Safety and Pharmacokinetics of Rezafungin

NCT ID: NCT04117607

Last Updated: 2021-07-16

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 14 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-12-04
• Study Completion Date: 2020-05-11

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.

Conditions

Fungal Infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: DOUBLE

Study Groups

BA1

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.

Group Type: EXPERIMENTAL

Rezafungin

Intervention Type: 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.

Rezafungin

Intervention Type: DRUG

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.

BA2

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.

Group Type: EXPERIMENTAL

Rezafungin

Intervention Type: 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.

Rezafungin

Intervention Type: DRUG

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.

MAD1

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.

Group Type: EXPERIMENTAL

Placebo

Intervention Type: 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.

Rezafungin

Intervention Type: 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.

MAD2

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.

Group Type: EXPERIMENTAL

Placebo

Intervention Type: 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.

Rezafungin

Intervention Type: 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.

MAD3

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.

Group Type: EXPERIMENTAL

Placebo

Intervention Type: 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.

Rezafungin

Intervention Type: 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.

MAD4

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.

Group Type: EXPERIMENTAL

Placebo

Intervention Type: 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.

Rezafungin

Intervention Type: 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.

SAD1

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.

Group Type: EXPERIMENTAL

Placebo

Intervention Type: 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.

Rezafungin

Intervention Type: 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.

SAD2

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.

Group Type: EXPERIMENTAL

Placebo

Intervention Type: 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.

Rezafungin

Intervention Type: 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.

SAD3

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.

Group Type: EXPERIMENTAL

Placebo

Intervention Type: 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.

Rezafungin

Intervention Type: 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.

SAD4

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.

Group Type: EXPERIMENTAL

Placebo

Intervention Type: 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.

Rezafungin

Intervention Type: 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.

SAD5

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.

Group Type: EXPERIMENTAL

Placebo

Intervention Type: 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.

Rezafungin

Intervention Type: 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.

SAD6

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.

Group Type: EXPERIMENTAL

Placebo

Intervention Type: 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.

Rezafungin

Intervention Type: 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.

Interventions

Placebo

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: OTHER

Rezafungin

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

Rezafungin

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.

Intervention Type: DRUG

Eligibility Criteria

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*,**.

Exclusion Criteria

• 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.

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

ICON Early Phase Services Clinical Research Unit

San Antonio, Texas, United States

Countries

United States

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

HHSN272201500007I

Identifier Type: -

Identifier Source: secondary_id

17-0088

Identifier Type: -

Identifier Source: org_study_id