A Pharmacokinetic and Pharmacodynamic Study of PF-04950615 (RN316) in Subjects With Hypercholesterolemia

A Phase 1, Open-label, Randomized, Single Dose, Parallel Group Study To Assess The Pharmacokinetics And Pharmacodynamics Of Pf-04950615 Following Subcutaneous And Intravenous Doses In Adult Subjects With Hypercholesterolemia

This Phase 1 study has been designed to evaluate the absolute bioavailability of PF-04950615 (RN316) in subjects with hypercholesterolemia who are not currently on lipid-lowering therapy.

Study Overview

• Status: Completed
• Conditions: Metabolic Diseases; Dyslipidemias; Lipid Metabolism Disorders; Hypercholesterolemia; Hyperlipidemias
• Intervention / Treatment: Biological: PF-04950615 (RN316); Biological: PF-04950615 (RN316); Biological: PF-04950615 (RN316); Biological: PF-04950615 (RN316)

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Chula Vista, California, United States, 91911
      • Profil Institute for Clinical Research, Inc.
  • Florida
    • Miami, Florida, United States, 33169
      • Elite Research Institute
  • Kansas
    • Overland Park, Kansas, United States, 66212
      • Vince and Associates Clinical Research
  • Maryland
    • Baltimore, Maryland, United States, 21225
      • Parexel International - Baltimore Early Phase Clinical Unit
  • Michigan
    • Kalamazoo, Michigan, United States, 49007
      • Jasper Clinic, Inc.
  • Minnesota
    • Saint Paul, Minnesota, United States, 55114
      • Prism Research
  • Ohio
    • Cincinnati, Ohio, United States, 45212
      • Medpace Clinical Pharmacology Unit

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Fasting LDL-C greater than or equal to 130 mg/dL at two qualifying screening visits.
• Total body weight greater than or equal to 50 kg (110 lbs) and less than or equal to 150 kg (330 lbs)

Exclusion Criteria:

• Lipid-lowering prescription medications, homeopaths, herbal medicines, or nutritional supplements.
• Poorly controlled type 1 or type 2 diabetes.
• History of a cardiovascular or cerebrovascular event or related procedure during the past year.
• Poorly controlled hypertension.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A	Biological: PF-04950615 (RN316); Dose A - single-dose intravenous infusion; Biological: PF-04950615 (RN316); Dose B - single-dose subcutaneous injection; Biological: PF-04950615 (RN316); Dose C - single-dose subcutaneous injection; Biological: PF-04950615 (RN316); Dose D - single-dose subcutaneous injection
Experimental: Group B	Biological: PF-04950615 (RN316); Dose A - single-dose intravenous infusion; Biological: PF-04950615 (RN316); Dose B - single-dose subcutaneous injection; Biological: PF-04950615 (RN316); Dose C - single-dose subcutaneous injection; Biological: PF-04950615 (RN316); Dose D - single-dose subcutaneous injection
Experimental: Group C	Biological: PF-04950615 (RN316); Dose A - single-dose intravenous infusion; Biological: PF-04950615 (RN316); Dose B - single-dose subcutaneous injection; Biological: PF-04950615 (RN316); Dose C - single-dose subcutaneous injection; Biological: PF-04950615 (RN316); Dose D - single-dose subcutaneous injection
Experimental: Group D	Biological: PF-04950615 (RN316); Dose A - single-dose intravenous infusion; Biological: PF-04950615 (RN316); Dose B - single-dose subcutaneous injection; Biological: PF-04950615 (RN316); Dose C - single-dose subcutaneous injection; Biological: PF-04950615 (RN316); Dose D - single-dose subcutaneous injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Plasma Concentration (Cmax) of PF-04950615		Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04950615		Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose
Area Under the Plasma Concentration-Time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) of PF-04950615		Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose
Area Under the Plasma Concentration-Time Curve From Time Zero To Infinity (AUCinf) of PF-04950615		Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose
Apparent Clearance (CL/F) of PF-04950615 Subcutaneous Groups	Clearance (CL) of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent clearance (CL/F) is influenced by the fraction of the dose absorbed from plasma after SC administration of drug.	Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose
Clearance (CL) of PF-04950615 Intravenous Group	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.	Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose
Apparent Volume of Distribution (Vz/F) of PF-04950615 Subcutaneous Groups	Volume of distribution (Vz) is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/F is influenced by the fraction of the dose absorbed from plasma after SC administration of drug.	Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose
Volume of Distribution at Steady State (Vss) of PF-04950615 Intravenous Group	Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss is determined when overall intake of drug is in dynamic equilibrium with its elimination.	Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose
Terminal Elimination Half-life (t1/2) of PF-04950615	t1/2 is the time measured for the plasma concentration of drug to decrease by one half.	Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose
Absolute Bioavailability of PF-04950615 Subcutaneous Groups	Bioavailability is defined as the rate and extent to which the active moiety administered drug reaches the systemic circulation. Absolute bioavailability of the subcutaneous doses was estimated by comparing log-transformed dose-normalized AUClast for subcutaneous to intravenous dose.	Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Value of Fasting Low-density Lipoprotein Cholesterol (LDL-C)		Day 2, 3, 4, 5, 6, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 85
Percent Change From Baseline in Fasting Low-density Lipoprotein Cholesterol (LDL-C) at Day 2, 3, 4, 5, 6, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 85	Baseline was the average of observations collected on Days 7 and 1 prior to the study treatment administration.	Baseline, Day 2, 3, 4, 5, 6, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 85
Duration of Fasting LDL-C Suppressed Below 70 mg/dL and 100 mg/dL		Day 1 up to Day 85

