To Evaluate Ezetimibe/Simvastatin and Niacin (Extended Release Tablet) in Patients With Type IIa or Type IIb Hyperlipidemia - Study Results

Study Type:	Interventional
Study Design:	Randomized, Double Blind (Subject, Investigator), Active Control, Parallel Assignment
Condition:	Hypercholesterolemia
Interventions:	Drug: Comparator: ezetimibe/simvastatin + niacin (ER) Drug: Comparator: Placebo to ezetimibe/simvastatin Drug: Comparator: niacin (ER) tablet Drug: Comparator: ezetimibe (+) simvastatin Drug: Comparator: Placebo to Niacin (ER) Drug: Comparator: ezetimibe/simvastatin and niacin (ER) Drug: Comparator: ezetimibe and simvastatin Drug: Comparator: Placebo to niacin (ER)

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups

	Description
Niacin	(Part 1): Niacin titrated to 2000 mg taken orally once daily for 24 weeks. During the first 12 weeks of the study, patients randomized to the niacin containing arms started taking niacin 500 mg and had their niacin dose increased 500 mg every 4 weeks to 2000 mg. Patients in this treatment group were ramdomly reassigned for Part 2 of the study to one of two treatment groups- two-thirds of the patients enrolled in the niacin treatment group were randomly assigned to receive ezetimibe/simvastatin + niacin (ER) and the other one-third were randomly assigned to receive ezetimibe/simvastatin alone.
Ezetimibe/Simvastatin	(Part 1): Ezetimibe/Simvastatin 10/20 mg taken orally once daily for 24 weeks. (Part 2): Ezetimibe/Simvastatin 10/20 mg taken orally once daily for 40 additional weeks for a total of 64 weeks.
Ezetimibe/Simvastatin + Niacin	(Part 1): Ezetimibe/Simvastatin 10/20 mg + Niacin (titrated to 2000 mg as noted above) taken orally once daily for 24 weeks. (Part 2): Ezetimibe/Simvastatin 10/20 mg + Niacin 2000 mg taken orally once daily for 40 additional weeks for a total of 64 weeks.

Description

Niacin

(Part 1): Niacin titrated to 2000 mg taken orally once daily for 24 weeks. During the first 12 weeks of the study, patients randomized to the niacin containing arms started taking niacin 500 mg and had their niacin dose increased 500 mg every 4 weeks to 2000 mg. Patients in this treatment group were ramdomly reassigned for Part 2 of the study to one of two treatment groups- two-thirds of the patients enrolled in the niacin treatment group were randomly assigned to receive ezetimibe/simvastatin + niacin (ER) and the other one-third were randomly assigned to receive ezetimibe/simvastatin alone.

Ezetimibe/Simvastatin

(Part 1): Ezetimibe/Simvastatin 10/20 mg taken orally once daily for 24 weeks.

(Part 2): Ezetimibe/Simvastatin 10/20 mg taken orally once daily for 40 additional weeks for a total of 64 weeks.

Ezetimibe/Simvastatin + Niacin

(Part 1): Ezetimibe/Simvastatin 10/20 mg + Niacin (titrated to 2000 mg as noted above) taken orally once daily for 24 weeks.

(Part 2): Ezetimibe/Simvastatin 10/20 mg + Niacin 2000 mg taken orally once daily for 40 additional weeks for a total of 64 weeks.

Participant Flow for 2 periods

Period: Part 1

	Niacin	Ezetimibe/Simvastatin	Ezetimibe/Simvastatin + Niacin
STARTED	272	272	676
COMPLETED	166^[1]	213^[2]	391^[3]
NOT COMPLETED	106	59	285
Adverse Event	68	25	156
Lost to Follow-up	6	8	24
Protocol Violation	5	4	7
Patient Moved	3	1	5
Withdrawal by Subject	23	17	45
LDL < 50 mg/dL	1	4	48

[1]	6 patients who completed Part 1 did not continue to Part 2; 1 patient never received drug in Part 2
[2]	1 patient who completed Part 1 did not continue to Part 2
[3]	11 patients who completed Part 1 did not continue to Part 2

Period: Part 2

	Niacin	Ezetimibe/Simvastatin	Ezetimibe/Simvastatin + Niacin
STARTED	0^[1]	266^[2]	485^[3]
COMPLETED	0	234	401
NOT COMPLETED	0	32	84
Adverse Event	0	17	33
Lack of Efficacy	0	1	6
Lost to Follow-up	0	6	18
Protocol Violation	0	3	5
Patient Moved	0	0	5
Withdrawal by Subject	0	2	13
LDL < 50 mg/dL	0	3	4

