
Number of Participants With Abnormal Hematology Laboratory Toxicity Results for Single Ascending Dose (SAD) on Day 30
Description
Laboratory parameters and associated thresholds for adverse events include hemoglobin <= 12.2 g/dL (male) or <= 10.8 g/dL (female), hematocrit <= 36.1 % (male) or <= 32.6 % (female), red blood cell (RBC) count <= 4.1 x 10^6/uL (male) or <= 3.7 x 10^6/uL (female), white blood cell (WBC) count >= 9,001 cell/mm3 or <= 2,499 cell/mm3 (African American Males) or >= 11,001 cell/mm3 or <= 2,499 cell/mm3 (African American Females) or >= 10,001 cell/mm3 or <= 3,999 cell/mm3 (all others), neutrophil count <= 1,299 cell/mm3 (African Americans) or <= 1,699 cell/mm3 (all others), lymphocyte count <= 799 cell/mm3, monocyte count >= 1001 cell/mm3, eosinophil count >= 871 cell/mm3, basophil count >= 101 cell/mm3, and platelet count <= 149 x 10^3/mm3. If a result met the threshold for an AE at baseline, subsequent results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 30
Title
Number of Participants With Abnormal Hematology Laboratory Toxicity Results for Multiple Ascending Dose (MAD)
Description
Laboratory parameters and associated thresholds for adverse events include hemoglobin <= 12.2 g/dL (male) or <= 10.8 g/dL (female), hematocrit <= 36.1 % (male) or <= 32.6 % (female), red blood cell (RBC) count <= 4.1 x 10^6/uL (male) or <= 3.7 x 10^6/uL (female), white blood cell (WBC) count >= 9,001 cell/mm3 or <= 2,499 cell/mm3 (African American Males) or >= 11,001 cell/mm3 or <= 2,499 cell/mm3 (African American Females) or >= 10,001 cell/mm3 or <= 3,999 cell/mm3 (all others), neutrophil count <= 1,299 cell/mm3 (African Americans) or <= 1,699 cell/mm3 (all others), lymphocyte count <= 799 cell/mm3, monocyte count >= 1001 cell/mm3, eosinophil count >= 871 cell/mm3, basophil count >= 101 cell/mm3, and platelet count <= 149 x 10^3/mm3. If a result met the threshold for an AE at baseline, subsequent results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 2 through Day 45
Title
Number of Participants With Abnormal Coagulation Laboratory Toxicity Results for Single Ascending Dose (SAD), Day 2
Description
Laboratory parameters include prothrombin time (PT), activated partial prothrombin time (PTT), and prothrombin international normalized ratio (INR). Thresholds for adverse events were considered as PT >= 11.1 s (before 23DEC2019) or >= 11.6 s (on or after 23DEC2019), PTT >= 34.1 s (before 23DEC2019) or >= 30.1 (on or after 23DEC2019), INR >= 1.2. If a coagulation laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 2
Title
Number of Participants With Abnormal Coagulation Laboratory Toxicity Results for Single Ascending Dose (SAD), Day 7
Description
Laboratory parameters include prothrombin time (PT), activated partial prothrombin time (PTT), and prothrombin international normalized ratio (INR). Thresholds for adverse events were considered as PT >= 11.1 s (before 23DEC2019) or >= 11.6 s (on or after 23DEC2019), PTT >= 34.1 s (before 23DEC2019) or >= 30.1 (on or after 23DEC2019), INR >= 1.2. If a coagulation laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 7
Title
Number of Participants With Abnormal Coagulation Laboratory Toxicity Results for Single Ascending Dose (SAD), Day 30
Description
Laboratory parameters include prothrombin time (PT), activated partial prothrombin time (PTT), and prothrombin international normalized ratio (INR). Thresholds for adverse events were considered as PT >= 11.1 s (before 23DEC2019) or >= 11.6 s (on or after 23DEC2019), PTT >= 34.1 s (before 23DEC2019) or >= 30.1 (on or after 23DEC2019), INR >= 1.2. If a coagulation laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 30
Title
Number of Participants With Abnormal Coagulation Laboratory Toxicity Results for Multiple Ascending Dose (MAD)
Description
Laboratory parameters include prothrombin time (PT), activated partial prothrombin time (PTT), and prothrombin international normalized ratio (INR). Thresholds for adverse events were considered as PT >= 11.1 s (before 23DEC2019) or >= 11.6 s (on or after 23DEC2019), PTT >= 34.1 s (before 23DEC2019) or >= 30.1 (on or after 23DEC2019), INR >= 1.2. If a coagulation laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 2 through Day 45
Title
Number of Participants With Abnormal Urinalysis Laboratory Toxicity Results for Single Ascending Dose (SAD), Day 2
