Other objectives of interest
Although efficacy objectives were not specified in the protocol for the open-label extension, it
was of interest to evaluate long-term efficacy of rosuvastatin. Thus, efficacy endpoints from
the main period were provided in the statistical analysis plan for the extension period in order
to address key questions about long-term efficacy for this open-label extension period,
namely:
The effect of rosuvastatin on low-density lipoprotein cholesterol (LDL-C),
high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC) and
triglycerides (TG)
Achievement of National Cholesterol Education Programme Adult Treatment Panel
III (NCEP ATP III) guideline treatment LDL-C target goal
Achievement of NCEP ATP III guideline treatment nonHDL-C target goal for
patients with high TG (³ 200 mg/dL [2.26 mmol/L])
Achievement of (Joint) European Atherosclerosis Society (EAS) LDL-C target goal
Achievement of optimal LDL-C target goal <100 mg/dL (2.59 mmol/L)
Modifying glucose and insulin resistance.
METHODS
Study design
This was a multicentre study conducted in non-diabetic, non-atherosclerotic patients with
metabolic syndrome, elevated LDL-C and a 10-year risk for coronary heart disease (CHD) of
>10%, comprising:
A 4-week dietary lead-in period, followed by
A main (randomised) 12-week, 2-period, 3-arm, parallel group, double-blind,
double-dummy, randomised, force-titration period comparing the efficacy and
safety of rosuvastatin with atorvastatin and placebo, and
An optional open-label extension period (non-fixed duration).
Patients who successfully completed the 12 weeks of randomised treatment in the main period
of the study had the option of entering the open-label extension period and were initially
treated with rosuvastatin 20 mg. If necessary, patients were dose-titrated in order to meet their
target NCEP LDL-C and nonHDL-C goals, according to their risk category. They were also
back-titrated if thought appropriate by the investigator.
The last visit of the main period was the first visit of the extension period (Week 12, Visit 5).
Patients were initially administered rosuvastatin 20 mg for 6 weeks and were then titrated to
rosuvastatin 40 mg if they failed to achieve their NCEP ATP III LDL-C and nonHDL-C target
goals, or continued on rosuvastatin 20 mg if lipid target goals were achieved. If patients failed
to achieve their lipid target goals after 6 weeks of rosuvastatin 40 mg treatment, they were
either discontinued or continued with other permitted lipid-lowering therapy (excluding
gemfibrozil) co-administered with their rosuvastatin 40 mg treatment. During the open-label
extension period, rosuvastatin could be down-titrated to the next lowest dose for safety or
efficacy reasons (see duration of treatment for a further description of titration).
Target patient population and sample size
The study population in the main period was defined by the selection criteria at study entry:
namely, male and female patients, aged 18 years or older, with metabolic syndrome (as
defined by the NCEP-ATP III guidelines), plus a raised LDL-C (³ 130 mg/dL [3.36 mmol/L]).
Patients had multiple risk factors that conferred a 10-year risk score >10% for CHD, without
CHD or other atherosclerotic disease (as defined by NCEP-ATP III). Diabetic patients were
excluded and all patients were statin-naïve.
In order to enter the extension period, patients had to complete the main treatment period.
The sample size of the extension period was therefore dependent on the number of patients
completing the main period of the study. No separate inclusion/exclusion criteria were
assessed before entering the extension period. Patients completing the main period of the
study were given the option to enter the extension period
Investigational product and comparator(s): dosage, mode of administration and batch
numbers
Duration and titration of treatment
At the end of the 4-week, dietary lead-in period, eligible patients who entered the main period
were randomised at Visit 3 (Week 0) to 1 of 3 treatment groups: rosuvastatin 10 mg,
atorvastatin 10 mg or placebo for 6 weeks of treatment (Period 1 of the main period). Patients
were then force-titrated to receive rosuvastatin 20 mg (if they initially received
rosuvastatin 10 mg or placebo) or atorvastatin 20 mg (if they initially received
atorvastatin 10 mg), for a further 6 weeks (Period 2).
Patients entering the extension period at Week 12 were administered rosuvastatin 20 mg and
returned after the first 6 weeks of open-label treatment for Visit 5.1 (Week 18). Thereafter,
for patients achieving their NCEP ATP III LDL-C and nonHDL-C target goals, rosuvastatin
20 mg treatment was continued and visits took place at 12-week intervals. Patients not
achieving their lipid target goals at Week 18 were titrated to rosuvastatin 40 mg and,
thereafter, attended visits at 6-week intervals. After 6 weeks of rosuvastatin 40 mg treatment
(Visit 5.2, Week 24), patients who did not achieve their lipid target goals could either be
discontinued or have permitted lipid-lowering therapies co-administered with rosuvastatin
40 mg. Study medication was continued until rosuvastatin became commercially available in
that country.
Patients whose LDL-C fell to below 50 mg/dL (1.30 mmol/L) at any time during the extension
period could be down-titrated - from rosuvastatin 40 mg to 20 mg and from rosuvastatin
20 mg to 10 mg - at the discretion of the investigator. Rosuvastatin could also be downtitrated
1 dose level at the investigator’s discretion and after consultation with the AstraZeneca
physician, when there was an increase of >30% from baseline (Week 0) in serum creatinine at
2 consecutive visits, or when there was a ³ 1 grade shift in urine dipstick protein to a grade of
³++ at 2 consecutive visits (where the urine protein/creatinine ratio was >0.50 mg protein/mg
creatinine [US] or >56 mg protein /μmol creatinine [Europe]). A maximal dose of rosuvastatin 20 mg was administered to patients with serum creatinine >3.0 mg/dL (265 mmol/L).
Rosuvastatin treatment was continued in the open-label extension period until the drug
became commercially available in that country. The exception was Norway: although
rosuvastatin was not commercially available at the time of writing this report, all patients had
their last visit on or before 09 February 2005. The majority of patients (55%) had at least
36 weeks’ open-label extension treatment with rosuvastatin (mean 42 weeks).
Treatment groups
Patients choosing to enter the extension period at Week 12 were administered rosuvastatin
20 mg for 6 weeks. Thereafter, as previously described, patients could continue on
rosuvastatin 20 mg, or be titrated to rosuvastatin 40 mg (with or without other permitted
lipid-lowering therapy). Rosuvastatin could also be down-titrated from rosuvastatin 40 mg to
rosuvastatin 20 mg, and from rosuvastatin 20 mg to 10 mg for safety or efficacy reasons.
Thus, any of the following treatments could be administered during the open-label extension
period: rosuvastatin 40 mg alone, rosuvastatin 40 mg plus other lipid-lowering therapy,
rosuvastatin 20 mg, or rosuvastatin 10 mg.
Treatment groups analysed were:
There was a large degree of overlap between the above categories since patients could appear
in more than 1 category during the course of the extension period. The majority of patients
were on rosuvastatin 20 mg at final visit of the extension period (N=245, 85%). Thus, this
group and the total rosuvastatin groups were considered as the principal groups of interest for
the long-term effect of rosuvastatin treatment. Results for the other treatment groups are not
presented in the tables in the main body of the report, but can be found in the appropriate
summary tables in Section 11.
Note that efficacy and safety comparisons should not be made between treatment groups
because of the absence of a random allocation of treatment.
Safety (overall safety population)
Primary variable (endpoint):
Effects on the liver (by measurement of alanine aminotransferase [ALT] and assessment of
AEs and symptoms related to liver effects) and on muscle (by measurement of creatine kinase
[CK] and assessment of AEs and symptoms related to muscle effects) were carefully
monitored in this study, as these are known side effects of rosuvastatin and of statins in
general. Renal effects of rosuvastatin were also carefully monitored and included AEs and
symptoms related to the renal-urinary system, including frequency of shift in urine dipstick
protein from ‘none’ or ‘trace’ at baseline to ³++ (‘proteinuria’).
