Acute Coronary Syndromes, Atherosclerotic Cardiovascular Disease
Conditions
Keywords
Atherosclerosis, 7-ketocholesterol (7KC), Cyclodextrin, Plaque burden reduction, Healthy Participants, Acute coronary syndrome
Brief summary
The goal of this clinical trial is to learn if UDP-003 is safe in healthy human participants and patients, assess the pharmacokinetics (PK)/pharmacodynamics (PD) of UDP-003 in healthy human participants and patients and its potential efficacy in patients. Researchers will compare UDP-003 to a placebo in a blinded manner. This first in human, randomised, double-blind, placebo-controlled, prospective, single-centre trial with a modular dose-finding design will be conducted in 3 parts: * Part 1: 6 cohorts of 6 healthy participants receiving Single Ascending Doses (SADs), * Part 2: 3 cohorts of 12 healthy participants receiving Multiple Ascending Doses (MADs) (6 doses over 16 days), * Part 3: 1 cohort of up to 9 evaluable participants diagnosed with acute coronary syndrome (ACS; non-ST elevation myocardial infarction \[NSTEMI\] or unstable angina) at least 12 months post-event receiving multiple doses (6 administrations of the 25 mg/kg dose over 6 weeks). The planned duration of the study for each participant will be: * 4 weeks for SAD Participants (1-day treatment period, 4-week safety follow-up) * 6 weeks for MAD Participants (16-day treatment period,4-week safety follow-up) * 180 Days for MD Patients (6-week treatment period, 6-month safety follow-up) Prior to participants being randomised to panels of increasing doses, all safety data will be reviewed for completed panels.
Detailed description
This trial's objective will be to collect the preliminary clinical safety and clinical pharmacology data. The study objective in the patient cohort is obtaining preliminary information on the safety of UDP-003 in those carrying a detectable plaque burden and obtaining preliminary indication of efficacy in respect to reducing the plaque burden. This first in human, randomised, double-blind, placebo-controlled, prospective, single-centre trial with a modular dose-finding design will be conducted in 3 parts: * Part 1: 6 cohorts of 6 healthy participants receiving SADs, * Part 2: 3 cohorts of 12 healthy participants receiving MADs (6 doses over 16 days), * Part 3: 1 cohort of 12 participants diagnosed with acute coronary syndrome (ACS; non-ST elevation myocardial infarction \[NSTEMI\] or unstable angina) at least 12 months post-event receiving multiple doses (6 administrations of the 25 mg/kg dose over 6 weeks). The SAD part will include healthy participants randomised to either active or placebo with a 2:1 ratio (24 active, 12 placebo) and the MAD parts with a 3:1 ratio (27 active, 9 placebo), in addition to up to 12 MD patient cohort receiving UDP-003. Prior to participants being randomised to panels of increasing doses, all safety data will be reviewed for completed panels. Within each dose group in the SAD portion of the study, sentinel dosing will be implemented wherein 2 participants (1 active, 1 placebo) will be dosed at least 24 hours before the remaining participants in the cohort. Dosing in the MAD portion of the study will commence only after the Data Safety Monitoring Committee (DSMC) reviews the safety data from the 5th (20 mg/kg) SAD cohort. Investigational Products A. UDP-003, formulated as a sterile solution for injection, 300 mg/mL. Volume of administration is weight dependent and target doses are 1-25 mg/kg. B. Placebo formulated as sterile solution for injection. Volume injected will match the volumes of UDP-003 for each panel and each participant. The investigational products will be administered as intravenous (IV) bolus push injection, in a blinded manner to sitting or supine participants. Doses lower than the highest dose will be diluted with vehicle (identical to placebo) to ensure the same dosing volume per body mass across placebo and active groups. No fasting is required. In the MD panels, a single IV bolus push injection will be administered on Days 1, 8,15, 22, 29 and 36.
Interventions
DRUGUDP-003
The UDP-003 finished product is clear, colourless to yellow liquid that is intended to be a sterile solution for IV bolus push administration in sterile water at a concentration of 300 mg/mL.
OTHERPlacebo
Placebo will be provided as a sterile clear, colourless solution formulated to match viscosity of the UDP-003 solution.
Sponsors
Cyclarity Therapeutics, Inc.
