A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of PF-06882961 in Japanese Adults With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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This is a Phase 1, randomized, double blind (sponsor open), parallel, placebo controlled, twice daily oral dosing study of PF 06882961 in adult Japanese participants with T2DM inadequately controlled on diet and exercise alone.

Official Title
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AN 8-WEEK PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, PLACEBO-CONTROLLED, PARALLEL GROUP STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF TWICE DAILY PF-06882961 ADMINISTRATION IN JAPANESE ADULTS WITH TYPE 2 DIABETES MELLITUS

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Placebo
* Drug: PF-06882961


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with T2DM who are treated with diet and exercise HbA1c greater than or equal to 7% and less than or equal to 10.5% Total body weight >50 kg (110 lb) with BMI 22.5 to 45.4 kg/m^2 Exclusion Criteria: Any condition possibly affecting drug absorption Diagnosis of Type 1 diabetes History of myocardial infarction, unstable angina, arterial revascularization, stroke, heart failure, or transient ischemic attack within 6 months of screening Any malignancy not considered cured Personal or family history of MTC or MEN2, or participants with suspected MTC Acute pancreatitis or history of chronic pancreatitis Symptomatic gallbladder disease Known medical history of active proliferative retinopathy and/or macular edema Known history of HIV, hepatitis B, hepatitis C or syphilis Supine blood pressure greater than or equal to 160 mmHg (systolic) or greater than or equal to 100 mmHg (diastolic) Clinically relevant ECG abnormalities Positive urine drug test

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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 |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* 3 matching placebo tablets taken twice a day (BID)<br>|
| Experimental: PF-06882961 40 mg<br>Participants will be titrated up to 2 weeks to reach desired dose level | Drug: PF-06882961<br>* Participants will be randomized to one of 3 active doses (40, 80, or 120 mg), taking 3 tablets twice daily for 8 weeks.<br>|
| Experimental: PF-06882961 80 mg<br>Participants will be titrated up to 4 weeks to reach desired dose level | Drug: PF-06882961<br>* Participants will be randomized to one of 3 active doses (40, 80, or 120 mg), taking 3 tablets twice daily for 8 weeks.<br>|
| Experimental: PF-06882961 120 mg<br>Participants will be titrated up to 6 weeks to reach desired dose level | Drug: PF-06882961<br>* Participants will be randomized to one of 3 active doses (40, 80, or 120 mg), taking 3 tablets twice daily for 8 weeks.<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 (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. 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 AEs were events between first dose of study drug and approximately 4 weeks after last dose of study drug, that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and all non-serious AEs. | Day 1 of dosing up to approximately 4 weeks after last dose (up to maximum of approximately 12 weeks) | 
| Number of Participants With Clinical Laboratory Abnormalities | Leukocytes (10^9/liter [L]) bilirubin (micromol/L), glucose (millimoles [mmol]/L), triacylglycerol lipase (microkatals [microkat]/L): greater than (>) 1.5*upper limit normal (ULN); activated partial thromboplastin time (s): 1.1*ULN; HDL cholesterol (mmol/L), thyroid stimulating hormone (TSH) (milliunits [mU]/L): less than (<) 0.8*lower limit normal (LLN); LDL cholesterol (mmol/L), urate (mmol/L): >1.2*ULN; triglycerides: >1.3*ULN; aspartate aminotransferase (microkat/L), alanine aminotransferase (microkat/L), gamma glutamyl transferase (microkat/L): >3.0*ULN; cholesterol (mmol/L): >1.3*ULN; urine glucose, ketones urine protein, urine hemoglobin, urobilinogen, nitrite, leukocyte esterase: greater than or equal to (>=) 1; granular casts, hyaline casts: >1. | Day 1 of dosing up to approximately 4 weeks after last dose (up to maximum of approximately 12 weeks) | 
| Number of Participants With Absolute Vital Signs (SBP, DBP and Pulse Rate) Values; Increased and Decreased Vital Signs (SBP, DBP) Values From Time-Matched Baseline | Supine systolic blood pressure (SBP) measured in millimeter of mercury (mmHg) had following categories: minimum of absolute SBP <90 mmHg, maximum of SBP >=30 mmHg decrease from baseline and maximum of SBP >=30 mmHg increase from baseline. Supine diastolic blood pressure (DBP) measured in mmHg had following categories: minimum of absolute DBP <50 mmHg, maximum of DBP >20 mmHg decrease from baseline and maximum of DBP >=20 mmHg increase from baseline. Supine pulse rate measured in beats per minute (BPM) had following categories: minimum of absolute supine pulse rate <40 BPM and maximum of absolute supine pulse rate >120 BPM. Baseline was defined as the time-matched value from the average of the triplicate recordings on Day -1. | Baseline (1 Day before dosing) up to last dose (maximum up to Week 8) | 
| Number of Participants With Absolute Electrocardiogram (ECG) Values and Increased ECG Values From Time-Matched Baseline | PR interval had following categories: maximum absolute PR interval >=300 milliseconds (msec); when baseline PR interval >200 msec and maximum increase from baseline in PR interval >=25 percent; when baseline PR interval less than or equal to (<=) 200 msec and maximum increase from baseline in PR interval >=50 percent. QRS interval had following categories: maximum absolute QRS interval >=140 msec; maximum increase from baseline in QRS interval >=50 percent. QTC interval with Frederica's correction (QTCF) had following categories: absolute QTCF interval >450 msec to <=480 msec; absolute QTCF interval >480 msec to <=500 msec; absolute QTCF interval >500 msec; QTCF interval increase from baseline >=30 msec to <=60 msec; QTCF interval increase from baseline >60 msec. | Baseline (1 Day before dosing) up to last dose (maximum up to Week 8) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-time Profile From Zero to Time 24 Hours (AUC24) of PF-06882961 | AUC24= Area under the plasma concentration versus time curve from time zero (pre-dose) to time 24 hours (0-24). | Pre-dose (0 hour), 1, 2, 4, 6, 8, 10, 12, 14 and 24 hours post dose on Day 1 and 56 | 
| Maximum Plasma Concentration (Cmax) Observed of PF-06882961 |  | Pre-dose (0 hour), 1, 2, 4, 6, 8, 10, 12, 14 and 24 hours post dose on Day 1; Pre-dose (0 hour), 1, 2, 4, 6, 8, 10, 12, 14, 24, 36 and 48 hours on Day 56 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06882961 |  | Pre-dose (0 hour), 1, 2, 4, 6, 8, 10, 12, 14 and 24 hours post dose on Day 1; Pre-dose (0 hour), 1, 2, 4, 6, 8, 10, 12, 14, 24, 36 and 48 hours on Day 56 | 
| Terminal Phase Half-Life (t1/2) of PF-06882961 | t1/2 was calculated as loge (2) per kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. | Pre-dose (0 hour), 1, 2, 4, 6, 8, 10, 12, 14, 24, 36 and 48 hours on Day 56 |