Multiple Dose Study Of PF-05231023 In Adult Subjects Who Have Poor Lipid Control With And Without Type 2 Diabetes Mellitus

A Phase 1, Placebo-controlled, Randomized Trial To Assess The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of Multiple Iv Doses Of Pf-05231023 In Obese Hyperlipidemic Adult Subjects With And Without Type 2 Diabetes Mellitus On A Background Of Atorvastatin

This is a trial in obese subjects who have poor lipid control with and without Type 2 diabetes mellitus to study the safety, tolerability and pharmacokinetics of multiple doses of PF-05231023

Study Overview

• Status: Completed
• Conditions: Diabetes Melliuts, Type 2
• Intervention / Treatment: Other: Placebo; Drug: 25 mg PF-05231023; Drug: 50 mg PF-05231023; Drug: 100 mg PF-05231023; Drug: 150 mg PF-05231023

• Study Type: Interventional
• Enrollment (Actual): 107
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Anaheim, California, United States, 92801
      • Anaheim Clinical Trials, LLC
    • Chula Vista, California, United States, 91911
      • Profil Institute for Clinical Research, Inc.
    • Walnut Creek, California, United States, 94598
      • Diablo Clinical Research, Inc.
  • Florida
    • DeLand, Florida, United States, 32720
      • Avail Clinical Research, LLC
    • Miami, Florida, United States, 33169
      • Elite Research Institute
    • South Miami, Florida, United States, 33143
      • MRA Clinical Research, LLC
    • South Miami, Florida, United States, 33143
      • Miami Research Associates, Inc.
  • Kentucky
    • Lexington, Kentucky, United States, 40509
      • Central Kentucky Research Associates, Inc.
    • Louisville, Kentucky, United States, 40213
      • L-MARC Research Center
  • Minnesota
    • Saint Paul, Minnesota, United States, 55114
      • Prism Research
  • North Carolina
    • High Point, North Carolina, United States, 27265
      • High Point Clinical Trials Center, LLC
    • Raleigh, North Carolina, United States, 27612
      • Carolina Phase 1 Research
    • Raleigh, North Carolina, United States, 27612
      • Wake Internal Medicine Consultants
  • Ohio
    • Cincinnati, Ohio, United States, 45255
      • Community Research
    • Cincinnati, Ohio, United States, 45227
      • Medpace Clinical Pharmacology Unit
    • Cincinnati, Ohio, United States, 45255
      • Mercy Hospital Pharmacy
  • Texas
    • Dallas, Texas, United States, 75247
      • Covance Clinical Research Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and female subjects of non-childbearing potential between the ages of 30 and 70 years with and without a diagnosis of Type 2 diabetes mellitus (according to the American Diabetes Association guidelines).
• Subjects with poor lipid control as confirmed by laboratory tests.
• BMI of 30 to 40 Kg/m2 and a total body weight of >50 kg (110 lbs).

Exclusion Criteria:

• Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding asymptomatic, seasonal allergies at time of dosing).
• Levels of blood enzymes indicating pancreatitis or elevated liver function enzymes outside of the laboratory's reference range as confirmed by laboratory tests.
• Subjects with Type 1 Diabetes Mellitus.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 50 mg	Drug: 50 mg PF-05231023; 50 mg IV once a week for 4 weeks
Experimental: 100 mg	Drug: 100 mg PF-05231023; 100 mg IV once a week for 4 weeks
Placebo Comparator: Placebo Arm	Other: Placebo; 0.9% w/v sodium chloride injection, United States Pharmacopeia (USP), once a week for 4 weeks
Experimental: 25 mg	Drug: 25 mg PF-05231023; 25 mg IV once a week for 4 weeks
Experimental: 150 mg	Drug: 150 mg PF-05231023; 150 mg IV once a week for 4 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent events were between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state.	Baseline up to 28 days after last dose
Number of Participants With Laboratory Abnormalities	Criteria for laboratory test abnormality: Hematology (hemoglobin, hematocrit, red blood corpuscles [RBC] count: less than [<]0.8*lower limit of normal [LLN], platelets: <0.5*LLN/greater than [>]1.75*upper limit of normal [ULN], leukocytes: <0.6*LLN or >1.5*ULN, lymphocytes, total neutrophils: <0.8*LLN or >1.2*ULN, basophils, eosinophil: <0.8*LLN, monocytes: >1.2*ULN); Liver Function (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase: >0.3*ULN, total protein, albumin: <0.8*LLN or >1.2*ULN); total bilirubin, direct bilirubin, indirect bilirubin: >1.5*ULN; Renal Function (blood urea nitrogen, creatinine: >1.3*ULN, uric acid: >1.2*ULN); Electrolytes (sodium: <0.95*LLN or >1.05*ULN, potassium, chloride, calcium, bicarbonate: <0.9*LLN or >1.1*ULN; creatine kinase: >2.0*ULN; glucose fasting: <0.6*LLN or >1.5*ULN, urine white blood corpuscles [WBC] and RBC: greater than or equal to (>=) 20/High Power Field [HPF]).	Baseline up to Day 49
Number of Participants With Clinically Significant Vital Sign Abnormalities	Criteria for clinically significant vital signs abnormalities included supine/sitting pulse rate of <40 beats per minute (bpm) or >120 bpm, supine systolic blood pressure (SBP) of <90 millimeter of mercury (mmHg), >=30 mmHg maximum increase and decrease from baseline in same posture, supine diastolic blood pressure (DBP) of <50 mmHg; >=20 mmHg maximum increase and decrease from baseline in same posture.	Baseline up to Day 49
Number of Participants With Clinically Significant Electrocardiogram Findings	Clinically significant ECG findings included PR interval >=300 milliseconds (msec) or >=25 percent (%) increase from baseline (if baseline PR interval >200 msec) or >=50% increase (if baseline PR interval less than or equal to [<=] 200 msec); QRS interval >=140 msec or >=50% increase from baseline; QT interval >=500 msec, corrected QT interval based on Fridericia's formula (QTcF) 450 to <480 msec, 480 to <500 msec, >=500 msec or >=30 msec but <60 msec increase from baseline or >=60 msec increase from baseline.	Baseline up to Day 49
Number of Participants With Abnormal Physical Examinations	Physical examination included general examination and examination of head, ears, eyes, nose, mouth, throat, neck, abdomen, skin, heart, lungs, lymph nodes, and gastrointestinal and musculoskeletal and neurological system.	Baseline up to Day 49
Thyroid Stimulating Hormone (TSH) Level at Baseline	Results are reported in micro international units per milliliter (mcIU/mL).	Baseline
