Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3

Hyperlipidemia Clinical Trial

— GAUSS-3  

Official title:

A Double-blind, Randomized, Multicenter Study to Evaluate the Safety and Efficacy of Evolocumab, Compared With Ezetimibe, in Hypercholesterolemic Subjects Unable to Tolerate an Effective Dose of a HMG-CoA Reductase Inhibitor Due to Muscle Related Side Effects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01984424
• Other study ID #: 20120332
• Secondary ID: 2013-000935-29
• Status: Completed
• Phase: Phase 3
• Start date: December 10, 2013
• Est. completion date: November 21, 2017

Study information

• Verified date: November 2018
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective of this study was to evaluate the effect of 24 weeks of evolocumab administered subcutaneously (SC) every month, compared with ezetimibe, on low-density lipoprotein cholesterol (LDL-C) levels in adults with high cholesterol who are unable to tolerate an effective dose of a statin due to muscle-related side effects (MRSE).

Description:

The study is divided into 3 parts (A, B, C). After an initial 4-week washout period in which any statins, ezetimibe, or other lipid-lowering agents were discontinued, participants were enrolled in phase A, a double-blind, placebo-controlled crossover procedure to rechallenge patients with atorvastatin. Patients were randomly assigned in a 1:1 ratio to receive either atorvastatin (20 mg daily) or matching placebo for the first 10 weeks (period 1), then underwent a 2-week washout period, followed by crossover to the alternate therapy for a second 10-week period (period 2). Patients who experienced intolerable muscle symptoms during the first period did not complete the full 10 weeks of exposure but entered a 2-week washout period before proceeding to period 2.

Participants who did not develop muscle-related side effects were removed from the study, as were patients who reported muscle-related side effects during a placebo period.

After completion of phase A, patients who experienced muscle-related adverse effects while taking atorvastatin but not placebo were eligible for phase B, a 24-week, double-blind randomization to ezetimibe or evolocumab using a double-dummy design in which patients received either injectable placebo and oral ezetimibe or injectable evolocumab and oral placebo. A patient could proceed directly to phase B if they had a documented history of creatine kinase (CK) elevation more than 10 times the upper limit of normal accompanied by muscle symptoms while taking statin therapy, with documented resolution of both CK elevation and symptoms upon discontinuation of statin therapy.

These study procedures were designed to ensure that only patients with reproducible statin-associated muscle symptoms entered phase B of the study. For phase B, participants were randomized 2:1 to receive subcutaneously administered evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily). Randomization in part B was stratified by screening LDL-C level (< 180 mg/dL [4.66 mmol/L] vs. ≥ 180 mg/dL) at study baseline.

Participants who completed phase B and did not discontinue SC investigational product for any reason, including an adverse event, were eligible to proceed to the 2-year open-label extension phase C to evaluate the long-term safety and efficacy of evolocumab in statin-intolerant patients. Participants in phase C were allowed to choose quarterly between evolocumab 420 mg SC QM or evolocumab 140 mg SC every 2 weeks (Q2W).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 511
• Est. completion date: November 21, 2017
• Est. primary completion date: November 10, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Male or female = 18 to = 80 years of age

• Subject not at LDL-C goal

• History of statin intolerance

• Lipid lowering therapy has been stable prior to enrolment for at least 4 weeks

• Fasting triglycerides = 400 mg/dL

Exclusion Criteria:

• New York Heart Association (NYHA) III or IV heart failure

• Uncontrolled cardiac arrhythmia

• Uncontrolled hypertension

• Type 1 diabetes

• Poorly controlled type 2 diabetes

• Uncontrolled hypothyroidism or hyperthyroidism

Related Conditions & MeSH terms

• Hyperlipidemia
• Hyperlipidemias
• Hyperlipoproteinemias

Intervention

Drug:
• Atorvastatin
Atorvastatin was supplied as over-encapsulated 20 mg tablets
• Placebo to Atorvastatin
Placebo matching to atorvastatin supplied as over-encapsulated tablets

Other:
• Placebo to Ezetimibe
Placebo matching to Ezetimibe supplied as over-encapsulated tablets.

Drug:
• Ezetimibe
Ezetimibe was supplied as 10 mg tablets, over-encapsulated for blinding.

Other:
• Placebo to Evolocumab
Placebo matching to evolocumab supplied as single-use prefilled autoinjector/pen(s)

Drug:
• Evolocumab
Evolocumab supplied as single-use prefilled autoinjector/pen(s)

Locations

Country	Name	City	State
Australia	Research Site	Ashford	South Australia
Australia	Research Site	Camperdown	New South Wales
Australia	Research Site	Woolloongabba	Queensland
Canada	Research Site	Hamilton	Ontario
Canada	Research Site	London	Ontario
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Peterborough	Ontario
Canada	Research Site	Quebec
Canada	Research Site	St-Charles-Borromee	Quebec
Canada	Research Site	Vancouver	British Columbia
Czechia	Research Site	Hradec Kralove
Czechia	Research Site	Praha 2
Czechia	Research Site	Praha 4
Denmark	Research Site	Aarhus N
Denmark	Research Site	Glostrup
France	Research Site	Nantes Cedex 1
France	Research Site	Paris Cedex 13
France	Research Site	Vénissieux
Germany	Research Site	Berlin
Germany	Research Site	Köln
Germany	Research Site	München
Italy	Research Site	Bologna
Italy	Research Site	Cagliari
Italy	Research Site	Cinisello Balsamo (MI)
Italy	Research Site	Ferrara
Italy	Research Site	Perugia
Italy	Research Site	Pisa
Netherlands	Research Site	Amsterdam
Netherlands	Research Site	Rotterdam
Netherlands	Research Site	Zwijndrecht
New Zealand	Research Site	Christchurch
Norway	Research Site	Ålesund
Norway	Research Site	Oslo
South Africa	Research Site	Johannesburg	Gauteng
South Africa	Research Site	Midrand	Gauteng
South Africa	Research Site	Observatory	Western Cape
South Africa	Research Site	Parow	Western Cape
United Kingdom	Research Site	Birmingham
United Kingdom	Research Site	Glasgow
United Kingdom	Research Site	Newcastle upon Tyne
United States	Research Site	Ann Arbor	Michigan
United States	Research Site	Atlanta	Georgia
United States	Research Site	Baltimore	Maryland
United States	Research Site	Beverly Hills	California
United States	Research Site	Charleston	South Carolina
United States	Research Site	Cleveland	Ohio
United States	Research Site	Durham	North Carolina
United States	Research Site	Houston	Texas
United States	Research Site	Huntington Beach	California
United States	Research Site	Kansas City	Kansas
United States	Research Site	Los Angeles	California
United States	Research Site	New York	New York
United States	Research Site	Rochester	Minnesota
United States	Research Site	Saint Louis	Missouri
United States	Research Site	San Pedro	California
United States	Research Site	Sterling	Illinois
United States	Research Site	Towson	Maryland
United States	Research Site	York	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Czechia,  Denmark,  France,  Germany,  Italy,  Netherlands,  New Zealand,  Norway,  South Africa,  United Kingdom, 

References & Publications (1)

Cho L, Dent R, Stroes ESG, Stein EA, Sullivan D, Ruzza A, Flower A, Somaratne R, Rosenson RS. Persistent Safety and Efficacy of Evolocumab in Patients with Statin Intolerance: a Subset Analysis of the OSLER Open-Label Extension Studies. Cardiovasc Drugs Ther. 2018 Aug;32(4):365-372. doi: 10.1007/s10557-018-6817-7. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent Change From Baseline in LDL-C at the Mean of Weeks 22 and 24		Baseline and weeks 22 and 24
Primary	Percent Change From Baseline in LDL-C at Week 24		Baseline and week 24
Secondary	Change From Baseline in LDL-C at the Mean of Weeks 22 and 24		Baselie and weeks 22 and 24
Secondary	Change From Baseline in LDL-C at Week 24		Baseline and week 24
Secondary	Percentage of Participants Who Achieved a Mean LDL-C at Weeks 22 and 24 of Less Than 70 mg/dL		Weeks 22 and 24
Secondary	Percentage of Participants Who Achieved LDL-C at Week 24 of Less Than 70 mg/dL		Week 24
Secondary	Percent Change From Baseline in Total Cholesterol at the Mean of Weeks 22 and 24		Baseline and weeks 22 and 24
Secondary	Percent Change From Baseline in Total Cholesterol at Week 24		Baseline and week 24
Secondary	Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) at the Mean of Weeks 22 and 24		Baseline and weeks 22 and 24
Secondary	Percent Change From Baseline in Non-HDL-C at Week 24		Baseline and week 24
Secondary	Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 22 and 24		Baseline and weeks 22 and 24
Secondary	Percent Change From Baseline in Apolipoprotein B at Week 24		Baseline and week 24
Secondary	Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at the Mean of Weeks 22 and 24		Baseline and weeks 22 and 24
Secondary	Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at Week 24		Baseline and week 24
Secondary	Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at the Mean of Weeks 22 and 24		Baseline and Weeks 22 and 24
Secondary	Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 24		Baseline and week 24
Secondary	Percent Change From Baseline in Lipoprotein(a) at the Mean of Weeks 22 and 24		Baseline and Weeks 22 and 24
Secondary	Percent Change From Baseline in Lipoprotein(a) at Week 24		Baseline and week 24
Secondary	Percent Change From Baseline in Triglycerides at the Mean of Weeks 22 and 24		Baseline and weeks 22 and 24
Secondary	Percent Change From Baseline in Triglycerides at Week 24		Baseline and week 24
Secondary	Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) at Week 24		Baseline and weeks 22 and 24
Secondary	Percent Change From Baseline in HDL-C at Week 24		Baseline and week 24
Secondary	Percent Change From Baseline in Very Low-density Lipoprotein Cholesterol (VLDL-C) at the Mean of Weeks 22 and 24		Baseline and weeks 22 and 24
Secondary	Percent Change From Baseline in VLDL-C at Week 24		Baseline and week 24

External Links

•   AmgenTrials clinical trials website