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

Study Overview
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Brief Summary
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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

Official Title
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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

Conditions
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Diabetes Melliuts, Type 2

Intervention / Treatment
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* Other: Placebo
* Drug: 25 mg PF-05231023
* Drug: 50 mg PF-05231023
* Drug: 100 mg PF-05231023
* Drug: 150 mg PF-05231023


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 30 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 diabetes, safety, multiple dose, intravenous