A Phase 1 Single/Multiple Dose Study Of PF-06293620 To Assess Safety, Tolerability And Pharmacokinetics In Subjects With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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A first in human study to determine the safety, tolerability and pharmacokinetics of single and multiple ascending doses of PF-06293620 in subjects with Type 2 Diabetes Mellitus

Official Title
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A Phase 1 Double-blind, Placebo-controlled, Randomized, Single- And Multiple-ascending Dose Study To Assess The Safety, Tolerability, And Pharmacokinetics Of Pf-06293620 In Subjects With Type 2 Diabetes Mellitus

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Biological: PF-06293620
* Biological: Placebo
* Biological: PF-06293620
* Biological: Placebo
* Biological: PF-06293620
* Biological: Placebo
* Biological: PF-06293620
* Biological: Placebo
* Biological: PF-06293620
* Biological: Placebo
* Biological: PF-06293620
* Biological: Placebo
* Biological: PF-06293620
* Biological: Placebo
* Biological: PF-06293620
* Biological: Placebo
* Biological: PF-06293620
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women of non-childbearing potential with Type 2 Diabetes Mellitus Subjects on stable doses of metformin >/= 1500 mg daily (SAD cohorts) or >/= 1000 mg daily (MAD cohorts) x 30 days prior to screening HbA1c 7-10% (SAD Cohorts) or 6.5-10% (MAD cohorts) inclusive at screening Fasting C-peptide >1.12 ng/mL (SAD cohorts) or >/= 0.8 mg/mL (MAD cohorts) at screening Exclusion Criteria: History of Type 1 diabetes mellitus Evidence of diabetic complications with significant end-organ damage History of chronic pancreatitis or at high risk for pancreatitis Poorly controlled hypertension History of cardiovascular or cerebrovascular event or procedure

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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1-PF-06293620 or placebo<br>Single Ascending Dose PF-06293620 or placebo | Biological: PF-06293620<br>* subcutaneous, single dose 0.3 mg/kg<br>Biological: Placebo<br>* Subcutaneous normal saline single dose<br>|
| Experimental: Cohort 2-PF-06293620 or placebo<br>Single Ascending Dose PF-06293620 or placebo | Biological: PF-06293620<br>* Subcutaneous, single dose 1.0 mg/kg<br>Biological: Placebo<br>* Subcutaneous normal saline single dose<br>|
| Experimental: Cohort 3-PF-06293620 or placebo<br>Single Ascending Dose PF-06293620 or placebo | Biological: PF-06293620<br>* Subcutaneous single dose 3 mg/kg<br>Biological: Placebo<br>* Subcutaneous normal saline single dose<br>|
| Experimental: Cohort 4-PF-06293620 or placebo<br>Single Ascending Dose PF-06293620 or placebo | Biological: PF-06293620<br>* Subcutaneous single dose 6 mg/kg<br>Biological: Placebo<br>* Subcutaneous normal saline single dose<br>|
| Experimental: Cohort 5-PF-06293620 or placebo<br>Single Ascending Dose PF-06293620 or placebo | Biological: PF-06293620<br>* Intravenous infusion single dose 1 mg/kg<br>Biological: Placebo<br>* Intravenous infusion normal saline single dose<br>|
| Experimental: Cohort 6-PF-06293620 or placebo<br>Multiple Ascending Dose PF-06293620 or placebo | Biological: PF-06293620<br>* Subcutaneous injection multiple dose 75 mg (Days 1, 29 and 57)<br>Biological: Placebo<br>* Subcutaneous injection normal saline multiple dose (Days 1, 29 and 57)<br>|
| Experimental: Cohort 7 PF-06293620 or placebo<br>Multiple Ascending Dose PF-06293620 or placebo | Biological: PF-06293620<br>* Subcutaneous injection multiple dose 150 mg (Days 1, 29 and 57)<br>Biological: Placebo<br>* Subcutaneous injection normal saline multiple dose (Days 1, 29 and 57)<br>|
| Experimental: Cohort 8-PF-06293620 or placebo<br>Multiple Ascending Dose PF-06293620 or placebo | Biological: PF-06293620<br>* Subcutaneous injection multiple dose 250 mg (Days 1, 29 and 57)<br>Biological: Placebo<br>* Subcutaneous injection normal saline multiple dose (Days 1, 29 and 57)<br>|
| Experimental: Cohort 9-PF-06293620 or placebo<br>Multiple Ascending Dose PF-06293620 or placebo | Biological: PF-06293620<br>* Subcutaneous injection multiple dose TBD mg (Days TBD)<br>Biological: Placebo<br>* Subcutaneous injection normal saline multiple dose (Days TBD)<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 (AEs) or Serious Adverse Events | An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device, regardless of its causal relationship with study treatment. 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; was life-threatening (immediate risk of death); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs are events between first dose of study drug and up to Day 85 (for SAD cohorts) or Day 169 (for MAD cohorts) that were absent before treatment or that worsened after treatment. AEs included both serious and non-serious AEs. Causality with the study treatment was determined by the investigator. | Days 1 to 85 for SAD cohorts and Days 1 to 169 for MAD cohorts; participants with positive anti-drug antibody (ADA) results were followed up to stabilization of ADA titers or up to 9 months after Day 169 visit. | 
| Number of Participants With Dose Limiting or Intolerable Adverse Events | Dose limiting or intolerable AEs were originally planned to be collected. However, this outcome measure was not actually summarized, since collection and monitoring of treatment-emergent AEs was performed during the study, and deemed sufficient to ensure the participants safety. | Days 1 to 85 for SAD cohorts; Days 1 to 169 for MAD Cohorts | 
| Number of Participants With Positive Anti-drug Antibody (ADA) Result | ADA against PF-06293620 in human serum samples was determined following a tiered approach using screening, confirmation, and titer/quantification by semi-quantitative enzyme linked immunosorbent assay (ELISA). Endpoint titer >=1.88 was considered positive. | Days 1 to 85 for SAD cohorts; Days 1 to 169 for MAD Cohorts | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Serum Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of PF-06293620 (SAD Cohorts) | AUCinf was calculated as AUClast +(Clast*/kel), where AUClast is area under the serum concentration-time profile from time 0 to the time of the last quantifiable concentration, Clast* is the predicted serum concentration at the last quantifiable time point estimated from the log-linear regression analysis, kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression. | Pre-dose, 1, 4, 8 and 12 hours post-dose on Day 1; 24 and 36 hours post-dose on Day 2; Days 3, 4, 5, 8, 15, 22, 29, 43, 57, 85 | 
| Dose-normalized AUCinf (AUCinf(dn)) of PF-06293620 (SAD Cohorts) | AUCinf(dn) was calculated as AUCinf/dose, where AUCinf is area under the serum concentration-time profile from time 0 extrapolated to infinite time. | Pre-dose, 1, 4, 8 and 12 hours post-dose on Day 1; 24 and 36 hours post-dose on Day 2; Days 3, 4, 5, 8, 15, 22, 29, 43, 57, 85 | 
| Area Under the Serum Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of PF-06293620 (SAD Cohorts) | Area under the serum concentration-time profile from time 0 to the time of the last quantifiable concentration (AUClast) of PF-06293620 was determined using linear/log trapezoidal method. | Pre-dose, 1, 4, 8 and 12 hours post-dose on Day 1; 24 and 36 hours post-dose on Day 2; Days 3, 4, 5, 8, 15, 22, 29, 43, 57, 85 | 