Description
Laboratory parameters include protein, glucose, and occult blood. Thresholds for adverse events were considered as protein >= 1+, glucose >= 1+, and occult blood >= 5 (before 23DEC2019) or >=3 (on or after 23DEC2019). If a urinalysis laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 2
Title
Number of Participants With Abnormal Urinalysis Laboratory Toxicity Results for Single Ascending Dose (SAD), Day 7
Description
Laboratory parameters include protein, glucose, and occult blood. Thresholds for adverse events were considered as protein >= 1+, glucose >= 1+, and occult blood >= 5 (before 23DEC2019) or >=3 (on or after 23DEC2019). If a urinalysis laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 7
Title
Number of Participants With Abnormal Urinalysis Laboratory Toxicity Results for Single Ascending Dose (SAD), Day 30
Description
Laboratory parameters include protein, glucose, and occult blood. Thresholds for adverse events were considered as protein >= 1+, glucose >= 1+, and occult blood >= 5 (before 23DEC2019) or >=3 (on or after 23DEC2019). If a urinalysis laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 30
Title
Number of Participants With Abnormal Urinalysis Laboratory Toxicity Results for Multiple Ascending Dose (MAD)
Description
Each subject is only counted once per toxicity grade for the worst severity recorded. Laboratory parameters include protein, glucose, and occult blood. Thresholds for adverse events were considered as protein >= 1+, glucose >= 1+, and occult blood >= 5 (before 23DEC2019) or >=3 (on or after 23DEC2019). If a urinalysis laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 2 through Day 45
Title
Number of Participants With Abnormal ECG Toxicity Results for Single Ascending Dose (SAD), Day 1
Description
Each subject is only counted once per toxicity grade for the worst severity recorded. ECG parameters include PR interval and QTcF interval. Thresholds for adverse events were considered as PR interval >= 0.21 sec, a type II 2nd degree AV block, or ventricular pause >3 sec and QTcF interval >= 450 msec or >= 30 msec above baseline. If an ECG value met the threshold for an AE at baseline, subsequent safety ECG results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 1
Title
Number of Participants With Abnormal ECG Toxicity Results for Single Ascending Dose (SAD), Day 7
Description
Each subject is only counted once per toxicity grade for the worst severity recorded. ECG parameters include PR interval and QTcF interval. Thresholds for adverse events were considered as PR interval >= 0.21 sec, a type II 2nd degree AV block, or ventricular pause >3 sec and QTcF interval >= 450 msec or >= 30 msec above baseline. If an ECG value met the threshold for an AE at baseline, subsequent safety ECG results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 7
Title
Number of Participants With Abnormal ECG Toxicity Results for Single Ascending Dose (SAD), Day 30
Description
Each subject is only counted once per toxicity grade for the worst severity recorded. ECG parameters include PR interval and QTcF interval. Thresholds for adverse events were considered as PR interval >= 0.21 sec, a type II 2nd degree AV block, or ventricular pause >3 sec and QTcF interval >= 450 msec or >= 30 msec above baseline. If an ECG value met the threshold for an AE at baseline, subsequent safety ECG results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 30
Title
Number of Participants With Abnormal ECG Toxicity Results for Multiple Ascending Doses (MAD)
Description
This table includes the maximum severity experienced over all post-baseline time points. ECG parameters include PR interval and QTcF interval. Thresholds for adverse events were considered as PR interval >= 0.21 sec, a type II 2nd degree AV block, or ventricular pause >3 sec and QTcF interval >= 450 msec or >= 30 msec above baseline. If an ECG value met the threshold for an AE at baseline, subsequent safety ECG results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 1 through Day 45
Title
Number of Participants With Abnormal Physical Exams for Single Ascending Dose (SAD), Day 1
Description
Physical examination includes general appearance; head, eyes, nose and throat; neck; chest and lungs; cardiovascular system, abdomen, musculoskeletal system, lymph nodes, extremities/skin, and neurological system.
