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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
68
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Infusion every week
Infusion every week
California Clinical Trials Medical Group
Culver City, California, United States
Glendale Adventist Medical Center
Glendale, California, United States
SeaView Research, Inc.
Miami, Florida, United States
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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline up to Follow-up period (Day 78)
Number of Participants With Laboratory Test Abnormalities
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Infusion every week
Infusion every week
SeaView Research, Inc.
Miami, Florida, United States
Covance Clinical Research Unit, Inc.
Honolulu, Hawaii, United States
Vince and Associates Clinical Research
Overland Park, Kansas, United States
Vince and Associates Clinical Research
Overland Park, Kansas, United States
Prism Research
Saint Paul, Minnesota, United States
Healthcare Discoveries, LLC dba ICON Development Solutions
San Antonio, Texas, United States
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline up to Follow-up period (Day 78)
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.
Time frame: 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.
Time frame: Day 1 and 22: pre-dose and 1, 6, 9, 24 and 72 hours post dose
Maximum Observed Plasma Concentration (Cmax) of PF-04950615
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: Day 8, 15, 22, 29 and 78
Number of Participants Achieving LDL-C Less Than (<) 70 Milligram Per Deciliter (mg/dL)
Time frame: Day 15, 22, 29 and 36
Number of Participants Achieving LDL-C Less Than (<) 100 Milligram Per Deciliter (mg/dL)
Time frame: Day 15, 22, 29 and 36
Number of Participants With Greater Than or Equal to (>=) 50 Percent (%) Reduction in LDL-C From Baseline
Time frame: Baseline, Day 15, 22, 29 and 36
Change From Baseline in Lipid Parameters: Apolipoprotein A1 (ApoA1) at Day 8, 15, 22, 29 and 78
Time frame: 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
Time frame: Baseline, Day 8, 15, 22, 29 and 78
Change From Baseline in Lipid Parameters: Total Cholesterol at Day 8, 15, 22, 29 and 78
Time frame: 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
Time frame: 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
Time frame: Baseline, Day 8, 15, 22, 29 and 78
Change From Baseline In Lipid Parameters: Triglycerides (TG) at Day 8, 15, 22, 29 and 78
Time frame: 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
Time frame: 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
Time frame: Day 8, 15, 22, 29 and 78
Percent Change From Baseline In Lipid Parameters: Total Cholesterol at Day 8, 15, 22, 29 and 78
Time frame: 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
Time frame: 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
Time frame: Day 8, 15, 22, 29 and 78
Percent Change From Baseline In Lipid Parameters: Triglycerides (TG) at Day 8, 15, 22, 29 and 78
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Baseline, Day 8, 15, 22, 36, 50, 64 and 78
C-Reactive Protein Levels at Day 8, 15, 21, 36, 57 and 78
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Day 8, 15, 22, 36, 50, 64 and 78