A 12-WEEK TITRATE STUDY TO EVALUATE SAFETY, TOLERABILITY AND PHARMACODYNAMICS OF PF-06882961 IN ADULTS WITH TYPE 2 DIABETES MELLITUS AND IN NON-DIABETIC ADULTS WITH OBESITY

Study Overview
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Brief Summary
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This study will assess tolerability, safety, and pharmacodynamics (PD) of twice daily (BID) administration of PF- 06882961 in adult participants with Type 2 Diabetes Mellitus (T2DM) who are treated with metformin and in non-diabetic adults with obesity

Official Title
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A 12-WEEK, PHASE 2A, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, PLACEBO-CONTROLLED, PARALLEL GROUP STUDY TO ASSESS THE SAFETY, TOLERABILITY, AND PHARMACODYNAMICS OF PF-06882961 TITRATION IN ADULTS WITH TYPE 2 DIABETES MELLITUS TREATED WITH METFORMIN AND IN NON-DIABETIC ADULTS WITH OBESITY

Conditions
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Obesity, Diabetes

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants between the ages of 18 and 75 years, inclusive, at Visit 1 (screening). Exclusion Criteria: Diagnosis of type 1 diabetes mellitus or secondary forms of diabetes. History of myocardial infarction, unstable angina, arterial revascularization, stroke, New York Heart Association Functional Class II IV heart failure, or transient ischemic attack within 6 months of screening (Visit 1). Participants with a known medical history of active liver disease (other than non alcoholic hepatic steatosis), including chronic active hepatitis B or C, or primary biliary cirrhosis. History of major depressive disorder or history of other severe psychiatric disorders (eg, schizophrenia or bipolar disorder) within the last 2 years. Any lifetime history of a suicide attempt.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1-PF-06882961 starting dose of 5 milligram (mg) BID titrated to 120 mg in participants with T2DM<br>The dose will be titrated over 12 weeks, starting with a dose of 5 mg BID to reach the target dose of 120 mg BID. Titration steps include: 5 mg BID, 10 mg BID, 20 mg BID, 40 mg BID, 60 mg BID, 80 mg BID, 100 mg BID and 120 mg BID | Drug: PF-06882961<br>* PF-68882961 will be provided as tablets twice a day (BID)<br>|
| Experimental: Arm 2-PF-06882961 starting dose of 10 mg BID titrated to 100 mg in participants with T2DM<br>The dose will be titrated over 12 weeks, starting with a dose of 10 mg BID to reach the target dose of 120 mg BID. Titration steps include: 10 mg BID, 20 mg BID, 40 mg BID, 60 mg BID, 80 mg BID, 100 mg BID and 120 mg BID | Drug: PF-06882961<br>* PF-68882961 will be provided as tablets twice a day (BID)<br>|
| Experimental: Arm 3-PF-06882961 starting dose of 5 mg BID titrated to 80 mg in participants with T2DM<br>The dose will be titrated over 12 weeks, starting with a dose of 5 mg BID to reach the target dose of 80 mg BID. Titration steps include: 5 mg BID, 10 mg BID, 20 mg BID, 40 mg BID, 60 mg BID and 80 mg BID | Drug: PF-06882961<br>* PF-68882961 will be provided as tablets twice a day (BID)<br>|
| Experimental: Arm 4-PF-06882961 starting dose of 10 mg BID titrated to 80 mg in participants with T2DM<br>The dose will be titrated over 12 weeks, starting with a dose of 10 mg BID to reach the target dose of 80 mg BID. Titration steps include: 10 mg BID, 20 mg BID, 40 mg BID, 60 mg BID and 80 mg BID | Drug: PF-06882961<br>* PF-68882961 will be provided as tablets twice a day (BID)<br>|
| Placebo Comparator: Arm 5 - Placebo in subjects with T2DM and Obesity<br>Matching Placebo tablets taken twice a day (BID) | Other: Placebo<br>* Placebo comparator will be provided as tablets twice daily for 12 weeks<br>|
| Experimental: Arm 6-PF-06882961 starting dose of 10 mg BID titrated to 200 mg in participants with T2DM<br>The dose will be titrated over 12 weeks, starting with a dose of 10 mg BID to reach the target dose of 200 mg BID. Titration steps include: 10 mg BID, 20 mg BID, 40 mg BID, 60 mg BID, 80 mg BID, 100 mg BID and 120 mg BID,140 mg BID, 160 mg BID, 180 MG BID, 200 mg BID | Drug: PF-06882961<br>* PF-68882961 will be provided as tablets twice a day (BID)<br>|
