Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): a randomised, double-blind, placebo-controlled phase 2 trial.

MedStar author(s):
Citation: Lancet. 386(9992):452-60, 2015 Aug 1.PMID: 26047975Institution: MedStar Health Research InstituteForm of publication: Journal ArticleMedline article type(s): Clinical Trial, Phase II | Journal Article | Multicenter Study | Randomized Controlled Trial | Research Support, Non-U.S. Gov'tSubject headings: *Cholesterol Ester Transfer Proteins/ai [Antagonists & Inhibitors] | *Dyslipidemias/dt [Drug Therapy] | *Fluorobenzenes/ad [Administration & Dosage] | *Heptanoic Acids/ad [Administration & Dosage] | *Hydroxymethylglutaryl-CoA Reductase Inhibitors/ad [Administration & Dosage] | *Pyrimidines/ad [Administration & Dosage] | *Pyrroles/ad [Administration & Dosage] | *Quinolines/pd [Pharmacology] | *Sulfonamides/ad [Administration & Dosage] | Adolescent | Adult | Aged | Cholesterol, HDL/bl [Blood] | Cholesterol, HDL/de [Drug Effects] | Cholesterol, LDL/bl [Blood] | Cholesterol, LDL/de [Drug Effects] | Denmark | Double-Blind Method | Female | Humans | Male | Middle Aged | Netherlands | Quinolines/ad [Administration & Dosage] | Treatment Outcome | Young AdultYear: 2015Local holdings: Available online from MWHC library: 1995 - present, Available in print through MWHC library: 1983 - 2007ISSN:
  • 0140-6736
Name of journal: Lancet (London, England)Abstract: BACKGROUND: Dyslipidaemia remains a significant risk factor for cardiovascular disease and additional lipid-modifying treatments are warranted to further decrease the cardiovascular disease burden. We assessed the safety, tolerability and efficacy of a novel cholesterol esterase transfer protein (CETP) inhibitor TA-8995 in patients with mild dyslipidaemia.FINDINGS: Between Aug 15, 2013, and Jan 10, 2014, 364 patients were enrolled. At week 12, LDL cholesterol levels were reduced by 274% in patients assigned to the 1 mg dose, 327% in patients given the 25 mg dose, 453% in those given the 5 mg dose, and 453% in those given the 10 mg dose (p<00001). LDL cholesterol levels were reduced by 682% in patients given 10 mg TA-8995 plus atorvastatin, and by 633% in patients given rosuvastatin plus 10 mg TA-8995 (p<00001). A daily dose of 1 mg TA-8995 increased HDL cholesterol levels by 758%, 25 mg by 1243%, 5 mg by 1571%, and 10 mg dose by 1790% (p<00001). In patients receiving 10 mg TA-8995 and 20 mg atorvastatin HDL cholesterol levels increased by 1521% and in patients receiving 10 mg TA-8995 and 10 mg rosuvastatin by 1575%. We recorded no serious adverse events or signs of liver or muscle toxic effects.FUNDING: Dezima.Copyright � 2015 Elsevier Ltd. All rights reserved.INTERPRETATION: TA-8995, a novel CETP inhibitor, is well tolerated and has beneficial effects on lipids and apolipoproteins in patients with mild dyslipidaemia. A cardiovascular disease outcome trial is needed to translate these effects into a reduction of cardiovascular disease events.METHODS: In this randomised, double-blind, placebo-controlled, parallel-group phase 2 trial, we recruited patients (aged 18-75 years) from 17 sites (hospitals and independent clinical research organisations) in the Netherlands and Denmark with fasting LDL cholesterol levels between 25 mmol/L and 45 mmol/L, HDL cholesterol levels between 08 and 18 mmol/L and triglyceride levels below 45 mmol/L after washout of lipid-lowering treatments. Patients were randomly allocated (1:1) by a computer-generated randomisation schedule to receive one of the following nine treatments: a once a day dose of 1 mg, 25 mg, 5 mg, or 10 mg TA-8995 or matching placebo; 10 mg TA-8995 plus 20 mg atorvastatin; 10 mg TA-8995 plus 10 mg rosuvastatin or 20 mg atorvastatin or 10 mg rosuvastatin alone. We overencapsulated statins to achieve masking. The primary outcome was percentage change in LDL cholesterol and HDL cholesterol from baseline at week 12, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01970215.All authors: Barter PJ, Brewer HB, Ford J, Hovingh GK, Kastelein JJ, Rader DJ, Round P, Saleheen D, van Deventer SJFiscal year: FY2016Digital Object Identifier: Date added to catalog: 2016-01-13
Holdings
Item type Current library Collection Call number Status Date due Barcode
Journal Article MedStar Authors Catalog Article 26047975 Available 26047975

Available online from MWHC library: 1995 - present, Available in print through MWHC library: 1983 - 2007

BACKGROUND: Dyslipidaemia remains a significant risk factor for cardiovascular disease and additional lipid-modifying treatments are warranted to further decrease the cardiovascular disease burden. We assessed the safety, tolerability and efficacy of a novel cholesterol esterase transfer protein (CETP) inhibitor TA-8995 in patients with mild dyslipidaemia.

FINDINGS: Between Aug 15, 2013, and Jan 10, 2014, 364 patients were enrolled. At week 12, LDL cholesterol levels were reduced by 274% in patients assigned to the 1 mg dose, 327% in patients given the 25 mg dose, 453% in those given the 5 mg dose, and 453% in those given the 10 mg dose (p<00001). LDL cholesterol levels were reduced by 682% in patients given 10 mg TA-8995 plus atorvastatin, and by 633% in patients given rosuvastatin plus 10 mg TA-8995 (p<00001). A daily dose of 1 mg TA-8995 increased HDL cholesterol levels by 758%, 25 mg by 1243%, 5 mg by 1571%, and 10 mg dose by 1790% (p<00001). In patients receiving 10 mg TA-8995 and 20 mg atorvastatin HDL cholesterol levels increased by 1521% and in patients receiving 10 mg TA-8995 and 10 mg rosuvastatin by 1575%. We recorded no serious adverse events or signs of liver or muscle toxic effects.

FUNDING: Dezima.Copyright � 2015 Elsevier Ltd. All rights reserved.

INTERPRETATION: TA-8995, a novel CETP inhibitor, is well tolerated and has beneficial effects on lipids and apolipoproteins in patients with mild dyslipidaemia. A cardiovascular disease outcome trial is needed to translate these effects into a reduction of cardiovascular disease events.

METHODS: In this randomised, double-blind, placebo-controlled, parallel-group phase 2 trial, we recruited patients (aged 18-75 years) from 17 sites (hospitals and independent clinical research organisations) in the Netherlands and Denmark with fasting LDL cholesterol levels between 25 mmol/L and 45 mmol/L, HDL cholesterol levels between 08 and 18 mmol/L and triglyceride levels below 45 mmol/L after washout of lipid-lowering treatments. Patients were randomly allocated (1:1) by a computer-generated randomisation schedule to receive one of the following nine treatments: a once a day dose of 1 mg, 25 mg, 5 mg, or 10 mg TA-8995 or matching placebo; 10 mg TA-8995 plus 20 mg atorvastatin; 10 mg TA-8995 plus 10 mg rosuvastatin or 20 mg atorvastatin or 10 mg rosuvastatin alone. We overencapsulated statins to achieve masking. The primary outcome was percentage change in LDL cholesterol and HDL cholesterol from baseline at week 12, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01970215.

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