Time Frame
Day 1
Title
Number of Participants With Abnormal Physical Exams for Single Ascending Dose (SAD), Day 2
Description
Physical examination includes general appearance; head, eyes, nose and throat; neck; chest and lungs; cardiovascular system, abdomen, musculoskeletal system, lymph nodes, extremities/skin, and neurological system.
Time Frame
Day 2
Title
Number of Participants With Abnormal Physical Exams for Single Ascending Dose (SAD), Day 4
Description
Physical examination includes general appearance; head, eyes, nose and throat; neck; chest and lungs; cardiovascular system, abdomen, musculoskeletal system, lymph nodes, extremities/skin, and neurological system.
Time Frame
Day 4
Title
Number of Participants With Abnormal Physical Exams for Single Ascending Dose (SAD), Day 7
Description
Physical examination includes general appearance; head, eyes, nose and throat; neck; chest and lungs; cardiovascular system, abdomen, musculoskeletal system, lymph nodes, extremities/skin, and neurological system.
Time Frame
Day 7
Title
Number of Participants With Abnormal Physical Exams for Single Ascending Dose (SAD), Day 30
Description
Physical examination includes general appearance; head, eyes, nose and throat; neck; chest and lungs; cardiovascular system, abdomen, musculoskeletal system, lymph nodes, extremities/skin, and neurological system.
Time Frame
Day 30
Title
Number of Participants With Abnormal Physical Exams for Multiple Ascending Dose (MAD)
Description
Physical examination includes general appearance; head, eyes, nose and throat; neck; chest and lungs; cardiovascular system, abdomen, musculoskeletal system, lymph nodes, extremities/skin, and neurological system.
Time Frame
Day 1 through Day 45
Title
Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 1, 15 Minutes Post-dose
Description
Each subject is only counted once per toxicity grade for the worst severity recorded. Vital sign parameters include systolic blood pressure (BP), diastolic BP, heart rate, respiratory rate, and temperature. Thresholds for abnormal vital signs were considered as systolic BP >= 141 mmHg or <= 89 mmHg, diastolic BP >= 91 mmHg, heart rate <= 54 bpm (baseline >= 60 bpm) or <=50 (baseline < 60 bpm) or >= 101 bpm, respiratory rate >= 23 breaths per minute, and temperature >= 38.0 degrees Celsius. If a vital sign result met the threshold for an AE at baseline, subsequent vital sign results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 1, 15 minutes post-dose
Title
Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 1, 1 Hour Post-dose
Description
Each subject is only counted once per toxicity grade for the worst severity recorded. Vital sign parameters include systolic blood pressure (BP), diastolic BP, heart rate, respiratory rate, and temperature. Thresholds for abnormal vital signs were considered as systolic BP >= 141 mmHg or <= 89 mmHg, diastolic BP >= 91 mmHg, heart rate <= 54 bpm (baseline >= 60 bpm) or <=50 (baseline < 60 bpm) or >= 101 bpm, respiratory rate >= 23 breaths per minute, and temperature >= 38.0 degrees Celsius. If a vital sign result met the threshold for an AE at baseline, subsequent vital sign results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 1, 1 hour post-dose
Title
Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 1, 2 Hours Post-dose
Description
Each subject is only counted once per toxicity grade for the worst severity recorded. Vital sign parameters include systolic blood pressure (BP), diastolic BP, heart rate, respiratory rate, and temperature. Thresholds for abnormal vital signs were considered as systolic BP >= 141 mmHg or <= 89 mmHg, diastolic BP >= 91 mmHg, heart rate <= 54 bpm (baseline >= 60 bpm) or <=50 (baseline < 60 bpm) or >= 101 bpm, respiratory rate >= 23 breaths per minute, and temperature >= 38.0 degrees Celsius. If a vital sign result met the threshold for an AE at baseline, subsequent vital sign results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 1, 2 hours post-dose
Title
Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 2
Description
