A Phase 1 Single/Multiple Dose Study Of PF-06293620 To Assess Safety, Tolerability And Pharmacokinetics In Subjects With Type 2 Diabetes Mellitus
- Conditions
- Type 2 Diabetes Mellitus
- Interventions
- Biological: PF-06293620Biological: Placebo
- Registration Number
- NCT02211261
- Lead Sponsor
- Pfizer
- Brief Summary
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
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 84
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort 6-PF-06293620 or placebo PF-06293620 Multiple Ascending Dose PF-06293620 or placebo Cohort 1-PF-06293620 or placebo PF-06293620 Single Ascending Dose PF-06293620 or placebo Cohort 4-PF-06293620 or placebo PF-06293620 Single Ascending Dose PF-06293620 or placebo Cohort 1-PF-06293620 or placebo Placebo Single Ascending Dose PF-06293620 or placebo Cohort 3-PF-06293620 or placebo Placebo Single Ascending Dose PF-06293620 or placebo Cohort 5-PF-06293620 or placebo Placebo Single Ascending Dose PF-06293620 or placebo Cohort 3-PF-06293620 or placebo PF-06293620 Single Ascending Dose PF-06293620 or placebo Cohort 5-PF-06293620 or placebo PF-06293620 Single Ascending Dose PF-06293620 or placebo Cohort 4-PF-06293620 or placebo Placebo Single Ascending Dose PF-06293620 or placebo Cohort 7 PF-06293620 or placebo PF-06293620 Multiple Ascending Dose PF-06293620 or placebo Cohort 7 PF-06293620 or placebo Placebo Multiple Ascending Dose PF-06293620 or placebo Cohort 8-PF-06293620 or placebo PF-06293620 Multiple Ascending Dose PF-06293620 or placebo Cohort 9-PF-06293620 or placebo PF-06293620 Multiple Ascending Dose PF-06293620 or placebo Cohort 2-PF-06293620 or placebo PF-06293620 Single Ascending Dose PF-06293620 or placebo Cohort 2-PF-06293620 or placebo Placebo Single Ascending Dose PF-06293620 or placebo Cohort 6-PF-06293620 or placebo Placebo Multiple Ascending Dose PF-06293620 or placebo Cohort 8-PF-06293620 or placebo Placebo Multiple Ascending Dose PF-06293620 or placebo Cohort 9-PF-06293620 or placebo Placebo Multiple Ascending Dose PF-06293620 or placebo
- Primary Outcome Measures
Name Time Method Number of Participants With All-Causality and Treatment Related Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events 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. 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.
Number of Participants With Dose Limiting or Intolerable Adverse Events Days 1 to 85 for SAD cohorts; Days 1 to 169 for MAD Cohorts 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.
Number of Participants With Positive Anti-drug Antibody (ADA) Result Days 1 to 85 for SAD cohorts; Days 1 to 169 for MAD Cohorts 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.
- Secondary Outcome Measures
Name Time Method Area Under the Serum Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of PF-06293620 (SAD Cohorts) 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 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.
Apparent Volume of Distribution (Vz/F) of PF-06293620 (SAD Cohorts) 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 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.
Time for Maximum Serum Concentration (Tmax) 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 Time for maximum serum concentration (Tmax) of PF-06293620 was observed directly from data as time of first occurrence.
Clearance (CL) of PF-06293620 (SAD Cohorts) 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) 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.
Time for Maximum Serum Concentration (Tmax) of PF-06293620 (SAD Cohorts) 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 was observed directly from data as time of first occurrence.
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 Apparent Volume of Distribution (Vz/F) 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 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.
Dose-normalized AUCinf (AUCinf(dn)) of PF-06293620 (SAD Cohorts) 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 AUCinf(dn) was calculated as AUCinf/dose, where AUCinf is area under the serum concentration-time profile from time 0 extrapolated to infinite time.
Steady-state Volume of Distribution (Vss) of PF-06293620 (SAD Cohorts) 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 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.
Average Concentration (Cav) 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 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).
Terminal Elimination Half-life (Thalf) 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 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.
Area Under the Serum Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of PF-06293620 (SAD Cohorts) 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 was determined using linear/log trapezoidal method.
Dose-normalized AUClast (AUClast(dn)) of PF-06293620 (SAD Cohorts) 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 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.
Apparent Clearance (CL/F) of PF-06293620 (SAD Cohorts) 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 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.
Maximum Serum Concentration (Cmax) of PF-06293620 (SAD Cohorts) 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 was observed directly from data.
Apparent Clearance (CL/F) 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 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).
Observed Accumulation Ratio Based on Cmax (Rac,Cmax) of PF-06293620 (MAD Cohorts) 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 was calculated as Cmax(Day57)/Cmax(Day1).
Terminal Elimination Half-life (Thalf) of PF-06293620 (SAD Cohorts) 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 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.
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 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 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.
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 Observed Accumulation Ratio Based on AUC (Rac) of PF-06293620 (MAD Cohorts) 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 AUC (Rac) of PF-06293620 was calculated as AUCtau(Day57)/AUCtau(Day1).
Trial Locations
- Locations (7)
Avail Clinical Research, LLC
🇺🇸DeLand, Florida, United States
Profil Institute for Clinical Research, Inc.
🇺🇸Chula Vista, California, United States
Profil Institute for Clinical Research, Incorporated
🇺🇸Chula Vista, California, United States
Orlando Clinical Research Center
🇺🇸Orlando, Florida, United States
Qps-Mra Llc
🇺🇸South Miami, Florida, United States
Qps Mra, Llc
🇺🇸South Miami, Florida, United States
High Point Clinical Trials Center, LLC
🇺🇸High Point, North Carolina, United States