RESULTS
Efficacy (extension intention-to-treat population)
Efficacy endpoints were not specified in the protocol for the extension period of this study;
however, the following endpoints were provided in the extension statistical analysis plan in
order to address key questions about long-term efficacy for the extension period:
Percentage change from baseline in LDL-C, TC, HDL-C, TG, nonHDL-C,
LDL-C/HDL-C, TC/HDL-C and nonHDL-C/HDL-C at the final visit of the
extension period
Number and percentage of patients (overall and by risk category) achieving NCEP
ATP III guideline treatment target for LDL-C at the final visit of the extension
period
Number and percentage of patients (overall and by risk category) achieving NCEP
ATP III guideline treatment target for nonHDL-C (patients with baseline TG
³ 200 mg/dL [2.26 mmol/L] only) at the final visit of the extension period
Number and percentage of patients (overall and by risk category) achieving Joint
European 2003 guideline target treatment for LDL-C at the final visit of the
extension period
Number and percentage of patients achieving optimal LDL-C target goal of
<100 mg/dL at the final visit of the extension period. (This is not a recognised
LDL-C target for patients with metabolic syndrome but was pre-defined as an
‘optimal’ target in the protocol for patients in this study.)
Percentage change from baseline in blood glucose, insulin, and homeostasis model
assessment (HOMA) for insulin resistance.
Statistical methods
The overall safety population included all patients who received at least 1 dose of rosuvastatin
therapy in the main, or main and extension periods of the study.
The extension safety population included all patients who received at least 1 dose of
rosuvastatin therapy during the extension period.
The extension intention-to-treat (ITT) population included all patients who received at least
1 dose of rosuvastatin therapy in the extension period, and who had a lipid measurement from
the main period of the study and at least 1 scheduled lipid assessment during the extension
period of the study.
No per protocol (PP) population was defined for the extension period of the study.
Efficacy data were evaluated based on the extension ITT population. Efficacy analyses were
performed by final dose of rosuvastatin and total rosuvastatin at the final visit of the extension
period. For comparison, lipid data for the same patients were summarised (again by
rosuvastatin dose at the final visit and total rosuvastatin) at baseline (Visit 3 of the main
period, Week 0) and at the end of the main period (Week 12). Patients’ NCEP ATP III and
Joint European 2003 risk categories calculated at baseline (Week 0) were used for the analysis
of lipid data during the open-label extension period. All analyses were based on observed
data.
Safety analyses were based on the overall safety and extension safety populations. Laboratory
safety parameters (clinical biochemistry, haematology, urinalysis and renal biochemistry, and
vital signs) were summarised for the extension safety population by final rosuvastatin dose
and total rosuvastatin at baseline, end of the main period and at final visit of the extension
period. Adverse event data were summarised by dose at onset/worsening for the overall safety
population. Number and percentage of patients with key elevations in ALT (>3 times at a
single or 2 consecutive visits), CK (>5 x and >10 x upper limit of normal [ULN]) and serum
creatinine (increase >30%, >50% and >100% from baseline) were evaluated at any time
during the main or extension periods.
All safety and efficacy endpoints were summarised using descriptive statistics. No formal
statistical analyses were performed.
Patient population
In total, 401 patients were randomised to the 3 treatment groups. A total of 289 patients
entered the extension period at Week 12.
For the overall safety population, the majority of patients were Caucasian, and approximately
two-thirds were males. The majority of patients had normal renal function at baseline (70%).
Almost all patients had more than 1 CHD risk factor; hypertension and age ≥45 years for
males or ³ 55 years for females were the most commonly reported risk factors. The overall
risk profile of the patients was in keeping with the target population for the investigational product. Demographic characteristics of the extension safety population were similar to those of the overall safety population.
In the total treatment group there were 348 patients in the overall safety population,
289 patients in the extension safety population and 288 patients in the extension ITT
population by final dose. By final dose in the extension period, a total of 245 patients took
rosuvastatin 20 mg, 23 patients took rosuvastatin 40 mg alone, 19 patients took rosuvastatin
10 mg and 2 patients took rosuvastatin 40 mg plus other lipid-lowering therapy.
Overall mean treatment duration with rosuvastatin was 42 weeks and 34% of patients spent at
least 48 weeks on rosuvastatin treatment. The overall exposure was 278 person-years,
calculated from an overall mean exposure of 0.80 years x 348 evaluable patients.
Safety results (extension and overall safety populations)
Key safety results are summarised in Table S1.
