Safety and Pharmacokinetics of Rezafungin

NCT04117607 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 17-0088HHSN272201500007I
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

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.

Conditions

Fungal Infection

Keywords

Dose Escalation Study; Double-Blind; Healthy Adult Subjects; Phase 1; Rezafungin; Safety and Pharmacokinetic

Outcome Measures

Primary Outcomes (52)

• 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.

  Day 2

• 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.

  Day 7

• 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.

  Day 30

• 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.

  Day 2 through Day 45

• 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.

  Day 2

• 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.

  Day 7

• 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.

  Day 30

• 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.

  Day 2 through Day 45

• 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.

  Day 2

• 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.

  Day 7

• 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.

  Day 30

• 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.

  Day 2 through Day 45

• 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.

  Day 2

• 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.

  Day 7

• 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.

  Day 30

• 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.

  Day 2 through Day 45

• 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.

  Day 1

• 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.

  Day 7

• 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.

  Day 30

• 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.

  Day 1 through Day 45

• 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.

  Day 1

• 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.

  Day 2

• 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.

  Day 4

• 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.

  Day 7

• 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.

  Day 30

• 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.

  Day 1 through Day 45

• 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.

  Day 1, 15 minutes post-dose

• 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.

  Day 1, 1 hour post-dose

• 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.

  Day 1, 2 hours post-dose

• 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.

  Day 2

• 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.

  Day 4

• 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.

  Day 7

• 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.

  Day 14

• 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.

  Day 30

• 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.

  Day 1 through Day 45

• 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.

  Day 1 through Day 30.

• 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.

  Day 1 through Day 45

• 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.

  Day 1 through Day 30.

• 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.

  Day 1 through Day 45

• 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.

  Day 1 through Day 30

• 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.

  Day 1 through Day 45

• 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.

  Day 1 through Day 30

• 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.

  Day 1 through Day 45

• 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)).

  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

• 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.

  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

• 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.

  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

• 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.

  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

• 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.

  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

• 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.

  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

• 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.

  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

• 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)

  Day 1 through Day 45

• 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).

  Day 1 through Day 45

Secondary Outcomes (1)

• Bioavailability (BA) of Rezafungin in BA Cohorts

  Day 1 through Day 52

Study Arms (12)

BA1

EXPERIMENTAL

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.

Drug: Rezafungin

BA2

EXPERIMENTAL

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.

Drug: Rezafungin

MAD1

EXPERIMENTAL

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.

Other: Placebo; Drug: Rezafungin

MAD2

EXPERIMENTAL

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.

Other: Placebo; Drug: Rezafungin

MAD3

EXPERIMENTAL

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.

Other: Placebo; Drug: Rezafungin

MAD4

EXPERIMENTAL

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.

Other: Placebo; Drug: Rezafungin

SAD1

EXPERIMENTAL

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.

Other: Placebo; Drug: Rezafungin

SAD2

EXPERIMENTAL

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.

Other: Placebo; Drug: Rezafungin

SAD3

EXPERIMENTAL

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.

Other: Placebo; Drug: Rezafungin

SAD4

EXPERIMENTAL

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.

Other: Placebo; Drug: Rezafungin

SAD5

EXPERIMENTAL

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.

Other: Placebo; Drug: Rezafungin

SAD6

EXPERIMENTAL

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.

Other: Placebo; Drug: Rezafungin

Interventions

Placebo OTHER

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.

MAD1; MAD2; MAD3; MAD4; SAD1; SAD2; SAD3; SAD4; SAD5; SAD6

Rezafungin DRUG

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.

BA1; BA2; MAD1; MAD2; MAD3; MAD4; SAD1; SAD2; SAD3; SAD4; SAD5; SAD6

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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\*,\*\*.

You may not qualify if:

• 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.
• 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).

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

ICON Early Phase Services Clinical Research Unit

San Antonio, Texas, 78209-1015, United States

Location

MeSH Terms

Conditions

Mycoses

Interventions

Rezafungin

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Infections

Results Point of Contact

• Title: Dr. Dennis Ruff, Senior Medical Director
• Organization: ICON CRU

Dennis.Ruff@iconplc.com

210-283-4572

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 12, 2019
• First Posted: October 7, 2019
• Study Start: December 4, 2019
• Primary Completion: May 11, 2020
• Study Completion: May 11, 2020
• Last Updated: July 16, 2021
• Results First Posted: July 16, 2021

Record last verified: 2020-06-18

Locations

US (1)