LDL-C Assessment With PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy-2 (LAPLACE-2)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Amgen
ClinicalTrials.gov Identifier:
NCT01763866
First received: January 7, 2013
Last updated: November 18, 2015
Last verified: November 2015
  Purpose
The primary objective was to evaluate the effect of 12 weeks of evolocumab administered subcutaneously every 2 weeks (Q2W) and monthly (QM) when used in combination with a statin, compared with placebo, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in patients with primary hypercholesterolemia and mixed dyslipidemia.

Condition Intervention Phase
Hyperlipidemia
Biological: Evolocumab
Drug: Ezetimibe
Drug: Placebo to Evolocumab
Drug: Placebo to Ezetimibe
Drug: Atorvastatin
Drug: Rosuvastatin
Drug: Simvastatin
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Double-blind, Randomized, Placebo and Ezetimibe Controlled, Multicenter Study to Evaluate Safety, Tolerability and Efficacy of AMG 145 on LDL-C in Combination With Statin Therapy in Subjects With Primary Hypercholesterolemia and Mixed Dyslipidemia

Resource links provided by NLM:


Further study details as provided by Amgen:

Primary Outcome Measures:
  • Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
  • Percent Change From Baseline in LDL-C at the Mean of Weeks 10 and 12 [ Time Frame: Baseline and Weeks 10 and 12 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Change From Baseline in LDL-C at at the Mean of Weeks 10 and 12 [ Time Frame: Baseline and Weeks 10 and 12 ] [ Designated as safety issue: No ]
  • Change From Baseline in LDL-C at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
  • Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) at the Mean of Weeks 10 and 12 [ Time Frame: Baseline and Weeks 10 and 12 ] [ Designated as safety issue: No ]
  • Percent Change From Baseline in Non-HDL-C at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
  • Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 10 and 12 [ Time Frame: Baseline and Weeks 10 and 12 ] [ Designated as safety issue: No ]
  • Percent Change From Baseline in Apolipoprotein B at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
  • Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at the Mean of Weeks 10 and 12 [ Time Frame: Baseline and Weeks 10 and 12 ] [ Designated as safety issue: No ]
  • Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
  • Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at the Mean of Weeks 10 and 12 [ Time Frame: Baseline and Weeks 10 and 12 ] [ Designated as safety issue: No ]
  • Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
  • Percentage of Participants Who Achieved a Mean LDL-C at Weeks 10 and 12 of Less Than 70 mg/dL [ Time Frame: Weeks 10 and 12 ] [ Designated as safety issue: No ]
  • Percentage of Participants Who Achieved LDL-C < 70 mg/dL at Week 12 [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
  • Percent Change From Baseline in Lipoprotein(a) at the Mean of Weeks 10 and 12 [ Time Frame: Baseline and Weeks 10 and 12 ] [ Designated as safety issue: No ]
  • Percent Change From Baseline in Lipoprotein(a) at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
  • Percent Change From Baseline in Triglycerides at the Mean of Weeks 10 and 12 [ Time Frame: Baseline and Weeks 10 and 12 ] [ Designated as safety issue: No ]
  • Percent Change From Baseline in Triglycerides at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
  • Percent Change From Baseline in Very Low-Density Cholesterol (VLDL-C) at the Mean of Weeks 10 and 12 [ Time Frame: Baseline and Weeks 10 and 12 ] [ Designated as safety issue: No ]
  • Percent Change From Baseline in Very Low-Density Cholesterol (VLDL-C) at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
  • Percent Change From Baseline in HDL-C at the Mean of Weeks 10 and 12 [ Time Frame: Baseline and Weeks 10 and 12 ] [ Designated as safety issue: No ]
  • Percent Change From Baseline in HDL-C at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]

Enrollment: 2067
Study Start Date: January 2013
Study Completion Date: December 2013
Primary Completion Date: November 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: A10 PBO Q2W
Participants received atorvastatin 10 mg once daily during the 4 week lipid stabilization period and then in combination with placebo (PBO) subcutaneous injection once every 2 weeks (Q2W) and placebo tablets once daily for up to 12 weeks.
Drug: Placebo to Evolocumab
Administered by subcutaneous injection
Drug: Placebo to Ezetimibe
Administered orally once a day
Drug: Atorvastatin
Administered orally once a day
Other Name: Lipitor
Placebo Comparator: A10 PBO QM
Participants received atorvastatin 10 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every month (QM) and placebo tablets once a day for up to 12 weeks.
Drug: Placebo to Evolocumab
Administered by subcutaneous injection
Drug: Placebo to Ezetimibe
Administered orally once a day
Drug: Atorvastatin
Administered orally once a day
Other Name: Lipitor
Active Comparator: A10 EZE (Q2W)
Participants received atorvastatin 10 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every 2 weeks and 10 mg ezetimibe (EZE) orally once a day for up to 12 weeks.
Drug: Ezetimibe
Administered orally once a day
Other Name: Zetia
Drug: Placebo to Evolocumab
Administered by subcutaneous injection
Drug: Atorvastatin
Administered orally once a day
Other Name: Lipitor
Active Comparator: A10 EZE (QM)
Participants received atorvastatin 10 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once a month and 10 mg ezetimibe orally once a day for up to 12 weeks.
Drug: Ezetimibe
Administered orally once a day
Other Name: Zetia
Drug: Placebo to Evolocumab
Administered by subcutaneous injection
Drug: Atorvastatin
Administered orally once a day
Other Name: Lipitor
Experimental: A10 EvoMab Q2W
Participants received atorvastatin 10 mg a day during the 4-week lipid stabilization period and then with 140 mg evolocumab (EvoMab) by subcutaneous injection once every 2 weeks and placebo tablets once a day for up to 12 weeks.
Biological: Evolocumab
Administered by subcutaneous injection
Other Names:
  • AMG 145
  • Repatha
Drug: Placebo to Ezetimibe
Administered orally once a day
Drug: Atorvastatin
Administered orally once a day
Other Name: Lipitor
Experimental: A10 EvoMab QM
Participants received atorvastatin 10 mg a day during the 4-week lipid stabilization period and then with 420 mg evolocumab by subcutaneous injection once a month and placebo tablets once a day for up to 12 weeks.
Biological: Evolocumab
Administered by subcutaneous injection
Other Names:
  • AMG 145
  • Repatha
Drug: Placebo to Ezetimibe
Administered orally once a day
Drug: Atorvastatin
Administered orally once a day
Other Name: Lipitor
Placebo Comparator: A80 PBO Q2W
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every 2 weeks and placebo tablets once a day for up to 12 weeks.
Drug: Placebo to Evolocumab
Administered by subcutaneous injection
Drug: Placebo to Ezetimibe
Administered orally once a day
Drug: Atorvastatin
Administered orally once a day
Other Name: Lipitor
Placebo Comparator: A80 PBO QM
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every month and placebo tablets once a day for up to 12 weeks.
Drug: Placebo to Evolocumab
Administered by subcutaneous injection
Drug: Placebo to Ezetimibe
Administered orally once a day
Drug: Atorvastatin
Administered orally once a day
Other Name: Lipitor
Active Comparator: A80 EZE (Q2W)
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every 2 weeks and 10 mg ezetimibe orally once a day for up to 12 weeks.
Drug: Ezetimibe
Administered orally once a day
Other Name: Zetia
Drug: Placebo to Evolocumab
Administered by subcutaneous injection
Drug: Atorvastatin
Administered orally once a day
Other Name: Lipitor
Active Comparator: A80 EZE (QM)
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once a month and 10 mg ezetimibe orally once a day for up to 12 weeks.
Drug: Ezetimibe
Administered orally once a day
Other Name: Zetia
Drug: Placebo to Evolocumab
Administered by subcutaneous injection
Drug: Atorvastatin
Administered orally once a day
Other Name: Lipitor
Experimental: A80 EvoMab Q2W
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with 140 mg evolocumab by subcutaneous injection once every 2 weeks and placebo tablets once a day for up to 12 weeks.
Biological: Evolocumab
Administered by subcutaneous injection
Other Names:
  • AMG 145
  • Repatha
Drug: Placebo to Ezetimibe
Administered orally once a day
