A Pharmacokinetic and Pharmacodynamic Study of PF-04950615 (RN316) in Subjects With Hypercholesterolemia
Primary Purpose
Hypercholesterolemia, Dyslipidemias, Hyperlipidemias
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
PF-04950615 (RN316)
PF-04950615 (RN316)
PF-04950615 (RN316)
PF-04950615 (RN316)
Sponsored by
About this trial
This is an interventional basic science trial for Hypercholesterolemia focused on measuring PF-04950615, RN316
Eligibility Criteria
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.
Sites / Locations
- Profil Institute for Clinical Research, Inc.
- Elite Research Institute
- Vince and Associates Clinical Research
- PAREXEL International - Baltimore Early Phase Clinical Unit
- Jasper Clinic, Inc.
- Prism Research
- Medpace Clinical Pharmacology Unit
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Experimental
Experimental
Arm Label
Group A
Group B
Group C
Group D
Arm Description
Outcomes
Primary Outcome Measures
Maximum Observed Plasma Concentration (Cmax) of PF-04950615
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04950615
Area Under the Plasma Concentration-Time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) of PF-04950615
Area Under the Plasma Concentration-Time Curve From Time Zero To Infinity (AUCinf) of PF-04950615
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.
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.
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.
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.
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.
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.
Secondary Outcome Measures
Absolute Value of Fasting Low-density Lipoprotein Cholesterol (LDL-C)
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.
Duration of Fasting LDL-C Suppressed Below 70 mg/dL and 100 mg/dL
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01435382
Brief Title
A Pharmacokinetic and Pharmacodynamic Study of PF-04950615 (RN316) in Subjects With Hypercholesterolemia
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
October 2017
Overall Recruitment Status
Completed
Study Start Date
October 2011 (Actual)
Primary Completion Date
February 2012 (Actual)
Study Completion Date
April 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Pfizer
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypercholesterolemia, Dyslipidemias, Hyperlipidemias, Lipid Metabolism Disorders, Metabolic Diseases
Keywords
PF-04950615, RN316
7. Study Design
Primary Purpose
Basic Science
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
49 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Group A
Arm Type
Experimental
Arm Title
Group B
Arm Type
Experimental
Arm Title
Group C
Arm Type
Experimental
Arm Title
Group D
Arm Type
Experimental
Intervention Type
Biological
Intervention Name(s)
PF-04950615 (RN316)
Intervention Description
Dose A - single-dose intravenous infusion
Intervention Type
Biological
Intervention Name(s)
PF-04950615 (RN316)
Intervention Description
Dose B - single-dose subcutaneous injection
Intervention Type
Biological
Intervention Name(s)
PF-04950615 (RN316)
Intervention Description
Dose C - single-dose subcutaneous injection
Intervention Type
Biological
Intervention Name(s)
PF-04950615 (RN316)
Intervention Description
Dose D - single-dose subcutaneous injection
Primary Outcome Measure Information:
Title
Maximum Observed Plasma Concentration (Cmax) of PF-04950615
Time Frame
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
Title
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04950615
Time Frame
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
Title
Area Under the Plasma Concentration-Time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) of PF-04950615
Time Frame
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
Title
Area Under the Plasma Concentration-Time Curve From Time Zero To Infinity (AUCinf) of PF-04950615
Time Frame
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
Title
Apparent Clearance (CL/F) of PF-04950615 Subcutaneous Groups
Description
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.
Time Frame
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
Title
Clearance (CL) of PF-04950615 Intravenous Group
Description
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
Time Frame
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
Title
Apparent Volume of Distribution (Vz/F) of PF-04950615 Subcutaneous Groups
Description
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.
Time Frame
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
Title
Volume of Distribution at Steady State (Vss) of PF-04950615 Intravenous Group
Description
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.
Time Frame
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
Title
Terminal Elimination Half-life (t1/2) of PF-04950615
Description
t1/2 is the time measured for the plasma concentration of drug to decrease by one half.
Time Frame
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
Title
Absolute Bioavailability of PF-04950615 Subcutaneous Groups
Description
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.
Time Frame
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 Measure Information:
Title
Absolute Value of Fasting Low-density Lipoprotein Cholesterol (LDL-C)
Time Frame
Day 2, 3, 4, 5, 6, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 85
Title
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
Description
Baseline was the average of observations collected on Days 7 and 1 prior to the study treatment administration.
Time Frame
Baseline, Day 2, 3, 4, 5, 6, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 85
Title
Duration of Fasting LDL-C Suppressed Below 70 mg/dL and 100 mg/dL
Time Frame
Day 1 up to Day 85
Other Pre-specified Outcome Measures:
Title
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description
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.
Time Frame
Day 1 up to Day 85
Title
Number of Adverse Events (AEs) by Severity
Description
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).
Time Frame
Day 1 up to Day 85
Title
Number of Participants With Treatment Related Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description
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.
Time Frame
Day 1 up to Day 85
Title
Number of Participants With Injection Site Reactions
Description
The injection site reaction included erythema, induration, ecchymosis, injection site pain, injection site pruritus.
Time Frame
Day 1 up to Day 3
Title
Number of Injection Site Reactions Reported as Adverse Events
Description
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.
Time Frame
Day 1 up to Day 3
Title
Visual Analogue Scale (VAS)
Description
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.
Time Frame
Day 1: Immediately post-dose, 0.5, 1.0, 2.0, 8.0 hours post-dose; Day 2, 3
Title
Number of Participants With Clinically Significant Laboratory Abnormalities
Description
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.
Time Frame
Day 1 up to Day 85
Title
Number of Participants With Clinically Significant Changes in Vital Signs
Description
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.
Time Frame
Day 1 up to Day 85
Title
Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG)
Description
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.
Time Frame
Day 1 up to Day 85
Title
Percentage of Participants With Positive Anti-drug (Anti-PF 04950615) Antibodies
Description
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).
Time Frame
Day 1 up to Day 85
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Pfizer CT.gov Call Center
Organizational Affiliation
Pfizer
Official's Role
Study Director
Facility Information:
Facility Name
Profil Institute for Clinical Research, Inc.
City
Chula Vista
State/Province
California
ZIP/Postal Code
91911
Country
United States
Facility Name
Elite Research Institute
City
Miami
State/Province
Florida
ZIP/Postal Code
33169
Country
United States
Facility Name
Vince and Associates Clinical Research
City
Overland Park
State/Province
Kansas
ZIP/Postal Code
66212
Country
United States
Facility Name
PAREXEL International - Baltimore Early Phase Clinical Unit
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21225
Country
United States
Facility Name
Jasper Clinic, Inc.
City
Kalamazoo
State/Province
Michigan
ZIP/Postal Code
49007
Country
United States
Facility Name
Prism Research
City
Saint Paul
State/Province
Minnesota
ZIP/Postal Code
55114
Country
United States
Facility Name
Medpace Clinical Pharmacology Unit
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45212
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
28181260
Citation
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.
Results Reference
derived
Links:
URL
https://trialinfoemail.pfizer.com/pages/landing.aspx?StudyID=B1481006&StudyName=A%20Pharmacokinetic%20and%20Pharmacodynamic%20Study%20of%20PF-04950615%20%28RN316%29%20in%20Subjects%20with%20Hypercholesterolemia
Description
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A Pharmacokinetic and Pharmacodynamic Study of PF-04950615 (RN316) in Subjects With Hypercholesterolemia
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