A 12-week Open-Label, Randomised, Parallel-group, Multicentre, Phase IIIb Study to compare the Efficacy and Safety of rosuvastatin (CRESTOR) 10 mg and 20 mg in Combination with Ezetimibe 10 mg and Sivastatin 40 mg and 80 mg in Combination with Ezetimibe 10 mg (fixed dose combination) in Patients with Hypercholesterolaemia and Coronary Heart Disease (CHD) or a CHD Risk Equivalent, Atherosclerosis or a 10-year CHD Risk of >20% (GRAVITY) - Gauging the lipid effects of RosuvAstatin plus ezetimibe Versus sImvastatin plus ezetimibe TherapY

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2007-002810-20-NL
• Date of registration: 07/08/2007
• Prospective Registration: Yes
• Primary sponsor: AstraZeneca AB
• Public title: A 12-week Open-Label, Randomised, Parallel-group, Multicentre, Phase IIIb Study to compare the Efficacy and Safety of rosuvastatin (CRESTOR) 10 mg and 20 mg in Combination with Ezetimibe 10 mg and Sivastatin 40 mg and 80 mg in Combination with Ezetimibe 10 mg (fixed dose combination) in Patients with Hypercholesterolaemia and Coronary Heart Disease (CHD) or a CHD Risk Equivalent, Atherosclerosis or a 10-year CHD Risk of >20% (GRAVITY) - Gauging the lipid effects of RosuvAstatin plus ezetimibe Versus sImvastatin plus ezetimibe TherapY
• Scientific title: A 12-week Open-Label, Randomised, Parallel-group, Multicentre, Phase IIIb Study to compare the Efficacy and Safety of rosuvastatin (CRESTOR) 10 mg and 20 mg in Combination with Ezetimibe 10 mg and Sivastatin 40 mg and 80 mg in Combination with Ezetimibe 10 mg (fixed dose combination) in Patients with Hypercholesterolaemia and Coronary Heart Disease (CHD) or a CHD Risk Equivalent, Atherosclerosis or a 10-year CHD Risk of >20% (GRAVITY) - Gauging the lipid effects of RosuvAstatin plus ezetimibe Versus sImvastatin plus ezetimibe TherapY
• Date of first enrolment: 20/09/2007
• Target sample size: 800
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2007-002810-20
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: yes Other specify the comparator: Simvastatin, simvastatin/ezetimibe

Countries of recruitment

Lithuania, Netherlands

Key inclusion & exclusion criteria

Inclusion criteria:
At Visit 1 (Week -6)
For inclusion in the dietary lead-in phase, patients must fulfil all of the following criteria at Visit 1:
1. Provision of signed written informed consent
2. Male or female patients aged 18 years of age or older.
3. A history of CHD or a CHD risk equivalent, clinical evidence of atherosclerosis (definitions given in Appendix G) or a 10-year Framingham risk score of >20% for CHD, as described in NCEP ATP III guidelines
4. The patient must have a reasonable likelihood of attaining LDL-C values of = 130 mg/dL to <220 mg/dL at Visit 2, in the opinion of the Investigator. Based upon the experience of previous studies, the following guidance can be used in interpreting Visit 1 LDL-C results:
o = 125 mg/dL (3.24 mmol/L) to <220 mg/dL (5.69 mmol/L) in statin-naïve patients (patients who have not taken any lipid-lowering therapy known to affect LDL-C in the 4 weeks prior to Visit 1)
o = 90 mg/dL (2.33 mmol/L) to <180 mg/dL (4.66 mmol/L) in patients who have taken lovastatin, fluvastatin, or pravastatin within 4 weeks of Visit 1
o = 70 mg/dL (1.81 mmol/L) to <160 mg/dL (4.14 mmol/L) in patients who have taken simvastatin, atorvastatin, rosuvastatin or any statin in combination with ezetimibe within 4 weeks of Visit 1
5. Fasting TG concentrations <400 mg/dL (4.52 mmol/L)
6. Patients willing to follow all study procedures including attendance at clinics for scheduled study visits, fasting prior to clinic visits (all visits blood draws) and compliance with study treatment regimen
For inclusion in the biomarker research, patients must fulfil the following criterion:
· Provision of written informed consent for biomarker research.
For inclusion in the genetic research, patients must fulfil the following criterion:
· Provision of written informed consent for genetic research. Any additional criteria are provided in Appendix K
If a patient declines to participate in the biomarker or genetic research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study described in this CSP, so long as they consent.
Randomised treatment period
For inclusion into the randomised treatment phase of the study, patients must fulfil the following criteria:
1. Fasting LDL-C concentrations of = 130 mg/dL (3.36 mmol/L) to <220 mg/dL (5.69 mmol/L) at Visit 2
2. Fasting TG concentrations <400 mg/dL (4.52 mmol/L) at Visit 2

