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'''Click [[media:ILLUMINATE_TRIAL.ppt|here]] to download slides for ILLUMINATE Trial.'''
==Official Title==
Phase 3 Multi Center, Double Blind, Randomized, Parallel Group Evaluation Of The Fixed Combination Torcetrapib/Atorvastatin, Administered Orally, Once Daily (Qd), Compared With Atorvastatin Alone, On The Occurrence Of Major Cardiovascular Events In Subjects With Coronary Heart Disease Or Risk Equivalents
==Objective==
==Objective==
Raising HDL levels by a combination of torcetrapib, a CETP inhibitor, and atorvastatin, an HGM-CoA reductase inhibitor.
Raising [[HDL]] levels by a combination of [[torcetrapib]], a [[CETP inhibitor]], and [[atorvastatin]], an HGM-CoA reductase inhibitor
==Sponsor==
Pfizer
==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%"| July 2004
|-
| '''End Date'''||June 2007
|-
| '''Status'''||Terminated
|-
|}
<span style="font-size:85%">The previous information was derived from ClinicalTrials.gov on 09/20/2013 using the identification number NCT00134264.</span>


==Timeline==
==Study Description==
===Start Date===
 
August 23, 2004 
{| class="wikitable" border="1" style="background:WhiteSmoke" width="40%"
===End Date===
|-
Premature Termination on December 2, 2006.  Data collection continued till July 15, 2007.
| Colspan="2" style="background:Gainsboro" align="center"|'''Study Description'''
|-
| Style="width:30%"|'''Study Type'''|| Style="width:70%"|Interventional
|-
| '''Study Phase''' ||Phase 3
|-
| Colspan="2" style="background:Gainsboro" align="center"|'''Study Design'''
|-
| '''Allocation'''||Randomized
|-
| '''Endpoint'''||Safety/Efficacy Study
|-
| '''Interventional Model'''||Parallel Assignment
|-
| '''Masking'''||Double-Blind
|-
| Colspan="2" style="background:Gainsboro" align="center"|'''Study Details'''
|-
| '''Primary Purpose'''||Treatment
|-
| '''Condition'''||Coronary Disease<br>Diabetes Mellitus
|-
| '''Intervention'''||Drug: torcetrapib/atorvastatin<br>Drug: atorvastatin
|-
| '''Study Arms'''||Not provided
|-
| '''Population Size'''||15067
|-
|}
 
 
<span style="font-size:85%">The previous information was derived from ClinicalTrials.gov on 09/20/2013 using the identification number NCT00134264.</span>


==Methods==
==Eligibility Criteria==
* Phase III trial
===Inclusion Criteria===
* Prospective, randomized, multicenter, double-blind clinical trial that recuited 15,067 patients.
*Diagnosis of coronary heart disease or risk equivalents that place the patient at high risk for cardiovascular disease events
* Inclusion criteria: Patients aged 45-75 years who have a history of cardiovascular disease 30 days to 5 years before screening; patients who have type 2 diabetes mellitus that meet criteria of the American Diabetes Association or receive anti-diabetic agents, even without previous cardiovascular disease.
===Exclusion Criteria===
* Exclusion criteria: Unstable medical condition, life expectancy less than 5 years, LDL-C levels < 100 mg/dL, those not receiving anti-lipidemic medications, if LDL-C target level not achieved at termination of run-in period, and those who have cardiovascular event during run-in period or uncontrolled hypertension: SBP>140 mmHg or DBP>90 mmHg,
*Women who are pregnant or lactating, or planning to become pregnant.
* Run-in period: 4-10 weeks
*Subjects with a clinically indicated need for statin (HMG-CoA reductase inhibitor) therapy other than atorvastatin or other concomitant therapy with known *Lipid altering effects on LDL-C and HDL-C including fibrates and nicotinic acid
* Cardiovascular disease was defined as myocardial infarction, stroke, acute coronary syndrome, unstable angina, peripheral vascular disease, and cardiac revascularization.
*Subjects taking any drugs known to be associated with an increased risk of myositis in combination with HMG-CoA reductase inhibitors
* Two arms of the study: Atorvastatin alone or atorvastatin plus torcetrapib 60 mg. Dosage of atorvastatin was determined while achieving of target LDL-C levels during run-in period and can be changed during the study period according to LDL-C levels.
*Subjects with any other medical condition or laboratory abnormality which could affect subject safety, preclude evaluationof response, or render unlikely that :the subject would complete the study
* Primary Outcome was defined as the time to first “cardiovascular event”.
* “Cardiovascular event” defined as death from coronary artery disease, nonfatal myocardial infarction, stroke, or hospitalization for unstable angina. Procedure-related deaths and events were excluded.
*  Secondary outcome: time to the first occurrence of a primary outcome. Time to death regardless of the etiology, change from baseline LDL and HDL levels.
* Outcomes based on 1,3,6,9, and 12 months scheduled visits.


