Study of PBI-0451 in Healthy Subjects.
Study Details
Study Description
Brief Summary
This is a phase 1, placebo-controlled, blinded, randomized, dose escalation study of PBI-0451 in healthy subjects. PBI-0451 is a new chemical entity and inhibitor of the main protease of coronaviruses, including the SARS-CoV-2 that causes COVID-19 disease. The study is designed to evaluate the safety, tolerability and pharmacokinetics of PBI-0451 after single and multiple ascending doses and also to explore drug-drug interaction potential of PBI-0451.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
Combined Three part, double blind, (sponsor open) study. Part 1: Single ascending dose study. Part 2: Multiple ascending dose study. Part 3: Drug-drug interaction study.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Part 1, Treatment A Dose level 1 of PBI-0451 |
Drug: PBI-0451 Dose 1
Dose level 1 of PBI-0451
Other Names:
Drug: Placebo
Placebo to match
|
| Experimental: Part 1, Treatment B Dose level 2 of PBI-0451 |
Drug: PBI-0451 Dose 2
Dose level 2 of PBI-0451
Other Names:
Drug: Placebo
Placebo to match
|
| Experimental: Part 1, Treatment C Dose level 3 of PBI-0451 |
Drug: PBI-0451 Dose 3
Dose level 3 of PBI-0451
Other Names:
Drug: Placebo
Placebo to match
|
| Experimental: Part 1, Treatment D Dose level 4 of PBI-0451 |
Drug: PBI-0451 Dose 4
Dose level 4 of PBI-0451
Other Names:
Drug: Placebo
Placebo to match
|
| Experimental: Part 2, Treatment E PBI-0451 =/< Dose level 1 |
Drug: PBI-0451 Dose 1
Dose level 1 of PBI-0451
Other Names:
Drug: Placebo
Placebo to match
|
| Experimental: Part 2, Treatment F PBI-0451 =/< Dose level 2 |
Drug: PBI-0451 Dose 2
Dose level 2 of PBI-0451
Other Names:
Drug: Placebo
Placebo to match
|
| Experimental: Part 2, Treatment G PBI-0451 =/< Dose level 3 |
Drug: PBI-0451 Dose 3
Dose level 3 of PBI-0451
Other Names:
Drug: Placebo
Placebo to match
|
| Experimental: Part 2, Treatment H PBI-0451 =/< Dose level 4 |
Drug: PBI-0451 Dose 4
Dose level 4 of PBI-0451
Other Names:
Drug: Placebo
Placebo to match
|
| Experimental: Part 3, Treatment J PBI-0451 + ritonavir (a CYP450 3A inhibitor) |
Drug: Ritonavir
Ritonavir will be co-administered with the study drug in Treatments J and K
Other Names:
Drug: Placebo
Placebo to match
Drug: PBI-0451
Dose level of PBI-0451 with a projected exposure
|
| Experimental: Part 3, Treatment K PBI-0451 + ritonavir |
Drug: Ritonavir
Ritonavir will be co-administered with the study drug in Treatments J and K
Other Names:
Drug: Placebo
Placebo to match
Drug: PBI-0451
Dose level of PBI-0451 with a projected exposure
|
| Experimental: Part 3, Treatment L PBI-0451 dose TBD + midazolam (a sensitive CYP450 3A substrate) |
Drug: Midazolam
Midazolam will be co-administered with the study drug in Treatment L
Drug: Placebo
Placebo to match
Drug: PBI-0451
Dose level of PBI-0451 with a projected exposure
|
| Experimental: Part 1, Treatment M Dose level 2 of PBI-0451 with food |
Drug: PBI-0451 Dose 2
Dose level 2 of PBI-0451
Other Names:
Drug: Placebo
Placebo to match
|
| Experimental: Part 2, Treatment I PBI-0451 =/< Dose level 5 |
Drug: Placebo
Placebo to match
Drug: PBI-0451 Dose 5
Dose level 5 of PBI-0451
Other Names:
|
| Experimental: Part 1, Treatment N Dose Level 5 of PBI-0451 |
Drug: Placebo
Placebo to match
Drug: PBI-0451 Dose 5
Dose level 5 of PBI-0451
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Number of subjects with treatment emergent adverse events (TEAEs) in Single Ascending Dose (SAD) compared to placebo [Day 1- Day 14 (From start of study medication till 14 days of last administration of study drug)]
An adverse event is any untoward medical occurrence in patient or clinical study participant temporarily associated with the use of study intervention, whether or not considered related to the study intervention. A serious adverse event (SAE) is defined as any untoward medical occurrence at any dose that results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; results in congenital anomaly/birth defect. AEs include both SAEs and AEs. TAEs are AEs that occur following the start of treatment or AEs increasing in severity during treatment.
- Number of subjects with clinically significant change from Baseline in vital signs in SAD [Day 1-Day 14 (From start of study medication till 14 days of last administration of study drug)]
Vital signs include blood pressure, heart rate, respiratory rate, and temperature
- Number of patients with laboratory abnormalities in SAD [Day 1-Day 14 (From start of study medication till 14 days of last administration of study drug)]
Hematology and serum chemistry
- Number of subjects with treatment emergent adverse events (TEAEs) in Multiple Ascending Dose (MAD) compared to placebo [Day 1-Day 11, and Follow up (after 14 days)]
An adverse event is any untoward medical occurrence in patient or clinical study participant temporarily associated with the use of study intervention, whether or not considered related to the study intervention. A serious adverse event (SAE) is defined as any untoward medical occurrence at any dose that results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; results in congenital anomaly/birth defect. AEs include both SAEs and AEs. TAEs are AEs that occur following the start of treatment or AEs increasing in severity during treatment.
