ILLUMINATE 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]

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

Sponsor

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

• Median follow-up: 550 days
• Follow-up completion: 99.7% of patients
• Early discontinuation: 11% in atorvastatin group and 13.4% in torcetrapib group
• One year follow-up:
  • Increase of HDL (72.1%)
  • Decrease of LDL (24.9%)
  • Decrease of 9% of triglyceride level among patients on torcetrapib vs. minimal change in lipid profile in atorvastatin group (p<0.001)
• After 3 months follow-up, there was a small, but significant, change in CRP levels (p=0.01).
• 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.

• 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).
• Significant increase in adverse events in torcetrapib group was reported: Hypertension, peripheral edema, angina pectoris, dyspnea, and headache (p<0.001).

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.