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document
Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging ( dal-PLAQUE ) : a randomised clinical trial . 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 .
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Intervention_Pharmacological
dalcetrapib
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Intervention_Surgical
novel non-invasive multimodality imaging ( dal-PLAQUE
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Intervention_Physical
)
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Intervention_Pharmacological
Dalcetrapib
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Intervention_Pharmacological
dalcetrapib 600 mg/day
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Intervention_Control
placebo
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Intervention_Control
placebo
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Intervention_Pharmacological
dalcetrapib
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Intervention_Pharmacological
dalcetrapib
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Intervention_Pharmacological
dalcetrapib
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Intervention_Control
placebo
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Outcome_Other
MRI-assessed indices
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Outcome_Other
total vessel area
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Outcome_Physical
,
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Outcome_Other
wall area
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Outcome_Physical
,
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Outcome_Other
wall thickness
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Outcome_Physical
, and
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Outcome_Other
normalised wall index
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Outcome_Other
MRI-derived change in total vessel area
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Participant_Age
( aged 18-75 years )
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Participant_Condition
with , or with high risk of , coronary heart disease
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Participant_Sample-size
189
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Participant_Sample-size
130
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Participant_Sample-size
assigned
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Participant_Sample-size
66
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Participant_Sample-size
64