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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01163851
First Posted: July 16, 2010
Last Update Posted: November 6, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Pfizer
  Purpose
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.

Condition Intervention Phase
Hypercholesterolemia Dyslipidemia Biological: 4 mg/kg Biological: 0.5 mg/kg Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study Evaluating The Pharmacokinetics And Pharmacodynamics Of Rn316 In Combination With Atorvastatin In Hypercholesterolemic Subjects

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-04950615 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 is the time measured for the plasma concentration of PF-04950615 to decrease by one half.

  • Systemic Clearance (CL) of PF-04950615 [ Time Frame: 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 ]
    CL is a quantitative measure of the rate at which a drug substance is removed from the body.

  • Volume of Distribution at Steady State (Vss) of PF-04950615 [ Time Frame: 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 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.

  • Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC0-inf) of PF-04950615 [ Time Frame: 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 [ Time Frame: 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8 and 12 hrs post-dose on Day 4 ]
    AUCtau was the AUC from time 0 to the end of the dosing interval, where the dosing interval was 12 hours.

  • Time to Reach Maximum Observed Plasma Concentration (Tmax) of Atorvastatin [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 is the time measured for the plasma concentration of atorvastatin to decrease by one half.

  • Apparent Oral Clearance (CL/F) of Atorvastatin [ Time Frame: 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8 and 12 hrs post-dose on Day 4 ]
    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.

  • Apparent Volume of Distribution (Vz/F) of Atorvastatin [ Time Frame: 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8 and 12 hrs post-dose on Day 4 ]
    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.


Secondary Outcome Measures:
  • 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 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ]
    Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration.

  • Change From Baseline in Fasting Total Cholesterol at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ]
    Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration.

  • 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 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ]
    Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration.

  • Change From Baseline in Fasting Triglycerides at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ]
    Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration.

  • Change From Baseline in Fasting Apolipoprotein B (ApoB) at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ]
    Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration.

  • Change From Baseline in Fasting Apolipoprotein A1 (ApoA1) at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ]
    Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 (RN316) administration.

  • Change From Baseline in Fasting High-Density Lipoprotein (HDL) Cholesterol at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ]
    Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration.

  • 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 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ]
    Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration.

  • Percent Change From Baseline in Total Cholesterol at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ]
    Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration.

  • 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 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ]
    Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration.

  • Percent Change From Baseline in Fasting Triglycerides Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ]
    Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 (RN316) administration.

  • Percent Change From Baseline in Fasting Apolipoprotein B (ApoB) Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ]
    Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 (RN316) administration.

  • 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 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ]
    Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration.

  • Percent Change From Baseline in Fasting Apolipoprotein A1 (ApoA1) Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ]
    Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 (RN316) administration.

  • Duration of Low Density Lipoprotein (LDL) Lowering Effects [ Time Frame: Day 4 to Day 64 ]
    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.

  • Number of Participants With Toxicity or Intolerable Dose Criteria [ Time Frame: Day 1 up to Day 64 ]
    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.

  • Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Day 1 up to Day 64 ]
    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.

  • Number of Participants With Treatment-Emergent Adverse Events by Severity [ Time Frame: Day 1 up to Day 64 ]
    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

  • Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Day 1 up to Day 64 ]
    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.

  • Number of Participants With Systemic Treatment Emergent Adverse Events Identified by Physical Examination [ Time Frame: Day 1 up to Day 64 ]
    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.

  • Number of Participants With Systemic Treatment Emergent Adverse Events Identified by Vital Signs [ Time Frame: Day 1 up to Day 64 ]
    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

  • Number of Participants With Systemic Treatment Emergent Adverse Events Identified by Electrocardiogram (ECG) Parameters [ Time Frame: Day 1 up to Day 64 ]
    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.

  • Number of Participants With Systemic Treatment Emergent Adverse Events Identified by Laboratory Parameters [ Time Frame: Day 1 up to Day 64 ]
    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.

  • Number of Participants With Positive Anti-drug Antibodies (ADA) [ Time Frame: Day 1 up to Day 64 ]
    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.


Enrollment: 25
Actual Study Start Date: July 2010
Study Completion Date: April 2011
Primary Completion Date: February 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: PF-04950615 (RN316) Biological: 4 mg/kg
RN316 10 mg/ml vial sd. Infusion based on weight Infusion duration = 60 minutes.
Other Name: PF-04950615 (RN316)
Biological: 0.5 mg/kg
RN316 10 mg/ml vial sd. Infusion based on weight Infusion duration = 60 minutes.
Other Name: PF-04950615 (RN316)

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01163851


Locations
United States, Arizona
Premier Research Group, Limited
Peoria, Arizona, United States, 85381
Dedicated Phase 1, Inc.
Phoenix, Arizona, United States, 85013
Premier Research Group Limited
Phoenix, Arizona, United States, 85027
United States, Kansas
Vince and Associates Clinical Research
Overland Park, Kansas, United States, 66211
Vince and Associates Clinical Research
Overland Park, Kansas, United States, 66212
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01163851     History of Changes
Other Study ID Numbers: B1481003
First Submitted: July 14, 2010
First Posted: July 16, 2010
Results First Submitted: April 20, 2015
Results First Posted: May 7, 2015
Last Update Posted: November 6, 2017
Last Verified: October 2017

Keywords provided by Pfizer:
Hypercholesterolemia
Dyslipidemia
LDL
Cholesterol
High Cholesterol
PF-04950615
RN316

Additional relevant MeSH terms:
Hypercholesterolemia
Dyslipidemias
Hyperlipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Atorvastatin Calcium
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors