STUDY OF PF-07321332 IN HEALTHY PARTICIPANTS

Study Overview
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Brief Summary
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A Phase 1, double blind, sponsor open, single and multiple ascending dose study to evaluate safety, tolerability and pharmacokinetics of PF-07321332 in healthy participants.

Detailed Description
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Combined 5-part study. Part-1: Single Ascending dose Part-2: Multiple Ascending Dose Part-3: Relative bioavailability and food effect Part-4: Metabolism and Excretion Part-5: Supra-therapeutic Exposure Part-1,2 and 5 are double blind, sponsor open and Part-3 and 4 are open label study.

Official Title
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A PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, PLACEBO CONTROLLED, SINGLE- AND MULTIPLE-DOSE ESCALATION STUDY TO EVALUATE THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF PF-07321332 IN HEALTHY ADULT PARTICIPANTS

Conditions
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Healthy Participants

Intervention / Treatment
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* Drug: PF-07321332 Dose 1
* Drug: PF-07321332 Dose 2
* Drug: PF-07321332 Dose 3
* Drug: PF-07321332 Dose 4
* Drug: PF-07321332 Dose 5
* Drug: PF-07321332 Dose 4 or Placebo (Fed)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male or female subjects between ages of 18-60 years. Male only in part-4. Body Mass Index (BMI) of 17.5 to 30.5kg/m2; and a total body weight >50kg (110lbs) Japanese subjects who have four Japanese biologic grandparents born in Japan Exclusion Criteria: Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing) Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy, intestinal resection). Positive test result for SARS-CoV-2 infection at the time of screening or Day-1. Have received COVID-19 vaccine within 7 days before screening or have received only one of the 2 required doses of COVID-19 vaccine Use of tobacco or nicotine containing products in excess of the equivalents of 5 cigarettes per day or 2 chews of tobacco per day

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-07321332 Dose 1<br>Dose level 1 of PF-07321332 | Drug: PF-07321332 Dose 1<br>* PF-07321332 Dose 1 or Placebo<br>|
| Experimental: PF-07321332 Dose 2<br>Dose level 2 of PF-07321332 | Drug: PF-07321332 Dose 2<br>* PF-07321332 Dose 2 or Placebo<br>|
| Experimental: PF-07321332 Dose 3<br>Dose level 3 of PF-07321332 | Drug: PF-07321332 Dose 3<br>* PF-07321332 Dose 3 or Placebo<br>|
| Experimental: PF-07321332 Dose 4<br>Dose level 4 of PF-07321332 | Drug: PF-07321332 Dose 4<br>* PF-07321332 Dose 4 or Placebo<br>|
| Experimental: PF-07321332 Dose 5<br>Dose level 5 of PF-07321332 | Drug: PF-07321332 Dose 5<br>* PF-07321332 Dose 5 or Placebo<br>|
| Experimental: PF-07321332 Dose 4 (Fed)<br>Dose level 4 of PF-07321332 with high fat meal | Drug: PF-07321332 Dose 4 or Placebo (Fed)<br>* PF-07321332 Dose 5 or Placebo with high fat meal<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Treatment Emergent Adverse Events (TEAEs) in single ascending dose (SAD) | An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical study participant, temporally 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. TEAEs are AEs that occur following the start of treatment or AEs increasing in severity during treatment | Day 1 to Day 4 | 
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs in SAD |  | Day 1 to Day 4 | 
| Number of Participants With Laboratory Abnormalities in SAD |  | Day 1 to Day 4 | 
| Number of Participants with Clinically Significant Change From Baseline in Electrocardiogram (ECG) Findings in SAD | Criteria for clinically significant changes in ECG (12-lead) are defined as: a postdose QTc interval increase by ≥30 msec from the baseline and is >450 msec; or an absolute QTc value is ≥500 msec for any scheduled ECG | Day 1 to Day 4 | 
