Single Dose, Repeated Dose, and Conditional Food Effect Study of PF-05221304 in Healthy Subjects

Study Overview
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Brief Summary
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The current study is the first clinical trial proposed with PF-05221304. It is designed to evaluate the safety, tolerability, and pharmacokinetics (PK) following administration of single and repeated doses of PF-05221304 to healthy adult subjects. The study may also evaluate effect of food on PK of PF-05221304.

Official Title
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A Phase 1, 3-part Study Of Pf-05221304 In Healthy Adults: Part 1 - Randomized, Double-blind, Placebo-controlled Assessment Of Safety And Pharmacokinetics Of Single, Escalating, Oral Doses; Part 2 - Randomized, Double-blind, Placebo-controlled Assessment Of Safety And Pharmacokinetics Of Repeated, Escalating, Oral Doses; Conditional Part 3 - Effect Of Food On The Pharmacokinetics Of Pf-05221304

Conditions
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Normal Healthy

Intervention / Treatment
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* Drug: PF-05221304
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males and female of non-childbearing potential; Body Mass Index 17.5-30.5 kg/m2; Body weight >50 kg; Exclusion Criteria: Evidence of history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergises, but excluding untreated, asymptomatic, seasonal allergies at time of dosing

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Basic Science
Allocation: Randomized
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1_Cohort 1_Active<br>Single, escalating dose of PF-05221304 | Drug: PF-05221304<br>* Single or repeated, escalating dose of PF-05221304<br>|
| Placebo Comparator: Part 1_Cohort 1_Placebo<br>Single dose of Placebo | Other: Placebo<br>* single or repeated dose of placebo<br>|
| Experimental: Part 1_Cohort 2_Active<br>Single, escalating dose of PF-05221304 | Drug: PF-05221304<br>* Single or repeated, escalating dose of PF-05221304<br>|
| Experimental: Part 1_Cohort 2_Placebo<br>Single dose of Placebo | Other: Placebo<br>* single or repeated dose of placebo<br>|
| Experimental: Part 2_Active<br>Repeated, escalating doses of PF-05221304 | Drug: PF-05221304<br>* Single or repeated, escalating dose of PF-05221304<br>|
| Placebo Comparator: Part 2_Placebo<br>Repeated doses of placebo | Other: Placebo<br>* single or repeated dose of placebo<br>|
| Experimental: Part 3<br>Single dose of PF-05221304 with and without food | Drug: PF-05221304<br>* Single or repeated, escalating dose of PF-05221304<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Subjects experiencing an Adverse Event | Assessment by adverse event monitoring, 12 lead ECGs, telemetry, vital signs and clinical safety laboratory measurements. Treatment-related AE was any untoward medical occurrence attributed to study drug in a subject who received study drug. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. Relatedness to Drug was assessed by the investigator (Yes/No). Subjects with multiple occurrences of an AE within a category were counted once within the category. | Screening up to 28 days after last dose of study medication | 
| Part 2: Number of Subjects experiencing an Adverse Event | Assessment by adverse event monitoring, 12 lead ECGs, telemetry, vital signs and clinical safety laboratory measurements. Treatment-related AE was any untoward medical occurrence attributed to study drug in a subject who received study drug. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. Relatedness to Drug was assessed by the investigator (Yes/No). Subjects with multiple occurrences of an AE within a category were counted once within the category. | Screening up to 28 days after last dose of study medication | 
| Part 3: Maximum Observed Plasma Concentration (Cmax) for PF-05221304 | Maximum Observed Plasma Concentration (Cmax) | 0, 0.5, 1, 2, 3, 4, 5, 8, 12, 16, 24, 36, and 48 hours post dose | 
| Part 3: Time to Reach Maximum Observed Concentration for PF-05221304 | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 0, 0.5, 1, 2, 3, 4, 5, 8, 12, 16, 24, 36, and 48 hours post dose | 
| Part 3: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for PF-05221304 | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) | 0, 0.5, 1, 2, 3, 4, 5, 8, 12, 16, 24, 36, and 48 hours post dose | 
| Part 3: Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0- infinity)] for PF-05221304 (as permitted) | AUC (0-infinity)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-infinity). It is obtained from AUC (0-t) plus AUC (t-infinity). | 0, 0.5, 1, 2, 3, 4, 5, 8, 12, 16, 24, 36, and 48 hours post dose | 
| Part 3: Plasma Decay Half-Life (t1/2) for PF-05221304 (as permitted) | Plasma Decay Half-Life (t1/2) | 0, 0.5, 1, 2, 3, 4, 5, 8, 12, 16, 24, 36, and 48 hours post dose | 
| Part 3: Apparent Total Body Clearance (CL/F) for PF-05221304 (as permitted) | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after apparent total body clearance is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | 0, 0.5, 1, 2, 3, 4, 5, 8, 12, 16, 24, 36, and 48 hours post dose | 
