Rationale and design of dal-VESSEL: a study to assess the safety and efficacy of dalcetrapib on endothelial function using brachial artery flow-mediated vasodilatation

Abstract

Objective:

Dalcetrapib increases high-density lipoprotein cholesterol (HDL-C) levels through effects on cholesteryl ester transfer protein (CETP). As part of the dalcetrapib dal-HEART clinical trial programme, the efficacy and safety of dalcetrapib is assessed in coronary heart disease (CHD) patients in the dal-VESSEL study (ClinicalTrials.gov identifier: NCT00655538), the design and methods of which are presented here.

Research design and study method:

Men and women with CHD or CHD risk equivalent, with HDL-C levels <50 mg/dL were recruited for a 36-week, double-blinded, placebo-controlled trial. After a pre-randomisation phase of up to 8 weeks, patients received dalcetrapib 600 mg/day or placebo in addition to their existing treatments. Brachial flow-mediated dilatation (FMD) measured by B-mode ultrasound represents endothelial function and is a validated marker for early atherosclerosis and cardiovascular disease risk.

Main outcome measures:

The primary efficacy outcome is change from baseline in brachial FMD after 12 weeks. The primary safety endpoint is 24-hour ambulatory blood pressure monitoring (ABPM) assessed at week 4. Secondary endpoints include brachial FMD at 36 weeks, ABPM at 12 and 36 weeks, lipid profile, CETP mass and activity, and markers of inflammation, oxidation, and cardiovascular risk. Clinical endpoints are assessed as a composite endpoint for the dal-HEART Program.

Current status:

In 19 European clinical centres, 476 subjects met inclusion criteria and have entered the study. In conclusion, the dal-VESSEL study is the largest multicentre trial with brachial FMD ever performed. The study assesses efficacy and safety of dalcetrapib on endothelial function, blood pressure, lipids, and clinical outcomes in CHD patients with below average HDL-C and will therefore provide vital information regarding its potential role in the preventative treatment of CHD risk.

Trial registration: ClinicalTrials.gov identifier: NCT00655538.

Key words::

• Atherosclerosis
• CETP inhibition
• Endothelial function
• Flow-mediated dilatation

Transparency

Declaration of funding

This study was funded by F. Hoffmann-La Roche Ltd.

Declaration of financial/other relationships

T.B., D.K. and V.L. have disclosed that they are employees of F. Hoffmann-La Roche. J.J.P.K. has disclosed that he has received research funding from AstraZeneca, Roche, Eli Lilly, Novartis, Merck, Merck Schering Plough, Isis Pharmaceuticals and Genzyme. He also has served as an advisor to AstraZeneca, Pfizer, Isis Pharmaceuticals, Genzyme, Roche, Novartis, Merck, Merck Schering Plough, Boehringer Ingelheim, Karo Bio, Bristol-Myers Squibb, Eli Lilly, Amarin, Omthera Pharmaceuticals and Sanofi-aventis. J.D. has disclosed that he has received funding from Colgate and Roche and is on the speakers’ bureaus of Pfizer, Takeda, MSD and Sanofi-aventis. E.D. has disclosed that he is an advisor to Roche. J.W.J. has disclosed that he has received funding from Astellas, AstraZeneca, Biotronik, Boston Scientific, Bristol-Myers Squibb, Cordis, Daiichi Sankyo, Eli Lilly, Medtronic, Merck Schering Plough, Pfizer, OrbusNeich, Novartis, Roche and Servier. J-C.K. has disclosed that he is on the speakers’ bureaus of Servier and Menarini. S.T. has disclosed that he has received grant money from, and is on the speakers’ bureaus of Servier, Recordati, Novartis and Boehringer Ingelheim. T.F.L. has disclosed that he has served as a consultant to Roche, MSD and Eli Lilly. S.R.D. and T.M. have no affiliations to disclose.

Acknowledgements

The authors acknowledge the contribution of M. Charakida and S. Loukogeorgakis, The London Core Lab, in the set up of the dal-VESSEL study and the FMD data analysis. Also, M. Okorie and J. Morgan, The London Core Lab, for analysis of the FMD data in the in-trial phase. The work provided by The London Core Lab was supervised by M. Deanfield and K. Mitchell. The authors also acknowledge the contribution of J. Wientjes and T. Postma, AMC Vascular Imaging, for QC data analysis and W. Hanselaar, AMC Vascular Imaging, for designing the integrated arm and probe holder and the ultrasound machine application protocol. The secure internet connections were implemented and supervised under auspices of C. Goddard and W. Scholten, AMC Vascular Imaging. The data management was supervised by J. Groeneveld, AMC Vascular Imaging. Editorial assistance was provided by K. Whitfield, Prime Healthcare, during the preparation of this report and that work was funded by F. Hoffmann-La Roche Ltd.

The dal-VESSEL study methods and design were previously presented at the European Atherosclerosis Society (EAS) Congress, June 20–23, 2010, Hamburg, Germany, and published as an abstract in Atherosclerosis Supplement 2010;11(2):182.