Each subject is only counted once per toxicity grade for the worst severity recorded. Vital sign parameters include systolic blood pressure (BP), diastolic BP, heart rate, respiratory rate, and temperature. Thresholds for abnormal vital signs were considered as systolic BP >= 141 mmHg or <= 89 mmHg, diastolic BP >= 91 mmHg, heart rate <= 54 bpm (baseline >= 60 bpm) or <=50 (baseline < 60 bpm) or >= 101 bpm, respiratory rate >= 23 breaths per minute, and temperature >= 38.0 degrees Celsius. If a vital sign result met the threshold for an AE at baseline, subsequent vital sign results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 2
Title
Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 4
Description
Each subject is only counted once per toxicity grade for the worst severity recorded. Vital sign parameters include systolic blood pressure (BP), diastolic BP, heart rate, respiratory rate, and temperature. Thresholds for abnormal vital signs were considered as systolic BP >= 141 mmHg or <= 89 mmHg, diastolic BP >= 91 mmHg, heart rate <= 54 bpm (baseline >= 60 bpm) or <=50 (baseline < 60 bpm) or >= 101 bpm, respiratory rate >= 23 breaths per minute, and temperature >= 38.0 degrees Celsius. If a vital sign result met the threshold for an AE at baseline, subsequent vital sign results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 4
Title
Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 7
Description
Each subject is only counted once per toxicity grade for the worst severity recorded. Vital sign parameters include systolic blood pressure (BP), diastolic BP, heart rate, respiratory rate, and temperature. Thresholds for abnormal vital signs were considered as systolic BP >= 141 mmHg or <= 89 mmHg, diastolic BP >= 91 mmHg, heart rate <= 54 bpm (baseline >= 60 bpm) or <=50 (baseline < 60 bpm) or >= 101 bpm, respiratory rate >= 23 breaths per minute, and temperature >= 38.0 degrees Celsius. If a vital sign result met the threshold for an AE at baseline, subsequent vital sign results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 7
Title
Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 14
Description
Each subject is only counted once per toxicity grade for the worst severity recorded. Vital sign parameters include systolic blood pressure (BP), diastolic BP, heart rate, respiratory rate, and temperature. Thresholds for abnormal vital signs were considered as systolic BP >= 141 mmHg or <= 89 mmHg, diastolic BP >= 91 mmHg, heart rate <= 54 bpm (baseline >= 60 bpm) or <=50 (baseline < 60 bpm) or >= 101 bpm, respiratory rate >= 23 breaths per minute, and temperature >= 38.0 degrees Celsius. If a vital sign result met the threshold for an AE at baseline, subsequent vital sign results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 14
Title
Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 30
Description
Each subject is only counted once per toxicity grade for the worst severity recorded. Vital sign parameters include systolic blood pressure (BP), diastolic BP, heart rate, respiratory rate, and temperature. Thresholds for abnormal vital signs were considered as systolic BP >= 141 mmHg or <= 89 mmHg, diastolic BP >= 91 mmHg, heart rate <= 54 bpm (baseline >= 60 bpm) or <=50 (baseline < 60 bpm) or >= 101 bpm, respiratory rate >= 23 breaths per minute, and temperature >= 38.0 degrees Celsius. If a vital sign result met the threshold for an AE at baseline, subsequent vital sign results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 30
Title
Number of Participants With Abnormal Vital Signs for Multiple Ascending Dose (MAD)
Description
Each subject is only counted once per toxicity grade for the worst severity recorded. Vital sign parameters include systolic blood pressure (BP), diastolic BP, heart rate, respiratory rate, and temperature. Thresholds for abnormal vital signs were considered as systolic BP >= 141 mmHg or <= 89 mmHg, diastolic BP >= 91 mmHg, heart rate <= 54 bpm (baseline >= 60 bpm) or <=50 (baseline < 60 bpm) or >= 101 bpm, respiratory rate >= 23 breaths per minute, and temperature >= 38.0 degrees Celsius. If a vital sign result met the threshold for an AE at baseline, subsequent vital sign results were only considered to be an AE if the grading worsened in severity.
Time Frame
Day 1 through Day 45
Title
Number of Participants With Unsolicited Adverse Events (AEs) for Single Ascending Dose (SAD)
Description
Number of participants with an AE are summarized by MedDRA System Organ Class (SOC) and severity. If a condition was present at screening it was not considered an AE unless the severity worsened.
Time Frame
Day 1 through Day 30.
Title
Number of Participants With Unsolicited Adverse Events (AEs) for Multiple Ascending Dose (MAD)
Description
Number of participants with an AE are summarized by MedDRA System Organ Class (SOC). Each subject was counted once per SOC. If a condition was present at screening, it was not considered an AE unless the severity worsened.
Time Frame
Day 1 through Day 45
Title
Number of Unsolicited Adverse Events Reported for Single Ascending Dose (SAD)
Description
The total number of unsolicited AE events reported summarized by MedDRA System Organ Class (SOC). If a condition was present at screening it was not considered an AE unless the severity worsened.
Time Frame
Day 1 through Day 30.
Title
Number of Unsolicited Adverse Events Reported for Multiple Ascending Dose (MAD)
Description
The total number of unsolicited AE events reported summarized by MedDRA System Organ Class (SOC). If a condition was present at screening it was not considered an AE unless the severity worsened.
Time Frame
Day 1 through Day 45
Title
Number of Participants With at Least One Severe Adverse Event (SAE) for Single Ascending Dose (SAD)
Description
The number of participants who reported at least one SAE. SAEs include any AE that resulted in death, a life-threatening event, an inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or, or a congenital anomaly/birth defect.
Time Frame
Day 1 through Day 30
Title
Number of Participants With at Least One Severe Adverse Event (SAE) for Multiple Ascending Dose (MAD)
Description
The number of participants who reported at least one SAE. SAEs include any AE that resulted in death, a life-threatening event, an inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or, or a congenital anomaly/birth defect.
Time Frame
Day 1 through Day 45
Title
Number of Participants With Solicited Local Reactogenicity Symptom(s) for Single Ascending Dose (SAD)
Description
The number of participants who experienced solicited local reactogenicity events (injection site evaluation), summarized by symptom. Specified solicited events include pain, tenderness, pruritus, ecchymosis, erythema, induration, nodule, ulcer, healed, and scar. Thresholds for measurement grades of solicited local reactogenicity events were considered as ecchymosis >= 25 mm, erythema >=25 mm, induration >=25 mm, nodule >=25 mm, ulcer >=1 mm. For functional grades of solicited local reactogenicity events, the threshold for tenderness was considered as discomfort only to the touch or worse. For ecchymosis, erythema, induration, nodule, or ulcer thresholds for functional grade was interference with daily activity or worse, or any measurement over 1mm.
Time Frame
Day 1 through Day 30
Title
Number of Participants With Solicited Local Reactogenicity Symptom(s) for Multiple Ascending Dose (MAD)
Description
The number of participants who experienced solicited local reactogenicity events (injection site evaluation), summarized by symptom. Specified solicited events include pain, tenderness, pruritus, ecchymosis, erythema, induration, nodule, ulcer, healed, and scar. Thresholds for measurement grades of solicited local reactogenicity events were considered as ecchymosis >= 25 mm, erythema >=25 mm, induration >=25 mm, nodule >=25 mm, ulcer >=1 mm. For functional grades of solicited local reactogenicity events, the threshold for tenderness was considered as discomfort only to the touch or worse. For ecchymosis, erythema, induration, nodule, or ulcer thresholds for functional grade was interference with daily activity or worse, or any measurement over 1mm.