| Dose-normalized AUClast (AUClast(dn)) of PF-06293620 (SAD Cohorts) | AUClast(dn) of PF-06293620 was calculated as AUClast/dose, where AUClast was area under the serum concentration-time profile from time 0 to the time of the last quantifiable concentration. | Pre-dose, 1, 4, 8 and 12 hours post-dose on Day 1; 24 and 36 hours post-dose on Day 2; Days 3, 4, 5, 8, 15, 22, 29, 43, 57, 85 | 
| Clearance (CL) of PF-06293620 (SAD Cohorts) | Clearance (CL) was calculated as dose/AUCinf, where AUCinf was area under the serum concentration-time profile from time 0 extrapolated to infinite time. This outcome measure only applies to IV arms. | Pre-dose, 1, 4, 8 and 12 hours post-dose on Day 1; 24 and 36 hours post-dose on Day 2; Days 3, 4, 5, 8, 15, 22, 29, 43, 57, 85 | 
| Apparent Clearance (CL/F) of PF-06293620 (SAD Cohorts) | Apparent Clearance (CL/F) of PF-06293620 was calculated as dose/AUCinf, where AUCinf was area under the serum concentration-time profile from time 0 extrapolated to infinite time. This outcome measure only applies to SC arms. | Pre-dose, 1, 4, 8 and 12 hours post-dose on Day 1; 24 and 36 hours post-dose on Day 2; Days 3, 4, 5, 8, 15, 22, 29, 43, 57, 85 | 
| Maximum Serum Concentration (Cmax) of PF-06293620 (SAD Cohorts) | Maximum serum concentration (Cmax) of PF-06293620 was observed directly from data. | Pre-dose, 1, 4, 8 and 12 hours post-dose on Day 1; 24 and 36 hours post-dose on Day 2; Days 3, 4, 5, 8, 15, 22, 29, 43, 57, 85 | 
| Time for Maximum Serum Concentration (Tmax) of PF-06293620 (SAD Cohorts) | Time for Maximum serum concentration (Tmax) of PF-06293620 was observed directly from data as time of first occurrence. | Pre-dose, 1, 4, 8 and 12 hours post-dose on Day 1; 24 and 36 hours post-dose on Day 2; Days 3, 4, 5, 8, 15, 22, 29, 43, 57, 85 | 
| Steady-state Volume of Distribution (Vss) of PF-06293620 (SAD Cohorts) | Steady-state volume of distribution (Vss) of PF-06293620 was calculated as CL*MRT, where MRT was the mean residence time calculated as (AUMCinf/AUCinf - infusion duration/2), AUMCinf was area under the moment curve from time 0 extrapolated to infinity; CL was the clearance. This outcome measure only applies to IV arms. | Pre-dose, 1, 4, 8 and 12 hours post-dose on Day 1; 24 and 36 hours post-dose on Day 2; Days 3, 4, 5, 8, 15, 22, 29, 43, 57, 85 | 
| Apparent Volume of Distribution (Vz/F) of PF-06293620 (SAD Cohorts) | Apparent Volume of Distribution (Vz/F) of PF-06293620 was calculated as dose/(AUCinf*kel), where AUCinf was area under the serum concentration-time profile from time 0 extrapolated to infinite time, kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. This outcome measure only applies to SC arms. | Pre-dose, 1, 4, 8 and 12 hours post-dose on Day 1; 24 and 36 hours post-dose on Day 2; Days 3, 4, 5, 8, 15, 22, 29, 43, 57, 85 | 
| Terminal Elimination Half-life (Thalf) of PF-06293620 (SAD Cohorts) | Terminal elimination half-life (Thalf) of PF-06293620 was calculated as ln(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression. | Pre-dose, 1, 4, 8 and 12 hours post-dose on Day 1; 24 and 36 hours post-dose on Day 2; Days 3, 4, 5, 8, 15, 22, 29, 43, 57, 85 | 
| Area Under the Concentration-Time Profile From Time 0 to Time Tau (AUCtau) of PF-06293620 (MAD Cohorts) After Day 1 and Day 57 Administration | Tau refers to the dosing interval, which was 4 weeks (672 hours). Area under the concentration-time profile from time 0 to time tau (AUCtau) was determined using linear/log trapezoidal method. | Pre-dose, 1 and 4 hours post-dose on Day 1; Days 2, 3, 7, 8, 15, 27, 28; pre-dose, 1 and 4 hours post-dose on Day 29; Days 36, 43; pre-dose, 1 and 4 hours post-dose on Day 57; Days 58, 59, 63, 64, 71, 78, 84, 85, 99, 113, 141, 169 | 