Drug: Atorvastatin
Administered orally once a day
Other Name: Lipitor
Experimental: A80 EvoMab QM
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with 420 mg evolocumab by subcutaneous injection once a month and placebo tablets once a day for up to 12 weeks.
Biological: Evolocumab
Administered by subcutaneous injection
Other Names:
  • AMG 145
  • Repatha
Drug: Placebo to Ezetimibe
Administered orally once a day
Drug: Atorvastatin
Administered orally once a day
Other Name: Lipitor
Placebo Comparator: R5 PBO Q2W
Participants received rosuvastatin 5 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every 2 weeks for up to 12 weeks.
Drug: Placebo to Evolocumab
Administered by subcutaneous injection
Drug: Rosuvastatin
Administered orally once a day
Other Name: Crestor
Placebo Comparator: R5 PBO QM
Participants received rosuvastatin 5 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every month for up to 12 weeks.
Drug: Placebo to Evolocumab
Administered by subcutaneous injection
Drug: Rosuvastatin
Administered orally once a day
Other Name: Crestor
Experimental: R5 EvoMab Q2W
Participants received rosuvastatin 5 mg a day during the 4-week lipid stabilization period and then with 140 mg evolocumab by subcutaneous injection once every 2 weeks for up to 12 weeks.
Biological: Evolocumab
Administered by subcutaneous injection
Other Names:
  • AMG 145
  • Repatha
Drug: Rosuvastatin
Administered orally once a day
Other Name: Crestor
Experimental: R5 EvoMab QM
Participants received rosuvastatin 5 mg a day during the 4-week lipid stabilization period and then with 420 mg evolocumab by subcutaneous injection once a month for up to 12 weeks.
Biological: Evolocumab
Administered by subcutaneous injection
Other Names:
  • AMG 145
  • Repatha
Drug: Rosuvastatin
Administered orally once a day
Other Name: Crestor
Placebo Comparator: R40 PBO Q2W
Participants received rosuvastatin 40 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every 2 weeks for up to 12 weeks.
Drug: Placebo to Evolocumab
Administered by subcutaneous injection
Drug: Rosuvastatin
Administered orally once a day
Other Name: Crestor
Placebo Comparator: R40 PBO QM
Participants received rosuvastatin 40 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every month for up to 12 weeks.
Drug: Placebo to Evolocumab
Administered by subcutaneous injection
Drug: Rosuvastatin
Administered orally once a day
Other Name: Crestor
Experimental: R40 EvoMab Q2W
Participants received rosuvastatin 40 mg a day during the 4-week lipid stabilization period and then with 140 mg evolocumab by subcutaneous injection once every 2 weeks for up to 12 weeks.
Biological: Evolocumab
Administered by subcutaneous injection
Other Names:
  • AMG 145
  • Repatha
Drug: Rosuvastatin
Administered orally once a day
Other Name: Crestor
Experimental: R40 EvoMab QM
Participants received rosuvastatin 40 mg a day during the 4-week lipid stabilization period and then with 420 mg evolocumab by subcutaneous injection once a month for up to 12 weeks.
Biological: Evolocumab
Administered by subcutaneous injection
Other Names:
  • AMG 145
  • Repatha
Drug: Rosuvastatin
Administered orally once a day
Other Name: Crestor
Placebo Comparator: S40 PBO Q2W
Participants received simvastatin 40 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every 2 weeks for up to 12 weeks.
Drug: Placebo to Evolocumab
Administered by subcutaneous injection
Drug: Simvastatin
Administered orally once a day
Other Name: Zocor
Placebo Comparator: S40 PBO QM
Participants received simvastatin 40 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every month for up to 12 weeks.
Drug: Placebo to Evolocumab
Administered by subcutaneous injection
Drug: Simvastatin
Administered orally once a day
Other Name: Zocor
Experimental: S40 EvoMab Q2W
Participants received simvastatin 40 mg a day during the 4-week lipid stabilization period and then with 140 mg evolocumab by subcutaneous injection once every 2 weeks for up to 12 weeks.
Biological: Evolocumab
Administered by subcutaneous injection
Other Names:
  • AMG 145
  • Repatha
Drug: Simvastatin
Administered orally once a day
Other Name: Zocor
Experimental: S40 EvoMab QM
Participants received simvastatin 40 mg a day during the 4-week lipid stabilization period and then with 420 mg evolocumab by subcutaneous injection once a month for up to 12 weeks.
Biological: Evolocumab
Administered by subcutaneous injection
Other Names:
  • AMG 145
  • Repatha
Drug: Simvastatin
Administered orally once a day
Other Name: Zocor

