Study of PBI-0451 in Healthy Subjects.

Study Overview
=================
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.

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.

Official Title
-----------------
A Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of PBI-0451 in Healthy Subjects.

Conditions
-----------------
Covid19

Intervention / Treatment
-----------------
* Drug: PBI-0451 Dose 1
* Drug: PBI-0451 Dose 2
* Drug: PBI-0451 Dose 3
* Drug: PBI-0451 Dose 4
* Drug: Ritonavir
* Drug: Midazolam
* Drug: Placebo
* Drug: PBI-0451
* Drug: PBI-0451 Dose 5


Participation Criteria
=================
Eligibility 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 59 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1, Treatment A<br>Dose level 1 of PBI-0451 | Drug: PBI-0451 Dose 1<br>* Dose level 1 of PBI-0451<br>* Other names: PBI-0451;Drug: Placebo<br>* Placebo to match<br>|
| Experimental: Part 1, Treatment B<br>Dose level 2 of PBI-0451 | Drug: PBI-0451 Dose 2<br>* Dose level 2 of PBI-0451<br>* Other names: PBI-0451;Drug: Placebo<br>* Placebo to match<br>|
| Experimental: Part 1, Treatment C<br>Dose level 3 of PBI-0451 | Drug: PBI-0451 Dose 3<br>* Dose level 3 of PBI-0451<br>* Other names: PBI-0451;Drug: Placebo<br>* Placebo to match<br>|
| Experimental: Part 1, Treatment D<br>Dose level 4 of PBI-0451 | Drug: PBI-0451 Dose 4<br>* Dose level 4 of PBI-0451<br>* Other names: PBI-0451;Drug: Placebo<br>* Placebo to match<br>|
| Experimental: Part 2, Treatment E<br>PBI-0451 =/< Dose level 1 | Drug: PBI-0451 Dose 1<br>* Dose level 1 of PBI-0451<br>* Other names: PBI-0451;Drug: Placebo<br>* Placebo to match<br>|
| Experimental: Part 2, Treatment F<br>PBI-0451 =/< Dose level 2 | Drug: PBI-0451 Dose 2<br>* Dose level 2 of PBI-0451<br>* Other names: PBI-0451;Drug: Placebo<br>* Placebo to match<br>|
| Experimental: Part 2, Treatment G<br>PBI-0451 =/< Dose level 3 | Drug: PBI-0451 Dose 3<br>* Dose level 3 of PBI-0451<br>* Other names: PBI-0451;Drug: Placebo<br>* Placebo to match<br>|
| Experimental: Part 2, Treatment H<br>PBI-0451 =/< Dose level 4 | Drug: PBI-0451 Dose 4<br>* Dose level 4 of PBI-0451<br>* Other names: PBI-0451;Drug: Placebo<br>* Placebo to match<br>|
| Experimental: Part 3, Treatment J<br>PBI-0451 + ritonavir (a CYP450 3A inhibitor) | Drug: Ritonavir<br>* Ritonavir will be co-administered with the study drug in Treatments J and K<br>* Other names: Norvir;Drug: Placebo<br>* Placebo to match<br>Drug: PBI-0451<br>* Dose level of PBI-0451 with a projected exposure<br>|
| Experimental: Part 3, Treatment K<br>PBI-0451 + ritonavir | Drug: Ritonavir<br>* Ritonavir will be co-administered with the study drug in Treatments J and K<br>* Other names: Norvir;Drug: Placebo<br>* Placebo to match<br>Drug: PBI-0451<br>* Dose level of PBI-0451 with a projected exposure<br>|
| Experimental: Part 3, Treatment L<br>PBI-0451 dose TBD + midazolam (a sensitive CYP450 3A substrate) | Drug: Midazolam<br>* Midazolam will be co-administered with the study drug in Treatment L<br>Drug: Placebo<br>* Placebo to match<br>Drug: PBI-0451<br>* Dose level of PBI-0451 with a projected exposure<br>|
| Experimental: Part 1, Treatment M<br>Dose level 2 of PBI-0451 with food | Drug: PBI-0451 Dose 2<br>* Dose level 2 of PBI-0451<br>* Other names: PBI-0451;Drug: Placebo<br>* Placebo to match<br>|
| Experimental: Part 2, Treatment I<br>PBI-0451 =/< Dose level 5 | Drug: Placebo<br>* Placebo to match<br>Drug: PBI-0451 Dose 5<br>* Dose level 5 of PBI-0451<br>* Other names: PBi-0451;|
| Experimental: Part 1, Treatment N<br>Dose Level 5 of PBI-0451 | Drug: Placebo<br>* Placebo to match<br>Drug: PBI-0451 Dose 5<br>* Dose level 5 of PBI-0451<br>* Other names: PBi-0451;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with treatment emergent adverse events (TEAEs) in Single Ascending Dose (SAD) compared to placebo | 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. | Day 1- Day 14 (From start of study medication till 14 days of last administration of study drug) | 
| Number of subjects with clinically significant change from Baseline in vital signs in SAD | Vital signs include blood pressure, heart rate, respiratory rate, and temperature | Day 1-Day 14 (From start of study medication till 14 days of last administration of study drug) | 
| Number of patients with laboratory abnormalities in SAD | Hematology and serum chemistry | Day 1-Day 14 (From start of study medication till 14 days of last administration of study drug) | 
| Number of subjects with treatment emergent adverse events (TEAEs) in Multiple Ascending Dose (MAD) compared to placebo | 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. | Day 1-Day 11, and Follow up (after 14 days) | 
| Number of subjects with clinically significant change from Baseline in vital signs in MAD | Vital signs include blood pressure, heart rate, respiratory rate, and temperature | Day 1-Day 11, and Follow up (after 14 days) | 
| Number of patients with laboratory abnormalities in MAD | Hematology and serum chemistry | Day 1-Day 11, and Follow up (after 14 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To collect ECG data for PBI-0451 for the purpose of concentration-QT/QTc modeling | 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. | Day 1, 4, 6 and 11 | 
| Plasma concentration of each dose of study drug to determine AUCinf in SAD | AUCinf = Area under the plasma concentration versus time curve (AUC) from time 0 to extrapolated infinite time. | Day 1-Day 6 | 
| Plasma concentration of each dose of study drug to determine AUClast in SAD | AUClast is summarized by dosing regimen and determined by linear/log trapezoidal method. | Day 1-Day 6 | 
| Plasma concentration of each dose of study drug to determine %AUCexp in SAD | %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 | Day 1-Day 6 | 
| Plasma concentration of each dose of study drug to determine CL/F in SAD | CL/F is a measure of the rate at which a drug is metabolized or eliminated by normal biological process | Day 1-Day 6 | 
| Plasma concentration of each dose of study drug to determine CLss/F in MAD | CLss/F is the total body clearance for extravascular administration divided by the fraction of dose absorbed | Day 4, Day 6, Day 8 | 
| Plasma concentration of each dose of study drug to determine AUCtau in MAD | Area under the plasma concentration- Time profile from Time zero to end of dosing interval. AUCtau is summarized by dosing regimen and period. | Day 4, Day 6, Day 8 | 
| Plasma concentration of each dose of study drug to determine Cmax in MAD | Observed Cmax is estimated based on the plasma concentrations. | Day 4, Day 6, Day 8 (Pre dose to 24 hours) | 
| Plasma concentration of each dose of study drug to determine Tmax in MAD | Tmax is summarized by dosing regimen | Day 4, Day 6, Day 8 (Pre dose to 24 hours) | 
| Plasma concentration of each dose of study drug to determine Tlast in MAD | Tlast is the time of last measurable concentration | Day 4, Day 6, Day 8 | 
| Plasma concentration of each dose of study drug to determine Clast in MAD | Clast is the last measurable concentration (above the quantification limit) | Day 4, Day 6, Day 8 | 
| Plasma concentration of each dose of study drug to determine Ctau in MAD | Ctau is the concentration at the end of dosing interval | Day 4, Day 6, Day 8 | 
| Plasma concentration of each dose of study drug to determine λz in MAD | Individual estimate of terminal elimination rate constant, calculated using log-linear regression of the terminal portions of the plasma concentration-versus-time curves. | Day 4, Day 6, Day 8 | 
| Plasma concentration of each dose of study drug to determine t1/2 | 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. | Day 1(0 hours- 24 hours post dose), Day 4, Day 6, Day 8 | 
| Plasma concentration of each dose of study drug to determine Vz/F | 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. | Day 4, Day 6, Day 8 |