4-Week, Multiple-dose, Dose-escalating Study In Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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This is a dose-escalating study in patients with Type 2 diabetes on metformin. Participants will receive an investigational product or placebo for 28 days.

Official Title
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A PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, PLACEBO-CONTROLLED STUDY TO ASSESS THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF MULTIPLE ESCALATING ORAL DOSES OF PF-06882961 IN ADULT SUBJECTS 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
* Drug: PF-06882961
* Drug: PF-06882961
* Drug: PF-06882961
* Drug: PF-06882961
* Drug: PF-06882961
* Drug: PF-06882961
* Drug: PF-06882961


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes treated with a stable dose of metformin at least 500 mg HbA1c value between 7.0 and 10.5% Exclusion Criteria: - Type 1 diabetes or secondary forms of diabetes

Ages Eligible for Study
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Minimum Age: 18 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: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Tablet, 0 mg, twice daily, 28 days<br>|
| Experimental: PF-06882961 30 mg<br> | Drug: PF-06882961<br>* Tablet, 15 mg twice daily, 28 days<br>|
| Experimental: PF-06882961 100 mg<br> | Drug: PF-06882961<br>* Tablet, 50 mg twice daily, 28 days<br>|
| Experimental: PF-06882961 300 mg<br> | Drug: PF-06882961<br>* Tablet, 150 mg twice daily, 28 days<br>|
| Experimental: PF-06882961 600 mg<br> | Drug: PF-06882961<br>* Tablet, 300 mg twice daily, 28 days<br>|
| Experimental: PF-06882961 dose TBD Cohort 5<br> | Drug: PF-06882961<br>* Tablet, dose TBD, twice daily, Cohort 5, 28 days<br>|
| Experimental: PF-06882961 dose TBD Cohort 6<br> | Drug: PF-06882961<br>* Tablet, dose TBD, twice daily, Cohort 6, 28 days<br>|
| Experimental: PF-06882961 dose TBD Cohort 7<br> | Drug: PF-06882961<br>* Tablet, dose TBD, twice daily, Cohort 7, 28 days<br>|
| Experimental: PF-06882961 dose TBD Cohort 8<br> | Drug: PF-06882961<br>* Tablet, dose TBD, twice daily, Cohort 8, 28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With All-causality and Treatment-related Treatment-emergent Adverse Events (TEAEs) | Treatment-related adverse event (AE) was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. A serious AE (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening; initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. Any such events with initial onset or increasing in severity after the first dose of study treatment were counted as treatment-emergent. | From baseline to up to 35 days after last dose for a total of approximately 63 days | 
| Number of Participants With Laboratory Abnormalities Without Regard to Baseline Abnormality | Following laboratory parameters were assessed against pre-defined abnormality criteria: hematology (hemoglobin, hematocrit, erythrocytes, reticulocytes, platelets, leukocytes, lymphocytes, neutrophils, basophils, eosinophils, monocytes, activated partial thromboplastin time, prothrombin time [PT], PT/international normalized ratio, reticulocytes); chemistry (indirect bilirubin, direct bilirubin, protein, albumin, blood urea nitrogen, creatinine, creatine kinase, urate, calcium, sodium, potassium, chloride, bicarbonate, urine urobilinogen); urinalysis (pH, urine glucose, urine ketones, urine protein, urine hemoglobin, nitrites, leukocyte esterase, urine erythrocytes, urine leukocytes, urine hyaline casts, urine bilirubin). | From baseline to up to 14 days after last dose for a total of approximately 42 days | 
| Number of Participants With Abnormal Vital Signs | Vital signs categorical summarization criteria: 1) supine systolic blood pressure (SBP) <90 millimeters of mercury (mmHg); 2) supine diastolic blood pressure (DBP) <50 mmHg; 3) supine pulse rate <40 or >120 beats per minute (bpm); 4) change from baseline (increase or decrease) in supine SBP greater than or equal to (>=) 30 mmHg; 5) change from baseline (increase or decrease) in supine DBP >= 20 mmHg. | From baseline to up to 14 days after last dose for a total of approximately 42 days | 
| Number of Participants With Abnormal Electrocardiogram (ECG) Interval | ECG categorical summarization criteria: 1. PR interval (the interval between the start of the P wave and the start of the QRS complex, corresponding to the time between the onset of the atrial depolarization and onset of ventricular depolarization): a) greater than or equal to (>=) 300 millisecond (msec), b) >=25% increase when baseline is > 200 msec or >=50% increase when baseline is less than or equal to (<=) 200 msec. 2. QRS duration (time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization): a) >=140 msec, b) >=50% increase from baseline. 3. QTcF interval (QT corrected using the Fridericia formula): a) >450 msec and <=480 msec, b) >480 msec and <=500 msec, c) >500 msec, d) >30 msec and <=60 msec increase from baseline, e) >60 msec increase from baseline | From baseline to up to 14 days after last dose for a total of approximately 42 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC24 and AUCtau of PF-06882961 on Day 1, Day 14 or 21 and Day 28 | Area under the concentration-time profile from time zero to time 24 hours (AUC24) was calculated as AUCtau1 +AUCtau2, where AUCtau was area under the plasma concentration-time profile from time zero to time tau (tau1 = 0 to 10 hours and tau2=10 to 24 hours). AUCtau was determined using linear/log trapezoidal method. | 0, 1, 2, 4, 6, 8, 10, 12, 14 and 24 hrs post dose on Day 1, 14 or 21, and 28 | 
| Maximum Plasma Concentration (Cmax) of PF-06882961 on Day 1, Day 14 or 21 and Day 28 | For BID dosing, parameters were calculated for both dosing intervals (0-10 hr = interval 1 and 10-24 hr = interval 2) and were displayed as Cmax1, Cmax2. Cmax1: maximum plasma concentration during the dosing interval τ1 =0 to 10 hours. Cmax2: maximum plasma concentration during the dosing interval τ2=10 to 24 hours. | 0, 1, 2, 4, 6, 8, 10, 12, 14 and 24 hours post dose on Day 1, 14 or 21, and 28 | 
| Time for Cmax (Tmax) of PF-06882961 on Day 1, Day 14 or 21 and Day 28 | Time for Cmax, Cmax1 and Cmax2 (Tmax, Tmax1 and Tmax2) of PF-06293620 was observed directly from data as time of first occurrence. | 0, 1, 2, 4, 6, 8, 10, 12, 14 and 24 hrs post dose on Day 1, 14 or 21, and 28 | 
| Terminal Half-life (t½) of PF-06882961 on Day 28 | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | 0, 1, 2, 4, 6, 8, 10, 12, 14 and 24 hrs post dose on Day 28 | 
| Amount of Unchanged Drug Recovered in Urine Over 24 Hours (Ae24) of PF-06882961 on Day 28 | Ae was the cumulative amount of drug recovered unchanged in urine during the dosing interval, where the dosing interval was 24 hours. Cumulative amount was calculated as sum of urine drug concentration in sample volume for each collection interval. Sample volume = (urine weight in gram [g]/1.020), where 1.020 g/mL was the approximate specific gravity of urine. | 0 to 24 hours post-dose on Day 28 | 
| Ae24 (%) of PF-06882961 on Day 28 | Percent of dose recovered in urine as unchanged drug. Ae24% = 100* Ae24/Dose | 0 to 24 hours post-dose on Day 28 | 
| Renal Clearance (CLr) of PF-06882961 on Day 28 | CLr was calculated as Ae divided by AUCtau, where dosing interval is 24 hours. | 0 to 24 hours post-dose on Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 diabetes mellitus