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

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ClinicalTrials.gov Identifier: NCT01984424
Recruitment Status : Completed
First Posted : November 14, 2013
Results First Posted : March 13, 2018
Last Update Posted : March 13, 2018
Sponsor:
Information provided by (Responsible Party):
Amgen

November 8, 2013
November 14, 2013
December 4, 2017
March 13, 2018
March 13, 2018
December 10, 2013
November 10, 2015   (Final data collection date for primary outcome measure)
  • Percent Change From Baseline in LDL-C at the Mean of Weeks 22 and 24 [ Time Frame: Baseline and weeks 22 and 24 ]
  • Percent Change From Baseline in LDL-C at Week 24 [ Time Frame: Baseline and week 24 ]
  • Mean percent change from baseline in low density lipoprotein-cholesterol [ Time Frame: 22 and 24 Weeks ]
    Mean percent change from baseline in low density lipoprotein-cholesterol
  • Percent change from baseline in low density lipoprotein-cholesterol [ Time Frame: 24 Weeks ]
    Percent change from baseline in low density lipoprotein-cholesterol
Complete list of historical versions of study NCT01984424 on ClinicalTrials.gov Archive Site
  • Change From Baseline in LDL-C at the Mean of Weeks 22 and 24 [ Time Frame: Baselie and weeks 22 and 24 ]
  • Change From Baseline in LDL-C at Week 24 [ Time Frame: Baseline and week 24 ]
  • Percentage of Participants Who Achieved a Mean LDL-C at Weeks 22 and 24 of Less Than 70 mg/dL [ Time Frame: Weeks 22 and 24 ]
  • Percentage of Participants Who Achieved LDL-C at Week 24 of Less Than 70 mg/dL [ Time Frame: Week 24 ]
  • Percent Change From Baseline in Total Cholesterol at the Mean of Weeks 22 and 24 [ Time Frame: Baseline and weeks 22 and 24 ]
  • Percent Change From Baseline in Total Cholesterol at Week 24 [ Time Frame: Baseline and week 24 ]
  • Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) at the Mean of Weeks 22 and 24 [ Time Frame: Baseline and weeks 22 and 24 ]
  • Percent Change From Baseline in Non-HDL-C at Week 24 [ Time Frame: Baseline and week 24 ]
  • Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 22 and 24 [ Time Frame: Baseline and weeks 22 and 24 ]
  • Percent Change From Baseline in Apolipoprotein B at Week 24 [ Time Frame: Baseline and week 24 ]
  • Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at the Mean of Weeks 22 and 24 [ Time Frame: Baseline and weeks 22 and 24 ]
  • Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at Week 24 [ Time Frame: Baseline and week 24 ]
  • Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at the Mean of Weeks 22 and 24 [ Time Frame: Baseline and Weeks 22 and 24 ]
  • Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 24 [ Time Frame: Baseline and week 24 ]
  • Percent Change From Baseline in Lipoprotein(a) at the Mean of Weeks 22 and 24 [ Time Frame: Baseline and Weeks 22 and 24 ]
  • Percent Change From Baseline in Lipoprotein(a) at Week 24 [ Time Frame: Baseline and week 24 ]
  • Percent Change From Baseline in Triglycerides at the Mean of Weeks 22 and 24 [ Time Frame: Baseline and weeks 22 and 24 ]
  • Percent Change From Baseline in Triglycerides at Week 24 [ Time Frame: Baseline and week 24 ]
  • Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) at Week 24 [ Time Frame: Baseline and weeks 22 and 24 ]
  • Percent Change From Baseline in HDL-C at Week 24 [ Time Frame: Baseline and week 24 ]
  • Percent Change From Baseline in Very Low-density Lipoprotein Cholesterol (VLDL-C) at the Mean of Weeks 22 and 24 [ Time Frame: Baseline and weeks 22 and 24 ]
  • Percent Change From Baseline in VLDL-C at Week 24 [ Time Frame: Baseline and week 24 ]
  • Mean change from baseline in low density lipoprotein-cholesterol [ Time Frame: 22 and 24 Weeks ]
    Mean change from baseline in low density lipoprotein-cholesterol
  • Change from baseline in low density lipoprotein-cholesterol [ Time Frame: 24 Weeks ]
    Change from baseline in low density lipoprotein-cholesterol
  • Mean low density lipoprotein-cholesterol response (low density lipoprotein-cholesterol < 70 mg/dL [1.8 mmol/L]) [ Time Frame: 22 and 24 Weeks ]
    Mean low density lipoprotein-cholesterol response (low density lipoprotein-cholesterol < 70 mg/dL [1.8 mmol/L])
  • Low density lipoprotein-cholesterol response (low density lipoprotein-cholesterol < 70 mg/dL [1.8 mmol/L]) [ Time Frame: 24 Weeks ]
    Low density lipoprotein-cholesterol response (low density lipoprotein-cholesterol < 70 mg/dL [1.8 mmol/L])
  • Mean percent change from baseline in total cholesterol [ Time Frame: 22 and 24 Weeks ]
    Mean percent change from baseline in total cholesterol
  • Percent change from baseline in total cholesterol [ Time Frame: 24 Weeks ]
    Percent change from baseline in total cholesterol
  • Mean percent change from baseline in non-high density lipoprotein-cholesterol [ Time Frame: 22 and 24 Weeks ]
    Mean percent change from baseline in non-high density lipoprotein-cholesterol
  • Percent change from baseline in non-high density lipoprotein-cholesterol [ Time Frame: 24 Weeks ]
    Percent change from baseline in non-high density lipoprotein-cholesterol
  • Mean percent change from baseline in apolipoprotein B [ Time Frame: 22 and 24 Weeks ]
    Mean percent change from baseline in apolipoprotein B
  • Percent change from baseline in apolipoprotein B [ Time Frame: 24 Weeks ]
    Percent change from baseline in apolipoprotein B
  • Mean percent change from baseline in the total cholesterol/high density lipoprotein-cholesterol ratio [ Time Frame: 22 and 24 Weeks ]
    Mean percent change from baseline in the total cholesterol/high density lipoprotein-cholesterol ratio
  • Percent change from baseline in the total cholesterol/high density lipoprotein-cholesterol ratio [ Time Frame: 24 Weeks ]
    Percent change from baseline in the total cholesterol/high density lipoprotein-cholesterol ratio
  • Mean percent change from baseline in apolipoprotein B/apolipoprotein A1 ratio [ Time Frame: 22 and 24 Weeks ]
    Mean percent change from baseline in apolipoprotein B/apolipoprotein A1 ratio
  • Percent change from baseline in apolipoprotein B/apolipoprotein A1 ratio [ Time Frame: 24 Weeks ]
    Percent change from baseline in apolipoprotein B/apolipoprotein A1 ratio
  • Mean percent change from baseline in lipoprotein (a) [ Time Frame: 22 and 24 Weeks ]
    Mean percent change from baseline in lipoprotein (a)
  • Percent change from baseline in lipoprotein (a) [ Time Frame: 24 Weeks ]
    Percent change from baseline in lipoprotein (a)
  • Mean percent change from baseline in triglycerides [ Time Frame: 22 and 24 Weeks ]
    Mean percent change from baseline in triglycerides
  • Percent change from baseline in triglycerides [ Time Frame: 24 Weeks ]
    Percent change from baseline in triglycerides
  • Mean percent change from baseline in high density lipoprotein-cholesterol [ Time Frame: 22 and 24 Weeks ]
    Mean percent change from baseline in high density lipoprotein-cholesterol
  • Percent change from baseline in high density lipoprotein-cholesterol [ Time Frame: 24 Weeks ]
    Percent change from baseline in high density lipoprotein-cholesterol
  • Mean percent change from baseline in very low density lipoprotein-cholesterol [ Time Frame: 22 and 24 Weeks ]
    Mean percent change from baseline in very low density lipoprotein-cholesterol
  • Percent change from baseline in very low density lipoprotein-cholesterol [ Time Frame: 24 Weeks ]
    Percent change from baseline in very low density lipoprotein-cholesterol
Not Provided
Not Provided
 
Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3
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
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).

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).

Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Hyperlipidemia
  • Drug: Atorvastatin
    Atorvastatin was supplied as over-encapsulated 20 mg tablets
    Other Name: Lipitor
  • Drug: 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 Name: Zetia
  • 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)
    Other Name: Repatha
  • Part A: Atorvastatin 20 mg => Placebo
    Participants received atorvastatin 20 mg orally for 10 weeks (period 1) followed by placebo orally for 10 weeks (period 2), separated by a 2-week washout period.
    Interventions:
    • Drug: Atorvastatin
    • Drug: Placebo to Atorvastatin
  • Part A: Placebo => Atorvastatin 20 mg
    Participants received placebo orally for 10 weeks (period 1) followed by atorvastatin 20 mg orally for 10 weeks (period 2), separated by a 2-week washout period.
    Interventions:
    • Drug: Atorvastatin
    • Drug: Placebo to Atorvastatin
  • Active Comparator: Part B: Ezetimibe
    Participants received 10 mg ezetimibe orally only a day and placebo to evolocumab by subcutaneous injection once a month for 24 weeks.
    Interventions:
    • Drug: Ezetimibe
    • Other: Placebo to Evolocumab
  • Experimental: Part B: Evolocumab
    Participants received 420 mg evolocumab by subcutaneous injection once a month and placebo to ezetimibe orally once a day for 24 weeks.
    Interventions:
    • Other: Placebo to Ezetimibe
    • Drug: Evolocumab
  • Experimental: Part C: Open-label Evolocumab
    Participants who completed part B and were eligible to proceed to open-label extension part C and could choose quarterly between evolocumab 420 mg once a month or evolocumab 140 mg every 2 weeks for up to 2 years.
    Intervention: Drug: Evolocumab
Nissen SE, Stroes E, Dent-Acosta RE, Rosenson RS, Lehman SJ, Sattar N, Preiss D, Bruckert E, Ceška R, Lepor N, Ballantyne CM, Gouni-Berthold I, Elliott M, Brennan DM, Wasserman SM, Somaratne R, Scott R, Stein EA; GAUSS-3 Investigators. Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial. JAMA. 2016 Apr 19;315(15):1580-90. doi: 10.1001/jama.2016.3608.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
511
500
November 21, 2017
November 10, 2015   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
18 Years to 80 Years   (Adult, Older Adult)
No
Contact information is only displayed when the study is recruiting subjects
Australia,   Canada,   Czechia,   Denmark,   France,   Germany,   Italy,   Netherlands,   New Zealand,   Norway,   South Africa,   United Kingdom,   United States
Czech Republic
 
NCT01984424
20120332
2013-000935-29 ( EudraCT Number )
Yes
Not Provided
Not Provided
Amgen
Amgen
Not Provided
Study Director: MD Amgen
Amgen
February 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP