Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial

Abstract

Background: Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high-density lipoprotein cholesterol (HDL-C). After the failure of torcetrapib it was unknown if HDL produced by interaction with CETP had pro-atherogenic or pro-inflammatory properties. dal-PLAQUE is the first multicentre study using novel non-invasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints.

Methods: In this phase 2b, double-blind, multicentre trial, patients (aged 18-75 years) with, or with high risk of, coronary heart disease were randomly assigned (1:1) to dalcetrapib 600 mg/day or placebo for 24 months. Randomisation was done with a computer-generated randomisation code and was stratified by centre. Patients and investigators were masked to treatment. Coprimary endpoints were MRI-assessed indices (total vessel area, wall area, wall thickness, and normalised wall index [average carotid]) after 24 months and (18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT assessment of arterial inflammation within an index vessel (right carotid, left carotid, or ascending thoracic aorta) after 6 months, with no-harm boundaries established before unblinding of the trial. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00655473.

Findings: 189 patients were screened and 130 randomly assigned to placebo (66 patients) or dalcetrapib (64 patients). For the coprimary MRI and PET/CT endpoints, CIs were below the no-harm boundary or the adverse change was numerically lower in the dalcetrapib group than in the placebo group. MRI-derived change in total vessel area was reduced in patients given dalcetrapib compared with those given placebo after 24 months; absolute change from baseline relative to placebo was -4·01 mm(2) (90% CI -7·23 to -0·80; nominal p=0·04). The PET/CT measure of index vessel most-diseased-segment target-to-background ratio (TBR) was not different between groups, but carotid artery analysis showed a 7% reduction in most-diseased-segment TBR in the dalcetrapib group compared with the placebo group (-7·3 [90% CI -13·5 to -0·8]; nominal p=0·07). Dalcetrapib did not increase office blood pressure and the frequency of adverse events was similar between groups.

Interpretation: Dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months. Moreover, this trial suggests possible beneficial vascular effects of dalcetrapib, including the reduction in total vessel enlargement over 24 months, but long-term safety and clinical outcomes efficacy of dalcetrapib need to be analysed.

Funding: F Hoffmann-La Roche Ltd.

Figure 1. Trial profile

Figure 2. Mean carotid total vessel area and percent increase in average carotid total vessel area (by MRI)

(A) Raw mean data (90% CI) for total vessel area at baseline, 6, 12, and 24 months. Total vessel area increased after 24 months in the placebo group: model-derived, corrected average absolute change (24 months–baseline) was 5·72 mm² (90% CI 3·30–8·14), p=0·0002. However, in the dalcetrapib group, total vessel area did not change in the same period (1·71 [–0·68 to 4·10], p=0·24). The average reduction in total vessel area on dalcetrapib (versus placebo), after correction of baseline, was −4·01 (−7·23 to −0·80), p=0·04. (B) Group mean data for percent change in total vessel area at 6, 12, and 24 months (relative to baseline). In patients assigned placebo, model-derived, corrected total vessel area increased in the initial 24 months: percent change total vessel area was 10·8 (90% CI 5·8–15·8), p=0·001. However, in patients assigned dalcetrapib, total vessel area did not increase in the same period (4.0% [0.6–7·3], p=0·16). The average percent change in total vessel area in the dalcetrapib group (versus placebo), after correction of baseline, was −7·1% (−12·8 to −1·3), p=0·04.

Figure 3. Mean carotid MDS TBR and percent increase in average carotid most-diseased-segment TBR (by PET)

MDS=most-diseased-segment. TBR=target-to-background ratio. (A) Raw mean data for average carotid MDS TBR at baseline, and at 3 and 6 months. In the placebo group, MDS TBR did not change after 6 months: model-derived, corrected average absolute change for MDS TBR (6 months–baseline) was −0·043 (90% CI −0·14 to 0·06), p=0·48. However, in the dalcetrapib group, MDS TBR decreased in the same period (−0·19 [−0·29 to −0·09], p=0·001). The average reduction in MDS TBR on dalcetrapib (versus placebo), after correction for baseline, was −0·150 (–0·29 to −0·01), p=0·08. (B) Group mean (90% CI) data for percent change in average carotid MDS TBR after 3 and 6 months (relative to baseline). In the placebo group, model-derived, corrected average MDS TBR did not change over the initial 6 months: percent change in MDS TBR was 3·24 (90% CI −2·18 to 8·66), p=0·71. However, in the dalcetrapib group, MDS TBR decreased in the same period (−7·26% [−12·50 to −2·02], p=0·003). The estimated average percent change in MDS TBR on dalcetrapib (versus placebo), after correction for baseline, was −7·35% (90% CI −13·49 to −0·76), p=0·07.

Figure 4

Association between HDL-C and arterial inflammation as measured by MDS TBR on PET/CT and arterial inflammation and atherosclerotic burden HDL-C=high-density lipoprotein cholesterol. MDS=most-diseased-segment. TBR=target-to-background ratio. (A) Change in arterial inflammation (MDS TBR) over 6 months versus change in HDL-C over the same period grouped in tertiles (third tertile represents the greatest increase in HDL-C). (B) Early increases in arterial inflammation associated with subsequent increases in atherosclerotic burden. The change in carotid inflammation at 6 months was compared within subjects that were classified into tertiles according to the subsequent rate of change in total vessel area at 24 months.