Thyroid Stimulating Hormone (TSH) Level at Day 1		Day 1
Thyroid Stimulating Hormone (TSH) Level at Day 25		Day 25
Thyroid Stimulating Hormone (TSH) Level at Day 39		Day 39
Thyroid Stimulating Hormone (TSH) Level at Day 49		Day 49
Phosphate Level at Baseline		Baseline
Change From Baseline in Phosphate Level at Day 8		Baseline, Day 8
Change From Baseline in Phosphate Level at Day 15		Baseline, Day 15
Change From Baseline in Phosphate Level at Day 25		Baseline, Day 25
Change From Baseline in Phosphate Level at Day 49		Baseline, Day 49
Creatine Phosphokinase (CPK) Level at Baseline		Baseline
Change From Baseline in Creatine Phosphokinase (CPK) Level at Day 8		Baseline, Day 8
Change From Baseline in Creatine Phosphokinase (CPK) Level at Day 15		Baseline, Day 15
Change From Baseline in Creatine Phosphokinase (CPK) Level at Day 25		Baseline, Day 25
Change From Baseline in Creatine Phosphokinase (CPK) Level at Day 49		Baseline, Day 49
Serum N-terminal Propeptides of Type 1 Collagen (PINP) and C-Telopeptide Cross-Linking of Type 1 Collagen (CTX) Levels at Baseline		Baseline
Percent Change From Baseline in Serum N-terminal Propeptides of Type 1 Collagen (PINP) and C-Telopeptide Cross-Linking of Type 1 Collagen (CTX) Levels at Day 25		Baseline, Day 25
Percent Change From Baseline in Serum N-terminal Propeptides of Type 1 Collagen (PINP) and C-Telopeptide Cross-Linking of Type 1 Collagen (CTX) Levels at Day 39		Baseline, Day 39
Percent Change From Baseline Serum N-terminal Propeptides of Type 1 Collagen (PINP) and C-Telopeptide Cross-Linking of Type 1 Collagen (CTX) Levels at Day 49		Baseline, Day 49
Blood Osteocalcin and Bone-Specific Alkaline Phosphatase Levels at Baseline		Baseline
Percent Change From Baseline in Blood Osteocalcin and Bone-Specific Alkaline Phosphatase Levels at Day 25		Baseline, Day 25
Percent Change From Baseline in Blood Osteocalcin and Bone-Specific Alkaline Phosphatase Levels at Day 39		Baseline, Day 39
Percent Change From Baseline in Blood Osteocalcin and Bone-Specific Alkaline Phosphatase Levels at Day 49		Baseline, Day 49
Tartrate-resistant Acid Phosphatase Isoform 5b (TRAP 5b) Levels at Baseline		Baseline
Percent Change From Baseline in Tartrate-resistant Acid Phosphatase Isoform 5b (TRAP 5b) Levels at Day 25		Baseline, Day 25
Percent Change From Baseline in Tartrate-resistant Acid Phosphatase Isoform 5b (TRAP 5b) Levels at Day 39		Baseline, Day 39
Percent Change From Baseline in Tartrate-resistant Acid Phosphatase Isoform 5b (TRAP 5b) Levels at Day 49		Day 49
Average Urinary Calcium and Phosphate Levels Over 24 Hours at Baseline		Baseline
Change From Baseline in Average Urinary Calcium and Phosphate Levels Over 24 Hours at Day 24		Day 24
Number of Participants With Anti-PF-05231023 Antibodies and Neutralizing Antibodies at Day 1	Anti-PF-05231023 antibodies and neutralizing antibodies were analyzed only for participants who received PF-05231023 as per planned analysis. One sample at Day 1 was inadvertently tested for neutralizing antibody even though the corresponding anti-PF-05231023 antibody was negative.	Day 1
Number of Participants With Anti-PF-05231023 Antibodies and Neutralizing Antibodies at Day 39	Anti-PF-05231023 antibodies and neutralizing antibodies were analyzed only for participants who received PF-05231023 as per planned analysis. One sample at Day 39 was inadvertently tested for neutralizing antibody even though the corresponding anti-PF-05231023 antibody was negative.	Day 39
Number of Participants With Anti-PF-05231023 Antibodies and Neutralizing Antibodies at Day 49		Day 49