| Experimental: Arm 7-PF-06882961 starting dose of 10 mg BID titrated to 200 mg in participants with Obesity<br>The dose will be titrated over 12 weeks, starting with a dose of 10 mg BID to reach the target dose of 200 mg BID. Titration steps include: 10 mg BID, 20 mg BID, 40 mg BID, 60 mg BID, 80 mg BID, 100 mg BID and 120 mg BID,140 mg BID, 160 mg BID, 180 MG BID, 200 mg BID | Drug: PF-06882961<br>* PF-68882961 will be provided as tablets twice a day (BID)<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) by Severity | An AE was any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAEs were events between first dose of study drug and up to follow-up visit that were absent before treatment or that worsened after treatment. AEs presented below were TEAEs. The investigator was required to use clinical judgment to assess the potential relationship between investigational product and each AE, to define an treatment-related AE. Assessments of AE intensity were defined as mild (easily tolerated, causing minimal discomfort and not interfering with daily activities), moderate (causing sufficient discomfort and interferes with normal daily activities) and severe (preventing normal daily activities). | Baseline through follow-up (Day 112) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Laboratory Abnormalities (Without Regard to Baseline Abnormality) | Safety laboratory assessments included clinical chemistry, hematology, urinalysis, and other tests. Abnormality was determined at the investigator's discretion. | Baseline through Visit 10 (Day 91) | 
| Number of Participants With Vital Signs Meeting the Pre-defined Categorical Summarization Criteria | Vital signs abnormality 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 >=30 mmHg; 5) change from baseline (increase or decrease) in supine DBP >=20 mmHg. | Baseline through Visit 10 (Day 91) | 
| Number of Participants With Electrocardiogram (ECG) Data Meeting the Pre-defined Categorical Summarization Criteria | ECG assessments included pulse rate (PR), QT, heart rate, QTcF intervals and QRS complex. ECG abnormalities criteria included: PR interval value >= 300 msec, or baseline (BL) >200 msec and >=25% increase from BL, or BL <=200 msec and >=50% increase from BL; QRS interval value >= 140msec, or >=50% increase from BL; QTcF value >450 and <=480 msec, or >480 and <=500 msec, or >500 msec, or increase from BL>30 and <=60 msec, or >60msec. | Baseline through Visit 10 (Day 91) | 
| Number of Participants With Categorical Scores on the Columbia Suicide Severity Rating Scale (C-SSRS) | The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and suicidal behavior. Participants who responded yes to the questions will be counted. Data relevant to the assessment of suicidality were mapped to the Columbia-Classification Algorithm of Suicide Assessment (C-CASA) codes. | Week 0, 2, 4, 6, 8, 10, 12, 13-14 | 
| Number of Participants With Response to Patient Health Questionnaire-9 (PHQ-9) | The PHQ-9 is a 9 item self-report scale for the assessment of depressive symptoms. The PHQ-9 were completed by participants and reviewed by site staff at the pre-defined time points. | Week 0, 2, 4, 6, 8, 10, 12, 13-14. | 
| Change From Baseline (CFB) in Fasting Plasma Glucose at Week 2 | Baseline was defined as the result closest prior to dosing at Day1. The MMRM model included treatment, time, strata (male versus female) and treatment-by-time interaction as fixed effects, baseline as a covariate and the baseline-by-time interaction with time fitted as a repeated effect and participant as a random effect. An unstructured covariance matrix was used to estimate the variances and covariance within participant across time points. | Baseline, Week 2 | 
| CFB in Fasting Plasma Glucose at Week 4 | Baseline was defined as the result closest prior to dosing at Day1. The MMRM model included treatment, time, strata (male versus female) and treatment-by-time interaction as fixed effects, baseline as a covariate and the baseline-by-time interaction with time fitted as a repeated effect and participant as a random effect. An unstructured covariance matrix was used to estimate the variances and covariance within participant across time points. | Baseline, Week 4 | 
| CFB in Fasting Plasma Glucose at Week 6 | Baseline was defined as the result closest prior to dosing at Day1. The MMRM model included treatment, time, strata (male versus female) and treatment-by-time interaction as fixed effects, baseline as a covariate and the baseline-by-time interaction with time fitted as a repeated effect and participant as a random effect. An unstructured covariance matrix was used to estimate the variances and covariance within participant across time points. | Baseline, Week 6 | 
