Safety And Tolerability Of Multiple Doses Of PF-04950615 (RN316) In Subjects With Hypercholesterolemia

A Phase 1, Placebo-controlled, Randomized Study To Assess The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Following Multiple Intravenous Doses Of Pf-04950615 In Healthy Adult Subjects With Hypercholesterolemia

The primary objective of this study is to evaluate the safety and tolerability of repeated doses of PF-04950615 (RN316) in study volunteers with hypercholesterolemia. PF-04950615 is an investigational drug that is currently being studied as a lipid lowering agent.

Study Overview

• Status: Completed
• Conditions: Dyslipidemia; Hypercholesterolemia
• Intervention / Treatment: Biological: PF-04950615 (RN316)

• Study Type: Interventional
• Enrollment (Actual): 68
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Culver City, California, United States, 90232
      • California Clinical Trials Medical Group
    • Glendale, California, United States, 91206
      • Glendale Adventist Medical Center
  • Florida
    • Miami, Florida, United States, 33126
      • SeaView Research, Inc.
    • Miami, Florida, United States, 33134
      • SeaView Research, Inc.
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • Covance Clinical Research Unit, Inc.
  • Kansas
    • Overland Park, Kansas, United States, 66212
      • Vince and Associates Clinical Research
    • Overland Park, Kansas, United States, 66211
      • Vince and Associates Clinical Research
  • Minnesota
    • Saint Paul, Minnesota, United States, 55114
      • Prism Research
  • Texas
    • San Antonio, Texas, United States, 78209
      • Healthcare Discoveries, LLC dba ICON Development Solutions

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• LDL-C must be greater or equal to 130 mg/dl
• BMI must be between 18.5 and 40 kg/m2
• Japanese volunteers must have 4 Japanese grand parents born in Japan

Exclusion Criteria:

• History of cardiovascular or cerebrovascular event during the past year.
• Poorly controlled type 1 or type 2 diabetes mellitus
• Subjects who have taken lipid lowering therapies within the last 3 months of screening.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: E	Biological: PF-04950615 (RN316); Infusion every week
Experimental: B	Biological: PF-04950615 (RN316); Infusion every week
Experimental: C	Biological: PF-04950615 (RN316); Infusion every week
Experimental: D	Biological: PF-04950615 (RN316); Infusion every week
Placebo Comparator: A	Biological: PF-04950615 (RN316); Infusion every week