Other 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. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state.	Day 1 up to Day 85
Number of Adverse Events (AEs) by Severity	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An AE was assessed according to severity; mild (not causing any significant problem, dose adjustment not required), moderate (caused problem that does not interfere significantly with usual activities or the clinical status, dose adjustment needed due to adverse event) and severe (caused problem that interferes significantly with usual activities or the clinical status, study drug stopped due to adverse event).	Day 1 up to Day 85
Number of Participants With Treatment Related Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. 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.	Day 1 up to Day 85
Number of Participants With Injection Site Reactions	The injection site reaction included erythema, induration, ecchymosis, injection site pain, injection site pruritus.	Day 1 up to Day 3
Number of Injection Site Reactions Reported as Adverse Events	The injection site reactions included erythema, induration, ecchymosis, injection site pain and injection site pruritus. An adverse event was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.	Day 1 up to Day 3
Visual Analogue Scale (VAS)	Participants indicated the amount of pain experienced due to study drug injection, on a VAS of 0 (no pain) to 100 (very severe pain), where higher scores indicate higher intensity of pain.	Day 1: Immediately post-dose, 0.5, 1.0, 2.0, 8.0 hours post-dose; Day 2, 3
Number of Participants With Clinically Significant Laboratory Abnormalities	Laboratory parameters evaluated for abnormalities were: hematology (hemoglobin [Hgb], hematocrit, red blood cell [RBC] count, platelets, white blood cell count [WBC], lymphocytes, total neutrophils, basophils, eosinophils, monocytes); coagulation (partial thromboplastin time, prothrombin time [PT], PT international ratio); clinical chemistry (glucose, creatine kinase, amylase, lipase); liver function (total, direct and indirect bilirubin, aspartate aminotransferase [AT], alanine AT, gamma-glutamyl transferase, alkaline phosphatase, total protein, albumin, lactate dehydrogenase); renal function (blood urea nitrogen, creatinine, uric acid); urinalysis (urine- specific gravity, pH, glucose, ketones, blood/Hgb, nitrite, leukocyte, esterase, RBC, WBC, epithelial cells, hyaline cast and bacteria); lipid (cholesterol); electrolytes (sodium, potassium, chloride, calcium, magnesium, phosphate, bicarbonate). Clinical significance of laboratory abnormalities were judged by investigator.	Day 1 up to Day 85
Number of Participants With Clinically Significant Changes in Vital Signs	Vital signs abnormalities included: maximum increase or decrease from baseline in supine systolic blood pressure (BP) greater than or equal to (>=) 30 millimeter of mercury (mmHg); maximum increase or decrease from baseline in supine diastolic BP of >=20 mmHg; supine pulse rate less than (<) 40 beats per minute (bpm) and greater than (>) 120 bpm; standing pulse rate less than (<) 40 beats per minute (bpm) and greater than (>) 140 bpm. Clinical significance of vital signs were judged by investigator.	Day 1 up to Day 85
Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG)	ECG abnormalities included 1) PR interval: maximum >=300 maximum millisecond (msec), increase of >=25 percent (%) for baseline value of >200 msec and maximum increase of >=50% for baseline value of less than or equal to (<=) 200 msec; 2) QRS interval: maximum >=200 msec, maximum increase of >=25 % for baseline value of >100 msec and maximum increase of >=50% for baseline value of <=100 msec; 3) QT interval corrected using the Fridericia's formula (QTCF): 450 msec to <= 480 msec, 480 msec to <=500 msec, > 500 msec, maximum increase from baseline of >30 to <=60 msec and maximum increase from baseline of >60 msec. Clinical significance of ECG were judged by investigator.	Day 1 up to Day 85
Percentage of Participants With Positive Anti-drug (Anti-PF 04950615) Antibodies	Human serum samples of participants who received PF-04950615 were analyzed for the presence of anti-PF-04950615 antibodies by using the semi quantitative enzyme-linked immunosorbent assay (ELISA).	Day 1 up to Day 85

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.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2011
• Primary Completion (Actual): February 1, 2012
• Study Completion (Actual): April 1, 2012

Study Registration Dates

• First Submitted: September 7, 2011
• First Submitted That Met QC Criteria: September 15, 2011
• First Posted (Estimate): September 16, 2011

Study Record Updates

• Last Update Posted (Actual): July 23, 2018
• Last Update Submitted That Met QC Criteria: October 6, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: PF-04950615; RN316
• Additional Relevant MeSH Terms: Dyslipidemias; Hypercholesterolemia; Hyperlipidemias; Metabolic Diseases; Lipid Metabolism Disorders; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Bococizumab
• Other Study ID Numbers: B1481006