Clinical trial NCT04117607: 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
Overall status: TERMINATED
Phase: PHASE1
Conditions: Fungal Infection
Keywords: Dose Escalation Study
Double-Blind
Healthy Adult Subjects
Phase 1
Rezafungin
Safety and Pharmacokinetic
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2019-10-07
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: PREVENTION

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.

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\*,\*\*.

   * 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.

Primary outcomes:
measure: Number of Participants With Abnormal Chemistry Laboratory Toxicity Results for Single Ascending Dose (SAD) on Day 2
timeFrame: Day 2
measure: Number of Participants With Abnormal Chemistry Laboratory Toxicity Results for Single Ascending Dose (SAD) on Day 7
timeFrame: Day 7
measure: Number of Participants With Abnormal Chemistry Laboratory Toxicity Results for Single Ascending Dose (SAD) on Day 30
timeFrame: Day 30
measure: Number of Participants With Abnormal Chemistry Laboratory Toxicity Results for Multiple Ascending Dose (MAD)
timeFrame: Day 2 through Day 45
measure: Number of Participants With Abnormal Hematology Laboratory Toxicity Results for Single Ascending Dose (SAD) on Day 2
timeFrame: Day 2
measure: Number of Participants With Abnormal Hematology Laboratory Toxicity Results for Single Ascending Dose (SAD) on Day 7
timeFrame: Day 7
measure: Number of Participants With Abnormal Hematology Laboratory Toxicity Results for Single Ascending Dose (SAD) on Day 30
timeFrame: Day 30
measure: Number of Participants With Abnormal Hematology Laboratory Toxicity Results for Multiple Ascending Dose (MAD)
timeFrame: Day 2 through Day 45
measure: Number of Participants With Abnormal Coagulation Laboratory Toxicity Results for Single Ascending Dose (SAD), Day 2
timeFrame: Day 2
measure: Number of Participants With Abnormal Coagulation Laboratory Toxicity Results for Single Ascending Dose (SAD), Day 7
timeFrame: Day 7
measure: Number of Participants With Abnormal Coagulation Laboratory Toxicity Results for Single Ascending Dose (SAD), Day 30
timeFrame: Day 30
measure: Number of Participants With Abnormal Coagulation Laboratory Toxicity Results for Multiple Ascending Dose (MAD)
timeFrame: Day 2 through Day 45
measure: Number of Participants With Abnormal Urinalysis Laboratory Toxicity Results for Single Ascending Dose (SAD), Day 2
timeFrame: Day 2
measure: Number of Participants With Abnormal Urinalysis Laboratory Toxicity Results for Single Ascending Dose (SAD), Day 7
timeFrame: Day 7
measure: Number of Participants With Abnormal Urinalysis Laboratory Toxicity Results for Single Ascending Dose (SAD), Day 30
timeFrame: Day 30
measure: Number of Participants With Abnormal Urinalysis Laboratory Toxicity Results for Multiple Ascending Dose (MAD)
timeFrame: Day 2 through Day 45
measure: Number of Participants With Abnormal ECG Toxicity Results for Single Ascending Dose (SAD), Day 1
timeFrame: Day 1
measure: Number of Participants With Abnormal ECG Toxicity Results for Single Ascending Dose (SAD), Day 7
timeFrame: Day 7
measure: Number of Participants With Abnormal ECG Toxicity Results for Single Ascending Dose (SAD), Day 30
timeFrame: Day 30
measure: Number of Participants With Abnormal ECG Toxicity Results for Multiple Ascending Doses (MAD)
timeFrame: Day 1 through Day 45
measure: Number of Participants With Abnormal Physical Exams for Single Ascending Dose (SAD), Day 1
timeFrame: Day 1
measure: Number of Participants With Abnormal Physical Exams for Single Ascending Dose (SAD), Day 2
timeFrame: Day 2
measure: Number of Participants With Abnormal Physical Exams for Single Ascending Dose (SAD), Day 4
timeFrame: Day 4
measure: Number of Participants With Abnormal Physical Exams for Single Ascending Dose (SAD), Day 7
