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__NOTOC__
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{{High density lipoprotein}}
{{High density lipoprotein}}
{{CMG}}
{{CMG}}; {{AE}} {{Rim}}
 
==Official Title==
==Official Title==
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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==
{| class="wikitable" border="1" style="background:WhiteSmoke" width="40%"
|-
| Colspan="2" style="background:Gainsboro" align="center"|'''Timeline'''
|-
| Style="width:30%"| '''Start Date'''||Style="width:70%"| March 2008
|-
| '''End Date'''||November 2010
|-
| '''Status'''||Completed
|-
|}
<span style="font-size:85%">The previous information was derived from ClinicalTrials.gov on 09/20/2013 using the identification number NCT00655473.</span>


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 Factors
==Study Description==


==Objectives==
{| class="wikitable" border="1" style="background:WhiteSmoke" width="40%"
  Normal  0          false  false  false    EN-US X-NONE  AR-SA                                      MicrosoftInternetExplorer4
|-
| Colspan="2" style="background:Gainsboro" align="center"|'''Study Description'''
|-
| Style="width:30%"|'''Study Type'''|| Style="width:70%"|Interventional
|-
| '''Study Phase''' ||Phase 2
|-
| Colspan="2" style="background:Gainsboro" align="center"|'''Study Design'''
|-
| '''Allocation'''||Randomized
|-
| '''Endpoint'''||Efficacy Study
|-
| '''Interventional Model'''||Parallel Assignment
|-
| '''Masking'''||Double-Blind
|-
| Colspan="2" style="background:Gainsboro" align="center"|'''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
|-
|}


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
<span style="font-size:85%">The previous information was derived from ClinicalTrials.gov on 09/20/2013 using the identification number NCT00655473.</span>


==Timeline==
==Eligibility Criteria==
==Methods==
===Inclusion Criteria===
==Results==
*Adult patients, 18-75 years of age;
  Normal  0          false  false  false    EN-US  X-NONE  AR-SA                                      MicrosoftInternetExplorer4
*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.
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.
[[HDL-C]] levels increased by 31% and [[Apo-A1]] increased by 10% after 24 months of treatment in patients receiving dalcetrapib.


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 n dalcetrapib by 9.03%, but decreased in placebo by 0.36%.
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.
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 vascular 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.
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.
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.
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.


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.


8% 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.
==References==
{{Reflist|2}}


==Conclusion==
{{Lipopedia}}
  Normal  0          false  false  false    EN-US  X-NONE  AR-SA                                      MicrosoftInternetExplorer4


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.
[[Category:Lipopedia]]
[[Category:HDL]]
[[Category:Clinical trials]]
[[Category:HDLpedia]]

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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

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.

References