| Number of participants with TEAEs in multiple ascending dose (MAD) | An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An 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. TEAEs are AEs that occur following the start of treatment or AEs increasing in severity during treatment | Day 1 to Day 12 | 
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs in MAD | Vital signs evaluation includes: supine systolic and diastolic blood pressure (BP), temperature, respiratory rate and pulse rate. | Day 1 to Day 12 | 
| Number of Participants With Laboratory Abnormalities in MAD |  | Day 1 to Day 12 | 
| Number of Participants with Clinically Significant Change From Baseline in ECGs Findings in MAD | Criteria for clinically significant changes in ECG (12-lead) are defined as: a postdose QTc interval increase by ≥30 msec from the baseline and is >450 msec; or an absolute QTc value is ≥500 msec for any scheduled ECG | Day 1 to Day 12 | 
| Total % cumulative recovery of drug related material in metabolism and excretion (ME) | Drug related material excreted in urine and feces combined | Day 1 to Day 11 | 
| The ratio of AUClast in relative bioavailability (RBA) | The ratio of AUClast of test vs reference formulation | Day 1 to Day 3 | 
| The ratio of Cmax in RBA | The ratio of Cmax of test vs reference formulation | Day 1 to Day 3 | 
| Number of participants with Treatment Emergent Adverse Events (TEAEs) in supratherapeutic exposure (SE) | An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical study participant, temporally 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. TEAEs are AEs that occur following the start of treatment or AEs increasing in severity during treatment | Day 1 to Day 5 | 
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs in SE |  | Day 1 to Day 5 | 
| Number of Participants With Laboratory Abnormalities in SE |  | Day 1 to Day 5 | 
| Number of Participants with Clinically Significant Change From Baseline in Electrocardiogram (ECG) Findings in SE | Criteria for clinically significant changes in ECG (12-lead) are defined as: a postdose QTc interval increase by ≥30 msec from the baseline and is >450 msec; or an absolute QTc value is ≥500 msec for any scheduled ECG | Day 1 to Day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) in SAD | The maximum observed plasma concentration (Cmax) is estimated based on the plasma concentrations | Day 1 to Day 4 | 
| Dose Normalized Maximum Plasma Concentration (Cmax[dn]) in SAD | Cmax(dn) = Cmax / dose. | Day 1 to Day 4 | 
| Time for Cmax (Tmax) in SAD | Tmax was summarized by dosing regimen. It was observed directly from data as time of first occurrence. | Day 1 to Day 4 | 
| Area Under the Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) in SAD | AUClast is summarized by dosing regimen and determined by linear/log trapezoidal method. | Day 1 to Day 4 | 
| Dose Normalized Area Under the Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast[dn]) in SAD | AUClast /dose | Day 1 to Day 4 | 
| Cmax in MAD-Day 1 | Observed Cmax is estimated based on the plasma concentrations | Day 1 Pre-dose (0 hours) to 12 hours | 
| Cmax(dn) in MAD-Day 1 | Cmax/dose is summarized by dosing regimen. | Day 1 Pre-dose (0 hours) to 12 hours | 
| Cmax in MAD-Day 5 | Observed Cmax is estimated based on the plasma concentrations | Day 5 Pre-dose (0 hours) to 12 hours | 
| Dose Normalized Maximum Plasma Concentration (Cmax[dn]) in MAD-Day 5 | Cmax/dose is summarized by dosing regimen. | Day 5 Pre-dose (0 hours) to 12 hours | 
| Cmax in MAD-Day 10 | Observed Cmax is estimated based on the plasma concentrations | Day 10 (0h) Pre-dose (0 hours) to 12 hours | 
| Dose Normalized Maximum Plasma Concentration (Cmax[dn]) in MAD-Day 10 | Cmax/dose is summarized by dosing regimen. | Day 10 Pre-dose (0 hours) to 12 hours | 