| CFB in Fasting Plasma Glucose at Week 8 | Baseline was defined as the result closest prior to dosing at Day1. The MMRM model included treatment, time, strata (male versus female) and treatment-by-time interaction as fixed effects, baseline as a covariate and the baseline-by-time interaction with time fitted as a repeated effect and participant as a random effect. An unstructured covariance matrix was used to estimate the variances and covariance within participant across time points. | Baseline, Week 8 | 
| CFB in Fasting Plasma Glucose at Week 10 | Baseline was defined as the result closest prior to dosing at Day1. The MMRM model included treatment, time, strata (male versus female) and treatment-by-time interaction as fixed effects, baseline as a covariate and the baseline-by-time interaction with time fitted as a repeated effect and participant as a random effect. An unstructured covariance matrix was used to estimate the variances and covariance within participant across time points. | Baseline, Week 10 | 
| CFB in Fasting Plasma Glucose at Week 12 | Baseline was defined as the result closest prior to dosing at Day1. The MMRM model included treatment, time, strata (male versus female) and treatment-by-time interaction as fixed effects, baseline as a covariate and the baseline-by-time interaction with time fitted as a repeated effect and participant as a random effect. An unstructured covariance matrix was used to estimate the variances and covariance within participant across time points. | Baseline, Week 12 | 
| CFB in Glycolated Hemoglobin A1c (HbA1c) at Week 2 | Baseline was defined as the result closest prior to dosing at Day1. The MMRM model included treatment, time, strata (male versus female) and treatment-by-time interaction as fixed effects, baseline as a covariate and the baseline-by-time interaction with time fitted as a repeated effect and participant as a random effect. An unstructured covariance matrix was used to estimate the variances and covariance within participant across time points. | Baseline, Week 2 | 
| CFB in Glycolated HbA1c at Week 4 | Baseline was defined as the result closest prior to dosing at Day1. The MMRM model included treatment, time, strata (male versus female) and treatment-by-time interaction as fixed effects, baseline as a covariate and the baseline-by-time interaction with time fitted as a repeated effect and participant as a random effect. An unstructured covariance matrix was used to estimate the variances and covariance within participant across time points. | Baseline, Week 4 | 
| CFB in Glycolated HbA1c at Week 6 | Baseline was defined as the result closest prior to dosing at Day1. The MMRM model included treatment, time, strata (male versus female) and treatment-by-time interaction as fixed effects, baseline as a covariate and the baseline-by-time interaction with time fitted as a repeated effect and participant as a random effect. An unstructured covariance matrix was used to estimate the variances and covariance within participant across time points. | Baseline, Week 6 | 
| CFB in Glycolated HbA1c at Week 8 | Baseline was defined as the result closest prior to dosing at Day1. The MMRM model included treatment, time, strata (male versus female) and treatment-by-time interaction as fixed effects, baseline as a covariate and the baseline-by-time interaction with time fitted as a repeated effect and participant as a random effect. An unstructured covariance matrix was used to estimate the variances and covariance within participant across time points. | Baseline, Week 8 | 
| CFB in Glycolated HbA1c at Week 10 | Baseline was defined as the result closest prior to dosing at Day1. The MMRM model included treatment, time, strata (male versus female) and treatment-by-time interaction as fixed effects, baseline as a covariate and the baseline-by-time interaction with time fitted as a repeated effect and participant as a random effect. An unstructured covariance matrix was used to estimate the variances and covariance within participant across time points. | Baseline, Week 10 | 
| CFB in Glycolated HbA1c at Week 12 | Baseline was defined as the result closest prior to dosing at Day1. The MMRM model included treatment, time, strata (male versus female) and treatment-by-time interaction as fixed effects, baseline as a covariate and the baseline-by-time interaction with time fitted as a repeated effect and participant as a random effect. An unstructured covariance matrix was used to estimate the variances and covariance within participant across time points. | Baseline, Week 12 | 
