Effects of Evolocumab Versus Placebo Added to Standard Lipid-lowering Therapy on Fasting and Post Fat Load Lipids in Patients With Familial Dysbetalipoproteinemia

NCT03811223 | Unknown Phase 4

• 1 other identifier: UMCU-VASC-CO-002
• Study Type: interventional
• Target: 30
• Locations: 0 countries
• Sites: N/A

Brief Summary

Patients with familial dysbetalipoproteinemia (FD) have increased triglycerides, non-high-density lipoprotein cholesterol (non-HDL-C), beta VLDL, premature atherosclerosis and cardiovascular disease. They also have a delayed postprandial triglyceride and chylomicron (CM) remnant clearance. Postprandial hypertriglyceridemia is associated with increased vascular risk. Although combination therapy with statin and fibrate is recommended in the treatment of patients with FD, there is still a substantial amount of patient who do not reach their treatment target with this medication. Furthermore no information is available about the postprandial effects of adding evocolumab to standard lipid lowering therapy in FD patients.

Conditions

Familial Dysbetalipoproteinemia; Hyperlipoproteinemia Type III

Keywords

Postprandial hyperlipidemia; Evolocumab; PCSK9 monoclonal antibody

Outcome Measures

Primary Outcomes (1)

• AUC (area under the curve) non-HDL-cholesterol

  12 weeks

Secondary Outcomes (4)

• Fasting levels, AUC and iAUC of total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and ApoB, as well as fasting non-HDL-cholesterol.

  12 weeks

• Percentage change from baseline and absolute difference in fasting and post fat load non-HDL-cholesterol, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and ApoB.

  12 weeks

• Fasting and post fat load lipoprotein (VLDL1, VLDL2, IDL, LDL, HDL) concentrations and composition (triglycerides, cholesterol, ApoB and apolipoproteins).

  12 weeks

• Post fat load ApoB 48-containing lipoprotein concentrations (chylomicrons and chylomicron remnants) and proteins involved in postprandial lipid metabolism.

  12 weeks

Study Arms (2)

Evolocumab

EXPERIMENTAL

Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks

Drug: Evolocumab Auto-Injector [Repatha]

Placebo

PLACEBO COMPARATOR

Placebo injection once every 2 weeks for 12 weeks

Drug: Placebos

Interventions

Evolocumab Auto-Injector [Repatha] DRUG

Evolocumab 140 mg every 2 weeks for 12 weeks

Evolocumab

Placebos DRUG

Placebo subcutaneous injection every 2 weeks for 12 weeks

Also known as: Placebo

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients diagnosed with Familial Dysbetalipoproteinemia;
• ε2ε2 genotype or dominant APOE mutation genotype (confirmed by genotyping or isoelectric focusing) with any lipid-lowering treatment at a stable dose for at least three months and non-HDL-C \>1.6 mmol/L or;
• Patients with ε2ε2 genotype or dominant APOE mutation (confirmed by genotyping or isoelectric focusing) without lipid-lowering treatment and with an ApoB/TC ratio \< 0.15.
• \>18 years old (on the day of signing informed consent).
• Women are postmenopausal and not receiving hormone therapy (including cyclic and non-cyclical hormone replacement therapy or any estrogen antagonist/agonist). Postmenopausal status is defined as:
• no menses for ≥3 years or;
• no menses for ≥1 year but \<3 years and confirmed by FSH levels elevated into the postmenopausal range (15-150 IU/L).
• Willingness to maintain a stable diet for the duration of the study.
• Understanding of the study procedures, alternative treatments available, and risks involved with the study and voluntarily agreement to participate by giving written informed consent.

You may not qualify if:

• Intolerance, known allergy or hypersensitivity to evolocumab (or other PCSK-9 monoclonal antibodies), latex or any of the components of the medication.
• Current or prior exposure to evolocumab or another PCSK9-inhibitor mAb in the past 12 weeks.
• Unable or unwilling to drink an oral fat load.
• Premenopausal women.
• Uncontrolled diabetes as defined by a HbA1c \>69 mmol/mol.
• BMI \>40 kg/m2.
• Uncontrolled blood pressure with systolic blood pressure \>180 mmHg or diastolic blood pressure \>110 mmHg.
• Increased hepatic enzymes, defined as alanine transaminase (ALAT) or aspartate transaminase (ASAT) \>3 times the ULN, or active liver disease defined as non alcoholic steatohepatitis (NASH), cirrhosis or Child Pugh B and C, or history of chronic active hepatitis B or C; subjects with documented resolution after treatment are permitted.
• Impaired renal function, defined by an estimated glomerular filtration rate (eGFR) \<30 mL/min/1.73m2, and/or need of renal placement therapy or other clinically significant renal disease.
• (Sub)clinical hypothyroidism defined as TSH \>5.0 mcl/U/mL or (sub)clinical hyperthyroidism defined as TSH \< 0.35 mcl/U/ml.
• Increased levels of creatinine kinase defined as \>3 times the ULN.
• Increased fasting levels of triglycerides defined as \>10 mmol/L.
• History of organ transplantation and/or use of immunosuppressive medication.
• Use of fish oil or red yeast rice, bempedoic acid, niacin, CETP inhibitors, lomitapide, mipomersen \< 6 weeks prior to the study or the use of siRNA targeting PCSK9 inhibitors \< 36 weeks prior to the study.
• Active malignancy (\<2 year prior to informed consent), except non-melanoma skin cancer or carcinoma in situ of the cervix.

Sponsors & Collaborators

• UMC Utrecht: lead
• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): collaborator
• Erasmus Medical Center: collaborator
• University Medical Center Nijmegen: collaborator

MeSH Terms

Conditions

Hyperlipoproteinemia Type III

Interventions

evolocumab

Condition Hierarchy (Ancestors)

Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hyperlipoproteinemias; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Frank LJ Visseren, prof

  UMC Utrecht

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Frank LJ Visseren, prof

CONTACT

+31 88 7557324; f.l.j.visseren@umcutrecht.nl

Britt E Heidemann, MD

CONTACT

+31 88 75 579 94; b.e.heidemann@umcutrecht.nl

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: prof. dr. F.L.J. Visseren

Study Record Dates

• First Submitted: January 17, 2019
• First Posted: January 22, 2019
• Study Start: August 1, 2019
• Primary Completion: January 1, 2021
• Study Completion: March 1, 2021
• Last Updated: January 22, 2019

Record last verified: 2019-01