Monash University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
Yes
Inclusion criteria
All Participants: 1. Participant understands study procedures and provides written informed consent for the trial. 2. Participant is able to comply with the protocol and the assessments therein. Healthy Participants (SAD and MAD cohorts): 1. Healthy adult males and females, 18 to 65 years of age (inclusive) at the time of screening. 2. Adult males and females of body mass index (BMI) ≥ 18 and ≤ 32 kg/m² and body weight ≥ 50 and ≤ 120 kg. 3. Social smoking of less than 10 nicotine-containing products per month is acceptable. Absence of tobacco or nicotine containing product (including smoking cessation products) use, for a minimum of 2 weeks prior to dosing is required and will be confirmed by a negative cotinine test at check-in (one retest allowed at the discretion of the investigator). 4. Medically healthy with relevant renal parameters tests not exceeding 1.5 X the upper limits and no clinically significant screening results (e.g., laboratory profiles, medical history, vital signs, ECGs, physical examination) as deemed by the Principal Investigator; one retest is permitted at investigator discretion. Participants with ACS (MD Patient cohort): 1. Adult males and females, 40 to 79 years of age (inclusive) at the time of screening, diagnosed with acute coronary syndrome (ACS), at least 12 months post event (NSTEMI or unstable angina). 2. Adult males and females of body mass index (BMI) ≥ 18 3. Medically stable with no clinically significant screening results (e.g., laboratory profiles including relevant renal parameters and liver function tests, medical history, vital signs, ECGs, physical examination) as deemed by the Principal Investigator. 4. Participants on a stable regimen and dose of ACS treatment including statins, anticoagulants, blood thinners, anti-platelets or other standard of care for 3 months prior to screening and for whom no change in this treatment is planned during the participation in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety outcome measures (Adverse Events) | From enrolment through 4 weeks for SAD Participants, 6 weeks for MAD Participants and 28 weeks for MD Patients | Occurrence of adverse events (AEs) of any type and severity |
| Safety outcome measures (Vital Signs: Systolic Blood Pressure) | From enrolment through 4 weeks for SAD Participants, 6 weeks for MAD Participants and 28 weeks for MD Patients | SBP will be measured in mmHg |
| Safety outcome measures (Vital Signs: Diastolic Blood Pressure) | From enrolment through 4 weeks for SAD Participants, 6 weeks for MAD Participants and 28 weeks for MD Patients | DBP will be measured in mmHg |
| Safety outcome measures (Vital signs: Heart Rate) | From enrolment through 4 weeks for SAD Participants, 6 weeks for MAD Participants and 28 weeks for MD Patients | Heart Rate will be measured in bpm |
| Safety outcome measures (Vital signs: Respiratory Rate) | From enrolment through 4 weeks for SAD Participants, 6 weeks for MAD Participants and 28 weeks for MD Patients | RR will be measured in rpm |
| Safety outcome measures (Vital signs: Temperature) | From enrolment through 4 weeks for SAD Participants, 6 weeks for MAD Participants and 28 weeks for MD Patients | Body temperature will be measured in Celsius (0C) |
| Safety outcome measures (Clinical Laboratory Parameters) | From enrolment through 4 weeks for SAD Participants, 6 weeks for MAD Participants and 28 weeks for MD Patients | For parameters outside of the reference range an assessment of the significance (clinically significant / non-clinically significant) will be provided and all data outside the reference range of the clinical laboratory will be listed for all study participants |
| Safety outcome measures (ECG QTCF Interval) | From enrolment through 4 weeks for SAD Participants, 6 weeks for MAD Participants and 28 weeks for MD Patients | The QTcF interval will be calculated using the formula QTcF = QT/√R-R interval in seconds |
| Safety outcome measures (Injection site reactions) | From first dose administration (Day 1) through From enrolment through 4 weeks for SAD Participants, 6 weeks for MAD Participants and 28 weeks for MD Patients | Assessment for signs of phlebitis, extravasation, infection and pain before, during and after intravenous administration is vital to ensure the patency and viability of the vein. The reactions will be assessed using the current FDA Toxicity Grading Scale provides a measure for classifying injection site AEs by four grades \[Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe) and Grade 4 (life threatening)\]. |
| Safety outcome measures (Audiometry: PTA) | From enrolment through 24 hours post dose for SAD Participants (Day 2), 24 hours post dose for MAD and MD Patients Participants (Day 17), | Air/Bone Pure-tone audiometry (PTA) conduction testing will be done at 250, 500, 1000, 3000, 4000, 6000 and 8000Hz |
| Safety outcome measures (Audiometry: HFA) | From enrolment through 24 hours post dose for SAD Participants (Day 2), 24 hours post dose for MAD and MD Patients Participants (Day 17), | Bone/Air High-frequency audiometry (HFA) conduction testing will be done at 9000, 10 000, 11200 and 12500Hz, Tympanometry, Self-evaluation questionnaires (tinnitus handicap inventory \[THI\] and dizziness handicap inventory \[DHI\]) |
| Safety outcome measures (Audiometry: Self-evaluation questionnaire (THI)) | From enrolment through 24 hours post dose for SAD Participants (Day 2), 24 hours post dose for MAD and MD Patients Participants (Day 17), | Self-evaluation questionnaire: using Tinnitus Handicap Inventory \[THI\] questionnaire |
| Safety outcome measures (Audiometry: Self-evaluation questionnaire (DHI)) | From enrolment through 24 hours post dose for SAD Participants (Day 2), 24 hours post dose for MAD and MD Patients Participants (Day 17), | Self-evaluation questionnaire: using Dizziness Handicap Inventory \[DHI\] questionnaire |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics Outcome Measures (Cmax) | Day 1 for the SAD and Days 1 and 16 for the multiple dosing parts | The maximum concentration achieved by UDP-003 in a specified compartment area of the body after the drug has been administered and before the administration of a second dose |
| Pharmacokinetics Outcome Measures (Tmax) | Day 1 for the SAD and Days 1 and 16 for the multiple dosing parts | Time at which maximum concentration of UDP is reached |
| Pharmacokinetics Outcome Measures (half-life (t1/2)) | Day 1 for the SAD and Days 1 and 16 for the multiple dosing parts | The estimate of the time it takes for the concentration or amount in the body of that drug to be reduced by exactly one-half (50%). |
| Pharmacokinetics Outcome Measures (AUC0-t and AUC0-inf) | Day 1 for the SAD and Days 1 and 16 for the multiple dosing parts | Area under the concentration curve (AUC0-t and AUC0-inf) reflects the actual body exposure to drug after administration of a dose of the drug and is expressed in mg\*h/L |
| Pharmacokinetics Outcome Measures (Total Plasma Clearance (CL)) | Day 1 for the SAD and Days 1 and 16 for the multiple dosing parts | The volume of drug cleared from blood or plasma in unit time |
| Pharmacokinetics Outcome Measures (Volume of Distribution (Vd)) | Day 1 for the SAD and Days 1 and 16 for the multiple dosing parts | The participant's drug's propensity to either remain in the plasma or redistribute to other tissue compartments |
Countries
Australia
Contacts
CONTACTDaniel M Clemens, Ph.D.
CONTACTMatthew O'Connor, Ph.D.
Outcome results
None listed