Rosuvastatin overall, and at 20 mg/day, was well tolerated during the whole study. In the total
rosuvastatin group, 173 (49.7%) patients experienced a total of 420 treatment-emergent AEs.
The majority of AEs were of mild or moderate intensity. Overall, the pattern of AEs
experienced (including serious and those leading to discontinuation), was as expected given
the medical history and condition of the study population, long-term treatment and class of
drug to which rosuvastatin belongs (statins). There were no fatal events during rosuvastatin
treatment in either the randomised or extension period.
All patients started the extension period on rosuvastatin 20 mg and the majority of patients
(85%) were on rosuvastatin 20 mg at the final visit of the extension period. The extension
period did not have a fixed duration; mean treatment duration with rosuvastatin was 42 weeks
(range 2 to 901 days) and 34% of patients took rosuvastatin for at least 48 weeks. The overall
exposure was 278 person-years.
The study database was examined in detail for a combination of symptoms and abnormal
laboratory values suggestive of hepatic disturbance; it was found that no patient had any such
combination. One patient (0.3%) on rosuvastatin 20 mg had clinically significant elevations
in ALT, but remained asymptomatic. Other hepatic laboratory data (AST, bilirubin, GGT,
ALP), and other significant AEs of interest related to liver symptomatology were generally
unremarkable and, overall, did not give any safety concerns.
The study database was also examined for treatment-emergent AEs suggestive of muscle
damage, such as muscle pain, myalgia, muscle tenderness or muscle weakness. The frequency
and pattern of such AEs fell within the known safety profile of rosuvastatin 20 mg. One
patient (0.3%) on rosuvastatin 20 mg experienced CK >10 x ULN with associated muscle
symptoms during the randomised period, which met the criteria for myopathy. There were no
clinically relevant elevations in CK during the extension period.
Results of renal parameters during the whole study were as expected. Mean changes over
time for serum creatinine were small (decrease of approximately 4 μmol/L at final visit) and
no patient had an increase from baseline >100% in serum creatinine. Pooled safety analysis of
patients from the rosuvastatin clinical development programme indicated that 0.7% of
rosuvastatin 20 mg patients developed proteinuria at final visit (urine dipstick grade ³ ++ from
‘none’ or ‘trace’ at baseline); Vidt et al 2004. In this study only 1 patient receiving
rosuvastatin 20 mg developed proteinuria during the study, which was transient in nature. No
clinically important changes in other urinalysis parameters (including urine blood, colour,
glucose, ketones) were observed.
Overall, results for other laboratory parameters (haematology, renal biochemistry, other
biochemistry), vital signs and physical examination were unremarkable. There were no
notable individual changes.
Efficacy results (extension ITT population)
Table S2 presents key efficacy results: percentage change from baseline at final visit of the
extension period for LDL-C and HDL-C, and number and percentage of patients who
achieved NCEP ATP III guideline treatment target goal for L
In the total rosuvastatin group, percentage change from baseline in lipids and lipid ratios
indicated an overall improvement in atherogenic profile throughout the extension period,
which was consistent with that observed during the randomised period. Percentage reductions
from baseline were similar at the end of the randomised period (Week 12) and at the final visit
of the extension period (eg, 47% and 49%, respectively, for LDL-C; and 23% and 25%,
respectively, for TG). Of note, at the last visit of the extension period there was a 12%
increase from baseline in HDL-C, compared with an 8% increase at Week 12.
Overall, the large majority of patients achieved their NCEP, Joint European and optimal target
goals, in all risk categories combined and in the individual risk categories. By final dose there
were only 2 patients with co-administration of other lipid-lowering therapy.
Efficacy results from the other treatment groups were in agreement with the results from the
total rosuvastatin group.
Reference:
Stalenhoef AFH, Ballantyne CM, Sarti C, Murin J, Tonstad S, Rose H, et al. A Comparative
study with rosuvastatin in subjects with Metabolic Syndrome: results of the COMETS study.
Eur Heart J 2005; 5 Sept [epub ahead of print]:1-9.
As with any comprehensive clinical trial programme, individual studies may include both approved and non-approved treatment regimens, including doses higher than those approved for clinical use. Before prescribing Crestor™ (rosuvastatin), Healthcare Professionals should view their specific country information.