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 After Single Dose	AUCtau was calculated for the intact C-terminus and N-terminus PF-05231023 from the concentration-time data using standard non-compartmental method. Only participants who received PF-05231023 were to be analyzed for this outcome measure.	0 (pre-dose), 0.5 (end of infusion), 1, 2.5, 3.5, 5.5, 9.5, 11.5 hours after start of infusion on Day 1, Day 4, 0 hours (pre-dose) on Day 8
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 After Single Dose	Tmax was calculated for the intact C-terminus and N-terminus PF-05231023 from the concentration-time data using standard non-compartmental method. Only participants who received PF-05231023 were to be analyzed for this outcome measure.	0 (pre-dose), 0.5 (end of infusion), 1, 2.5, 3.5, 5.5, 9.5, 11.5 hours after start of infusion on Day 1, Day 4, 0 hour (pre-dose) on Day 8
Maximum Observed Plasma Concentration (Cmax) of PF-05231023 After Single Dose	Cmax was calculated for the intact C-terminus and N-terminus PF-05231023 from the concentration-time data using standard non-compartmental method. Only participants who received PF-05231023 were to be analyzed for this outcome measure.	0 (pre-dose), 0.5 (end of infusion), 1, 2.5, 3.5, 5.5, 9.5, 11.5 hours after start of infusion on Day 1, Day 4, 0 hour (pre-dose) on Day 8
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 After Last Dose	AUCtau was calculated for the intact C-terminus and N-terminus PF-05231023 from the concentration-time data using standard non-compartmental method. Only participants who received PF-05231023 were to be analyzed for this outcome measure.	0 (pre-dose), 0.5 (end of infusion), 1, 2.5, 3.5, 4.5 hours after start of infusion on Day 22, Day 24, 25, 29
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 After Last Dose	Tmax was calculated for the intact C-terminus and N-terminus PF-05231023 from the concentration-time data using standard non-compartmental method. Only participants who received PF-05231023 were to be analyzed for this outcome measure.	0 (pre-dose), 0.5 (end of infusion), 1, 2.5, 3.5, 4.5 hours after start of infusion on Day 22, Day 24, 25, 29, 39, 49
Maximum Observed Plasma Concentration (Cmax) of PF-05231023 After Last Dose	Cmax was calculated for the intact C-terminus and N-terminus PF-05231023 from the concentration-time data using standard non-compartmental method. Only participants who received PF-05231023 were to be analyzed for this outcome measure.	0 (pre-dose), 0.5 (end of infusion), 1, 2.5, 3.5, 4.5 hours after start of infusion on Day 22, Day 24, 25, 29, 39, 49
Accumulation Ratio for Area Under the Curve From Time Zero to End of Dosing Interval (Rac) of PF-05231023	Rac was obtained from AUCtau after last dose (Day 22) divided by AUCtau after single dose (Day 1). Rac was calculated for the intact C-terminus and N-terminus PF-05231023 from the concentration-time data using standard non-compartmental method. Only participants who received PF-05231023 were to be analyzed for this outcome measure.	0 (pre-dose), 0.5 (end of infusion ), 1, 2.5, 3.5, 5.5, 9.5, 11.5 hours after start of infusion on Day 1; Day 4, 0 hour (pre-dose) on Day 8; 0 (pre-dose), 0.5 (end of infusion), 1, 2.5, 3.5, 4.5 hours after start of infusion on Day 22; Day 24, 25, 29
Accumulation Ratio for Maximum Observed Plasma Concentration (Rac,Cmax) of PF-05231023	Rac was obtained from AUCtau after last dose (Day 22) divided by AUCtau after single dose (Day 1). Rac was calculated for the intact C-terminus and N-terminus PF-05231023 from the concentration-time data using standard non-compartmental method. Only participants who received PF-05231023 were to be analyzed for this outcome measure.	0 (pre-dose),0.5(end of infusion), 1, 2.5, 3.5, 5.5, 9.5, 11.5 hours after start of infusion on Day 1; Day 4, 0 hour (pre-dose) on Day 8; 0 (pre-dose), 0.5 (end of infusion), 1, 2.5, 3.5, 4.5 hours after start of infusion on Day 22; Day 24,25,29,39,49
Minimum Observed Plasma Trough Concentration (Cmin) of PF-05231023 After Last Dose	Cmin was calculated for the intact C-terminus and N-terminus PF-05231023 from the concentration-time data using standard non-compartmental method. Only participants who received PF-05231023 were to be analyzed for this outcome measure.	0 (pre-dose), 0.5 (end of infusion), 1, 2.5, 3.5, 4.5 hours after start of infusion on Day 22, Day 24, 25, 29, 39, 49
Average Plasma Concentration (Cav ) of PF-05231023 After the Last Dose	Cav was calculated for the intact C-terminus and N-terminus PF-05231023 from the concentration-time data using standard non-compartmental method. Only participants who received PF-05231023 were to be analyzed for this outcome measure.	0 (pre-dose), 0.5 (end of infusion), 1, 2.5, 3.5, 4.5 hours after start of infusion on Day 22, Day 24, 25, 29, 39, 49
Plasma Decay Half-Life (t1/2) of PF-05231023	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Half-Life was calculated for the intact C-terminus and N-terminus PF-05231023 from the concentration-time data using standard non-compartmental method. Only participants who received PF-05231023 were to be analyzed for this outcome measure.	0 (pre-dose), 0.5 (end of infusion), 1, 2.5, 3.5, 4.5 hours after start of infusion on Day 22, Day 24, 25, 29, 39, 49
Apparent Clearance (CL) of PF-05231023	CL is a quantitative measure of the rate at which a drug substance is removed from the body. CL was calculated for the intact C-terminus and N-terminus PF-05231023 from the concentration-time data using standard non-compartmental method. Only participants who received PF-05231023 were to be analyzed for this outcome measure.	0 (pre-dose), 0.5 (end of infusion), 1, 2.5, 3.5, 4.5 hours after start of infusion on Day 22, Day 24, 25, 29, 39, 49

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Kim AM, Somayaji VR, Dong JQ, Rolph TP, Weng Y, Chabot JR, Gropp KE, Talukdar S, Calle RA. Once-weekly administration of a long-acting fibroblast growth factor 21 analogue modulates lipids, bone turnover markers, blood pressure and body weight differently in obese people with hypertriglyceridaemia and in non-human primates. Diabetes Obes Metab. 2017 Dec;19(12):1762-1772. doi: 10.1111/dom.13023. Epub 2017 Jul 21.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Actual): August 1, 2013
• Study Completion (Actual): September 1, 2013

Study Registration Dates

• First Submitted: August 22, 2012
• First Submitted That Met QC Criteria: August 22, 2012
• First Posted (Estimate): August 27, 2012

Study Record Updates

• Last Update Posted (Estimate): February 16, 2015
• Last Update Submitted That Met QC Criteria: January 28, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Keywords: safety; Type 2 diabetes; intravenous; multiple dose
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: B2901011