[1]	Patients completing the niacin group in Part 1, were re-allocated to one of the two arms in Part 2
[2]	Includes 54 patients re-allocated from the niacin group in Part 1
[3]	Includes 105 patients re-allocated from the niacin group in Part 1

Baseline Characteristics

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Reporting Groups

	Description
Niacin	(Part 1): Niacin titrated to 2000 mg taken orally once daily for 24 weeks. During the first 12 weeks of the study, patients randomized to the niacin containing arms started taking niacin 500 mg and had their niacin dose increased 500 mg every 4 weeks to 2000 mg.
Ezetimibe/Simvastatin	(Part 1): Ezetimibe/Simvastatin 10/20 mg taken orally once daily for 24 weeks. (Part 2): Ezetimibe/Simvastatin 10/20 mg taken orally once daily for 40 additional weeks for a total of 64 weeks.
Ezetimibe/Simvastatin + Niacin	(Part 1): Ezetimibe/Simvastatin 10/20 mg + Niacin (titrated to 2000 mg as noted above) taken orally once daily for 24 weeks. (Part 2): Ezetimibe/Simvastatin 10/20 mg + Niacin 2000 mg taken orally once daily for 40 additional weeks for a total of 64 weeks.

Description

Niacin

Ezetimibe/Simvastatin

(Part 1): Ezetimibe/Simvastatin 10/20 mg taken orally once daily for 24 weeks.

(Part 2): Ezetimibe/Simvastatin 10/20 mg taken orally once daily for 40 additional weeks for a total of 64 weeks.

Ezetimibe/Simvastatin + Niacin

(Part 1): Ezetimibe/Simvastatin 10/20 mg + Niacin (titrated to 2000 mg as noted above) taken orally once daily for 24 weeks.

(Part 2): Ezetimibe/Simvastatin 10/20 mg + Niacin 2000 mg taken orally once daily for 40 additional weeks for a total of 64 weeks.

Baseline Measures

	Niacin	Ezetimibe/Simvastatin	Ezetimibe/Simvastatin + Niacin	Total
Number of Participants [units: participants]	272	272	676	1220
Age [units: years] Mean ± Standard Deviation	56.4 ± 10.6	57.5 ± 10.3	56.9 ± 10.9	56.9 ± 10.7
Gender [units: participants]
Female	136	120	352	608
Male	136	152	324	612
Race/Ethnicity, Customized [units: participants]
Asian	11	4	11	26
Black	13	17	38	68
Hispanic	14	11	49	74
Other	3	0	2	5
White	231	240	576	1047
Body Mass Index [units: Participants]
<25 kg/m2	48	39	135	222
25 to <30 kg/m2	110	119	252	481
30 to <40 kg/m2	97	94	251	442
≥ 40 kg/m2	16	19	34	69
No BMI Data	1	1	4	6

Outcome Measures

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1. Primary:

Percent Change From Baseline in Low-Density Lipoprotein-Cholesterol (LDL-C) [ Baseline and 24 Weeks ]

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2. Primary:

Percent Change From Baseline in Low-Density Lipoprotein-Cholesterol (LDL-C) [ Baseline and 24 weeks ]

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3. Secondary:

Percent Change From Baseline in Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C) [ Baseline and 24 weeks ]

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4. Secondary:

Percent Change From Baseline in High-Density Lipoprotein-Cholesterol (HDL-C) [ Baseline and 24 weeks ]

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5. Secondary:

Percent Change From Baseline in Triglycerides (TG) [ baseline and 24 Weeks ]

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6. Secondary:

Percent Change From Baseline in High-Density Lipoprotein-Cholesterol (HDL-C) [ Baseline and 64 weeks ]

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7. Secondary:

Percent Change From Baseline in Triglycerides (TG) [ Baseline and 64 weeks ]

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8. Secondary:

Percent Change From Baseline in Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C) [ Baseline and 64 weeks ]

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9. Secondary:

Percent Change From Baseline in Low-Density Lipoprotein-Cholesterol (LDL-C) [ Baseline and 64 weeks ]

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10. Secondary:

Percent Change From Baseline in Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C) [ Baseline and 24 weeks ]

