Safety, Tolerability, PK and PD of LGT209 in Healthy Volunteers and Patients With Hypercholesterolemia

A Randomized, Double-blind, Placebo-controlled, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intravenously Administered LGT209 in Healthy Volunteers and Patients With Hypercholesterolemia on Stable Doses of Statin Medications

This study is designed to measure the effects of LGT209 when given intravenously to patients with high cholesterol who are on stable doses of statin medications, and to healthy subjects with elevated cholesterol

Study Overview

• Status: Completed
• Conditions: Hypercholesterolemia
• Intervention / Treatment: Drug: Placebo; Drug: LGT209

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami Gardens, Florida, United States, 33169
      • Novartis Investigative Site
  • North Dakota
    • Fargo, North Dakota, United States, 58104
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy volunteers: Male and female subjects 18 to 70 years of age, in general good health but with high cholesterol
• Statin patients: Male and female patients 18 to 70 years of age, with high cholesterol on stable statin therapy for at least 3 months

Exclusion Criteria:

• Healthy volunteers: History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes
• Women of child-bearing potential unless using highly effective methods of contraception
• Statin patients: Use of any prescription drugs for lipid lowering other than HMG CO-A reductase inhibitors (statins); use of two concurrent antihypertensive medications is allowed, provided stable dosing has been achieved for the prior 3 months
• Women of child-bearing potential unless using highly effective methods of contraception

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

12

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Patient: LGT209 0.3 mg/kg; 0.3 mg/kg LGT209 intravenous administration in patients on stable doses of statins	Drug: LGT209; 150 mg lyophilized powder in glass vial
EXPERIMENTAL: Patient: LGT209 1 mg/kg; 1 mg/kg LGT209 intravenous administration in patients on stable doses of statins	Drug: LGT209; 150 mg lyophilized powder in glass vial
EXPERIMENTAL: Patient: LGT209 3 mg/kg; 3 mg/kg LGT209 intravenous administration in patients on stable doses of statins	Drug: LGT209; 150 mg lyophilized powder in glass vial
EXPERIMENTAL: Patient: LGT209 10 mg/kg; 10 mg/kg LGT209 intravenous administration in patients on stable doses of statins	Drug: LGT209; 150 mg lyophilized powder in glass vial
EXPERIMENTAL: Patient: LGT209 20 mg/kg; 20 mg/kg LGT209 intravenous administration in patients on stable doses of statins	Drug: LGT209; 150 mg lyophilized powder in glass vial
EXPERIMENTAL: Healthy Volunteers: LGT209 0.3 mg/kg; 0.3 mg/kg LGT209 intravenous administration in healthy volunteers	Drug: LGT209; 150 mg lyophilized powder in glass vial
EXPERIMENTAL: Healthy Volunteers: LGT209 1 mg/kg; 1 mg/kg LGT209 intravenous administration in healthy volunteers	Drug: LGT209; 150 mg lyophilized powder in glass vial
EXPERIMENTAL: Healthy Volunteers: LGT209 3 mg/kg; 3 mg/kg LGT209 intravenous administration in healthy volunteers	Drug: LGT209; 150 mg lyophilized powder in glass vial
EXPERIMENTAL: Healthy Volunteers: LGT209 10 mg/kg; 10 mg/kg LGT209 intravenous administration in healthy volunteers	Drug: LGT209; 150 mg lyophilized powder in glass vial
EXPERIMENTAL: Healthy Volunteers: 20 mg/kg; 20 mg/kg LGT209 intravenous administration in healthy volunteers	Drug: LGT209; 150 mg lyophilized powder in glass vial
PLACEBO_COMPARATOR: Patient: Placebo; Matching intravenous placebo in patients on stable doses of statins	Drug: Placebo; Placebo comparator
PLACEBO_COMPARATOR: Healthy Volunteers: Placebo; Matching intravenous placebo in healthy volunteers	Drug: Placebo; Placebo comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with adverse events, serious adverse events and death		from Screening until Day 141
Change from baseline in low density lipoprotein-cholesterol (LDL-C) concentration in healthy volunteers	Baseline was defined as the arithmetic mean of all the pre-treatment values (i.e. Screening, Day -1 and predose on Day 1)	Baseline, Day 29
Change from baseline in proprotein convertase subtilisin/kexin type 9 (PCSK9) in healthy volunteers	Baseline was defined as the arithmetic mean of all the pre-treatment values (i.e. Screening, Day -1 and predose on Day 1)	Baseline, Day 29
Pharmacokinetics of LGT209: : Area under the serum concentration-time curve from time zero to infinity (AUC0-inf) of LGT209 in patients and healthy volunteers following intravenous administration		Day 1 (1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2); 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141
Pharmacokinetics of LGT209: observed maximum serum concentrations (Cmax) of LGT209 in patients and healthy volunteers following intravenous administration		Day 1 (1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2) 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141
Pharmacokinetics of LGT209: Area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-last) of LGT209 in patients and healthy volunteers following intravenous administration		Day 1 (1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2) 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141
Pharmacokinetics of LGT209: Elimination half-life associated with the terminal slope of a semi-logarithmic concentration-time curve (T1/2) of LGT209 in patients and healthy volunteers following intravenous administration		Day 1 (1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2) 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141
Number of healthy volunteers with adverse events, serious adverse events and death		from Screening until Day 141

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics of intravenous LGT209 in relationship to concentrations of PCSK9 and LDL-C in patients and healthy volunteers		Day 1 (1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2) 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141
Change from baseline in low density lipoprotein-cholesterol (LDL-C) concentration in patients	Baseline was defined as the arithmetic mean of all the pre-treatment values (i.e. Screening, Day -1 and predose on Day 1)	Baseline, Day 29
Change from baseline in proprotein convertase subtilisin/kexin type 9 (PCSK9) in patients	Baseline was defined as the arithmetic mean of all the pre-treatment values (i.e. Screening, Day -1 and predose on Day 1)	Baseline, Day 29
Pharmacokinetics of LGT209: Area under the serum concentration-time curve from time zero to time 't' (AUC0-t)	In AUC 0-t, t is a defined as time point after administration of LGT209 in patients and healthy volunteers following intravenous administration	Day 1 (1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2) 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141
Pharmacokinetics of LGT209: Dose-normalized area under the serum concentration-time curve (AUC/D) of LGT209 in patients and healthy volunteers following intravenous administration		Day 1 (1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2) 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141
Pharmacokinetics of LGT209: Dose-normalized maximum serum concentrations (Cmax/D) of LGT209 in patients and healthy volunteers following intravenous administration		Day 1 ( 1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2) 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141
Pharmacokinetics of LGT209: Volume of distribution during the terminal elimination phase (Vz) of LGT209 in patients and healthy volunteers following intravenous administration		Day 1 (1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2) 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141
Pharmacokinetics of LGT209: Volume of distribution at steady state (Vss) of LGT209 in patients and healthy volunteers following intravenous administration		Day 1 (1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2) 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141
Pharmacokinetics of LGT209: Mean residence time (MRT) of LGT209 in patients and healthy volunteers following intravenous administration		Day 1 (1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2) 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141
Pharmacokinetics of LGT209: the systemic (or total body) clearance from serum following intravenous administration		Day 1 (1, 2, 4, 6, 8, 12 hrs post dose); Post-dose at 24 hr (Day 2) 48 hr (Day 3), 96 hr (Day 5), Days 8, 11, 15, 22, 29, 43, 57, 71, 85, 113, 141

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (ACTUAL): November 1, 2011
• Study Completion (ACTUAL): November 1, 2011

Study Registration Dates

• First Submitted: November 4, 2013
• First Submitted That Met QC Criteria: November 4, 2013
• First Posted (ESTIMATE): November 8, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): December 10, 2013
• Last Update Submitted That Met QC Criteria: December 9, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Keywords: LDL-C; LGT209,; hypercholesterolemia,; PCSK9,
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Hypercholesterolemia
• Other Study ID Numbers: CLGT209X2101