Time Frame
Day 1 through Day 45
Title
Rezafungin Concentrations in Plasma, SAD 10 mg Dose Group Concentrations of Rezafungin in Plasma Samples
Description
Mean and standard deviation of rezafungin concentrations in plasma from the SAD 10 mg Dose Group by nominal time point (0 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, 96 h, 144 h, 312 h, 696 h (post-dose)).
Time Frame
0 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, 96 h, 144 h, 312 h, and 696 h post-dose
Title
Rezafungin PK Parameter (Cmax) in Plasma, SAD 10 mg Dose Group
Description
Mean and standard deviation (SD) of the Cmax (ng/mL) PK parameter estimated from the rezafungin plasma concentration-time data.
Time Frame
0 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, 96 h, 144 h, 312 h, and 696 h post-dose
Title
Rezafungin PK Parameters (Tmax and t 1/2) in Plasma, SAD 10 mg Dose Group
Description
Mean and standard deviation (SD) of the Tmax (h) and t 1/2 (h) PK parameters were estimated from the rezafungin plasma concentration-time data using Phoenix WinNonlin Non-compartmental Analysis with the following Lambda Z Acceptance Criteria: rsq_adjusted (adjusted r squared) >= 0.90, span >= 3.0 half-lives, and includes at least 3 timepoints after tmax.
Time Frame
0 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, 96 h, 144 h, 312 h, and 696 h post-dose
Title
Rezafungin PK Parameters (AUC 0-last and AUC 0-inf ) in Plasma, SAD 10 mg Dose Group
Description
Mean and standard deviation (SD) of the AUC 0-last (h*ng/mL) and AUC 0-inf (h*ng/mL) PK parameters were estimated from the rezafungin plasma concentration-time data using Phoenix WinNonlin Non-compartmental Analysis with the following Lambda Z Acceptance Criteria: rsq_adjusted (adjusted r squared) >= 0.90, span >= 3.0 half-lives, and includes at least 3 timepoints after tmax.
Time Frame
0 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, 96 h, 144 h, 312 h, and 696 h post-dose
Title
Rezafungin PK Parameter (Lambda z) in Plasma, SAD 10 mg Dose Group
Description
Mean and standard deviation (SD) of the lambda z (1/h) PK parameter was estimated from the rezafungin plasma concentration-time data using Phoenix WinNonlin Non-compartmental Analysis with the following Lambda Z Acceptance Criteria: rsq_adjusted (adjusted r squared) >= 0.90, span >= 3.0 half-lives, and includes at least 3 timepoints after tmax.
Time Frame
0 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, 96 h, 144 h, 312 h, and 696 h post-dose
Title
Rezafungin PK Parameter (CL/F) in Plasma, SAD 10 mg Dose Group
Description
Mean and standard deviation (SD) of the CL/F (L/h) PK parameter was estimated from the rezafungin plasma concentration-time data using Phoenix WinNonlin Non-compartmental Analysis with the following Lambda Z Acceptance Criteria: rsq_adjusted (adjusted r squared) >= 0.90, span >= 3.0 half-lives, and includes at least 3 timepoints after tmax.
Time Frame
0 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, 96 h, 144 h, 312 h, and 696 h post-dose
Title
Rezafungin PK Parameter (Vz/F) in Plasma, SAD 10 mg Dose Group
Description
Mean and standard deviation (SD) of the Vz/F (L) PK parameter was estimated from the rezafungin plasma concentration-time data using Phoenix WinNonlin Non-compartmental Analysis with the following Lambda Z Acceptance Criteria: rsq_adjusted (adjusted r squared) >= 0.90, span >= 3.0 half-lives, and includes at least 3 timepoints after tmax.