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose Limiting and Intolerable Treatment-Related Adverse Events (AEs)	An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Dose limiting and intolerable treatment-related AEs were the AEs resulting from drug overdose, drug withdrawal, drug abuse, drug misuse, drug interactions, drug dependency, extravasation, exposure in utero, exposure during breast feeding.	Baseline up to Follow-up period (Day 78)
Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs) and Treatment-Related Adverse Events (AEs)	An AE was any untoward medical occurrence in 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-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Treatment-emergent are events between first dose of study drug and up to Day 78 that were absent before treatment or that worsened relative to pretreatment state.	Baseline up to Follow-up period (Day 78)
Number of Participants With Adverse Events (AEs) by Severity	An AE was any untoward medical occurrence in a participant who received study drug. AE was assessed according to common terminology criteria for adverse events (CTCAE) version 4.0 severity grades- Grade 1: mild (asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated); Grade 2: moderate (minimal, local or non invasive intervention indicated); Grade 3: severe (medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling); Grade 4: Life-threatening consequences; urgent intervention indicated and Grade 5: Death related to AE.	Baseline up to Follow-up period (Day 78)
Number of Participants With Laboratory Test Abnormalities	Criteria: Haemoglobin(Hgb), hematocrit, RBC: <0.8*lower limit of normal(LLN),mean corpuscular volume, mean corpuscular Hgb concentration <0.9*LLN or>1.1*upper limit of normal(ULN), platelet<0.5*LLN or>1.75*ULN, WBC<0.6*LLN or>1.5*ULN, lymphocyte, neutrophil<0.8*LLN or>1.2*ULN, basophil, eosinophil, monocyte>1.2*ULN; bilirubin>1.5*ULN, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma glutamyl transferase, lactate dehydrogenase>3.0*ULN,total protein,albumin<0.8*LLN or>1.2*ULN; blood urea nitrogen, creatinine>1.3*ULN,uric acid>1.2*ULN;sodium<0.95*LLNor>1.05*ULN,potassium,chloride,calcium,bicarbonate<0.9*LLN or>1.1*ULN; glucose<0.6*LLN or >1.5*ULN, urine specific gravity<1.003 or>1.030,urine pH<4.5or>8,urine glucose, ketones, urine protein,urine blood/Hgb,urobilinogen,bilirubin,nitrite, leukocyte esterase>=1; urine RBC,WBC>=20,urine epithelial cells>=6,urine granular casts,hyaline casts>1,urine bacteria>20,partial thromboplastin time,prothrombin:>1.1*ULN.	Baseline up to Follow-up period (Day 78)
Number of Participants With Clinically Relevant Changes in Vital Signs	Criteria for clinically relevant vital signs: supine and standing systolic blood pressure (SBP): less than (<) 90 millimeter of mercury (mmHg); supine and standing diastolic blood pressure (DBP): <50 mmHg. Maximum increase from baseline (IFB) or decrease from baseline (DFB) in supine and standing SBP: greater than or equal to (>=) 30 mmHg and maximum IFB or DFB in supine and standing DBP: >=20 mmHg. Supine pulse rate: <40 and greater than (>) 120 beats per minute (bpm); standing pulse rate: <40 and >140 bpm.	Baseline up to Follow-up period (Day 78)
Number of Participants With Clinically Relevant Changes in Electrocardiogram (ECG) Parameters	Criteria for clinically relevant ECG parameters: PR interval: maximum IFB of >=25 percent or 50 percent; QRS complex: maximum IFB of >=25 or 50 percent; QTcF interval (Fridericia's Correction): maximum IFB of >=30 millisecond (msec) to <60 msec and maximum IFB of >=60 msec.	Baseline up to Follow-up period (Day 78)
Number of Participants With Anti-drug Antibodies (ADA)	The number of participants with at least one positive ADA were summarized for each treatment arm. Participants with positive antibody titer of >4.32 milligram/milliliter (mg/mL) were considered as ADA positive.	Baseline up to Follow-up period (Day 78)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-04950615	AUCtau is area under the concentration-time profile from time zero to time tau (τ), the dosing interval, where tau =168 hours.	Day 1 and 22: pre-dose and 1, 6, 9, 24 and 72 hours post dose
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04950615	Tmax is the time at which maximum plasma concentration (Cmax) occurred.	Day 1 and 22: pre-dose and 1, 6, 9, 24 and 72 hours post dose
Maximum Observed Plasma Concentration (Cmax) of PF-04950615		Day 1 and 22: pre-dose and 1, 6, 9, 24 and 72 hours post dose
Plasma Decay Half-Life (t1/2) of PF-04950615	t1/2 was the time measured for the plasma concentration of PF-04950615 to decrease by one half. t1/2 was calculated as Loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.	Day 1 and 22: pre-dose and 1, 6, 9, 24 and 72 hours post dose
Apparent Clearance (CL) of PF-04950615	CL was calculated as Dose/AUCtau. AUCtau is area under the concentration-time profile from time zero to time tau, the dosing interval, where tau=168 hours.	Day 22: pre-dose and 1, 6, 9, 24 and 72 hours post dose
Volume of Distribution at Steady State (Vss) of PF-04950615	Vss was calculated as CL*MRT. CL was calculated as Dose/AUCtau, where AUCtau was area under the concentration-time profile from time zero to time tau (τ), the dosing interval, where tau=168 hours. MRT was mean residence time (predicted) extrapolated to infinity.	Day 22: pre-dose and 1, 6, 9, 24 and 72 hours post dose
Accumulation Ratio (Rac) of PF-04950615	Rac was calculated as Day 22 AUCtau divided by Day 1 AUCtau, where AUCtau is area under the concentration-time profile from time zero to time tau (τ), the dosing interval, where tau =168 hours.	Day 22: pre-dose and 1, 6, 9, 24 and 72 hours post dose
Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Day 8, 15, 22, 29 and 78		Baseline, Day 8, 15, 22, 29 and 78
Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Day 8, 15, 22, 29 and 78		Day 8, 15, 22, 29 and 78
Number of Participants Achieving LDL-C Less Than (<) 70 Milligram Per Deciliter (mg/dL)		Day 15, 22, 29 and 36
Number of Participants Achieving LDL-C Less Than (<) 100 Milligram Per Deciliter (mg/dL)		Day 15, 22, 29 and 36
Number of Participants With Greater Than or Equal to (>=) 50 Percent (%) Reduction in LDL-C From Baseline		Baseline, Day 15, 22, 29 and 36
Change From Baseline in Lipid Parameters: Apolipoprotein A1 (ApoA1) at Day 8, 15, 22, 29 and 78		Baseline, Day 8, 15, 22, 29 and 78
Change From Baseline in Lipid Parameters: Apolipoprotein B (ApoB) at Day 8, 15, 22, 29 and 78		Baseline, Day 8, 15, 22, 29 and 78
Change From Baseline in Lipid Parameters: Total Cholesterol at Day 8, 15, 22, 29 and 78		Baseline, Day 8, 15, 22, 29 and 78
Change From Baseline in Lipid Parameters: High Density Lipoprotein Cholesterol (HDL-C) at Day 8, 15, 22, 29 and 78		Baseline, Day 8, 15, 22, 29 and 78
Change From Baseline In Lipid Parameters: Non High Density Lipoprotein Cholesterol (Non HDL-C) at Day 8, 15, 22, 29 and 78		Baseline, Day 8, 15, 22, 29 and 78
Change From Baseline In Lipid Parameters: Triglycerides (TG) at Day 8, 15, 22, 29 and 78		Baseline, Day 8, 15, 22, 29 and 78
Percent Change From Baseline in Lipid Parameters: Apolipoprotein A1 (ApoA1) at Day 8, 15, 22, 29 and 78		Day 8, 15, 22, 29 and 78
Percent Change From Baseline In Lipid Parameters: Apolipoprotein B (ApoB) at Day 8, 15, 22, 29 and 78		Day 8, 15, 22, 29 and 78
Percent Change From Baseline In Lipid Parameters: Total Cholesterol at Day 8, 15, 22, 29 and 78		Day 8, 15, 22, 29 and 78
Percent Change From Baseline In Lipid Parameters: High Density Lipoprotein Cholesterol (HDL-C) at Day 8, 15, 22, 29 and 78		Day 8, 15, 22, 29 and 78
Percent Change From Baseline In Lipid Parameters: Non High Density Lipoprotein Cholesterol (Non HDL-C) at Day 8, 15, 22, 29 and 78		Day 8, 15, 22, 29 and 78
Percent Change From Baseline In Lipid Parameters: Triglycerides (TG) at Day 8, 15, 22, 29 and 78		Day 8, 15, 22, 29 and 78
Change From Baseline In Low Density Lipoprotein Cholesterol (LDL-C) Particle Size at Day 8, 15, 22, 36, 50, 64 and 78		Baseline, Day 8, 15, 22, 36, 50, 64 and 78
Change From Baseline In Small Low Density Lipoprotein Cholesterol (LDL-C) Particle Levels at Day 8, 15, 22, 36, 50, 64 and 78		Baseline, Day 8, 15, 22, 36, 50, 64 and 78
Change From Baseline In Medium Low Density Lipoprotein Cholesterol (LDL-C) Particle Levels at Day 8, 15, 22, 36, 50, 64 and 78		Baseline, Day 8, 15, 22, 36, 50, 64 and 78
Change From Baseline In Large Low Density Lipoprotein Cholesterol (LDL-C) Particle Levels at Day 8, 15, 22, 36, 50, 64 and 78		Baseline, Day 8, 15, 22, 36, 50, 64 and 78
Change From Baseline In Total Low Density Lipoprotein Cholesterol (LDL-C) Particle Levels at Day 8, 15, 22, 36, 50, 64 and 78		Baseline, Day 8, 15, 22, 36, 50, 64 and 78
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Levels at Baseline, Day 8, 15, 22, 36, 50, 64 and 78		Baseline, Day 8, 15, 22, 36, 50, 64 and 78
C-Reactive Protein Levels at Day 8, 15, 21, 36, 57 and 78		Day 8, 15, 21, 36, 57 and 78
Small High Density Lipoprotein-Cholesterol (HDL-C) Particle Levels at Day 8, 15, 22, 36, 50, 64 and 78		Day 8, 15, 22, 36, 50, 64 and 78
Medium High Density Lipoprotein-Cholesterol (HDL-C) Particle Levels at Day 8, 15, 22, 36, 50, 64 and 78		Day 8, 15, 22, 36, 50, 64 and 78
Large High Density Lipoprotein-Cholesterol (HDL-C) Particle Levels at Day 8, 15, 22, 36, 50, 64 and 78		Day 8, 15, 22, 36, 50, 64 and 78
Total High Density Lipoprotein-Cholesterol (HDL-C) Particle Levels at Day 8, 15, 22, 36, 50, 64 and 78		Day 8, 15, 22, 36, 50, 64 and 78
Small Very Low Density Lipoprotein-Cholesterol (VLDL-C) Particle Levels at Day 8, 15, 22, 36, 50, 64 and 78		Day 8, 15, 22, 36, 50, 64 and 78
Medium Very Low Density Lipoprotein-Cholesterol (VLDL-C) Particle Levels at Day 8, 15, 22, 36, 50, 64 and 78		Day 8, 15, 22, 36, 50, 64 and 78
Large Very Low Density Lipoprotein-Cholesterol (VLDL-C) Particle Levels at Day 8, 15, 22, 36, 50, 64 and 78		Day 8, 15, 22, 36, 50, 64 and 78
Total Very Low Density Lipoprotein-Cholesterol (VLDL-C) Particle Levels at Day 8, 15, 22, 36, 50, 64 and 78		Day 8, 15, 22, 36, 50, 64 and 78
High Density Lipoprotein-Cholesterol (HDL-C) Particle Size at Day 8, 15, 22, 36, 50, 64 and 78		Day 8, 15, 22, 36, 50, 64 and 78
Very Low Density Lipoprotein-Cholesterol (VLDL-C) Particle Size at Day 8, 15, 22, 36, 50, 64 and 78		Day 8, 15, 22, 36, 50, 64 and 78