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
At Visit 1 (Week -6)
Any of the following is regarded as a criterion for exclusion from the study:
1. Use of lipid lowering drugs and other prohibited concomitant medications from Visit 1 (see Section 3.7)
2. History of statin-induced myopathy, or serious hypersensitivity reaction to other HMG-CoA reductase inhibitors (statins), including rosuvastatin, simvastatin and/or a history of hypersensitivity to any components of ezetimibe
3. Pregnant women, women who are breast feeding, and women of childbearing potential who are not using chemical or mechanical contraception or have a positive serum pregnancy test (serum ß-HCG analysis)
4. Patients considered to be unstable by the Investigator after the following events (event within 8 to 12 weeks of study entry (Visit 1) at the Investigators discretion): a myocardial infarction, recent episode of unstable angina, myocardial revascularisation [percutaneous transluminal coronary angioplasty (PTCA), coronary artery bypass graft (CABG) surgery or another revascularisation procedure] or a transient ischaemic attack (TIA) or stroke. (These patients should be on a statin and should not be entered into a washout phase, therefore they are unsuitable for this study)
5. Severe congestive cardiac failure (New York Heart Association [NYHA] Class IIIb or IV) (see Appendix H). (There is no evidence that these patients benefit from statin therapy)
6. Patients awaiting a planned myocardial revascularisation prior to Visit 1. (These patients require statin therapy and so a washout phase is not appropriate; therefore they are unsuitable for this study)
7. History of malignancy with the exception of resected basal cell or squamous cell carcinoma of the skin. Women with a history of cervical dysplasia will be permitted to enter the study provided they have 3 consecutive clear Papanicolaou (Pap) smears. (So that patients who are at risk of recurrence of malignancy requiring treatment are not included)
8. History of homozygous familial hypercholesterolaemia (the severity of hypercholesterolaemia in these patients usually dictates the need for individualised treatment regimens which can include phoresis)
9. History of alcohol or drug abuse within the last 5 years
10. Current active liver disease [alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase (SGPT)) = 2 x upper limit of normal (ULN)] or severe hepatic impairment
11. Participation in another investigational drug study (including a previous rosuvastatin study) <4 weeks before enrolment in the study, or according to patient’s local ethics committee requirements where a longer period is stipulated
12. Patients previously screened for this study
13. Serious or unstable medical or psychological conditions that, in the opinion of the Investigator, would compromise the patient’s safety or successful participation in the study
14. Patients whose hormone replacement therapy (HRT) or oral contraceptive therapy (OCT) was initiated or changed within the 3 months prior to enrolment in the dietary lead in phase. (Changes in female hormones can have an effect on lipid measurements)
At randomisation visit
15. Patients with uncontrolled hypothyroidism within 3 months prior to enrolment in the dietary lead-in phase, defined as a TSH >1.5 x ULN (this is due to the relationship between myopathy and patients with hypothyroidism undergoing statin therapy)
16. Patients with unexplained creatine kinase (CK) within 3 months prior to enrolment in the dietary l

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Dyslipidemia - Expert groups have identified low-density lipoprotein cholesterol (LDL-C) as the primary target for cholesterol lowering therapy because it is strongly associated with coronary heart disease (CHD) risk but, more importantly, clinical studies document that lowering LDL-C reduces the risk for major CHD events (Expert Panel NCEP ATP III 2001: De Backer et al 2003; American Heart Association (AHA)/American College of Cardiology (ACC): Smith et al 2006).

