Pharmacokinetic And Pharmacodynamic Study Of A Single-Dose Of PF-04950615 (RN316) In Combination With Atorvastatin

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the pharmacokinetics and pharmacodynamics of a single dose of PF-04950615 (RN316) in volunteers on stable doses of atorvastatin. PF-04950615 (RN316) is an investigational drug that is currently being studies as a cholesterol lowering therapy.

Official Title
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A Phase 1 Study Evaluating The Pharmacokinetics And Pharmacodynamics Of Rn316 In Combination With Atorvastatin In Hypercholesterolemic Subjects

Conditions
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Hypercholesterolemia, Dyslipidemia

Intervention / Treatment
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* Biological: 4 mg/kg
* Biological: 0.5 mg/kg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: On stable doses of atorvastatin (40 mg daily) for 45 days prior to Day 1. BMI 18.5 to 40 kg/m2 inclusive, and body weight equal or lower than 150 kg. Exclusion Criteria: History of a cardiovascular event (e.g., MI ) during the past year. Poorly controlled Type 1 or Type 2 Diabetes mellitus (definition: uncontrolled diabetes is defined as HBIAc >9%). Poorly controlled hypertension (uncontrolled hypertension is defined as a systolic blood pressure greater than 140 mm Hg or a diastolic blood pressure greater than 90 mm Hg, even with treatment). Subjects who have hypertension and are controlled on stable dosages of anti-hypertensive medications can be included.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-04950615 (RN316)<br> | Biological: 4 mg/kg<br>* RN316 10 mg/ml vial sd. Infusion based on weight Infusion duration = 60 minutes.<br>* Other names: PF-04950615 (RN316);Biological: 0.5 mg/kg<br>* RN316 10 mg/ml vial sd. Infusion based on weight Infusion duration = 60 minutes.<br>* Other names: PF-04950615 (RN316);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-04950615 |  | 0 (pre-dose on Day 4), 1, 4, 8 and 12 hours (hrs) post intravenous PF-04950615 (RN316) dose, pre atorvastatin dose on Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04950615 |  | 0 (pre-dose on Day 4), 1, 4, 8 and 12 hours (hrs) post intravenous PF-04950615 (RN316) dose, pre atorvastatin dose on Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 | 
| Maximum Observed Plasma Concentration (Cmax) of PF-04950615 |  | 0 (pre-dose on Day 4), 1, 4, 8 and 12 hours (hrs) post intravenous PF-04950615 (RN316) dose, pre atorvastatin dose on Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 | 
| Plasma Decay Half-Life (t1/2) of PF-04950615 | Plasma decay half-life is the time measured for the plasma concentration of PF-04950615 to decrease by one half. | 0 (pre-dose on Day 4), 1, 4, 8 and 12 hours (hrs) post intravenous PF-04950615 (RN316) dose, pre atorvastatin dose on Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 | 
| Systemic Clearance (CL) of PF-04950615 | CL is a quantitative measure of the rate at which a drug substance is removed from the body. | 0 (pre-dose on Day 4), 1, 4, 8 and 12 hours (hrs) post intravenous PF-04950615 (RN316) dose, pre atorvastatin dose on Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 | 
| Volume of Distribution at Steady State (Vss) of PF-04950615 | 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 blood concentration of a drug. | 0 (pre-dose on Day 4), 1, 4, 8 and 12 hours (hrs) post intravenous PF-04950615 (RN316) dose, pre atorvastatin dose on Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC0-inf) of PF-04950615 |  | 0 (pre-dose on Day 4), 1, 4, 8 and 12 hours (hrs) post intravenous PF-04950615 (RN316) dose, pre atorvastatin dose on Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 | 
| Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Atorvastatin | AUCtau was the AUC from time 0 to the end of the dosing interval, where the dosing interval was 12 hours. | 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8 and 12 hrs post-dose on Day 4 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Atorvastatin |  | 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8 and 12 hrs post-dose on Day 4, pre atorvastatin dose on Day 5, 6 and 7 | 
| Maximum Observed Plasma Concentration (Cmax) of Atorvastatin |  | 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8 and 12 hrs post-dose on Day 4, pre atorvastatin dose on Day 5, 6 and 7 | 
| Plasma Decay Half-Life (t1/2) of Atorvastatin | Plasma decay half-life is the time measured for the plasma concentration of atorvastatin to decrease by one half. | 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8 and 12 hrs post-dose on Day 4, pre atorvastatin dose on Day 5, 6 and 7 | 
| Apparent Oral Clearance (CL/F) of Atorvastatin | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. | 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8 and 12 hrs post-dose on Day 4 | 
| Apparent Volume of Distribution (Vz/F) of Atorvastatin | 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. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. | 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8 and 12 hrs post-dose on Day 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Fasting Low Density Lipoprotein-Cholesterol (LDL-C) at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 | Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration. | Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 | 
| Change From Baseline in Fasting Total Cholesterol at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 | Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration. | Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 | 
| Change From Baseline in Fasting Non High-density Lipoprotein-Cholesterol (Non-HDL-C) at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 | Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration. | Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 | 
| Change From Baseline in Fasting Triglycerides at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 | Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration. | Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 | 
| Change From Baseline in Fasting Apolipoprotein B (ApoB) at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 | Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration. | Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 | 
| Change From Baseline in Fasting Apolipoprotein A1 (ApoA1) at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 | Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 (RN316) administration. | Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 | 
| Change From Baseline in Fasting High-Density Lipoprotein (HDL) Cholesterol at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 | Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration. | Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 | 
| Percent Change From Baseline in Fasting Low Density Lipoprotein-Cholesterol (LDL-C) at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 | Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration. | Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 | 