Time Frame
0 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, 96 h, 144 h, 312 h, and 696 h post-dose
Title
Rezafungin Concentrations in Plasma Samples, Multiple Ascending Dose (MAD)
Description
Mean and standard deviation of rezafungin concentrations in plasma from the SAD 10 mg Dose Group by nominal time point (0 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 12 h on Days 1 and 15, 24 h post-dose on Days 2 and 16, 48 h post-dose on Days 3 and 17; at 1 h and 4 h post-dose on Day 8; at 72 h post-dose on Days 4, 11, and 18; at 96 hours post-dose on Days 5, 12, and 19; at 120 h post-dose on Days 6, 13, and 20; at 144 h post-dose on Days 7, 14, and 21; on Days 30 and 45 post-dose)
Time Frame
Day 1 through Day 45
Title
Rezafungin PK Parameters in Plasma, Multiple Ascending Dose (MAD)
Description
Mean and standard deviation (SD) of PK parameters estimated from the rezafungin plasma concentration-time data. PK Parameters include Cmax (ng/nL), Tmax (h), AUC 0-last (h*ng/mL), AUC 0-inf (h*ng/mL), lambda z (1/h), t 1/2 (h), CL/F (L/h), Vz/F (L).
Time Frame
Day 1 through Day 45
Secondary Outcome Measure Information:
Title
Bioavailability (BA) of Rezafungin in BA Cohorts
Description
BA is calculated as the ratio of the area under the curve (AUC) for the subcutaneous (SC) injection to the AUC for the intravenous (IV) infusion, where AUC is assessed by plasma Rezafungin levels. Plasma rezafungin determined by LC-MS/MS methods.
Time Frame
Day 1 through Day 52

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Males and females aged 18 to 45 years, inclusive. Willing and able to provide written informed consent and authorization for use of protected health information. Willing and able to comply with protocol requirements, instructions, and protocol-stated restrictions (including confinement to the Clinical Research Unit) and is likely to complete the study as planned. Males must be vasectomized or agree to use barrier contraception (condom with spermicide) from first dose of study drug until at least 18 weeks following the last dose of study drug. Males must agree to refrain from sperm donation from first dose of investigational product (IP) through at least 18 weeks after last dose of IP. Females are eligible if they are of non-childbearing potential* or if they use a highly effective** method of contraception for 30 days prior to dosing and for a minimum of 30 days after dosing. *Non-childbearing potential is defined as: Pre-menopausal with documentation of irreversible surgical sterilization (i.e., hysterectomy, bilateral oophorectomy, or bilateral salpingectomy (but not tubal ligation alone); or, Post-menopausal defined as amenorrhea for at least 12 months following cessation of all exogenous hormonal treatments and with Follicle Stimulating Hormone (FSH) levels > / = 40 mIU/mL at Screening. **A highly effective contraceptive method is, defined by < 1 percent failure rate that is not affected by user adherence, include surgical sterilization and long-acting reversible contraception (LARC). LARC comes in three forms: progestin-releasing subdermal implants (Nexplanon and Implanon [Merck]); copper intrauterine devices (IUD) (ParaGard [Teva]); and levonorgestrel-releasing IUDs (Mirena [Bayer], Skyla [Bayer], and Liletta [Allergan/Medicines360]. Subjects must use one of these three methods. Subject is in good health as deemed by the Investigator*,**. Good health is defined by the absence of any medical condition described in the exclusion criteria in a subject who undergoes a medical history, with a normal complete physical examination including resting vital signs, and screening safety laboratory testing. If the subject has an active, ongoing medical condition, the condition cannot meet any of the following criteria: 1) first diagnosed within 3 months of enrollment; 2) is worsening in terms of clinical outcome in last 6 months; or 3) involves need for medication that may pose a risk to subject's safety or significantly impede assessment of adverse events if they participate in the study. Subjects with a body mass index (BMI) (weight in kg divided by height in m, squared) between 18.5 and/or 35.0 kg/m^2, inclusive, and a minimum weight of 50 kg. Subjects must refrain from strenuous physical activity that could cause muscle aches or injury, including contact sports, at any time from screening until completion of the trial. Subjects must refrain from over-the-counter and prescription medications* and nutritional supplements