Durable Effect of PCSK9 Antibody CompARed wiTh placEbo Study (DESCARTES)

• Sponsor: Amgen
• Information provided by (Responsible Party): Amgen

Study Description

Brief Summary:

To evaluate the efficacy, safety, and tolerability of 52 weeks of subcutaneous (SC) evolocumab (AMG 145) compared with placebo when added to assigned background lipid-lowering therapy.

Condition or disease	Intervention/treatment	Phase
Hypercholesterolemia	Biological: Evolocumab; Biological: Placebo; Drug: Atorvastatin; Drug: Ezetimibe; Other: Diet Only	Phase 3

Detailed Description:

Eligible participants with screening central laboratory low-density lipoprotein cholesterol (LDL-C) values ≥ 75 mg/dL (1.9 mmol/L) were instructed to follow National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP) Therapeutic Lifestyle Changes (TLC) diet and were assigned to 1 of the following 4 background lipid-lowering therapies for a 4-week stabilization period based upon their screening LDL-C and its distance from the individual's required goal as stipulated by their NCEP ATP III risk category:

1. no drug therapy required - diet alone
2. low dose drug therapy required - diet plus atorvastatin 10 mg orally (PO) once daily (QD)
3. high dose drug therapy required - diet plus atorvastatin 80 mg PO QD
4. maximal drug therapy required - diet plus atorvastatin 80 mg PO QD plus ezetimibe 10 mg PO QD.

If the participant met entry criteria at the end of the lipid stabilization period they were randomized 2:1 to receive evolocumab 420 mg or placebo subcutaneously once a month for 52 weeks in addition to their background therapy.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	905 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	A Double-Blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate Long-Term Tolerability and Durable Efficacy of AMG 145 (Evolocumab) on LDL-C in Hyperlipidemic Subjects
Actual Study Start Date :	January 5, 2012
Actual Primary Completion Date :	October 14, 2013
Actual Study Completion Date :	October 14, 2013

Arms and Interventions

Arm	Intervention/treatment
Experimental: Evolocumab; Participants received evolocumab 420 mg subcutaneously once a month for 52 weeks in addition to background lipid-lowering therapy.	Biological: Evolocumab; Administered by subcutaneous injection once a month; Other Names: AMG 145; Repatha; Drug: Atorvastatin; Background lipid lowering therapy: 10 mg or 80 mg atorvastatin orally once daily.; Drug: Ezetimibe; Background lipid lowering therapy: ezetimibe 10 mg orally once a day; Other: Diet Only; Diet only, no lipid lowering background drug given
Placebo Comparator: Placebo; Participants received placebo subcutaneously once a month for 52 weeks in addition to background lipid-lowering therapy.	Biological: Placebo; Administered by subcutaneous injection once a month; Drug: Atorvastatin; Background lipid lowering therapy: 10 mg or 80 mg atorvastatin orally once daily.; Drug: Ezetimibe; Background lipid lowering therapy: ezetimibe 10 mg orally once a day; Other: Diet Only; Diet only, no lipid lowering background drug given

Outcome Measures

Primary Outcome Measures :

1. Percent Change From Baseline in LDL-C at Week 52 [ Time Frame: Baseline and Week 52 ]
   Cholesterol was measured by means of ultracentrifugation.

Secondary Outcome Measures :

1. Change From Baseline in LDL-C at Week 52 [ Time Frame: Baseline and Week 52 ]
   Cholesterol was measured by means of ultracentrifugation.
2. Percentage of Participants With an LDL-C Response at Week 52 [ Time Frame: Week 52 ]
   An LDL-C response is defined as LDL-C level < 70 mg/dL (1.8 mmol/L) at Week 52.
3. Percent Change From Baseline in LDL-C at Week 12 [ Time Frame: Baseline and Week 12 ]
   Cholesterol was measured by means of ultracentrifugation.
4. Percent Change From Baseline in Total Cholesterol at Week 12 [ Time Frame: Baseline and Week 12 ]
5. Percent Change From Baseline in Total Cholesterol at Week 52 [ Time Frame: Baseline and Week 52 ]
6. Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) at Week 52 [ Time Frame: Baseline and Week 52 ]
7. Percent Change From Baseline in Apolipoprotein B at Week 52 [ Time Frame: Baseline and Week 52 ]
8. Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 52 [ Time Frame: Baseline and Week 52 ]
9. Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 52 [ Time Frame: Baseline and Week 52 ]
10. Percent Change From Baseline in Lipoprotein(a) at Week 52 [ Time Frame: Baseline and Week 52 ]
11. Percent Change From Baseline in Triglycerides at Week 52 [ Time Frame: Baseline and Week 52 ]
12. Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) at Week 52 [ Time Frame: Baseline and Week 52 ]
13. Percent Change From Baseline in Very Low-density Lipoprotein Cholesterol (VLDL-C) at Week 52 [ Time Frame: Baseline and Week 52 ]
    Cholesterol was measured by means of ultracentrifugation.
14. Percent Change From Week 12 to Week 52 in LDL-C [ Time Frame: Week 12 and Week 52 ]
    Cholesterol was measured by means of ultracentrifugation.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Subject has provided informed consent.