timeFrame: Day 7
measure: Number of Participants With Abnormal Physical Exams for Single Ascending Dose (SAD), Day 30
timeFrame: Day 30
measure: Number of Participants With Abnormal Physical Exams for Multiple Ascending Dose (MAD)
timeFrame: Day 1 through Day 45
measure: Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 1, 15 Minutes Post-dose
timeFrame: Day 1, 15 minutes post-dose
measure: Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 1, 1 Hour Post-dose
timeFrame: Day 1, 1 hour post-dose
measure: Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 1, 2 Hours Post-dose
timeFrame: Day 1, 2 hours post-dose
measure: Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 2
timeFrame: Day 2
measure: Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 4
timeFrame: Day 4
measure: Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 7
timeFrame: Day 7
measure: Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 14
timeFrame: Day 14
measure: Number of Participants With Abnormal Vital Signs for Single Ascending Dose (SAD), Day 30
timeFrame: Day 30
measure: Number of Participants With Abnormal Vital Signs for Multiple Ascending Dose (MAD)
timeFrame: Day 1 through Day 45
measure: Number of Participants With Unsolicited Adverse Events (AEs) for Single Ascending Dose (SAD)
timeFrame: Day 1 through Day 30.
measure: Number of Participants With Unsolicited Adverse Events (AEs) for Multiple Ascending Dose (MAD)
timeFrame: Day 1 through Day 45
measure: Number of Unsolicited Adverse Events Reported for Single Ascending Dose (SAD)
timeFrame: Day 1 through Day 30.
measure: Number of Unsolicited Adverse Events Reported for Multiple Ascending Dose (MAD)
timeFrame: Day 1 through Day 45
measure: Number of Participants With at Least One Severe Adverse Event (SAE) for Single Ascending Dose (SAD)
timeFrame: Day 1 through Day 30
measure: Number of Participants With at Least One Severe Adverse Event (SAE) for Multiple Ascending Dose (MAD)
timeFrame: Day 1 through Day 45
measure: Number of Participants With Solicited Local Reactogenicity Symptom(s) for Single Ascending Dose (SAD)
timeFrame: Day 1 through Day 30
measure: Number of Participants With Solicited Local Reactogenicity Symptom(s) for Multiple Ascending Dose (MAD)
timeFrame: Day 1 through Day 45
measure: Rezafungin Concentrations in Plasma, SAD 10 mg Dose Group Concentrations of Rezafungin in Plasma Samples
timeFrame: 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
measure: Rezafungin PK Parameter (Cmax) in Plasma, SAD 10 mg Dose Group
timeFrame: 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
measure: Rezafungin PK Parameters (Tmax and t 1/2) in Plasma, SAD 10 mg Dose Group
timeFrame: 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
measure: Rezafungin PK Parameters (AUC 0-last and AUC 0-inf ) in Plasma, SAD 10 mg Dose Group
timeFrame: 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
measure: Rezafungin PK Parameter (Lambda z) in Plasma, SAD 10 mg Dose Group
timeFrame: 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
measure: Rezafungin PK Parameter (CL/F) in Plasma, SAD 10 mg Dose Group
timeFrame: 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
measure: Rezafungin PK Parameter (Vz/F) in Plasma, SAD 10 mg Dose Group
timeFrame: 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
measure: Rezafungin Concentrations in Plasma Samples, Multiple Ascending Dose (MAD)
timeFrame: Day 1 through Day 45
measure: Rezafungin PK Parameters in Plasma, Multiple Ascending Dose (MAD)
timeFrame: Day 1 through Day 45
Secondary outcomes:
measure: Bioavailability (BA) of Rezafungin in BA Cohorts
timeFrame: Day 1 through Day 52
Other outcomes:
Locations:
city: San Antonio
country: United States
facility: ICON Early Phase Services Clinical Research Unit
state: Texas
Study officials:
References: