Trial Assessing Long Term USe of PCSK9 Inhibition in Subjects With Genetic LDL Disorders (TAUSSIG)

A Multicenter, Open-label Study to Assess the Long-term Safety, Tolerability, and Efficacy of Evolocumab (AMG145) on LDL-C in Subjects With Severe Familial Hypercholesterolemia

A study to assess the long term safety and tolerability of evolocumab (AMG 145) in adolescents and adults with severe familial hypercholesterolemia.

Study Overview

• Status: Completed
• Conditions: Severe Familial Hypercholesterolemia
• Intervention / Treatment: Biological: Evolocumab

Detailed Description

This phase 2/3 open-label extension study was designed to characterize the safety and tolerability of long-term administration of evolocumab to adults and adolescents with severe FH (HoFH or non-HoFH severe FH). Participants not on lipid apheresis at enrollment or within the prior 8 weeks initiated treatment with evolocumab 420 mg once monthly (QM). Participants on lipid apheresis at enrollment initiated treatment with evolocumab 420 mg once every 2 weeks (Q2W). Dose frequency changes (420 mg QM vs 420 mg Q2W) were permitted at week 12, 24, or other visits with Sponsor approval. Participants with < 5% LDL-C reduction from baseline and serum unbound proprotein convertase subtilisin/kexin type 9 (PCSK9) < 100 ng/mL could discontinue evolocumab. If serum unbound PCSK9 was ≥ 100 ng/mL with QM dosing, the participant could switch to evolocumab 420 mg Q2W treatment. Participants on apheresis with ≥ 5% LDL-C reduction from baseline and serum unbound PCSK9 < 100 ng/mL with Q2W treatment could switch to QM dosing.

Participants were to continue to receive open-label evolocumab for up to 5 years or until evolocumab became commercially available in the relevant patient population, whichever occurred first.

• Study Type: Interventional
• Enrollment (Actual): 300
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Australia
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
      • Research Site
  • Western Australia
    • Perth, Western Australia, Australia, 6000
      • Research Site
• Belgium
  • Bruxelles, Belgium, 1200
    • Research Site
  • La Louvière, Belgium, 7100
    • Research Site
• Brazil
  • São Paulo, Brazil, 05403-000
    • Research Site
  • São Paulo
    • Sao Paulo, São Paulo, Brazil, 04039-030
      • Research Site
• Canada
  • Quebec, Canada, G1V 4M6
    • Research Site
  • Ontario
    • London, Ontario, Canada, N6A 5K8
      • Research Site
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 7K9
      • Research Site
    • Montreal, Quebec, Canada, H3A 1A1
      • Research Site
    • Montreal, Quebec, Canada, H2W 1R7
      • Research Site
• Czechia
  • Brno, Czechia, 656 91
    • Research Site
  • Hradec Kralove, Czechia, 500 05
    • Research Site
  • Olomouc, Czechia, 775 20
    • Research Site
  • Praha 2, Czechia, 128 08
    • Research Site
  • Uherske Hradiste, Czechia, 686 01
    • Research Site
• France
  • Dijon, France, 21000
    • Research Site
  • Paris Cedex 13, France, 75651
    • Research Site
• Greece
  • Athens, Greece, 17674
    • Research Site
• Hong Kong
  • New Territories, Hong Kong
    • Research Site
• Israel
  • Ramat Gan, Israel, 52621
    • Research Site
• Italy
  • Cinisello Balsamo (MI), Italy, 20092
    • Research Site
  • Napoli, Italy, 80131
    • Research Site
  • Pisa, Italy, 56124
    • Research Site
• Japan
  • Ishikawa
    • Kanazawa, Ishikawa, Japan, 920-8641
      • Research Site
  • Osaka
    • Suita, Osaka, Japan, 565-8565
      • Research Site
• Lebanon
  • Beirut, Lebanon, 0000
    • Research Site
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Research Site
  • Rotterdam, Netherlands, 3045 PM
    • Research Site
• New Zealand
  • Christchurch, New Zealand, 8011
    • Research Site
• South Africa
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 2193
      • Research Site
  • Western Cape
    • Observatory, Western Cape, South Africa, 7925
      • Research Site
• Spain
  • Madrid, Spain, 28040
    • Research Site
  • Andalucía
    • Cordoba, Andalucía, Spain, 14004
      • Research Site
  • Cataluña
    • Barcelona, Cataluña, Spain, 08036
      • Research Site
  • Galicia
    • A Coruña, Galicia, Spain, 15001
      • Research Site
    • Lugo, Galicia, Spain, 27003
      • Research Site
• United Kingdom
  • Manchester, United Kingdom, M13 9WL
    • Research Site
• United States
  • California
    • Los Angeles, California, United States, 90048
      • Research Site
  • New York
    • New York, New York, United States, 10021
      • Research Site
    • New York, New York, United States, 10032
      • Research Site
    • New York, New York, United States, 10029
      • Research Site
  • Ohio
    • Cincinnati, Ohio, United States, 45227
      • Research Site
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 80 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

- Participated in Study 20110233 (NCT01588496) or another qualifying evolocumab parent protocol and have a diagnosis of familial hypercholesterolemia.

OR

• Have a diagnosis of familial hypercholesterolemia AND
• Males and females ≥ 12 to ≤ 80 years of age
• Stable low-fat diet and lipid-lowering therapies for at least 4 weeks
• Low-density lipoprotein cholesterol (LDL-C) >= 130 mg/dl (3.4 mmol/L) for subjects without diagnosed coronary heart disease (CHD)/CHD risk equivalent OR LDL-C >= 100 mg/dl (2.6 mmol/L) for subjects with diagnosed CHD or CHD risk equivalent OR apheresis patients have no LDL-C entry requirement
• Fasting triglycerides ≤ 400 mg/dL(4.5 mmol/L)
• Body weight of > 40 kg or greater at screening for subjects less than 18 years of age

Exclusion Criteria:

• New York Heart Failure Association (NYHA) class III or IV or last known left ventricular ejection fraction < 30%
• Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months of screening
• Planned cardiac surgery or revascularization
• Uncontrolled cardiac arrhythmia
• Uncontrolled hypertension

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Evolocumab; Participants received 420 mg evolocumab every month (participants not on lipid apheresis) or every 2 weeks (participants on lipid apheresis) for up to 5 years. Participants could switch dosing regimens at week 12 or 24 based on LDL-C and serum unbound proprotein convertase subtilisin/kexin type 9 (PCSK9) levels.	Biological: Evolocumab; Evolocumab was administered by subcutaneous injection either once a month (QM) or once every two weeks (Q2W).; Other Names: Repatha; AMG 145

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events	The severity of each adverse event (AE) was graded according to the National Cancer Institute Common Terminology Criteria for AEs (NCI-CTCAE) grading scale, where grade 1 = mild AE, grade 2 = moderate AE, grade 3 = severe AE, grade 4 = life-threatening AE and grade 5 = death due to AE.	From first dose of study drug in Study 20110271 up to 30 days after the last dose or until the end of study date, whichever was earlier; median duration of treatment was 48.7 months.

Secondary Outcome Measures

Outcome Measure	Time Frame
Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C)	Baseline and weeks 4, 6, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, and 216
Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C)	Baseline and weeks 4, 6, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, and 216
Percent Change From Baseline in Lipoprotein (a)	Baseline and weeks 4, 6, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, and 216
Percent Change From Baseline in Apolipoprotein B	Baseline and weeks 4, 6, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, and 216
Percent Change From Baseline in Total Cholesterol/HDL-C Ratio	Baseline and weeks 4, 6, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, and 216
Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio	Baseline and weeks 4, 6, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, and 216
Percentage of Participants With a 15% or Greater Reduction in LDL-C	Baseline and weeks 4, 6, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, and 216

Collaborators and Investigators

• Sponsor: Amgen
• Investigators: Study Director: MD, Amgen

Publications and helpful links

General Publications

• 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.
• Schmidt AF, Carter JL, Pearce LS, Wilkins JT, Overington JP, Hingorani AD, Casas JP. PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2020 Oct 20;10(10):CD011748. doi: 10.1002/14651858.CD011748.pub3.
• Raal FJ, Hovingh GK, Blom D, Santos RD, Harada-Shiba M, Bruckert E, Couture P, Soran H, Watts GF, Kurtz C, Honarpour N, Tang L, Kasichayanula S, Wasserman SM, Stein EA. Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolaemia: an interim subset analysis of the open-label TAUSSIG study. Lancet Diabetes Endocrinol. 2017 Apr;5(4):280-290. doi: 10.1016/S2213-8587(17)30044-X. Epub 2017 Feb 16.
• Santos RD, Stein EA, Hovingh GK, Blom DJ, Soran H, Watts GF, Lopez JAG, Bray S, Kurtz CE, Hamer AW, Raal FJ. Long-Term Evolocumab in Patients With Familial Hypercholesterolemia. J Am Coll Cardiol. 2020 Feb 18;75(6):565-574. doi: 10.1016/j.jacc.2019.12.020.
• Stein EA, Honarpour N, Wasserman SM, Xu F, Scott R, Raal FJ. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation. 2013 Nov 5;128(19):2113-20. doi: 10.1161/CIRCULATIONAHA.113.004678. Epub 2013 Sep 6.
• Raal FJ, Hegele RA, Ruzza A, Lopez JAG, Bhatia AK, Wu J, Wang H, Gaudet D, Wiegman A, Wang J, Santos RD. Evolocumab Treatment in Pediatric Patients With Homozygous Familial Hypercholesterolemia: Pooled Data From Three Open-Label Studies. Arterioscler Thromb Vasc Biol. 2024 May;44(5):1156-1164. doi: 10.1161/ATVBAHA.123.320268. Epub 2024 Mar 28.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2012
• Primary Completion (Actual): May 11, 2018
• Study Completion (Actual): May 11, 2018

Study Registration Dates

• First Submitted: June 5, 2012
• First Submitted That Met QC Criteria: June 18, 2012
• First Posted (Estimated): June 20, 2012

Study Record Updates

• Last Update Posted (Actual): May 28, 2024
• Last Update Submitted That Met QC Criteria: May 10, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Elevated Cholesterol; Hypercholesterolemia; High Cholesterol; Homozygous Familial Hypercholesterolemia; PCSK9 mutations; Severe Familial Hypercholesterolemia
• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Hypercholesterolemia; Hyperlipoproteinemia Type II; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Protease Inhibitors; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Serine Proteinase Inhibitors; PCSK9 Inhibitors; Evolocumab
• Other Study ID Numbers: 20110271; 2011-005400-15 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No