Dal-VESSEL Trial
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]
Official Title
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
Objective
To assess the therapeutic and adverse effects of dalcetrapib on endothelial function, blood pressure, inflammatory markers, and lipid levels in patients with coronary heart disease (CHD) or CHD risk equivalents
Sponsor
Hoffmann-La Roche
Timeline
| Timeline | |
| Start Date | February 2008 |
| End Date | May 2010 |
| Status | Completed |
The previous information was derived from ClinicalTrials.gov on 09/20/2013 using the identification number NCT00655538 .
Study Description
| Study Description | |
| Study Type | Interventional |
| Study Phase | Phase 2 |
| Study Design | |
| Allocation | Randomized |
| Endpoint | Safety/Efficacy Study |
| Interventional Model | Parallel Assignment |
| Masking | Double-Blind |
| Study Details | |
| Primary Purpose | Treatment |
| Condition | Coronary Heart Disease |
| Intervention | Drug: dalcetrapib (600mg po daily for 36 weeks) Drug: Placebo (po daily for 36 weeks) |
| Study Arms | Drug: dalcetrapib Drug: Placebo |
| Population Size | 476 |
The previous information was derived from ClinicalTrials.gov on 09/20/2013 using the identification number NCT00655538 .
Eligibility Criteria
Inclusion Criteria
- Adult patients, 18-75 years of age
- CHD or CHD risk equivalent
- Appropriately treated for accepted LDL-C level
Exclusion Criteria
- Treatment with drugs raising HDL-C (eg niacin, fibrates)
- Uncontrolled hypertension
- Recent (within 3 months) clinically significant coronary events, transient ischemic attacks or cerebrovascular accident
- Severe anemia
- Poorly controlled diabetes
Outcomes
Primary Outcomes
- Change from baseline in % flow mediated dilatation (FMD) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
- Change from baseline in mean BP, measured by BP monitoring [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
Secondary Outcomes
- Change from baseline in % FMD [ Time Frame: 36 weeks ] [ Designated as safety issue: No ]
- Blood lipids, lipoproteins [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
- CETP mass and activity [ Time Frame: Up to 36 weeks ] [ Designated as safety issue: No ]
- Biomarkers [ Time Frame: Up to 36 weeks ] [ Designated as safety issue: No ]
- Change from baseline in mean BP, measured by BP monitoring [ Time Frame: Up to 36 weeks ] [ Designated as safety issue: No ]
- AEs, lab parameters, vital signs, ECG [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Publications
Results
Baseline flow-mediated dilatation at the right brachial artery after 5 minutes of cuff occlusion is considered an endpoint that increases the vascular levels of endothelin and reactive oxygen species and decreases eNOS expression and nitrous oxide release. It was almost equal in patients receiving placebo and those receiving dalcetrapib at approximately 4%. Changes did not significantly with both groups either. Similarly, hyperemia, an assessment of blood flow velocity, was not significantly different in either groups or when comparing to baseline hyperemia.
Blood pressure levels throughout the study at 4, 12, and 36 weeks did not significantly differ either compared to baseline in any group or even between groups. However, it was shown that the percentage of patients who are considered "non-dippers", i.e. those who do not have a nocturnal decrease in blood pressures, were decreased with dalcetrapib, while increased in placebo group. Electrolytes, creatinine, or blood glucose were also unchanged.
Measured inflamamtory markers ICAM-1, VCAM-1, IL6, MPO, t-PA, and PAI-1 were all the same when comparing groups or when comparing to baseline values. Only placebo-corrected Lp-PLA2 mass showed a 17.4% increase (p<0.001).
At baseline, HDL was almost similar in both placebo and dalcetrapib. There was a significant gradual increase in HDL levels ranging between 25-31% during week 4-36 (p<0.0001). In converse, CETP activity decreased gradually as well from a 51% decrease at week 4 to a 56% decrease at week 36 of dalcetrapib therapy (p<0.0001).
With dalcetrapib, Apo-A1 levels increased, Apo-B100 decreased, and triglyceride levels decreased signifincantly. LDL-C level decrease was only 4% and limited at week 4 only, but the resulst significant nonetheless (p<0.05).
The list of adverse events included mainly mild to moderate events, such as diarrhea, back pain, headache, nasopharyngitis, and influenza. Two patients of the dalcetrapib group and 3 patients of the placebo group had a non-fatal myocardial infarction; whereas there was 1 death and 1 hospitalization for acute coronary syndrome that occurred only in the placebo group. A total of 16 revascularization procedures were documented, 9 of which were in patients of the dalcetrapib group.
Conclusion
Dal-VESSEL trial conveys a reassuring side effect profile of dalcetrapib. The promising findings of the dal-VESSEL trial regarding the role of dalcetrapib as a CETP inhibitor in atherosclerosis are in line with the previous findings documented by dal-PLAQUE and dal-OUTCOMES trials.