Antigen-Lipid-Driven Monoclonal Gammopathies Targeting Epicardial Fat

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Sponsorid

University of Miami

KLIINILISES UURINGUS: NCT02920190

BioSeek: nct02920190

Märksõnad

Abstraktne

Background

Antigen-driven selection has been implicated in the pathogenesis of monoclonal gammopathies. Patients with Gaucher's disease have an increased risk of monoclonal gammopathies and symptomatic myeloma. Clonal immunoglobulin in patients with Gaucher's disease and in mouse models of Gaucher's disease-associated gammopathy are reactive against lyso-glucosylceramide (LGL1), which is markedly elevated in these patients and mice. A recent report indicates that clonal immunoglobulins in 33% of sporadic human monoclonal gammopathies may also be specific for the lysolipids LGL1 and lysophosphatidylcholine. Substrate reduction ameliorates Gaucher's disease-associated gammopathy in mice. This principle (that antigen removal can induce tumor regression) has been proven in other hematologic malignancies, where H. Pylori eradication causes lymphoma regression is a significant group of patients. Thus, as longterm immune activation by lysolipids may underlie both Gaucher's disease-associated gammopathies and some sporadic monoclonal gammopathies, this may represent a focus for treatment.

Epicardial fat (EAT), the visceral fat of the heart, is highly enriched in genes involved in inflammation and lipid metabolism; it activates local and systemic inflammation and innate inflammatory response. EAT is rich in saturated fatty acids and has high protein content, and the greatest capacity for free fatty acids release and uptake among any other visceral fat depots. Of interest, EAT is highly enriched in sphingolipids, including ceramide. EAT clinical measurability with an ultrasound technique, first developed and validated by Iacobellis, and its rapid responsiveness and reduction to medications targeting the visceral fat, such as the glucagon-like peptide 1 analogues (GLP1A), as ongoing clinical trials are demonstrating, is of growing and remarkable interest.

Study Hypothesis

To target EAT, as marker of visceral fat, with GLP1A treatment to modulate/reduce/remove the antigen(s) (lipid/inflammatory/immune) stimulation for patients with monoclonal gammopathies that are lipid targeted.

Study Design

Interventional, single-group, open label pilot study. The investigators will identify monoclonal gammopathy patients whose antibodies are lipid/visceral fat targeted (goal is 10 initially as a pilot) and who are overweight/obese (BMI > 27). Eligible patients will be started on Liraglutide up to 1.8 mg sc once daily, as adjunct weight loss treatment for 12 months.

Study Endpoints

- Ultrasound measured EAT reduction by at least 20%

- Improvement in the monoclonal immunoglobulin profile Reduction in plasma ceramide and lipidomics levels

Parameters will be monitored at 3 months, 6 months and 12 months.

Kuupäevad

Viimati kinnitatud:	12/31/2019
Esmalt esitatud:	08/21/2016
Hinnanguline registreerumine on esitatud:	09/27/2016
Esmalt postitatud:	09/29/2016
Viimane värskendus on esitatud:	01/01/2020
Viimati värskendus postitatud:	01/02/2020
Õppe tegelik alguskuupäev:	08/31/2020
Eeldatav esmane lõpetamise kuupäev:	08/31/2021
Eeldatav uuringu lõpetamise kuupäev:	12/30/2021

Seisund või haigus

Monoclonal Gammopathies

Overweight

Obesity

Sekkumine / ravi

Drug: Liraglutide

Faas

Faas 4

Käerühmad

Arm	Sekkumine / ravi
Experimental: Liraglutide Eligible patients will be started on Liraglutide up to 1.8 mg sc once daily, as adjunct weight loss treatment for 12 months.	Drug: Liraglutide Interventional, single-group, open label pilot study. The investigators will identify monoclonal gammopathy patients whose antibodies are lipid/VAT targeted (goal is 10 initially as a pilot) and who are overweight/obese (BMI > 27). Eligible patients will be started on Liraglutide up to 1.8 mg sc once daily, as adjunct weight loss treatment for 12 months.

Abikõlblikkuse kriteeriumid

Õppimiseks sobivad vanused	18 Years To 18 Years
Uuringuks kõlblikud sood	All
Võtab vastu tervislikke vabatahtlikke	Jah
Kriteeriumid	Inclusion Criteria: - BMI ≥27 kg/m2 - At least one overweight/obesity related comorbidity (such as type 2 diabetes, pre-diabetes [IFG, IGT], hypertension, dyslipidemia) - Age > 18 and < 70 years old Exclusion Criteria: - Known contra-indications to Liraglutide, such as previous history of pancreatitis or medullary thyroid carcinoma, personal or family history of MEN, in accordance with risks and safety information included in the latest updated Prescribing Information for Victoza® - Type 1 diabetes, as defined by American Diabetes Association (ADA) criteria - Insulin dependent or treated type 2 diabetes - Current use of other injectable incretins - History of diabetes ketoacidosis - Advanced Chronic Kidney Disease, as defined by Glomerular Filtration Rate (GFR) < 30 mL/min/1.73m2 - Clinical signs or symptoms of New York Heart Association (NYHA) class III-IV heart failure - Clinical or laboratory evidences of chronic active liver diseases - Acute or chronic infective diseases - Known or suspected allergy to Liraglutide, excipients, or related products - Pregnant, breast-feeding or the intention of becoming pregnant - Females of childbearing potential who are not using adequate contraceptive methods

Tulemus

Esmased tulemusnäitajad

1. Ultrasound Epicardial Fat Thickness [6-12 months]

Epicardial fat thickness (mm) reduction by at least 20%

Sekundaarsed tulemusmõõdud

1. Monoclonal gammopathy [6-12 months]

Changes in serum immunoglobulins

2. Plasma ceramide [6-12 months]

Reduction in plasma ceramide levels (mcmol/L)

Antigen-Lipid-Driven Monoclonal Gammopathies Targeting Epicardial Fat

Märksõnad

ceramide

lysophosphatidylcholine

saturated fatty acid

vähk

põletik

lymphoma

rasvumus

paraproteinemias

kaalukaotus