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

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
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

Conditions
-----------------
Hypercholesterolemia, Dyslipidemia

Intervention / Treatment
-----------------
* Biological: PF-04950615 (RN316)
* Biological: PF-04950615 (RN316)
* Biological: PF-04950615 (RN316)
* Biological: PF-04950615 (RN316)
* Biological: PF-04950615 (RN316)


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hypercholesterolemia, Dyslipidemia, LDL, High Cholesterol, Japanese Volunteers, PF-04950615, RN316