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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

Brief 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).

Condition or disease Intervention/treatment Phase
Hyperlipidemia Drug: Atorvastatin Drug: Placebo to Atorvastatin Other: Placebo to Ezetimibe Drug: Ezetimibe Other: Placebo to Evolocumab Drug: Evolocumab Phase 3

Detailed 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).


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 511 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : December 10, 2013
Actual Primary Completion Date : November 10, 2015
Actual Study Completion Date : November 21, 2017


Arm Intervention/treatment
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.
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
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.
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
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.
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)
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.
Other: Placebo to Ezetimibe
Placebo matching to Ezetimibe supplied as over-encapsulated tablets.
Drug: Evolocumab
Evolocumab supplied as single-use prefilled autoinjector/pen(s)
Other Name: Repatha
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.
Drug: Evolocumab
Evolocumab supplied as single-use prefilled autoinjector/pen(s)
Other Name: Repatha



Primary Outcome Measures :
  1. Percent Change From Baseline in LDL-C at the Mean of Weeks 22 and 24 [ Time Frame: Baseline and weeks 22 and 24 ]
  2. Percent Change From Baseline in LDL-C at Week 24 [ Time Frame: Baseline and week 24 ]

Secondary Outcome Measures :
  1. Change From Baseline in LDL-C at the Mean of Weeks 22 and 24 [ Time Frame: Baselie and weeks 22 and 24 ]
  2. Change From Baseline in LDL-C at Week 24 [ Time Frame: Baseline and week 24 ]
  3. 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 ]
  4. Percentage of Participants Who Achieved LDL-C at Week 24 of Less Than 70 mg/dL [ Time Frame: Week 24 ]
  5. Percent Change From Baseline in Total Cholesterol at the Mean of Weeks 22 and 24 [ Time Frame: Baseline and weeks 22 and 24 ]
  6. Percent Change From Baseline in Total Cholesterol at Week 24 [ Time Frame: Baseline and week 24 ]
  7. 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 ]
  8. Percent Change From Baseline in Non-HDL-C at Week 24 [ Time Frame: Baseline and week 24 ]
  9. Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 22 and 24 [ Time Frame: Baseline and weeks 22 and 24 ]
  10. Percent Change From Baseline in Apolipoprotein B at Week 24 [ Time Frame: Baseline and week 24 ]
  11. 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 ]
  12. Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at Week 24 [ Time Frame: Baseline and week 24 ]
  13. 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 ]
  14. Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 24 [ Time Frame: Baseline and week 24 ]
  15. Percent Change From Baseline in Lipoprotein(a) at the Mean of Weeks 22 and 24 [ Time Frame: Baseline and Weeks 22 and 24 ]
  16. Percent Change From Baseline in Lipoprotein(a) at Week 24 [ Time Frame: Baseline and week 24 ]
  17. Percent Change From Baseline in Triglycerides at the Mean of Weeks 22 and 24 [ Time Frame: Baseline and weeks 22 and 24 ]
  18. Percent Change From Baseline in Triglycerides at Week 24 [ Time Frame: Baseline and week 24 ]
  19. Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) at Week 24 [ Time Frame: Baseline and weeks 22 and 24 ]
  20. Percent Change From Baseline in HDL-C at Week 24 [ Time Frame: Baseline and week 24 ]
  21. 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 ]
  22. Percent Change From Baseline in VLDL-C at Week 24 [ Time Frame: Baseline and week 24 ]


Information from the National Library of Medicine

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

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

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): NCT01984424


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Sponsors and Collaborators
Amgen
Investigators
Study Director: MD Amgen

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT01984424     History of Changes
Other Study ID Numbers: 20120332
2013-000935-29 ( EudraCT Number )
First Posted: November 14, 2013    Key Record Dates
Results First Posted: March 13, 2018
Last Update Posted: March 13, 2018
Last Verified: February 2018

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

Additional relevant MeSH terms:
Hyperlipidemias
Hyperlipoproteinemias
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Atorvastatin Calcium
Ezetimibe
Antibodies, Monoclonal
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors
Immunologic Factors
Physiological Effects of Drugs