Intervention(s)

Trade Name: CRESTOR
Product Name: rosuvastatin calcium
Pharmaceutical Form: Tablet
INN or Proposed INN: rosuvastatin calcium
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
INN or Proposed INN: rosuvastatin calcium
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-

Trade Name: ZOCOR
Product Name: simvastatin
Pharmaceutical Form: Tablet
INN or Proposed INN: simvastatin
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 40-

Trade Name: ZOCOR
Product Name: simvastatin
Pharmaceutical Form: Tablet
INN or Proposed INN: simvastatin
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 80-

Trade Name: EZETROL
Product Name: ezetimibe
Pharmaceutical Form: Tablet
INN or Proposed INN: ezetimibe
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-

Trade Name: Inegy
Product Name: simvastatin/ezetimibe
Pharmaceutical Form: Tablet
INN or Proposed INN: simvastatin/ezetimibe
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 40/10-
INN or Proposed INN: simvastatin/ezetimibe
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 80/10-

Primary Outcome(s)

Secondary Objective: 1. The percent change in LDL-C of rosuva 10mg/ezetimibe 10 vs simva 80mg/ezetimibe 10 mg
2. The percent change in HDL-C, TC, TG, nonHDL-C, ApoB, ApoA-1 of of rosuva 10mg/ezetimibe 10 vs simva 80mg/ezetimibe 10 mg
3. rosuva 20/ezetimibe 10 vs simva 40 mg/ezetimibe 10mg on the proportion of patients achieving lipid goals after 6 weeks.
4. rosuva 10/ezetimibe 10 vs simva 40 mg/ezetimibe 10mg on the proportion of patients achieving lipid goals after 6 weeks.
5. rosuva 20/ezetimibe 10 vs simva 80 mg/ezetimibe 10mg on the proportion of patients achieving lipid goals after 6 weeks.
6. rosuva 10/ezetimibe 10 vs simva 80 mg/ezetimibe 10mg on the proportion of patients achieving lipid goals after 6 weeks.
7. To assess rosuva 10mg and 20mg with ezetimibe 10mg vs the same dose of rosuva alone on the percent change in lab values

Primary end point(s): Primary outcome variable:
· Percentage LDL-C change from baseline to 6 weeks (mean of weeks 4 and 6) of combination therapy
· Statistical significance of the following 3 comparisons will be tested simultaneously by a Hochberg procedure to control for multiple comparisons:
1. Rosuvastatin 20 mg + ezetimibe 10mg vs simvastatin 40 mg+ 10 mg ezetimibe.
2. Rosuvastatin 10 mg + ezetimibe 10mg vs simvastatin 40 mg+ 10 mg ezetimibe.
3. Rosuvastatin 20 mg + ezetimibe 10mg vs simvastatin 80 mg+ 10 mg ezetimibe

Main Objective: The primary objective of this study is to evaluate the LDL-C lowering efficacy of rosuvastatin 10 mg and 20 mg in combination with ezetimibe relative to that of simvastatin in a fixed dose combination with ezetimibe. This objective has 3 specific components:
1. Percentage change from baseline in LDL-C for rosuvastatin 20mg in combination with ezetimibe 10mg vs simvastatin 40mg in combination with ezetimibe 10mg after 6 weeks combination therapy (mean value of 4 and 6 weeks of combination therapy will be used)
2. Percentage change from baseline in LDL-C for rosuvastatin 10mg in combination with ezetimibe 10mg vs simvastatin 40mg in combination with ezetimibe 10mg after 6 weeks combination therapy (mean value of 4 and 6 weeks of combination therapy will be used)
3. Percentage change from baseline in LDL-C for rosuvastatin 20mg in combination with ezetimibe 10mg vs simvastatin 80mg in combination with ezetimibe 10mg after 6 weeks combination therapy

Secondary ID(s)

2007-002810-20-LT

D356FC00003