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

Amgen

Status and phase: Completed; Phase 3

Conditions: Hyperlipidemia

Treatments: Drug: Evolocumab; Drug: Ezetimibe; Other: Placebo to Evolocumab; Other: Placebo to Ezetimibe; Drug: Placebo to Atorvastatin; Drug: Atorvastatin

Study type: Interventional

Funder types: Industry

Identifiers

NCT01984424

20120332

2013-000935-29 (EudraCT Number)

Details and patient eligibility

About

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).

Full 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).

Enrollment: 511 patients

Sex: All

Ages: 18 to 80 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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511 participants in 5 patient groups

Part A: Atorvastatin 20 mg => Placebo

Other group

Description:

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.

Treatment:

Drug: Atorvastatin

Drug: Placebo to Atorvastatin

Part A: Placebo => Atorvastatin 20 mg

Other group

Description:

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.

Treatment:

Drug: Atorvastatin

Drug: Placebo to Atorvastatin

Part B: Ezetimibe

Active Comparator group

Description:

Participants received 10 mg ezetimibe orally only a day and placebo to evolocumab by subcutaneous injection once a month for 24 weeks.

Treatment:

Other: Placebo to Evolocumab

Drug: Ezetimibe

Part B: Evolocumab

Experimental group

Description:

Participants received 420 mg evolocumab by subcutaneous injection once a month and placebo to ezetimibe orally once a day for 24 weeks.

Treatment:

Other: Placebo to Ezetimibe

Drug: Evolocumab

Part C: Open-label Evolocumab

Experimental group

Description:

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.

Treatment:

Drug: Evolocumab