Detailed Description:

Prior to the first randomization, participants entered a screening period to determine eligibility. During screening, all participants received subcutaneous placebo corresponding to the once monthly dose volume. Participants who completed the screening period and met eligibility criteria were randomized to 1 of 5 open-label statin cohorts (atorvastatin 10 mg or 80 mg, rosuvastatin 5 mg or 40 mg, or simvastatin 40 mg) for a 4 week lipid stabilization period based on statin therapy at the time of study entry (no statin use vs non-intensive statin use vs intensive statin use).

After the 4-week lipid-stabilization period, eligible patients taking rosuvastatin or simvastatin during the lipid-stabilization phase were then randomized to 1 of 4 treatment groups: evolocumab (140 mg, subcutaneous, every 2 weeks) or matching placebo (subcutaneous, every 2 weeks), or evolocumab (420 mg, subcutaneous, monthly) or matching placebo (subcutaneous, monthly). Patients taking atorvastatin during the lipid-stabilization phase were then randomized to 1 of 6 treatment groups: evolocumab (140 mg, subcutaneous, every 2 weeks) and placebo (oral, daily), evolocumab (420 mg, subcutaneous, monthly) and placebo (oral, daily), placebo (subcutaneous, every 2 weeks) and placebo (oral, daily) or ezetimibe (10 mg, oral, daily), or placebo (subcutaneous, monthly) and placebo (oral, daily) or ezetimibe (10 mg, oral, daily).

A participant was considered randomized into the study after successfully completing the screening period, meeting all inclusion/exclusion criteria, and undergoing both randomization procedures.

Participants randomized to simvastatin who were taking verapamil or diltiazem prior to randomization received simvastatin 10 mg once daily (QD) while participants who were taking amlodipine, amiodarone or ranolazine prior to randomization received simvastatin 20 mg QD. All other participants randomized to simvastatin received simvastatin 40 mg QD.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female ≥ 18 to ≤ 80 years of age
  • Subjects not taking a statin must have fasting LDL-C of at least 150 mg/dL (4.0 mmol/L)
  • Subjects already on a non-intensive statin must have fasting LDL-C at screening ≥ 100 mg/dL (2.6 mmol/L)
  • Subjects already on a intensive statin must have fasting LDL-C at screening ≥ 80 mg/dL (2.1 mmol/L)
  • Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L)

Exclusion Criteria:

  • Statin intolerance
  • New York Heart association (NYHA) III or IV heart failure
  • Uncontrolled hypertension
  • Uncontrolled cardiac arrhythmia
  • Type 1 diabetes, poorly controlled type 2 diabetes
  • Uncontrolled hypothyroidism or hyperthyroidism
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01763866

  Show 244 Study Locations
Sponsors and Collaborators
Amgen
Investigators
Study Director: MD Amgen
  More Information

Additional Information:
Publications:
Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT01763866     History of Changes
Other Study ID Numbers: 20110115  2012-001363-70 
Study First Received: January 7, 2013
Results First Received: September 1, 2015
Last Updated: November 18, 2015
Health Authority: Hong Kong: Department of Health
Czech Republic: State Institute for Drug Control
Russia: Ministry of Health of the Russian Federation
Australia: Department of Health and Ageing Therapeutic Goods Administration
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Paul-Ehrlich-Institut
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Belgium: Federal Agency for Medicinal Products and Health Products
Denmark: Danish Health and Medicines Authority
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Sweden: Medical Products Agency
Switzerland: Swissmedic
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Canada: Health Canada
United States: Food and Drug Administration
Hungary: National Institute of Pharmacy
Italy: Ethics Committee

Keywords provided by Amgen:
High cholesterol, Treatment for high cholesterol, Lowering cholesterol, Lowering high cholesterol, Hypercholesterolemia

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

ClinicalTrials.gov processed this record on July 21, 2016