==Results==
==Outcomes==
===Primary Outcomes===
The time to first occurrence of a major cardiovascular disease event
===Secondary Outcomes===
Various composites of major cardiovascular disease events and other lipid parameters
==Publications==
===Results===
* Median follow-up: 550 days
* Median follow-up: 550 days
* Follow-up completion: 99.7% of patients
* Follow-up completion: 99.7% of patients
* Early discontinuation: 11% in atorvastatin group and 13.4% in torcetrapib group.
* Early discontinuation: 11% in [[atorvastatin]] group and 13.4% in [[torcetrapib]] group
* One year follow-up showed increase of HDL (72.1%), a decrease of LDL (24.9%), and a decrease of 9% of triglycerides among patients on torcetrapib vs.  minimal change in lipid profile in atorvastatin group (p<0.001).
* One year follow-up:
* After 3 months follow-up, there was a small, but significant, change in CRP levels (p=0.01)
** Increase of [[HDL]] (72.1%)
* After 12 months follow-up, blood pressure decrease was 0.9% in atorvastatin group vs. 5.4 mmHg in torcetrapib group (p<0.001). Torcetrapib group also have a 0.08 mmol/L decrease in potassium, a 1.39 mmol/L increase in sodium, and a 2.28 mmol/L increase in bicarbonate vs. an increase in all 3 among the atorvastatin group with electrolyte values increasing 0.06 mmol/L, 0.78 mmol/L, and 1.93 mmol/L, respectively (p<0.001)..
** Decrease of [[LDL]] (24.9%)
*  In contrast, estimated glomerular filtration rate (eGFR) increased 0.8 ml/min/1.73m2 in torcetrapib group, but decreased 0.3 ml/min/1.73m2 in the atorvastatin group (p<0.001)
** Decrease of 9% of [[triglyceride]] level among patients on [[torcetrapib]] vs.  minimal change in [[lipid profile]] in [[atorvastatin]] group (p<0.001)
* QT interval changes after 12 months were 3.3 msec and 0.3 msec in torcetrapib and atorvastatin groups, respectively (p<0.001)
* After 3 months follow-up, there was a small, but significant, change in [[CRP]] levels (p=0.01).
* Measurements of aldosterone showed that after 3 months, there was a significant increase in aldosterone measurements in the torcetrapib group among 85th, 90th, and 95th percentile values.
* After 12 months follow-up, [[blood pressure]] decrease was 0.9 mmHg in [[atorvastatin]] group vs. 5.4 mmHg in [[torcetrapib]] group (p<0.001). [[Torcetrapib]] group also have a 0.08 mmol/L decrease in serum [[potassium]], a 1.39 mmol/L increase in serum [[sodium]], and a 2.28 mmol/L increase in serum [[bicarbonate]] vs. an increase in all 3 among the [[atorvastatin]] group with [[electrolyte]] values increasing 0.06 mmol/L, 0.78 mmol/L, and 1.93 mmol/L, respectively (p<0.001).
*  In contrast, estimated [[glomerular filtration rate]] ([[eGFR]]) increased 0.8 ml/min/1.73m2 in [[torcetrapib]] group, but decreased 0.3 ml/min/1.73m2 in the atorvastatin group (p<0.001)
* [[QT interval]] changes after 12 months were 3.3 msec and 0.3 msec in [[torcetrapib]] and [[atorvastatin]] groups, respectively (p<0.001)
* Measurements of [[aldosterone]] showed that after 3 months, there was a significant increase in [[aldosterone]] measurements in the [[torcetrapib]] group among 85th, 90th, and 95th percentile values.<ref name="pmid17984165">{{cite journal| author=Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M et al.| title=Effects of torcetrapib in patients at high risk for coronary events. | journal=N Engl J Med | year= 2007 | volume= 357 | issue= 21 | pages= 2109-22 | pmid=17984165 | doi=10.1056/NEJMoa0706628 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17984165  }} </ref>


==Study Outcomes==
* [[Hazard ratio]] for death was 1.58 in [[torcetrapib]] group at the end of the study (p=0.006).
* Hazard ratio for death was 1.58 in torcetrapib group at the end of the study (p=0.006).
* [[Torcetrapib]] group had a 1.25 hazard ratio for primary outcomes (p=0.001), mostly significant for [[unstable angina]] (p=0.001) and least important for [[stroke]] (0.74).
* Torcetrapib group had a 1.25 hazard ratio for primary outcomes (p=0.001), most notably significant for unstable angina (p=0.001) and least importanta for stroke (0.74).
* Significant increase in adverse events in torcetrapib group was reported: [[Hypertension]], [[peripheral edema]], [[angina pectoris]], [[dyspnea]], and [[headache]] (p<0.001).<ref name="pmid17984165">{{cite journal| author=Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M et al.| title=Effects of torcetrapib in patients at high risk for coronary events. | journal=N Engl J Med | year= 2007 | volume= 357 | issue= 21 | pages= 2109-22 | pmid=17984165 | doi=10.1056/NEJMoa0706628 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17984165  }} </ref>
* Significant increase in adverse events in torcetrapib group was reported: hypertension, peripheral edema, angina pectoris, dyspnea, and headache (p<0.001 – p=0.02).
[[Antidiabetic therapy]] was not stopped in any patient. On the contrary, [[insulin]] was added to approximatley 5% and other [[oral antidiabetics]] were added to approximately 12-13% of patients in both groups by the end of the trial.


==Conclusion==
[[Plasma glucose]] levels, however, differed significantly between both groups.  In patients receiving only [[atorvastatin]], [[plasma glucose]] levels increased after 1 month of treatment, whereas they decreased in patients receiving [[atorvastatin]] and [[torcetrapib]] by the same time frame; the significant net difference of [[plasma glucose]] levels between the two was approximately 0.25 mmol/L (p<0.0001).  The difference was further accentuated when measured during 3, 6, and 12 months of therapy; where net difference was 0.34 mmol/L (p<0.0001), 0.22 mmol/L (p<0.0001), and 0.26 mmol/L (p<0.0001), respectively.
* T There was an increased rate of death and morbidity in torcetrapib group due to unknown mechanism.
 
* Study terminated prematurely due to results of torcetrapib pertaining to increased cardiovascular morbidity and mortality.
Combination therapy with [[torcetrapib]] and [[atorvastatin]] was believed to improve [[insulin sensitivity]].  Serum [[insulin]] concentrations were significantly altered with both treatment arms.  Patients receiving only [[atorvastatin]] had an increase in fasting serum [[insulin]] after 3 months of treatment (p=0.02).  On the other hand, patients receiving a combination therapy had a significant decrease in serum insulin (p<0.0001). The net difference [[insulin]] concentration between the two arms of the study was 11.7 micro-units/mL (p<0.0001). [[Hemoglobina A1c]] ([[HbA1c]]) levels were significantly lower in patients receiving combination therapy after 1, 6, and 12 months of treatment (p<0.0001 at all times).
 
Similar to the initial observation from tha total [[ILLUMINATE]] cohort, there was a significant increase of 66.8% in HDL in patients using a combination therapy vs. minimal change in patients receiving [[atorvastatin]] alone (p<0.001).
 
However, it is notable to mention that when changes in [[glucose]], [[insulin]], and [[HbA1c]] were adjusted for HDL changes, statistical significance of these changes was eventually attenuated.
===Conclusion===
* Treatment with torcetrapib improved glycemic control in diabetic patients.  The exact association between the increase in HDL and the diabetic control requires validation.
* There was an increased rate of death and morbidity in torcetrapib group due to an unknown mechanism.
* Study was terminated prematurely due to results of torcetrapib pertaining to increased cardiovascular morbidity and mortality.<ref name="pmid17984165">{{cite journal| author=Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M et al.| title=Effects of torcetrapib in patients at high risk for coronary events. | journal=N Engl J Med | year= 2007 | volume= 357 | issue= 21 | pages= 2109-22 | pmid=17984165 | doi=10.1056/NEJMoa0706628 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17984165  }} </ref>


==References==
==References==
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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]

Click here to download slides for ILLUMINATE Trial.