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Udata C, Garzone PD, Gumbiner B, Joh T, Liang H, Liao KH, Williams JH, Meng X. A Mechanism-Based Pharmacokinetic/Pharmacodynamic Model for Bococizumab, a Humanized Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9, and Its Application in Early Clinical Development. J Clin Pharmacol. 2017 Jul;57(7):855-864. doi: 10.1002/jcph.867. Epub 2017 Feb 9.
• Wan H, Gumbiner B, Joh T, Riel T, Udata C, Forgues P, Garzone PD. Effects of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibition with Bococizumab on Lipoprotein Particles in Hypercholesterolemic Subjects. Clin Ther. 2017 Nov;39(11):2243-2259.e5. doi: 10.1016/j.clinthera.2017.09.009. Epub 2017 Oct 14.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2011
• Primary Completion (Actual): October 1, 2011
• Study Completion (Actual): October 1, 2011

Study Registration Dates

• First Submitted: November 3, 2010
• First Submitted That Met QC Criteria: November 16, 2010
• First Posted (Estimate): November 18, 2010

Study Record Updates

• Last Update Posted (Actual): January 22, 2019
• Last Update Submitted That Met QC Criteria: August 8, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Dyslipidemia; Hypercholesterolemia; High Cholesterol; LDL; PF-04950615; RN316; Japanese Volunteers
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Hypercholesterolemia; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Bococizumab
• Other Study ID Numbers: B1481009