| Percent Change From Baseline in Total Cholesterol at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 | Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration. | Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 | 
| Percent Change From Baseline in Fasting Non-High-density Lipoprotein-cholesterol (Non-HDL-C) at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 | Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration. | Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 | 
| Percent Change From Baseline in Fasting Triglycerides Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 | Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 (RN316) administration. | Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 | 
| Percent Change From Baseline in Fasting Apolipoprotein B (ApoB) Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 | Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 (RN316) administration. | Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 | 
| Percent Change From Baseline in Fasting High-Density Lipoprotein (HDL) Cholesterol Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 | Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration. | Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 | 
| Percent Change From Baseline in Fasting Apolipoprotein A1 (ApoA1) Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 | Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 (RN316) administration. | Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 | 
| Duration of Low Density Lipoprotein (LDL) Lowering Effects | In this outcome measure duration of the lipid-lowering effects was reported. Lipid lowering was defined as decrease in LDL-C levels by greater than or equal to 15 percent. | Day 4 to Day 64 | 
| Number of Participants With Toxicity or Intolerable Dose Criteria | Toxicity criteria included any of the following: serious adverse event; increased liver transaminases (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]: increased to greater than [>] 5*upper limit of normal reference range [ULN]); increased bilirubin (in absence of ALT or AST elevations, common terminology criteria for adverse events [CTCAE] greater than or equal to [>=] Grade 2); pancreatitis, increased serum creatinine (CTCAE >= Grade 2); creatine kinase, hyperglycemia or hypoglycemia, diarrhea or enteritis or nausea (CTCAE >= Grade 3); decreased platelet count (less than [<] 100000 per microliter); prolongation of QT interval with Fridericia's Correction (QTcF) (QTcF >500 millisecond [msec] [CTCAE >= Grade 3] or increase from baseline of >=60 msec) and other considered appropriate by investigator. CTCAE Grade 4.0: Grade 1= mild; Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening consequences and Grade 5= death related to adverse event. | Day 1 up to Day 64 | 
| 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. Treatment-emergent are events between first dose of study drug and up to 64 days that were absent before treatment or that worsened relative to pretreatment state. Adverse events included both serious and non-serious adverse events. | Day 1 up to Day 64 | 
| Number of Participants With Treatment-Emergent Adverse Events by Severity | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent are events between first dose of study drug and up to 64 days that were absent before treatment or that worsened relative to pretreatment state. AEs were assessed for severity by CTCAE Grade 4.0: Grade 1= mild; Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening consequences and Grade 5= death related to adverse event. Categories with at least 1 participant were reported | Day 1 up to Day 64 | 
| 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 64 | 
| Number of Participants With Systemic Treatment Emergent Adverse Events Identified by Physical Examination | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent are events between first dose of study drug and up to 64 days that were absent before treatment or that worsened relative to pretreatment state. Complete physical examination was conducted to assess skin, ears, throat, cardiac, respiratory, gastrointestinal, and musculoskeletal systems for systemic AEs. | Day 1 up to Day 64 | 
| Number of Participants With Systemic Treatment Emergent Adverse Events Identified by Vital Signs | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent are events between first dose of study drug and up to 64 days that were absent before treatment or that worsened relative to pretreatment state. Vital sign parameters body temperature, blood pressure and heart rate were assessed to identify systemic adverse events. AEs (all causalities), treatment related AEs and CTCAE severity grades for AEs were reported. CTCAE Grade 4.0: Grade 1= mild; Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening consequences and Grade 5= death related to adverse event. Categories with at least 1 participant were reported | Day 1 up to Day 64 | 
| Number of Participants With Systemic Treatment Emergent Adverse Events Identified by Electrocardiogram (ECG) Parameters | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent are events between first dose of study drug and up to 64 days that were absent before treatment or that worsened relative to pretreatment state. ECG parameters RR interval, PR interval, QRS complex, QT interval, [Bazett's Correction], QTcF interval [Fridericia's Correction] were assessed to identify systemic AEs. AEs (all causalities), treatment related AEs and CTCAE severity grades for AEs were reported. CTCAE Grade 4.0: Grade 1= mild; Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening consequences and Grade 5= death related to adverse event. Categories with at least 1 participant were reported. | Day 1 up to Day 64 | 
| Number of Participants With Systemic Treatment Emergent Adverse Events Identified by Laboratory Parameters | Laboratory parameters alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma glutamyl transferase, lactate dehydrogenase, albumin, hemoglobin, protein, amylase, creatine kinase, lipase, basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelets, white blood cells, bicarbonate, chloride, potassium, sodium, bilirubin, blood urea nitrogen, c-reactive protein , calcium, creatinine, direct bilirubin, glucose, magnesium, phosphate, uric acid, hematocrit, partial thromboplastin time , prothrombin time, red blood cells , urine pH, urine specific gravity were assessed to identify systemic AEs. AEs (all causalities), treatment related AEs and CTCAE severity grades for AEs were reported. Same participant may be reported in more than 1 CTCAE severity grade. Categories with at least 1 participant were reported. | Day 1 up to Day 64 | 
| Number of Participants With Positive Anti-drug Antibodies (ADA) | Human serum ADA samples of participants who received PF-04950615 (RN316) were analyzed for the presence of anti-PF-04950615 (RN316) antibodies. Results with titer value >=4.32 nanogram per milliliter of anti-PF-04950615 antibodies were counted as positive. Number of participants with presence of anti-PF-04950615 antibodies were reported in this outcome measure. | Day 1 up to Day 64 | 

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