Dal-PLAQUE 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 Effect of RO4607381 on Progression or Regression of Atherosclerotic Plaque in Patients With Coronary Heart Disease (CHD) Including Patients With Other CHD Risk

Objective

To assess the therapeutic and adverse effects of dalcetrapib on atherotic plaques in patients known to have coronary heart disease (CHD) or CHD risk factors using PET/CT and MRI at baseline and at predetermined intervals for 2 years

Sponsor

Hoffmann-La Roche

Timeline

Timeline
Start Date	March 2008
End Date	November 2010
Status	Completed

The previous information was derived from ClinicalTrials.gov on 09/20/2013 using the identification number NCT00655473.

Study Description

Study Description
Study Type	Interventional
Study Phase	Phase 2
Study Design
Allocation	Randomized
Endpoint	Efficacy Study
Interventional Model	Parallel Assignment
Masking	Double-Blind
Study Details
Primary Purpose	Treatment
Condition	Coronary Heart Disease
Intervention	Dalcetrapib
Study Arms	Dalcetrapib: 600mg oral tablet once daily for 24 months Placebo: Placebo oral tablet onde daily for 24 months
Population Size	130

The previous information was derived from ClinicalTrials.gov on 09/20/2013 using the identification number NCT00655473.

Eligibility Criteria

Inclusion Criteria

• Adult patients, 18-75 years of age;
• CHD, including patients with other CHD risk factors;
• Treated appropriately for dyslipidemia;
• Clinically stable.

Exclusion Criteria

• Previous exposure to any CETP inhibitor or vaccine
• Recent (within 3 months) clinically significant coronary events, transient ischemic attacks or cerebrovascular accident
• Severe anemia
• Uncontrolled hypertension
• Poorly controlled diabetes

Outcomes

Primary Outcomes

• Change from baseline of MRI plaque size/burden [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Change from baseline in target (plaque) to background (blood) ratio from an index vessel. [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Secondary Outcomes

• Change from baseline in vessel MR determined compliance [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Change from baseline in vessel MR determined plaque anatomy [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
• Blood lipids, lipoproteins [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Biomarkers [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
• CHD, major coronary events, AEs, lab parameters, blood pressure [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

Publications

Results

Of note, the study authors utilized a 90% confidence interval in documenting the results.

HDL-C levels increased by 31% and Apo-A1 increased by 10% after 24 months of treatment in patients receiving dalcetrapib.

Remarkably, dalcetrapib group had a increase by 33% in the inflammatory marker hs-CRP after 24 weeks. These changes were not seen in patients receiving placebo. Lp-PLA mass increased in dalcetrapib by 9.03%, but decreased in placebo by 0.36%.

There was net difference of 4.01 mm2 decrease of total vessel area when comparing dalcetrapib to placebo after 24 weeks of therapy, as assessed by MRI. The difference between dalcetrapib and placebo showed a difference of wall area decrease by 2.2 mm2 , normalized wall index increase by 0.6%, and mean wall thickness decrease of 0.03 mm.

After 6 months, there was no worsened arterial inflammation with dalcetrapib compared to placebo. The arterial wall target to blood ratio (TBR), a measurement of arterial inflammation, of the index vessel showed no significant changes between the two groups. The mean decrease from baseline in patients using placebo of 0.26 vs. 0.19 in dalcetrapib. The total average carotid area was less in dalcetrapib after 24 months of therapy, based on PET/CT measured changes from baseline.

The average carotid most-diseased-segment TBR was unchagned in placebo, but was significantly decreased in dalcetrapib. However, the dalcetrapib reduction as not significant when comparing its change to baseline values.

Elevated levels of HDL correlated significantly with reduced TBR in the dalcetrapib group (p=0.04). When HDL levels were distributed in tertiles, it was found that every HDL tertile corresponded to a 4.3% decrease in TBR (p=0.04); but due to distribution of the patient population by having lower HDL mostly in placebo group and higher HDL mostly in dalcetrapib group, the authors do not confidently associate the dalcetrapib-mediated inverse relation between HDL and TBR. Significant changes on MRI, i.e. total vessel area, wall area, and wall index, were not seen when different HDL concentrations were compared.

There was no difference in adverse events between both groups. Vital signs, including blood pressures, were similar. Similarly, liver transaminase levels were the same. CPK levels were higher than the upper normal limit in 10% of dalcetrapib group vs. 5% in placebo; but these values were not significant.

8% of patients receiving dalcetrapib and 11% of patients receiving placebo discontinued the study for safety reasons. Death occurred in 3 patients, two of whom were in the placebo group due to coronary heart disease and electromechanical dissociation, and one from the dalcetrapib group due to metastatic cancer. Overall, more adjudicated cardiovascular events took place in the placebo group rather than in those on dalcetrapib.

Conclusion

Dalcetrapib, a CETP inhibitor, was associated with an increase in HDL and a decrease in vascular inflammation and structural vascular changes. There is still no evidence of major adverse effect that might prevent the use of dalcetrapib.