A Randomized, Double-blind, Placebo-controlled, Phase 1 Study of the Safety, Tolerability and Pharmacokinetics of Single and Multiple Ascending Doses of BWC0977 in Healthy Adult Volunteers
Overview
- Phase
- Phase 1
- Intervention
- BWC0977
- Conditions
- Infectious Diseases
- Sponsor
- Bugworks Research Inc.
- Enrollment
- 44
- Locations
- 1
- Primary Endpoint
- Incidence of treatment-emergent adverse events (TEAEs and serious adverse events (SAEs) overall and by intensity (Safety and tolerability).
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
The purpose of this study is to assess the safety, tolerability and pharmacokinetics of single and multiple intravenous doses of BWC0977 when administered to healthy adult volunteers.
Detailed Description
This Phase 1 study is designed to assess the safety, tolerabilty and pharmcokinetics of single and multiple intravenous doses of BWC0977 when administered to healthy adult volunteers. This is a randomized double-blind, placebo-controlled, ascending dose, multi-cohort trial. A total of 64 healthy volunteers are expected to be enrolled into 8 Cohorts. The study will be conducted in two phases: A single ascending dose (SAD) phase, followed by a multiple ascending dose (MAD) phase. In SAD, participants in Cohorts 1 - 5 will receive one dose of BWC0977 or placebo. In MAD, participants in Cohorts 6 - 8 will receive multiple doses of BWC0977 or placebo for 10 consecutive days at a dose deemed safe and tolerable as determined in the preceding SAD Cohorts. In both parts sequential cohorts will be exposed to increasing doses of BWC0977.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Each subject must meet all of the following criteria to be eligible for study participation:
- •Healthy male or female 18 to 55 years of age, inclusive, at time of consent.
- •Body mass index (BMI) ≥ 19.0 and ≤ 30.0 (kg/m2) and weight between 55.0 and 100.0 kg (inclusive).
- •Medically healthy without clinically significant abnormalities at the screening visit or Day -1, including:
- •No findings in Physical examination or vital signs (including temperature, heart rate, respiratory rate, and blood pressure) that the Principal Investigator (PI) determines would interfere with interpretation of study results.
- •Electrocardiograms (ECGs) without clinically significant abnormalities, including a QT duration corrected for heart rate by Fridericia's formula (QTcF) interval duration ≤450 msec (for males), and ≤470 msec (for females) obtained as an average from the triplicate screening ECGs after at least 5 minutes in a supine quiet-rest position.
- •Clinically significant abnormalities in the screening clinical laboratory tests, as determined by the Investigator. Repeat testing could be performed at the Investigator's discretion.
Exclusion Criteria
- •Volunteers who meet any of the following criteria will be excluded from the study:
- •Women who are pregnant and/or nursing.
- •History or presence of significant cardiovascular (including QT prolongation, clinically significant hypokalemia, or other proarrhythmic conditions), pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine (including glucose intolerance, diabetes mellitus), immunologic (including asthma or seasonal allergies \[that require intermittent use of steroids or other medication\]), musculoskeletal (including tendinopathy), dermatologic, or neurological disease (including seizure disorders, psychiatric disorders), including any acute illness or surgery within the past 3 months determined by the PI to be clinically relevant.
- •A serum creatinine value on Day -1 (check-in) that increased by more than 0.2 mg/dL (or 15.25 µmol/L) from the Screening value.
- •History of photosensitivity to quinolones.
- •History of known or suspected Clostridium difficile infection.
- •Any condition that necessitated hospitalisation within the 3 months prior to Day -1 or is likely to require so during the study.
- •Positive test for hepatitis B virus surface antigen (HBsAg), hepatitis C virus antibody (anti-HCV antibodies), or human immunodeficiency virus antibody (antibodies to HIV-1, HIV-2) or tuberculosis (TB) at screening.
- •Exposure to any prescription medications (small molecules, biologics including vaccines) or, systemically administered OTC drugs, dietary supplements or herbal remedies, within 30 days or 5 half-lives (if known), whichever is longer, prior to Day -
- •Discussion between the PI and the Sponsor Medical Monitor is encouraged regarding prior use of any medications during the pre-dose period.
Arms & Interventions
BWC0977
SAD Cohorts: Subjects will receive single doses of BWC0977 via IV infusion over 2 hours. Planned doses to be studied are 120, 240, 480, 720, and 1050mg. MAD Cohorts: Subjects will receive multiple doses of 240mg TID 7 days, 350mg TID 7 days BWC0977 via IV infusion over 2 hours in the first 2 cohorts. The dose for the B3 cohort will be determined based on safety and tolerability data from the previous two cohorts Up to three dose groups will be studied.