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Serious Adverse Events

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Reporting Groups

	Description
Niacin	Niacin group from Part 1
Ezetimibe/Simvastatin	Ezetimibe/Simvastatin group from Part 1
Ezetimibe/Simvastatin + Niacin	Ezetimibe/Simvastatin + Niacin group from Part 1
Ezetimibe/Simvastatin - Part 2	EZ/Simva group from Part 2 All-Treated Patient as Treated Population
Ezetimibe/Simvastatin + Niacin - Part 2	Ezetimibe/Simvastatin + Niacin group from Part 2 All-Treated Patient as Treated Population

Serious Adverse Events

	Niacin	Ezetimibe/Simvastatin	Ezetimibe/Simvastatin + Niacin	Ezetimibe/Simvastatin - Part 2	Ezetimibe/Simvastatin + Niacin - Part 2
Total, serious adverse events
# participants affected	8	13	16	29	59
Blood and lymphatic system disorders
Anaemia * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	1/670 (0.15%)	0/326 (0.00%)	1/775 (0.13%)
Aplastic Anaemia * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Leukocytosis * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Cardiac disorders
Acute Coronary Syndrome * # participants affected / at risk	0/272 (0.00%)	1/272 (0.37%)	1/670 (0.15%)	1/326 (0.31%)	1/775 (0.13%)
Acute Myocardial Infarction * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Angina Pectoris * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Atrial Fibrillation * # participants affected / at risk	0/272 (0.00%)	1/272 (0.37%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Cardiac Failure Congestive * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Coronary Artery Disease * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	1/670 (0.15%)	1/326 (0.31%)	2/775 (0.26%)
Coronary Artery Stenosis * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	1/326 (0.31%)	0/775 (0.00%)
Myocardial Infarction * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	1/326 (0.31%)	1/775 (0.13%)
Congenital, familial and genetic disorders
Spondylolisthesis * # participants affected / at risk	0/272 (0.00%)	1/272 (0.37%)	0/670 (0.00%)	1/326 (0.31%)	0/775 (0.00%)
Gastrointestinal disorders
Lower Gastrointestinal Haemorrhage * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	1/670 (0.15%)	0/326 (0.00%)	1/775 (0.13%)
Pancreatic Mass * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	1/326 (0.31%)	0/775 (0.00%)
Pancreatitis * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	1/326 (0.31%)	0/775 (0.00%)
General disorders
Chest Pain * # participants affected / at risk	1/272 (0.37%)	1/272 (0.37%)	0/670 (0.00%)	1/326 (0.31%)	1/775 (0.13%)
Non-Cardiac Chest Pain * # participants affected / at risk	1/272 (0.37%)	0/272 (0.00%)	1/670 (0.15%)	1/326 (0.31%)	1/775 (0.13%)
Pain ^† # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Hepatobiliary disorders
Cholecystitis * # participants affected / at risk	0/272 (0.00%)	1/272 (0.37%)	0/670 (0.00%)	1/326 (0.31%)	0/775 (0.00%)
Cholelithiasis * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Immune system disorders
Anaphylactic Reaction * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	1/326 (0.31%)	0/775 (0.00%)
Infections and infestations
Abdominal Abscess * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	1/326 (0.31%)	0/775 (0.00%)
Diverticulitis * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Herpes Zoster Oticus * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Influenza * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Osteomyelitis * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Perirectal Abscess * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	1/670 (0.15%)	0/326 (0.00%)	1/775 (0.13%)
Pneumonia * # participants affected / at risk	1/272 (0.37%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Rocky Mountain Spotted Fever * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Sepsis * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	1/326 (0.31%)	0/775 (0.00%)
Staphylococcal Infection * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	1/670 (0.15%)	0/326 (0.00%)	1/775 (0.13%)
Viral Labyrinthitis * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	1/326 (0.31%)	0/775 (0.00%)
Ligament Injury * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Injury, poisoning and procedural complications
Muscle Strain * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	1/670 (0.15%)	0/326 (0.00%)	0/775 (0.00%)
Ankle Fracture * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	1/326 (0.31%)	2/775 (0.26%)
Cervical Vertebral Fracture * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Fibula Fracture * # participants affected / at risk	0/272 (0.00%)	1/272 (0.37%)	0/670 (0.00%)	1/326 (0.31%)	1/775 (0.13%)
Tibia Fracture * # participants affected / at risk	0/272 (0.00%)	1/272 (0.37%)	0/670 (0.00%)	1/326 (0.31%)	1/775 (0.13%)
Investigations
Transaminases Abnormal * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Metabolism and nutrition disorders
Dehydration * # participants affected / at risk	0/272 (0.00%)	1/272 (0.37%)	0/670 (0.00%)	1/326 (0.31%)	0/775 (0.00%)
Hypovolaemia * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Musculoskeletal and connective tissue disorders
Intervertebral Disc Degeneration * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Osteoarthritis * # participants affected / at risk	1/272 (0.37%)	0/272 (0.00%)	2/670 (0.30%)	0/326 (0.00%)	3/775 (0.39%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal Cell Carcinoma * # participants affected / at risk	1/272 (0.37%)	0/272 (0.00%)	0/670 (0.00%)	2/326 (0.61%)	2/775 (0.26%)
Breast Cancer * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	2/670 (0.30%)	1/326 (0.31%)	3/775 (0.39%)
Breast Cancer Metastatic * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Endometrial Cancer * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Lip Neoplasm Malignant Stage Unspecified * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Lung Neoplasm Malignant * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	1/326 (0.31%)	0/775 (0.00%)
Metastases To Liver * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Metastases To Lung * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Prostate Cancer * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	4/775 (0.52%)
Nervous system disorders
Cerebral Infarction * # participants affected / at risk	0/272 (0.00%)	1/272 (0.37%)	0/670 (0.00%)	1/326 (0.31%)	0/775 (0.00%)
Cerebrovascular Accident * # participants affected / at risk	2/272 (0.74%)	0/272 (0.00%)	0/670 (0.00%)	1/326 (0.31%)	0/775 (0.00%)
Cervical Cord Compression * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Dizziness * # participants affected / at risk	1/272 (0.37%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	0/775 (0.00%)
Paraesthesia * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	1/670 (0.15%)	0/326 (0.00%)	1/775 (0.13%)
Syncope * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	2/670 (0.30%)	0/326 (0.00%)	3/775 (0.39%)
Renal and urinary disorders
Nephrolithiasis * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	1/326 (0.31%)	0/775 (0.00%)
Renal Failure Acute * # participants affected / at risk	0/272 (0.00%)	1/272 (0.37%)	0/670 (0.00%)	1/326 (0.31%)	0/775 (0.00%)
Reproductive system and breast disorders
Uterine Prolapse * # participants affected / at risk	0/272 (0.00%)	1/272 (0.37%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)
Respiratory, thoracic and mediastinal disorders
Asthma * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	1/326 (0.31%)	0/775 (0.00%)
Pulmonary Embolism * # participants affected / at risk	0/272 (0.00%)	1/272 (0.37%)	0/670 (0.00%)	1/326 (0.31%)	0/775 (0.00%)
Pulmonary Oedema * # participants affected / at risk	0/272 (0.00%)	1/272 (0.37%)	0/670 (0.00%)	1/326 (0.31%)	0/775 (0.00%)
Vascular disorders
Deep Vein Thrombosis * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	1/670 (0.15%)	0/326 (0.00%)	2/775 (0.26%)
Thrombosis * # participants affected / at risk	0/272 (0.00%)	0/272 (0.00%)	0/670 (0.00%)	0/326 (0.00%)	1/775 (0.13%)