| Part 3: Apparent Volume of Distribution (Vz/F) for PF-05221304 (as permitted) | Volume of distribution 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. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. | 0, 0.5, 1, 2, 3, 4, 5, 8, 12, 16, 24, 36, and 48 hours post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1:Maximum Observed Plasma Concentration (Cmax) for PF-05221304 | Maximum Observed Plasma Concentration (Cmax) | 0, 0.5, 1, 2, 3, 4, 5, 8, 12, 16, 24, 36, and 48 hours post dose | 
| Part 1: Time to Reach Maximum Observed Concentration for PF-05221304 | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 0, 0.5, 1, 2, 3, 4, 5, 8, 12, 16, 24, 36, and 48 hours post dose | 
| Part 1: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for PF-05221304 | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) | 0, 0.5, 1, 2, 3, 4, 5, 8, 12, 16, 24, 36, and 48 hours post dose | 
| Part 1: dose-normalized Cmax and AUClast for PF05221304 |  | 0, 0.5, 1, 2, 3, 4, 5, 8, 12, 16, 24, 36, and 48 hours post dose | 
| Part 1: Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0- infinity)] for PF-05221304 (as permitted) | AUC (0-infinity)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-infinity). It is obtained from AUC (0-t) plus AUC (t-infinity). | 0, 0.5, 1, 2, 3, 4, 5, 8, 12, 16, 24, 36, and 48 hours post dose | 
| Part 1: Plasma Decay Half-Life (t1/2) for PF-05221304 (as permitted) | Plasma Decay Half-Life (t1/2) | 0, 0.5, 1, 2, 3, 4, 5, 8, 12, 16, 24, 36, and 48 hours post dose | 
| Part 1: Apparent Total Body Clearance (CL/F) for PF-05221304 (as permitted) | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after apparent total body clearance is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | 0, 0.5, 1, 2, 3, 4, 5, 8, 12, 16, 24, 36, and 48 hours post dose | 
| Part 1: Apparent Volume of Distribution (Vz/F) for PF-05221304 (as permitted) | Volume of distribution 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. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. | 0, 0.5, 1, 2, 3, 4, 5, 8, 12, 16, 24, 36, and 48 hours post dose | 
| Part 2: Single dose plasma parameters of Cmax for PF-05221304 | Maximum Observed Plasma Concentration (Cmax) | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose on Day 1 | 
| Part 2: Single-dose plasma parameters of Tmax for PF-05221304 | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose on Day 1 | 
| Part 2: Single-dose plasma parameters of Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) for PF-05221304 | Area under the concentration curve from time 0 to end of dosing interval (AUCtau) | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose on Day 1 | 
| Part 2: Multiple-dose plasma parameters of Cmax for PF-05221304 | Maximum Observed Plasma Concentration (Cmax) | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose for Day 7; (and Day 14, as permitted) | 
| Part 2: Multiple-dose plasma parameters of Tmax for PF-05221304 | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose for Day 7; (and Day 14, as permitted) | 
| Part 2: Multiple-dose plasma parameters of AUCtau for PF-05221304 | Area under the concentration curve from time 0 to end of dosing interval (AUCtau) | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose for Day 7; (and Day 14, as permitted) | 
| Part 2: Multiple-dose plasma parameters of Minimum Observed Plasma Trough Concentration (Cmin) for PF-05221304 |  | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose for Day 7; (and Day 14, as permitted) | 
| Part 2: Multiple-dose plasma parameters of CL/F for PF-05221304 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after apparent total body clearance is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose for Day 7; (and Day 14, as permitted) | 
| Part 2: Multiple-dose plasma parameters of Vz/F for PF-05221304 (as permitted) | Volume of distribution 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. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 16 hours on Day 1 and 7, and 0 hr on Day 2, Day 4, Day 8, Day 10, Day 13, Day 15, and Day 16 post dose | 
| Part 2: Multiple-dose plasma parameters of Peak-trough ratio (PTR) for PF-05221304 |  | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose for Day 7; (and Day 14, as permitted) | 
| Part 2: Multiple-dose plasma parameters of Observed accumulation ratio for Cmax (Rac(Cmax)) for PF-05221304 |  | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose for Day 7; (and Day 14, as permitted) | 
| Part 2: Multiple-dose plasma parameters of Observed accumulation ratio (Rac(AUCtau)) |  | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose for Day 7; (and Day 14, as permitted) | 
| Part 2: Multiple-dose plasma parameters of Plasma Decay Half-Life (t1/2) for PF-05221304 (as permitted) | Plasma Decay Half-Life (t1/2) | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 16 hours on Day 1 and 7, and 0 hr on Day 2, Day 4, Day 8, Day 10, Day 13, Day 15, and Day 16 post dose | 
| Part 3: Number of Subjects experiencing an Adverse Event | Assessment by adverse event monitoring, 12 lead ECGs, telemetry, vital signs and clinical safety laboratory measurements. Treatment-related AE was any untoward medical occurrence attributed to study drug in a subject who received study drug. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. Relatedness to Drug was assessed by the investigator (Yes/No). Subjects with multiple occurrences of an AE within a category were counted once within the category. | Screening up to 28 days after last dose of study medication |