| CFB in Body Weight at Week 2 (Participants With T2DM) | Baseline was defined as the average of a duplicate measurement closest prior to dosing at Day 1. The MMRM model included treatment, time, strata (male versus female) and treatment-by-time interaction as fixed effects, baseline as a covariate and the baseline-by-time interaction with time fitted as a repeated effect and participant as a random effect. An unstructured covariance matrix was used to estimate the variances and covariance within participant across time points. Average of the duplicate measurements (where applicable) was used in analyses. | Baseline, Week 2 | 
| CFB in Body Weight at Week 4 (Participants With T2DM) | Baseline was defined as the average of a duplicate measurement closest prior to dosing at Day 1. The MMRM model included treatment, time, strata (male versus female) and treatment-by-time interaction as fixed effects, baseline as a covariate and the baseline-by-time interaction with time fitted as a repeated effect and participant as a random effect. An unstructured covariance matrix was used to estimate the variances and covariance within participant across time points. Average of the duplicate measurements (where applicable) was used in analyses. | Baseline, Week 4 | 
| CFB in Body Weight at Week 6 (Participants With T2DM) | Baseline was defined as the average of a duplicate measurement closest prior to dosing at Day 1. The MMRM model included treatment, time, strata (male versus female) and treatment-by-time interaction as fixed effects, baseline as a covariate and the baseline-by-time interaction with time fitted as a repeated effect and participant as a random effect. An unstructured covariance matrix was used to estimate the variances and covariance within participant across time points. Average of the duplicate measurements (where applicable) was used in analyses. | Baseline, Week 6 | 
| CFB in Body Weight at Week 8 (Participants With T2DM) | Baseline was defined as the average of a duplicate measurement closest prior to dosing at Day 1. The MMRM model included treatment, time, strata (male versus female) and treatment-by-time interaction as fixed effects, baseline as a covariate and the baseline-by-time interaction with time fitted as a repeated effect and participant as a random effect. An unstructured covariance matrix was used to estimate the variances and covariance within participant across time points. Average of the duplicate measurements (where applicable) was used in analyses. | Baseline, Week 8 | 
| CFB in Body Weight at Week 10 (Participants With T2DM) | Baseline was defined as the average of a duplicate measurement closest prior to dosing at Day 1. The MMRM model included treatment, time, strata (male versus female) and treatment-by-time interaction as fixed effects, baseline as a covariate and the baseline-by-time interaction with time fitted as a repeated effect and participant as a random effect. An unstructured covariance matrix was used to estimate the variances and covariance within participant across time points. Average of the duplicate measurements (where applicable) was used in analyses. | Baseline, Week 10 | 
| CFB in Body Weight at Week 12 (Participants With T2DM) | Baseline was defined as the average of a duplicate measurement closest prior to dosing at Day 1. The MMRM model included treatment, time, strata (male versus female) and treatment-by-time interaction as fixed effects, baseline as a covariate and the baseline-by-time interaction with time fitted as a repeated effect and participant as a random effect. An unstructured covariance matrix was used to estimate the variances and covariance within participant across time points. Average of the duplicate measurements (where applicable) was used in analyses. | Baseline, Week 12 | 
| CFB in Body Weight at Week 2 (Non-diabetic Participants With Obesity) | Body weight were measured in duplicate as indicated. The second weight measurement were obtained at least 1-2 minutes apart from the first weight measurement. Weight were recorded using a calibrated scale (with the same scale used if possible for the duration of the study) reporting weight in kilograms (kg), and accuracy to the nearest 0.1 kg; ie, the device distinguished a difference between 68.4 kg vs 68.3 kg. The scale was placed on a stable, flat surface. Weight measurement was taken under the following conditions: participant is in a fasted state; after void of urine; after removal of shoes, bulky layers of clothing and jackets so that only light clothing remained; while remaining was during the measurement. | Baseline, Week 2 | 