| Time for Cmax (Tmax) in MAD-Day 1 | Tmax was summarized by dosing regimen. It was observed directly from data as time of first occurrence. | Day 1 Pre-dose (0 hours) to 12 hours | 
| Tmax in MAD-Day 5 | Tmax was summarized by dosing regimen. It was observed directly from data as time of first occurrence. | Day 5 Pre-dose (0 hours) to 12 hours | 
| Tmax in MAD-Day 10 | Tmax was summarized by dosing regimen. It was observed directly from data as time of first occurrence. | Day 10 Pre-dose (0 hours) to 12 hours | 
| Area Under the Plasma Concentration-Time Profile From Time Zero To End of Dosing Interval (AUCtau) in MAD-Day 1 | AUCtau is summarized by dosing regimen and period. Dosing interval is the interval tau between administration of doses of drug. In this study, the dosing interval is 8 hours for three times daily (TID) dosing and 12 hours for twice daily (BID) dosing. It is determined by linear/log trapezoidal method. | Day 1 Pre-dose (0 hours) to 12 hours | 
| Dose Normalized Area Under the Plasma Concentration-Time Profile From Time Zero To End of Dosing Interval (AUCtau[dn]) in MAD-Day 1 | AUCtau/dose is summarized by dosing regimen and period. Dosing interval is the interval tau between administration of doses of drug. In this study, the dosing interval is 8 hours for TID dosing and 12 hours for BID dosing. I | Day 1 Pre-dose (0 hours) to 12 hours | 
| AUCtau in MAD-Day 5 | AUCtau is summarized by dosing regimen and period. Dosing interval is the interval tau between administration of doses of drug. In this study, the dosing interval is 8 hours for TID dosing and 12 hours for BID dosing. It is determined by linear/log trapezoidal method. | Day 5 Pre-dose (0 hours) to 12 hours | 
| AUCtau(dn) in MAD-Day 5 | AUCtau/dose is summarized by dosing regimen and period. Dosing interval is the interval tau between administration of doses of drug. In this study, the dosing interval is 8 hours for TID dosing and 12 hours for BID dosing. I | Day 5 Pre-dose (0 hours) to 12 hours | 
| AUCtau in MAD-Day 10 | AUCtau is summarized by dosing regimen and period. Dosing interval is the interval tau between administration of doses of drug. In this study, the dosing interval is 8 hours for TID dosing and 12 hours for BID dosing. It is determined by linear/log trapezoidal method. | Day 10 Pre-dose (0 hours) to 12 hours | 
| Dose Normalized Area Under the Plasma Concentration-Time Profile From Time Zero To End of Dosing Interval (AUCtau[dn]) in MAD-Day 10 | AUCtau/dose is summarized by dosing regimen and period. Dosing interval is the interval tau between administration of doses of drug. In this study, the dosing interval is 8 hours for TID dosing and 12 hours for BID dosing. I | Day 10 Pre-dose (0 hours) to 12 hours | 
| Lowest Concentration Observed During the Dosing Interval tau (Cmin) in MAD-Day 5 | Cmin is observed directly from data. It is summarized by dosing regimen. Dosing interval is the interval tau between administration of doses of drug. In this study, the dosing interval tau is 8 hours for TID dosing and 12 hours for BID dosing. | Day 5 Pre-dose (0 hours) to 12 hours | 
| Cmin in MAD-Day 10 | Cmin is observed directly from data. It is summarized by dosing regimen. Dosing interval is the interval tau between administration of doses of drug. In this study, the dosing interval tau is 8 hours for TID dosing and 12 hours for BID dosing. | Day 10 Pre-dose (0 hours) to 12 hours | 
| t½ in MAD-Day 10 | 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 10 Pre dose (0 hours) to Day 12 (48 hours post dose) | 
| Vz/F in MAD-Day 10 | 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 10 Pre-dose (0 hours) to 12 hours | 
| Peak Trough Ratio (PTR) in MAD-Day 5 | PTR = Cmax,ss / Cmin,ss, where ss means 'at steady state'. It is summarized by dosing regimen . | Day 5 Pre-dose (0 hours) to 12 hours | 
