A Study To Test The Safety, Amount And Effects Of PF-06282999 In Healthy Overweight Adults And A Study To Test The Effects Of PF-06282999 On The Amount Of The Approved Drug, Midazolam, In Healthy Adults

Study Overview
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Brief Summary
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Part A of the study will test the safety, the amount of drug in the body, and effects of the drug in the body after multiple doses. This will be conducted in healthy overweight adults. Part B of the study will test the effects of multiple doses of the investigational drug on the amount of midazolam, an approved drug, in healthy adults.

Official Title
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A Phase 1, Randomized, Placebo-Controlled, Multiple Dose Study To Evaluate The Safety, Pharmacokinetics And Pharmacodynamics Of PF-06282999 In Healthy Overweight Subjects And A Fixed-Sequence Study To Assess The Effect Of PF-06282999 On The Pharmacokinetics Of Midazolam In Healthy Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: PF-06282999
* Drug: Placebo
* Drug: PF-06282999
* Drug: Placebo
* Drug: PF-06282999
* Drug: Placebo
* Drug: PF-06282999
* Drug: Placebo
* Drug: PF-06282999
* Drug: Placebo
* Drug: midazolam
* Drug: PF-06282999
* Drug: midazolam
* Drug: PF-06282999


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male and/or female subjects between the ages of 18 and 55 years, inclusive (Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12-lead ECG and clinical laboratory tests). Women must be of non childbearing potential. Body Mass Index (BMI) of 27.0 to 35.0 kg/m2 (Part A) or 17.5 to 30.5 kg/m2 (Part B); and a total body weight >50 kg (110 lbs). Exclusion Criteria: Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including clinically significant drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing). Subject with any contraindication to midazolam according to the country specific labeling or subject with previous intolerance or allergy to benzodiazepines (applicable to Part B of study only). Subjects who were enrolled in Part A are excluded from participation in Part B of this study. Subjects who have previously participated in a study with PF-06282999.

