Safety and Pharmacokinetics of Rezafungin
Condition: Fungal Infection
MeSH terms: Mycoses
Intervention: Placebo; Rezafungin; Rezafungin
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.; 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, 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 MeSH terms: Rezafungin
Phase: Phase 1
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Sequential Assignment
Masking: Double (Participant, Investigator)
Enrollment: 14.0
Sex: All
Minimum age: 18 Years
Maximum age: 45 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Dose Escalation Study; Double-Blind; Healthy Adult Subjects; Phase 1; Rezafungin; Safety and Pharmacokinetic

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.
    

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.