Intervention: BWC0977
Placebo
Compounded solution minus BWC0977 The placebo used during this study is 5% Dextrose for injection. SAD Cohorts: Subjects will receive single infusions of placebo (Compounded solution minus BWC0977) over two hour. MAD Cohorts: Subjects will receive multiple infusions of placebo over 2 hour for 10 consecutive days. Frequency of infusions will be determined based on safety, tolerability and PK data obtained for BWC0977 in SAD Cohorts.
Intervention: Placebo
Outcomes
Primary Outcomes
Incidence of treatment-emergent adverse events (TEAEs and serious adverse events (SAEs) overall and by intensity (Safety and tolerability).
Time Frame: SAD: Up to 7 days; MAD: Up to 15 days.
This outcome combines the measure of the number of participants experiencing adverse events (AEs), the nature and severity of those AEs and their relationship to the study treatment.
Secondary Outcomes
- AUC[0-t] of BWC0977 following single dose administration(Day 1 pre-dose, 5, 10,15, 20, 30, 45, 60, 75, and 90 minutes and 2, 2.5, 3, 4, 6, 8, 10, 12, 24 and 48 hours post infusion start)
- AUC[0-inf]) of BWC0977 following single dose administration(Day 1 pre-dose, 5, 10,15, 20, 30, 45, 60, 75, and 90 minutes and 2, 2.5, 3, 4, 6, 8, 10, 12, 24 and 48 hours post infusion start)
- Cmax of BWC0977 following single dose administration(Day 1 pre-dose, 5, 10,15, 20, 30, 45, 60, 75, and 90 minutes and 2, 2.5, 3, 4, 6, 8, 10, 12, 24 and 48 hours post infusion start)
- Volume of distribution at steady state (Vdss) following single dose administration(Day 1 pre-dose, 5, 10,15, 20, 30, 45, 60, 75, and 90 minutes and 2, 2.5, 3, 4, 6, 8, 10, 12, 24 and 48 hours post infusion start)
- Observed accumulation ratio following repeat dose administration(Day 1 pre-dose, 30, 60, 75, and 90 minutes and 2, 2.5, 3, 4, 6, and 8 hours post infusion start Days 5, 6, 7, 8, and 9: pre-dose Day 10 pre-dose, 30, 60, 75, and 90 minutes and 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours post infusion start)
- Volume of distribution at steady state following repeat dose administration(Day 1 pre-dose, 30, 60, 75, and 90 minutes and 2, 2.5, 3, 4, 6, and 8 hours post infusion start Days 5, 6, 7, 8, and 9: pre-dose Day 10 pre-dose, 30, 60, 75, and 90 minutes and 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours post infusion start)
- Mean residence time (MRT) following single dose administration(Day 1 pre-dose, 5, 10,15, 20, 30, 45, 60, 75, and 90 minutes and 2, 2.5, 3, 4, 6, 8, 10, 12, 24 and 48 hours post infusion start)
- AUC[0-8], AUC[0-12], AUC[0-24]) of BWC0977 following single dose administration(Day 1 pre-dose, 5, 10,15, 20, 30, 45, 60, 75, and 90 minutes and 2, 2.5, 3, 4, 6, 8, 10, 12, 24 and 48 hours post infusion start)
- Cmax of BWC0977 following repeat dose administration(Day 1 pre-dose, 30, 60, 75, and 90 minutes and 2, 2.5, 3, 4, 6, and 8 hours post infusion start Days 5, 6, 7, 8, and 9: pre-dose Day 10 pre-dose, 30, 60, 75, and 90 minutes and 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours post infusion start)
- Terminal half-life (T1/2)(Day 1 pre-dose, 5, 10,15, 20, 30, 45, 60, 75, and 90 minutes and 2, 2.5, 3, 4, 6, 8, 10, 12, 24 and 48 hours post infusion start)
- Systemic clearance (CL) following single dose administration(Day 1 pre-dose, 5, 10,15, 20, 30, 45, 60, 75, and 90 minutes and 2, 2.5, 3, 4, 6, 8, 10, 12, 24 and 48 hours post infusion start)
- Systemic clearance (CL) following repeat dose administration(Day 1 pre-dose, 30, 60, 75, and 90 minutes and 2, 2.5, 3, 4, 6, and 8 hours post infusion start Days 5, 6, 7, 8, and 9: pre-dose Day 10 pre-dose, 30, 60, 75, and 90 minutes and 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours post infusion start)
- Pre-dose (trough) concentration (Cτ) at the end of the dosing interval(Day 1 pre-dose, 30, 60, 75, and 90 minutes and 2, 2.5, 3, 4, 6, and 8 hours post infusion start Days 5, 6, 7, 8, and 9: pre-dose Day 10 pre-dose, 30, 60, 75, and 90 minutes and 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours post infusion start)