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
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A Cohort 1<br> | Drug: PF-06282999<br>* Tablet, 10 mg, every 8 hours, 14 days<br>Drug: Placebo<br>* Tablet, 0 mg, every 8 hours, 14 days<br>|
| Experimental: Part A Cohort 2<br> | Drug: PF-06282999<br>* Tablet, 30 mg, every 8 hours, 14 days<br>Drug: Placebo<br>* Tablet, 0 mg, every 8 hours, 14 days<br>|
| Experimental: Part A Cohort 3<br> | Drug: PF-06282999<br>* Tablet, 100 mg, every 8 hours, 14 days<br>Drug: Placebo<br>* Tablet, 0 mg, every 8 hours, 14 days<br>|
| Experimental: Part A Cohort 4<br> | Drug: PF-06282999<br>* Tablet, 250 mg, every 8 hours, 14 days<br>Drug: Placebo<br>* Tablet, 0 mg, every 8 hours, 14 days<br>|
| Experimental: Part A Cohort 5<br> | Drug: PF-06282999<br>* Tablet, 350 mg every 8 hours or 500 mg every 12 hours, 14 days<br>Drug: Placebo<br>* Tablet, 0 mg, every 8 or 12 hours, 14 days<br>|
| Experimental: Part B Cohort 1<br> | Drug: midazolam<br>* Tablet, 7.5 mg, single dose on Period 1 Day 1 and Period 2 Day 14<br>Drug: PF-06282999<br>* Tablet, dose to be determined (determined in Part A), every 8 or 12 hours, 14 days<br>|
| Experimental: Part B Cohort 2<br> | Drug: midazolam<br>* Tablet, 7.5 mg, single dose on Period 1 Day 1 and Period 2 Day 14<br>Drug: PF-06282999<br>* Tablet, dose to be determined (determined in Part A), every 8 or 12 hours, 14 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) |  | Pre-dose,0.5,1,2,3,4,5,6,7,8 and 16 hrs post morning dose Day 1 Part A | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) |  | Pre-dose,0.5,1,2,3,4,5,6,7,8 and 16 hrs post morning dose Day 1 Part A | 
| Area Under the Curve from Time Zero to end of dosing interval (AUCtau) |  | Pre-dose,0.5,1,2,3,4,5,6,7,8 and 16 hrs post morning dose Day 1 Part A | 
| Apparent Oral Clearance (CL/F) |  | Pre-dose,0.5,1,2,3,4,5,6,7,8 and 16 hrs post morning dose Day 1 Part A | 
| Maximum Observed Plasma Concentration (Cmax) |  | Pre-dose,0.5,1,2,3,4,5,6,7,8,10,12,16,24,36, and 48 hrs post morning dose Day 14 Part A | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) |  | Pre-dose,0.5,1,2,3,4,5,6,7,8,10,12,16,24,36, and 48 hrs post morning dose Day 14 Part A | 
| Area Under the Curve from Time Zero to end of dosing interval (AUCtau) |  | Pre-dose,0.5,1,2,3,4,5,6,7,8,10,12,16,24,36, and 48 hrs post morning dose Day 14 Part A | 
| Minimum Observed Plasma Trough Concentration (Cmin) |  | Pre-dose,0.5,1,2,3,4,5,6,7,8,10,12,16,24,36, and 48 hrs post morning dose Day 14 Part A | 
| Apparent Oral Clearance (CL/F) |  | Pre-dose,0.5,1,2,3,4,5,6,7,8,10,12,16,24,36, and 48 hrs post morning dose Day 14 Part A | 
| Plasma Decay Half-Life (t1/2) |  | Pre-dose,0.5,1,2,3,4,5,6,7,8,10,12,16,24,36, and 48 hrs post morning dose Day 14 Part A | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) Midazolam | Pre-dose,0.5,1,2,3,4,5,6,8,10,12 and 16 hrs post dose Day 1 Period 1 Part B | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) Midazolam | -2,-1.5,-1,Pre-dose,1,2,4,6,8,10,14 Day 14 Period 2 Part B | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - 8)] | AUC (0 - 8)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - 8). It is obtained from AUC (0 - t) plus AUC (t - 8). Midazolam | Pre-dose,0.5,1,2,3,4,5,6,8,10,12 and 16 hrs post dose Day 1 Period 1 Part B | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - 8)] | AUC (0 - 8)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - 8). It is obtained from AUC (0 - t) plus AUC (t - 8). Midazolam | -2,-1.5,-1,Pre-dose,1,2,4,6,8,10,14 Day 14 Period 2 Part B | 
| Maximum Observed Plasma Concentration (Cmax) |  | Pre-dose,0.5,1,2,3,4,5,6,8,10,12 and 16 hrs post dose Day 1 Period 1 Part B | 
| Maximum Observed Plasma Concentration (Cmax) |  | -2,-1.5,-1,Pre-dose,1,2,4,6,8,10,14 Day 14 Period 2 Part B | 
| Average Concentration (Cav) |  | Pre-dose,0.5,1,2,3,4,5,6,7,8,10,12,16,24,36, and 48 hrs post morning dose Day 14 Part A | 
| Accumulation Ratio |  | Pre-dose,0.5,1,2,3,4,5,6,7,8,10,12,16,24,36, and 48 hrs post morning dose Day 14 Part A | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diastolic Blood Pressure | Mean 24-hour average diastolic blood pressure | Day 1 Pre-dose,1,2,4,8,12 and 16 hrs post dose Part A | 
| Diastolic Blood Pressure | Mean 24-hour average diastolic blood pressure | Day 13 Pre-dose,1,2,4,8,12 and 16 hrs post dose Part A | 
| Systolic Blood Pressure | Mean 24-hour average systolic blood pressure | Day 1 Pre-dose,1,2,4,8,12 and 16 hrs post dose Part A | 
| Systolic Blood Pressure | Mean 24-hour average systolic blood pressure | Day 13 Pre-dose,1,2,4,8,12 and 16 hrs post dose Part A | 
| interleukin-6 |  | Days 1 and 14 pre-dose Part A | 
| high-sensitivity C-reactive protein |  | Days 1 and 14 pre-dose Part A | 
| total cholesterol, HDL-C, triglycerides and calculated LDL-C |  | Days 1 and 14 pre-dose Part A | 
| ApoBTotal,ApoB48, ApoB100, ApoA-1 |  | Days 1 and 14 pre-dose Part A | 
| Diastolic Blood Pressure | Mean 24-hour average diastolic blood pressure | Day 1 Pre-dose,1,2,4,8,12 and 16 hrs post dose Part B | 
| Diastolic Blood Pressure | Mean 24-hour average diastolic blood pressure | Day 13 Pre-dose,1,2,4,8,12 and 16 hrs post dose Part B | 
| Systolic Blood Pressure | Mean 24-hour average systolic blood pressure | Day 1 Pre-dose,1,2,4,8,12 and 16 hrs post dose Part B | 
| Systolic Blood Pressure | Mean 24-hour average systolic blood pressure | Day 13 Pre-dose,1,2,4,8,12 and 16 hrs post dose Part B |