• Fasting LDL-C ≥ 75 mg/dL and meeting the following LDL-C values on background lipid-lowering therapy:

  • < 100 mg/dL for subjects with diagnosed coronary heart disease (CHD) or CHD risk equivalent
  • < 130 mg/dL for subjects without diagnosed CHD or CHD risk equivalent
  • OR on maximal background lipid-lowering therapy defined as atorvastatin 80 mg PO QD and ezetimibe 10 mg PO QD
• Fasting triglycerides ≤ 400 mg/dL

Exclusion Criteria:

• New York Heart Association (NYHA) II-IV heart failure, or last known left ventricular ejection fraction < 30%
• Uncontrolled cardiac arrhythmia
• Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months prior to randomization, type 1 diabetes, newly diagnosed or poorly controlled type 2 diabetes
• Uncontrolled hypertension

Contacts and Locations

  Show 96 Study Locations

Sponsors and Collaborators

Amgen

Investigators

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Study Director:	MD	Amgen

More Information

Additional Information:

AmgenTrials clinical trials website 

Publications:

Toth PP, Sattar N, Blom DJ, Martin SS, Jones SR, Monsalvo ML, Elliott M, Davis M, Somaratne R, Preiss D. Effect of Evolocumab on Lipoprotein Particles. Am J Cardiol. 2018 Feb 1;121(3):308-314. doi: 10.1016/j.amjcard.2017.10.028. Epub 2017 Nov 8.

Blom DJ, Koren MJ, Roth E, Monsalvo ML, Djedjos CS, Nelson P, Elliott M, Wasserman SM, Ballantyne CM, Holman RR. Evaluation of the efficacy, safety and glycaemic effects of evolocumab (AMG 145) in hypercholesterolaemic patients stratified by glycaemic status and metabolic syndrome. Diabetes Obes Metab. 2017 Jan;19(1):98-107. doi: 10.1111/dom.12788. Epub 2016 Oct 14.

Sattar N, Toth PP, Blom DJ, Koren MJ, Soran H, Uhart M, Elliott M, Cyrille M, Somaratne R, Preiss D. Effect of the Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Evolocumab on Glycemia, Body Weight, and New-Onset Diabetes Mellitus. Am J Cardiol. 2017 Nov 1;120(9):1521-1527. doi: 10.1016/j.amjcard.2017.07.047. Epub 2017 Jul 31.

Toth PP, Descamps O, Genest J, Sattar N, Preiss D, Dent R, Djedjos C, Wu Y, Geller M, Uhart M, Somaratne R, Wasserman SM; PROFICIO Investigators. Pooled Safety Analysis of Evolocumab in Over 6000 Patients From Double-Blind and Open-Label Extension Studies. Circulation. 2017 May 9;135(19):1819-1831. doi: 10.1161/CIRCULATIONAHA.116.025233. Epub 2017 Mar 1.

Kuchimanchi M, Grover A, Emery MG, Somaratne R, Wasserman SM, Gibbs JP, Doshi S. Population pharmacokinetics and exposure-response modeling and simulation for evolocumab in healthy volunteers and patients with hypercholesterolemia. J Pharmacokinet Pharmacodyn. 2018 Jun;45(3):505-522. doi: 10.1007/s10928-018-9592-y. Epub 2018 May 7.

Kasichayanula S, Grover A, Emery MG, Gibbs MA, Somaratne R, Wasserman SM, Gibbs JP. Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor. Clin Pharmacokinet. 2018 Jul;57(7):769-779. doi: 10.1007/s40262-017-0620-7. Review.

Wasserman SM, Sabatine MS, Koren MJ, Giugliano RP, Legg JC, Emery MG, Doshi S, Liu T, Somaratne R, Gibbs JP. Comparison of LDL-C Reduction Using Different Evolocumab Doses and Intervals: Biological Insights and Treatment Implications. J Cardiovasc Pharmacol Ther. 2018 Sep;23(5):423-432. doi: 10.1177/1074248418774043. Epub 2018 May 16.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Blom DJ, Djedjos CS, Monsalvo ML, Bridges I, Wasserman SM, Scott R, Roth E. Effects of Evolocumab on Vitamin E and Steroid Hormone Levels: Results From the 52-Week, Phase 3, Double-Blind, Randomized, Placebo-Controlled DESCARTES Study. Circ Res. 2015 Sep 25;117(8):731-41. doi: 10.1161/CIRCRESAHA.115.307071. Epub 2015 Jul 30.

Blom DJ, Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L, Ceska R, Roth E, Koren MJ, Ballantyne CM, Monsalvo ML, Tsirtsonis K, Kim JB, Scott R, Wasserman SM, Stein EA; DESCARTES Investigators. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014 May 8;370(19):1809-19. doi: 10.1056/NEJMoa1316222. Epub 2014 Mar 29.

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Responsible Party:	Amgen
ClinicalTrials.gov Identifier:	NCT01516879 History of Changes
Other Study ID Numbers:	20110109
First Posted:	January 25, 2012
Results First Posted:	September 29, 2015
Last Update Posted:	November 28, 2018
Last Verified:	November 2018

Keywords provided by Amgen:

Cholesterol; High Cholesterol; Elevated Cholesterol; Raised Cholesterol

Additional relevant MeSH terms:

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Hypercholesterolemia; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Atorvastatin; Ezetimibe; Evolocumab; 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