Study of PBI-0451 in Healthy Subjects.

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

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.

Study Overview

• Status: Completed
• Conditions: Covid19
• Intervention / Treatment: Drug: Placebo; Drug: PBI-0451 Dose 1; Drug: PBI-0451 Dose 2; Drug: PBI-0451 Dose 3; Drug: PBI-0451 Dose 4; Drug: Ritonavir; Drug: PBI-0451; Drug: Midazolam; Drug: PBI-0451 Dose 5

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 Type: Interventional
• Enrollment (Actual): 130
• Phase: Phase 1

Contacts and Locations

Study Locations

• New Zealand
  • Auckland, New Zealand, 1010
    • Auckland City Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 59 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Non-smoking, healthy male or female subjects aged 18-59 years.
2. Body Mass Index (BMI) of ≥ 19.0 and ≤ 30.0 kg/m2.
3. 12-Lead electrocardiogram (ECG) evaluation without clinically significant abnormalities.
4. Normal renal function, including having a creatinine clearance (CLcr) ≥90mL/min
5. Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception.
6. Screening laboratory assessments must be without clinically significant abnormalities as assessed by the investigator.

Exclusion Criteria:

1. Pregnant and lactating females
2. Have received any investigational drug (or vaccine) within the last 30 days prior to study dosing.
3. Have a positive test result for HIV or HBsAg.
4. Have poor venous access that limits phlebotomy
5. Have taken any prescription medications or over-the-counter medications, including herbal products and dietary supplements within 28 days prior to start of study.
6. 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.
7. 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.
8. 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.
9. Have received inactivated vaccinations within 4 weeks prior to randomization or receive live vaccinations within 4 weeks of Screening.
10. Received the COVID-19 vaccine either within 7 days or have not completed the series of required 2 doses.
11. Have a history of excessive alcohol use or other illicit drug use within 6 months of screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

14

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Part 1, Treatment A; Dose level 1 of PBI-0451	Drug: Placebo; Placebo to match; Drug: PBI-0451 Dose 1; Dose level 1 of PBI-0451; Other Names: PBI-0451
EXPERIMENTAL: Part 1, Treatment B; Dose level 2 of PBI-0451	Drug: Placebo; Placebo to match; Drug: PBI-0451 Dose 2; Dose level 2 of PBI-0451; Other Names: PBI-0451
EXPERIMENTAL: Part 1, Treatment C; Dose level 3 of PBI-0451	Drug: Placebo; Placebo to match; Drug: PBI-0451 Dose 3; Dose level 3 of PBI-0451; Other Names: PBI-0451
EXPERIMENTAL: Part 1, Treatment D; Dose level 4 of PBI-0451	Drug: Placebo; Placebo to match; Drug: PBI-0451 Dose 4; Dose level 4 of PBI-0451; Other Names: PBI-0451
EXPERIMENTAL: Part 2, Treatment E; PBI-0451 =/< Dose level 1	Drug: Placebo; Placebo to match; Drug: PBI-0451 Dose 1; Dose level 1 of PBI-0451; Other Names: PBI-0451
EXPERIMENTAL: Part 2, Treatment F; PBI-0451 =/< Dose level 2	Drug: Placebo; Placebo to match; Drug: PBI-0451 Dose 2; Dose level 2 of PBI-0451; Other Names: PBI-0451
EXPERIMENTAL: Part 2, Treatment G; PBI-0451 =/< Dose level 3	Drug: Placebo; Placebo to match; Drug: PBI-0451 Dose 3; Dose level 3 of PBI-0451; Other Names: PBI-0451
EXPERIMENTAL: Part 2, Treatment H; PBI-0451 =/< Dose level 4	Drug: Placebo; Placebo to match; Drug: PBI-0451 Dose 4; Dose level 4 of PBI-0451; Other Names: PBI-0451
EXPERIMENTAL: Part 3, Treatment J; PBI-0451 + ritonavir (a CYP450 3A inhibitor)	Drug: Placebo; Placebo to match; Drug: Ritonavir; Ritonavir will be co-administered with the study drug in Treatments J and K; Other Names: Norvir; Drug: PBI-0451; Dose level of PBI-0451 with a projected exposure
EXPERIMENTAL: Part 3, Treatment K; PBI-0451 + ritonavir	Drug: Placebo; Placebo to match; Drug: Ritonavir; Ritonavir will be co-administered with the study drug in Treatments J and K; Other Names: Norvir; 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: Placebo; Placebo to match; Drug: PBI-0451; Dose level of PBI-0451 with a projected exposure; Drug: Midazolam; Midazolam will be co-administered with the study drug in Treatment L
EXPERIMENTAL: Part 1, Treatment M; Dose level 2 of PBI-0451 with food	Drug: Placebo; Placebo to match; Drug: PBI-0451 Dose 2; Dose level 2 of PBI-0451; Other Names: PBI-0451
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: PBi-0451
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: 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

Collaborators and Investigators

• Sponsor: Pardes Biosciences, Inc.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 14, 2021
• Primary Completion (ACTUAL): March 26, 2022
• Study Completion (ACTUAL): March 26, 2022

Study Registration Dates

• First Submitted: August 11, 2021
• First Submitted That Met QC Criteria: August 13, 2021
• First Posted (ACTUAL): August 18, 2021

Study Record Updates

• Last Update Posted (ACTUAL): June 3, 2022
• Last Update Submitted That Met QC Criteria: June 1, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Protease Inhibitors; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Midazolam; Ritonavir
• Other Study ID Numbers: PBI-0451-0001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No