Official Title

Phase 3 Multi Center, Double Blind, Randomized, Parallel Group Evaluation Of The Fixed Combination Torcetrapib/Atorvastatin, Administered Orally, Once Daily (Qd), Compared With Atorvastatin Alone, On The Occurrence Of Major Cardiovascular Events In Subjects With Coronary Heart Disease Or Risk Equivalents

Objective

Raising HDL levels by a combination of torcetrapib, a CETP inhibitor, and atorvastatin, an HGM-CoA reductase inhibitor

Pfizer

Timeline

Timeline
Start Date July 2004
End Date June 2007
Status Terminated

The previous information was derived from ClinicalTrials.gov on 09/20/2013 using the identification number NCT00134264.

Study Description

Study Description
Study Type Interventional
Study Phase Phase 3
Study Design
Allocation Randomized
Endpoint Safety/Efficacy Study
Interventional Model Parallel Assignment
Masking Double-Blind
Study Details
Primary Purpose Treatment
Condition Coronary Disease
Diabetes Mellitus
Intervention Drug: torcetrapib/atorvastatin
Drug: atorvastatin
Study Arms Not provided
Population Size 15067


The previous information was derived from ClinicalTrials.gov on 09/20/2013 using the identification number NCT00134264.

Eligibility Criteria

Inclusion Criteria

  • Diagnosis of coronary heart disease or risk equivalents that place the patient at high risk for cardiovascular disease events

Exclusion Criteria

  • Women who are pregnant or lactating, or planning to become pregnant.
  • Subjects with a clinically indicated need for statin (HMG-CoA reductase inhibitor) therapy other than atorvastatin or other concomitant therapy with known *Lipid altering effects on LDL-C and HDL-C including fibrates and nicotinic acid
  • Subjects taking any drugs known to be associated with an increased risk of myositis in combination with HMG-CoA reductase inhibitors
  • Subjects with any other medical condition or laboratory abnormality which could affect subject safety, preclude evaluationof response, or render unlikely that :the subject would complete the study

Outcomes

Primary Outcomes

The time to first occurrence of a major cardiovascular disease event

Secondary Outcomes

Various composites of major cardiovascular disease events and other lipid parameters

Publications

Results

Antidiabetic therapy was not stopped in any patient. On the contrary, insulin was added to approximatley 5% and other oral antidiabetics were added to approximately 12-13% of patients in both groups by the end of the trial.

Plasma glucose levels, however, differed significantly between both groups. In patients receiving only atorvastatin, plasma glucose levels increased after 1 month of treatment, whereas they decreased in patients receiving atorvastatin and torcetrapib by the same time frame; the significant net difference of plasma glucose levels between the two was approximately 0.25 mmol/L (p<0.0001). The difference was further accentuated when measured during 3, 6, and 12 months of therapy; where net difference was 0.34 mmol/L (p<0.0001), 0.22 mmol/L (p<0.0001), and 0.26 mmol/L (p<0.0001), respectively.

Combination therapy with torcetrapib and atorvastatin was believed to improve insulin sensitivity. Serum insulin concentrations were significantly altered with both treatment arms. Patients receiving only atorvastatin had an increase in fasting serum insulin after 3 months of treatment (p=0.02). On the other hand, patients receiving a combination therapy had a significant decrease in serum insulin (p<0.0001). The net difference insulin concentration between the two arms of the study was 11.7 micro-units/mL (p<0.0001). Hemoglobina A1c (HbA1c) levels were significantly lower in patients receiving combination therapy after 1, 6, and 12 months of treatment (p<0.0001 at all times).

Similar to the initial observation from tha total ILLUMINATE cohort, there was a significant increase of 66.8% in HDL in patients using a combination therapy vs. minimal change in patients receiving atorvastatin alone (p<0.001).

However, it is notable to mention that when changes in glucose, insulin, and HbA1c were adjusted for HDL changes, statistical significance of these changes was eventually attenuated.

Conclusion

  • Treatment with torcetrapib improved glycemic control in diabetic patients. The exact association between the increase in HDL and the diabetic control requires validation.
  • There was an increased rate of death and morbidity in torcetrapib group due to an unknown mechanism.
  • Study was terminated prematurely due to results of torcetrapib pertaining to increased cardiovascular morbidity and mortality.[1]

References

  1. 1.0 1.1 1.2 Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M; et al. (2007). "Effects of torcetrapib in patients at high risk for coronary events". N Engl J Med. 357 (21): 2109–22. doi:10.1056/NEJMoa0706628. PMID 17984165.