Study design of Dal-GenE, a pharmacogenetic trial targeting reduction of cardiovascular events with dalcetrapib

Am Heart J. 2020 Apr;222:157-165. doi: 10.1016/j.ahj.2020.01.007. Epub 2020 Jan 17.

Abstract

The objectives of precision medicine are to better match patient characteristics with the therapeutic intervention to optimize the chances of beneficial actions while reducing the exposure to unneeded adverse drug experiences. In a retrospective genome-wide association study of the overall neutral placebo-controlled dal-Outcomes trial, the effect of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on the composite of cardiovascular death, myocardial infarction or stroke was found to be influenced by a polymorphism in the adenylate cyclase type 9 (ADCY9) gene. Whereas patients with the AA genotype at position rs1967309 experienced fewer cardiovascular events with dalcetrapib, those with the GG genotype had an increased rate and the heterozygous AG genotype exhibited no difference from placebo. Measurements of cholesterol efflux and C-reactive protein (CRP) offered directionally supportive genotype-specific findings. In a separate, smaller, placebo-controlled trial, regression of ultrasonography-determined carotid intimal-medial thickness was only observed in dalcetrapib-treated patients with the AA genotype. Collectively, these observations led to the hypothesis that the cardiovascular effects of dalcetrapib may be pharmacogenetically determined, with a favorable benefit-risk ratio only for patients with this specific genotype. We describe below the design of dal-GenE, a precision medicine, placebo-controlled clinical outcome trial of dalcetrapib in patients with a recent acute myocardial infarction with the unique feature of selecting only those with the AA genotype at rs1967309 in the ADCY9 gene.

Trial registration: ClinicalTrials.gov NCT02525939.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclases / genetics*
  • Adenylyl Cyclases / metabolism
  • Amides
  • Anticholesteremic Agents / administration & dosage
  • Atherosclerosis / epidemiology
  • Atherosclerosis / genetics
  • Atherosclerosis / prevention & control*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Esters
  • Female
  • Follow-Up Studies
  • Genetic Testing
  • Genome-Wide Association Study*
  • Genotype
  • Global Health
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Pharmacogenetics / methods*
  • Polymorphism, Genetic*
  • Precision Medicine / methods*
  • Prognosis
  • Prospective Studies
  • Retrospective Studies
  • Sulfhydryl Compounds / administration & dosage*

Substances

  • Amides
  • Anticholesteremic Agents
  • Esters
  • Sulfhydryl Compounds
  • dalcetrapib
  • Adenylyl Cyclases
  • adenylate cyclase 9

Associated data

  • ClinicalTrials.gov/NCT02525939