| PTR in MAD-Day 10 | PTR = Cmax,ss / Cmin,ss, where ss means 'at steady state'. It is summarized by dosing regimen . | Day 10 Pre-dose (0 hours) to 12 hours | 
| Observed Accumulation Ratio Based on AUC (Rac) in MAD-Day 5 | Rac = AUCtau,ss / AUCtau,sd, where ss means 'at steady state' and sd 'single dose'. In this study, Rac = AUCtau(Day 5) / AUCtau(Day 1). Rac is summarized by dosing regimen. | Day 5 Pre-dose (0 hours) to 12 hours | 
| Rac in MAD-Day 10 | Rac = AUCtau,ss / AUCtau,sd, where ss means 'at steady state' and sd 'single dose'. In this study, Rac = AUCtau(Day 10) / AUCtau(Day 1). Rac is summarized by dosing regimen. | Day 10 Pre-dose (0 hours) to 12 hours | 
| Observed Accumulation Ratio Based on Cmax (Rac,Cmax) in MAD-Day 5 | Rac,Cmax = Cmax,ss / Cmax,sd, where ss means 'at steady state' and sd 'single dose'. In this study, Rac,Cmax = Cmax(Day5) / Cmax(Day 1). Rac,Cmax is summarized by dosing regimen. | Day 5 Pre-dose (0 hours) to 12 hours | 
| Rac,Cmax in MAD-Day 10 | Rac,Cmax = Cmax,ss / Cmax,sd, where ss means 'at steady state' and sd 'single dose'. In this study, Rac,Cmax = Cmax(Day10) / Cmax(Day 1). Rac,Cmax is summarized by dosing regimen. | Day 10 Pre-dose (0 hours) to 12 hours | 
| CL/F in MAD-Day 5 | CL/F is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. calculated as Dose/AUC tau. Dosing interval (tau) is 8 h for TID dosing and 12 h for BID dosing. | Day 5 Pre-dose (0 hours) to 12 hours | 
| CL/F in MAD-Day 10 | CL/F is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. calculated as Dose/AUC tau. Dosing interval (tau) is 8 h for TID dosing and 12 h for BID dosing. | Day 10 Pre-dose (0 hours) to 12 hours | 
| Cumulative Amount of Drug Recovered Unchanged in Urine From Time 0 to the Dosing Interval tau Hours Post-Dose (Aetau) in MAD-Day 10 | Sum of (urine volume × urine concentration) for each collection over the dosing interval tau. Dosing interval (tau) is 8h for TID and 12 h for BID dosing. | Day 10 Pre-dose (0 hours) to 12 hours | 
| Percentage of Dose Recovered Unchanged in Urine From Time 0 to the Dosing Interval tau Hours Post-Dose (Aetau%) in MAD-Day 10 | Aetau% = Aetau / Dose * 100. Aetau% is summarized by dosing regimen. Dosing interval (tau) is 8h for TID and 12 h for BID dosing. | Day 10 Pre-dose (0 hours) to 12 hours | 
| Renal Clearance (Clr) in MAD-Day 10 | Renal clearance is calculated as cumulative amount of drug recovered unchanged in urine during the dosing interval (Aetau) divided by area under the plasma concentration time-curve from time zero to end of dosing interval (AUCtau), where dosing interval is 8 hours for TID dosing and 12 hours for BID dosing. | Day 10 Pre-dose (0 hours) to 12 hours | 
| Maximum Plasma Concentration (Cmax) in Metabolism and Excretion (ME) | The maximum observed plasma concentration (Cmax) is estimated based on the plasma concentrations | Day 1 to Day 11 | 
| Time for Cmax (Tmax) in Metabolism and Excretion (ME) | Tmax was summarized by dosing regimen. It was observed directly from data as time of first occurrence. | Day 1 to Day 11 | 
| Area Under the Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) in Metabolism and Excretion (ME) | AUClast is summarized by dosing regimen and determined by linear/log trapezoidal method. | Day 1 to Day 11 | 
| Maximum Plasma Concentration (Cmax) in SE | The maximum observed plasma concentration (Cmax) is estimated based on the plasma concentrations | Day 1 to Day 5 | 
| Time for Cmax (Tmax) in SE | Tmax was summarized by dosing regimen. It was observed directly from data as time of first occurrence. | Day 1 to Day 5 | 
| Area Under the Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) in SE | AUClast is summarized by dosing regimen and determined by linear/log trapezoidal method. | Day 1 to Day 5 |