^†	Indicates events were collected by systematic assessment.
*	Indicates events were collected by non-systematic assessment.

Other Adverse Events

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Certain Agreements:

All Principal Investigators ARE employed by the organization sponsoring the study.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
Part 1 population is all patients enrolled in Part 1 of the study. Part 2 is those patients who received either niacin, ezetimibe/simvastatin, or ezetimibe/simvastatin + niacin during Part 1 until they finished the study at week 64 or discontinued.

Results Point of Contact:

Name/Title: Executive Vice President, Clinical and Quantitative Sciences
Organization: Merck & Co., Inc.
phone: 1-800-672-6372

Publications:

Guyton JR, Brown BG, Fazio S, Polis A, Tomassini JE, Tershakovec AM. Lipid-altering efficacy and safety of ezetimibe/simvastatin coadministered with extended-release niacin in patients with type IIa or type IIb hyperlipidemia. J Am Coll Cardiol. 2008 Apr 22;51(16):1564-72.

Responsible Party:	Merck & Co., Inc. ( Executive Vice President, Clinical and Quantitative Sciences )
Study ID Numbers:	2005_091, MK0653A-091
Study First Received:	January 3, 2006
Results First Received:	February 13, 2009
Last Updated:	November 6, 2009
ClinicalTrials.gov Identifier:	NCT00271817 History of Changes
Health Authority:	United States: Food and Drug Administration