| Maximum Serum Concentration (Cmax) of PF-06293620 (MAD Cohorts) After Day 1 and Day 57 Administration |  | Pre-dose, 1 and 4 hours post-dose on Day 1; Days 2, 3, 7, 8, 15, 27, 28; pre-dose, 1 and 4 hours post-dose on Day 29; Days 36, 43; pre-dose, 1 and 4 hours post-dose on Day 57; Days 58, 59, 63, 64, 71, 78, 84, 85, 99, 113, 141, 169 | 
| Average Concentration (Cav) of PF-06293620 (MAD Cohorts) After Day 1 and Day 57 Administration | Average Concentration (Cav) of PF-06293620 was calculated as AUCtau/tau, where AUCtau was area under the concentration-time profile from time 0 to time tau, and tau was the dosing interval, 4 weeks (672 hours). | Pre-dose, 1 and 4 hours post-dose on Day 1; Days 2, 3, 7, 8, 15, 27, 28; pre-dose, 1 and 4 hours post-dose on Day 29; Days 36, 43; pre-dose, 1 and 4 hours post-dose on Day 57; Days 58, 59, 63, 64, 71, 78, 84, 85, 99, 113, 141, 169 | 
| Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-06293620 (MAD Cohorts) After Day 57 Administration |  | Pre-dose, 1 and 4 hours post-dose on Day 57; Days 58, 59, 63, 64, 71, 78, 84, 85, 99, 113, 141, 169 | 
| Time for Maximum Serum Concentration (Tmax) of PF-06293620 (MAD Cohorts) After Day 1 and Day 57 Administration | Time for maximum serum concentration (Tmax) of PF-06293620 was observed directly from data as time of first occurrence. | Pre-dose, 1 and 4 hours post-dose on Day 1; Days 2, 3, 7, 8, 15, 27, 28; pre-dose, 1 and 4 hours post-dose on Day 29; Days 36, 43; pre-dose, 1 and 4 hours post-dose on Day 57; Days 58, 59, 63, 64, 71, 78, 84, 85, 99, 113, 141, 169 | 
| Apparent Clearance (CL/F) of PF-06293620 (MAD Cohorts) After Day 57 Administration | Apparent clearance (CL/F) of PF-06293620 was calculated as dose/AUCtau, where AUCtau was area under the concentration-time profile from time 0 to time tau, and tau was the dosing interval, 4 weeks (672 hours). | Pre-dose, 1 and 4 hours post-dose on Day 57; Days 58, 59, 63, 64, 71, 78, 84, 85, 99, 113, 141, 169 | 
| Apparent Volume of Distribution (Vz/F) of PF-06293620 (MAD Cohorts) After Day 57 Administration | Apparent volume of distribution (Vz/F) of PF-06293620 was calculated as dose/(AUCtau/kel), where AUCtau was area under the concentration-time profile from time 0 to time tau, and tau was the dosing interval, 4 weeks (672 hours); and kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression. | Pre-dose, 1 and 4 hours post-dose on Day 57; Days 58, 59, 63, 64, 71, 78, 84, 85, 99, 113, 141, 169 | 
| Terminal Elimination Half-life (Thalf) of PF-06293620 (MAD Cohorts) After Day 57 Administration | Terminal elimination half-life (Thalf) of PF-06293620 was calculated as ln(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression. | Pre-dose, 1 and 4 hours post-dose on Day 57; Days 58, 59, 63, 64, 71, 78, 84, 85, 99, 113, 141, 169 | 
| Observed Accumulation Ratio Based on AUC (Rac) of PF-06293620 (MAD Cohorts) | Observed accumulation ratio based on AUC (Rac) of PF-06293620 was calculated as AUCtau(Day57)/AUCtau(Day1). | Pre-dose, 1 and 4 hours post-dose on Day 1; Days 2, 3, 7, 8, 15, 27, 28; pre-dose, 1 and 4 hours post-dose on Day 29; Days 36, 43; pre-dose, 1 and 4 hours post-dose on Day 57; Days 58, 59, 63, 64, 71, 78, 84, 85, 99, 113, 141, 169 | 
| Observed Accumulation Ratio Based on Cmax (Rac,Cmax) of PF-06293620 (MAD Cohorts) | Observed accumulation ratio based on Cmax (Rac,Cmax) of PF-06293620 was calculated as Cmax(Day57)/Cmax(Day1). | Pre-dose, 1 and 4 hours post-dose on Day 1; Days 2, 3, 7, 8, 15, 27, 28; pre-dose, 1 and 4 hours post-dose on Day 29; Days 36, 43; pre-dose, 1 and 4 hours post-dose on Day 57; Days 58, 59, 63, 64, 71, 78, 84, 85, 99, 113, 141, 169 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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first in human, single dose, multiple dose, escalation, safety study, Type 2 Diabetes Mellitus