within 14 days before first study drug administration, and until after the final study visit. *Except for hormonal contraceptives, acetaminophen, or ibuprofen. Subject has adequate venous access for blood collection. Exclusion Criteria: History of any hypersensitivity or allergic reaction to echinocandins or excipients (mannitol, polysorbate 80, histidine) of the rezafungin for injection and rezafungin for infusion formulations. Subjects presenting with a clinically significant condition*. *Subjects with any of the following must not be included into the study: clinically significant oncologic, infectious, cardiovascular, pulmonary, hepatic, gastrointestinal, hematologic, metabolic, endocrine, neurologic, immunologic, renal, psychiatric, or other condition that in the opinion of the Investigator would preclude the safe participation of the subject in the study or would prevent the subject from meeting the study requirements. Any condition that in the opinion of the Investigator could significantly impact drug absorption, distribution, or elimination. Symptoms of acute illness or chronic disease within 14 days of initial dosing. Positive screen for hepatitis B virus surface antigen, hepatitis C virus antibody, or Human Immunodeficiency Virus (HIV) antibody. Subjects with clinical laboratory values outside the site reference ranges* prior to initial dosing. *Clinical laboratory values outside the site reference ranges, if considered by the site investigator to be clinically insignificant, are acceptable if not exceeding Grade 1 severity. One repeat of lab testing is allowed to make this determination during screening. Abnormal Electrocardiograms (ECGs). Female subject of childbearing potential who is pregnant*, lactating, or planning to become pregnant during the study period or at least 30 days after the final dose of study product. *Having a positive serum pregnancy test at the Screening Visit or any other specified time point prior to the dose of study product. Received any prescription medications (except for hormonal contraceptives) within 14 days before first study drug administration. Received any non-prescription medications, vitamins, herbal or dietary supplements* within 14 days of initial dosing, unless prior approval is granted by both the Investigator and the Sponsor. *Excluded from this list is intermittent use of acetaminophen at doses of < / = 2 g/day or ibuprofen < / = 1200 mg/day. However, acetaminophen only is accepted to treat AEs for pain (ie. headaches) during in-clinic stay. Current smoker or tobacco* use within 90 days prior to screening or while a subject is enrolled in the study. *Tobacco use includes vaping, smoking tobacco, the use of snuff and chewing tobacco, and other nicotine or nicotine-containing products History of illicit/illegal drug use prior to dosing or while a subject is enrolled in the study* or reports an alcohol or substance abuse problem** within 6 months of dosing. *A urine drug test will be performed at screening and upon admission to the Clinical Research Unit (CRU). Drug screen includes amphetamines, barbiturates, cocaine, opiates, cannabinoids, phencyclidine, and benzodiazepines. **Inclusive of vaping of non-nicotine products. Consumed foods or beverages containing alcohol or xanthines/caffeine*,**: *Alcohol: < / = 48 hours before the first study drug administration, until discharge. **Xanthines/caffeine: < / = 24 hours before the first study drug administration, until discharge. Received any live or killed vaccines or immunoglobulins within 14 days of dosing. Donated blood or blood products or experienced significant blood loss within 60 days of dosing. Received a blood transfusion within 14 days of dosing. Previous participation in this trial, any other rezafungin trial, or any trial* within 28 days of dosing. Plans to enroll in another clinical trial**. *Includes trials that have a study intervention such as a drug, biologic, or device. **Includes trials that could interfere with safety assessment of the investigational product at any time during the study period. The PI considers that the subject should not participate in the trial.
Facility Information:
Facility Name
ICON Early Phase Services Clinical Research Unit
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78209-1015
Country
United States

12. IPD Sharing Statement

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Safety and Pharmacokinetics of Rezafungin

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