| CFB in Body Weight at Week 4 (Non-diabetic Participants With Obesity) | Body weight were measured in duplicate as indicated. The second weight measurement were obtained at least 1-2 minutes apart from the first weight measurement. Weight were recorded using a calibrated scale (with the same scale used if possible for the duration of the study) reporting weight in kilograms (kg), and accuracy to the nearest 0.1 kg; ie, the device distinguished a difference between 68.4 kg vs 68.3 kg. The scale was placed on a stable, flat surface. Weight measurement was taken under the following conditions: participant is in a fasted state; after void of urine; after removal of shoes, bulky layers of clothing and jackets so that only light clothing remained; while remaining was during the measurement. | Baseline, Week 4 | 
| CFB in Body Weight at Week 6 (Non-diabetic Participants With Obesity) | Body weight were measured in duplicate as indicated. The second weight measurement were obtained at least 1-2 minutes apart from the first weight measurement. Weight were recorded using a calibrated scale (with the same scale used if possible for the duration of the study) reporting weight in kilograms (kg), and accuracy to the nearest 0.1 kg; ie, the device distinguished a difference between 68.4 kg vs 68.3 kg. The scale was placed on a stable, flat surface. Weight measurement was taken under the following conditions: participant is in a fasted state; after void of urine; after removal of shoes, bulky layers of clothing and jackets so that only light clothing remained; while remaining was during the measurement. | Baseline, Week 6 | 
| CFB in Body Weight at Week 8 (Non-diabetic Participants With Obesity) | Body weight were measured in duplicate as indicated. The second weight measurement were obtained at least 1-2 minutes apart from the first weight measurement. Weight were recorded using a calibrated scale (with the same scale used if possible for the duration of the study) reporting weight in kilograms (kg), and accuracy to the nearest 0.1 kg; ie, the device distinguished a difference between 68.4 kg vs 68.3 kg. The scale was placed on a stable, flat surface. Weight measurement was taken under the following conditions: participant is in a fasted state; after void of urine; after removal of shoes, bulky layers of clothing and jackets so that only light clothing remained; while remaining was during the measurement. | Baseline, Week 8 | 
| CFB in Body Weight at Week 10 (Non-diabetic Participants With Obesity) | Body weight were measured in duplicate as indicated. The second weight measurement were obtained at least 1-2 minutes apart from the first weight measurement. Weight were recorded using a calibrated scale (with the same scale used if possible for the duration of the study) reporting weight in kilograms (kg), and accuracy to the nearest 0.1 kg; ie, the device distinguished a difference between 68.4 kg vs 68.3 kg. The scale was placed on a stable, flat surface. Weight measurement was taken under the following conditions: participant is in a fasted state; after void of urine; after removal of shoes, bulky layers of clothing and jackets so that only light clothing remained; while remaining was during the measurement. | Baseline, Week 10 | 
| CFB in Body Weight at Week 12 (Non-diabetic Participants With Obesity) | Body weight were measured in duplicate as indicated. The second weight measurement were obtained at least 1-2 minutes apart from the first weight measurement. Weight were recorded using a calibrated scale (with the same scale used if possible for the duration of the study) reporting weight in kilograms (kg), and accuracy to the nearest 0.1 kg; ie, the device distinguished a difference between 68.4 kg vs 68.3 kg. The scale was placed on a stable, flat surface. Weight measurement was taken under the following conditions: participant is in a fasted state; after void of urine; after removal of shoes, bulky layers of clothing and jackets so that only light clothing remained; while remaining was during the measurement. | Baseline, Week 12 |