A Randomized, Placebo-Controlled Study of the Safety, Tolerability, and Effect on Endothelial Function, as Measured by Flow-Mediated Dilatation, of RO4607381 in Patients With Coronary Heart Disease (CHD) or CHD Risk Equivalents - dal-VESSEL

Mar 10, 2012
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Hoffmann-La Roche
Date Presented:
01/01/2011
Date Published:
01/01/2012
Date Updated:
03/10/2012
Original Posted Date:
03/10/2012
References

Description:

Despite multiple attempts, no pharmacological agent thus far has been successful in increasing high-density lipoprotein (HDL) while reducing coronary events. Dalcetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that has not shown off-target effects such as blood pressure (BP) elevation (noted with torcetrapib, another CETP inhibitor in the ILLUSTRATE and ILLUMINATE trials) in early trials. The current trial was a phase II trial designed to assess the efficacy and safety of dalcetrapib on endothelial function, as compared with placebo.

Hypothesis:

Dalcetrapib would be noninferior as compared with placebo in preserving brachial flow-mediated dilation (a marker of endothelial dysfunction) and ambulatory BP in patients with established coronary heart disease (CHD) or at risk for CHD.

Study Design

  • Blinded
  • Parallel
  • Placebo Controlled
  • Randomized
  • Stratified

Patient Populations:

  • Age 18-75 years
  • Diagnosis of CHD or CHD risk equivalents based on the National Cholesterol Education Program Adult Treatment Panel III
  • Triglyceride level ≤400 mg/dl
  • HDL-C ≤50 mg/dl
  • Clinically stable
  • On appropriate treatment with statin and/or other LDL-C lowering drugs to a stable LDL-C level of <100 mg/dl unless taking maximum tolerated doses of therapy based on their medical condition or intolerant to statins 

    Number screened: 860
    Number of enrollees: 476
    Duration of follow-up: 36 weeks
    Mean patient age: 62.1
    Percentage female: 10%

Exclusions:

  • Concomitant HDL-C raising therapy (niacin, fibrates, bile acid sequestrants, rimonabant, CETP therapy, or other)
  • Uncontrolled BP
  • Patients likely to require alterations of antihypertensive treatment during the first 4 weeks of treatment
  • Uncontrolled diabetes (hemoglobin A1c ≥10%)
  • Recent (<3 months) clinically significant coronary or cerebral vascular event
  • Patients with familial hypercholesterolemia
  • Any clinically significant medical condition that could interfere with the conduct of the study
  • Presence of any abnormality on a laboratory evaluation performed prior to randomization that is considered by the investigator to be clinically important
  • History of receiving dalcetrapib in a clinical trial in the previous 12 months
  • Subjects previously exposed to torcetrapib
  • Women who were pregnant, breastfeeding, or of child-bearing potential, without effective contraception

Primary Endpoints:

  • Primary efficacy endpoint: effect on endothelial function,as measured by flow-mediated dilation at 12 weeks 
  • Primary safety endpoint: effect on BP, as measured by 24-hour ABPM after 4 weeks

Secondary Endpoints:

  • Effect on flow-mediated dilation at 36 weeks
  • Change in ABPM at 12 and 36 weeks
  • Change in lipid and inflammatory parameters

Drug/Procedures Used:

After a prerandomization period of up to 8 weeks to allow adjustment of lipid-lowering therapy, eligible participants were randomized 1:1 to receive double-blind treatment with either dalcetrapib 600 mg daily or placebo for 36 weeks, followed by a 2-week safety follow-up.

Concomitant Medications:

Statin (95%)

Principal Findings:

A total of 476 patients were randomized, 242 to dalcetrapib and 234 to placebo. About 45% had diabetes mellitus, 74% had hypertension, 65% had established CHD, 7% had symptomatic carotid disease, and 9% had peripheral arterial disease. The mean baseline total, low-density lipoprotein (LDL), and HDL cholesterol (HDL-C) values were 149.3, 80.1, and 38.7 mg/dl, respectively. At baseline, ambulatory blood pressure monitoring (ABPM) was 125.2/74.2 mm Hg for the placebo and 127.6/74.9 mm Hg for the dalcetrapib group.

Dalcetrapib reduced CETP by 50.9%, 52.5%, and 56%, and increased HDL-C levels by 25%, 27%, and 31% at 4, 12, and 36 weeks, respectively (p < 0.0001 for both). Levels of apolipoprotein (Apo) A1 were also increased, while LDL levels were reduced with dalcetrapib (4%). Markers of inflammation and oxidative stress were similar between the two arms.

Baseline flow-mediated dilatation was 4.1 ± 2.2% and 4.0 ± 2.4% in the placebo and dalcetrapib groups, respectively, and did not change with dalcetrapib for up to 36 weeks. At week 12, placebo-corrected change from baseline was -0.23 (p = 0.18), which met criteria for non inferiority. After 4 weeks, the placebo corrected change from baseline was similar for systolic BP (0.65 mm Hg, p = 0.34) and diastolic BP (0.64 mm Hg, p = 0.13), which also met criteria for noninferiority. At least one adverse event was noted in 72% versus 68% of the patients. Adjusted cardiovascular events were similar (4.7% vs. 5.1%).

Interpretation:

The results of this phase II trial indicate that dalcetrapib is not associated with any difference in nitric oxide-dependent endothelial function, as compared with placebo, in patients with established CHD or at risk for CHD. The results of larger ongoing phase III trials with dalcetrapib powered for clinical endpoints are awaited. Importantly, no indication of increased BP with dalcetrapib was noted in this trial.

References:

Lüscher TF, Taddei S, Kaski JC, et al., on behalf of the dal-VESSEL Investigators. Vascular Effects and Safety of Dalcetrapib in Patients With or at Risk of Coronary Heart Disease: The dal-VESSEL Randomized Clinical Trial. Eur Heart J 2012;Feb 16:[Epub ahead of print].

Presented by Dr. T. Luescher at the European Society of Cardiology Congress, Paris, France, August 2011.

Kastelein JJ, Duivenvoorden R, Deanfield J, et al. 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. Curr Med Res Opinion 2011;27:141-50.

Keywords: Inflammation, Follow-Up Studies, Sulfhydryl Compounds, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Quinolines, Oxidative Stress, Apolipoprotein A-I, Dilatation, Coronary Disease, Peripheral Arterial Disease, Nitric Oxide, Lipoproteins, LDL, Cholesterol Ester Transfer Proteins, Blood Pressure Monitoring, Ambulatory, Maximum Tolerated Dose, Cholesterol, HDL, Triglycerides, Hypertension, Diabetes Mellitus


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