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

Type 2 Diabetes Mellitus Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02211261
• Other study ID #: B3501001
• Status: Completed
• Phase: Phase 1
• Start date: September 15, 2014
• Est. completion date: January 27, 2017

Study information

• Verified date: October 2018
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 84
• Est. completion date: January 27, 2017
• Est. primary completion date: January 27, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Type 2 Diabetes Mellitus

Intervention

Biological:
• PF-06293620
subcutaneous, single dose 0.3 mg/kg
• Placebo
Subcutaneous normal saline single dose
• PF-06293620
Subcutaneous, single dose 1.0 mg/kg
• Placebo
Subcutaneous normal saline single dose
• PF-06293620
Subcutaneous single dose 3 mg/kg
• Placebo
Subcutaneous normal saline single dose
• PF-06293620
Subcutaneous single dose 6 mg/kg
• Placebo
Subcutaneous normal saline single dose
• PF-06293620
Intravenous infusion single dose 1 mg/kg
• Placebo
Intravenous infusion normal saline single dose
• PF-06293620
Subcutaneous injection multiple dose 75 mg (Days 1, 29 and 57)
• Placebo
Subcutaneous injection normal saline multiple dose (Days 1, 29 and 57)
• PF-06293620
Subcutaneous injection multiple dose 150 mg (Days 1, 29 and 57)
• Placebo
Subcutaneous injection normal saline multiple dose (Days 1, 29 and 57)
• PF-06293620
Subcutaneous injection multiple dose 250 mg (Days 1, 29 and 57)
• Placebo
Subcutaneous injection normal saline multiple dose (Days 1, 29 and 57)
• PF-06293620
Subcutaneous injection multiple dose TBD mg (Days TBD)
• Placebo
Subcutaneous injection normal saline multiple dose (Days TBD)

Locations

Country	Name	City	State
United States	Profil Institute for Clinical Research, Inc.	Chula Vista	California
United States	Profil Institute for Clinical Research, Incorporated	Chula Vista	California
United States	Avail Clinical Research, LLC	DeLand	Florida
United States	High Point Clinical Trials Center, LLC	High Point	North Carolina
United States	Orlando Clinical Research Center	Orlando	Florida
United States	Qps Mra, Llc	South Miami	Florida
United States	Qps-Mra Llc	South Miami	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

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