- Number of subjects with clinically significant change from Baseline in vital signs in MAD [Day 1-Day 11, and Follow up (after 14 days)]
Vital signs include blood pressure, heart rate, respiratory rate, and temperature
- Number of patients with laboratory abnormalities in MAD [Day 1-Day 11, and Follow up (after 14 days)]
Hematology and serum chemistry
Secondary Outcome Measures
- To collect ECG data for PBI-0451 for the purpose of concentration-QT/QTc modeling [Day 1, 4, 6 and 11]
Criteria for clinically significant changes in ECG (12 lead) are defined as: a postdose QTc interval increase by =/>30msec from the baseline and is >450 msec; or an absolute QTc value is =/> 500 msec for any scheduled ECG.
- Plasma concentration of each dose of study drug to determine AUCinf in SAD [Day 1-Day 6]
AUCinf = Area under the plasma concentration versus time curve (AUC) from time 0 to extrapolated infinite time.
- Plasma concentration of each dose of study drug to determine AUClast in SAD [Day 1-Day 6]
AUClast is summarized by dosing regimen and determined by linear/log trapezoidal method.
- Plasma concentration of each dose of study drug to determine %AUCexp in SAD [Day 1-Day 6]
%AUCexp is summarized by dosing regimen and expressed as area under the plasma concentration-time curve extrapolated from time (tau) to infinity as a percentage of total AUC
- Plasma concentration of each dose of study drug to determine CL/F in SAD [Day 1-Day 6]
CL/F is a measure of the rate at which a drug is metabolized or eliminated by normal biological process
- Plasma concentration of each dose of study drug to determine CLss/F in MAD [Day 4, Day 6, Day 8]
CLss/F is the total body clearance for extravascular administration divided by the fraction of dose absorbed
- Plasma concentration of each dose of study drug to determine AUCtau in MAD [Day 4, Day 6, Day 8]
Area under the plasma concentration- Time profile from Time zero to end of dosing interval. AUCtau is summarized by dosing regimen and period.
- Plasma concentration of each dose of study drug to determine Cmax in MAD [Day 4, Day 6, Day 8 (Pre dose to 24 hours)]
Observed Cmax is estimated based on the plasma concentrations.
- Plasma concentration of each dose of study drug to determine Tmax in MAD [Day 4, Day 6, Day 8 (Pre dose to 24 hours)]
Tmax is summarized by dosing regimen
- Plasma concentration of each dose of study drug to determine Tlast in MAD [Day 4, Day 6, Day 8]
Tlast is the time of last measurable concentration
- Plasma concentration of each dose of study drug to determine Clast in MAD [Day 4, Day 6, Day 8]
Clast is the last measurable concentration (above the quantification limit)
- Plasma concentration of each dose of study drug to determine Ctau in MAD [Day 4, Day 6, Day 8]
Ctau is the concentration at the end of dosing interval
- Plasma concentration of each dose of study drug to determine λz in MAD [Day 4, Day 6, Day 8]
Individual estimate of terminal elimination rate constant, calculated using log-linear regression of the terminal portions of the plasma concentration-versus-time curves.
- Plasma concentration of each dose of study drug to determine t1/2 [Day 1(0 hours- 24 hours post dose), Day 4, Day 6, Day 8]
t1/2 is summarized by dosing regimen . It is determined by loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log linear concentration time curve. Only those data points judged to describe the terminal log linear decline is used in the regression.
- Plasma concentration of each dose of study drug to determine Vz/F [Day 4, Day 6, Day 8]
Vz/F is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. VZ/F after oral dose is influenced by the fraction absorbed.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Non-smoking, healthy male or female subjects aged 18-59 years.
-
Body Mass Index (BMI) of ≥ 19.0 and ≤ 30.0 kg/m2.
-
12-Lead electrocardiogram (ECG) evaluation without clinically significant abnormalities.
-
Normal renal function, including having a creatinine clearance (CLcr) ≥90mL/min
-
Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception.
-
Screening laboratory assessments must be without clinically significant abnormalities as assessed by the investigator.
Exclusion Criteria:
-
Pregnant and lactating females
-
Have received any investigational drug (or vaccine) within the last 30 days prior to study dosing.
-
Have a positive test result for HIV or HBsAg.
-
Have poor venous access that limits phlebotomy
-
Have taken any prescription medications or over-the-counter medications, including herbal products and dietary supplements within 28 days prior to start of study.
-
Have been treated with systemic steroids, immunosuppressant therapies, or chemotherapeutic agents within 3 months prior to Screening or is expected to receive these agents during the study.
-
Have a history of lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years.
-
Have a history of significant drug sensitivity, cardiac disease, syncope, palpitations, or unexplained dizziness, implanted defibrillator or pacemaker, liver disease, severe peptic ulcer disease, gastroesophageal reflux disease and a medical or surgical treatment that permanently altered gastric absorption.
-
Have received inactivated vaccinations within 4 weeks prior to randomization or receive live vaccinations within 4 weeks of Screening.
-
Received the COVID-19 vaccine either within 7 days or have not completed the series of required 2 doses.
-
Have a history of excessive alcohol use or other illicit drug use within 6 months of screening.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Auckland City Hospital | Auckland | New Zealand | 1010 |
Sponsors and Collaborators
- Pardes Biosciences, Inc.
Investigators
- Principal Investigator: Mark Marshall, New Zealand Clinical Research
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- PBI-0451-0001