Common use of Study Objectives Clause in Contracts

Study Objectives. The primary end point of the study was the change in mean IMT of the common carotid artery after 24 months. Secondary end points were the changes in mean and maximum IMT of the carotid bifurcation, internal carotid artery, common femoral artery, and superficial femoral artery and the changes in aggregate carotid IMT (defined as the average of the mean IMT of the three carotid segments), all after 24 months. The change in mean IMT after 12 months was also considered a secondary end point. The following predefined cardiovascular events were evaluated during the study: cardiovascular death, nonfatal myocardial infarction, per- cutaneous transluminal coronary angioplasty, coronary artery bypass graft surgery, nonfatal stroke, peripheral artery bypass graft, percutaneous transluminal angioplasty, or amputation because of atherosclerotic disease. After giving written informed consent, 250 patients participated at least 1 week after the screening visit. Patients were randomly assigned to receive 0.4 mg cerivastatin (Bayer, Mij- drecht, the Netherlands) or placebo daily for a period of 2 years. Double-blind study medica- tion was assigned using a predetermined computer- generated randomization scheme with a block size of 10. On 8 August 2001, cerivastatin was withdrawn from the market due to reports of serious morbidity and mortality possibly related to the drug 17. At that moment, all 250 patients had been included in the study with a mean follow-up of 15.4 months (range 6–23). All patients were instructed to discontinue the study drug. The study was not unblinded at any time point. No patient had developed myopathy, and creatinine kinase values above five times the upper limit of normal had not been observed. After consultation with independent experts in lipid-lowering treatment studies, it was decided to continue the study. Cerivastatin (0.4 mg) was replaced by simvastatin (20 mg) daily, on the basis of a comparable LDL reduc- tion18,19. Both simvastatin and matching placebo tablets (Merck Sharp & Dohme, Haarlem, the Netherlands) were given according to the original allocation. The study was continued 1 month after the discontinuation of cerivastatin. The total use of study medication was kept at 24 months, resulting in the study being prolonged for 1 month. Patients returned to the study site after a 12-h fast at 3, 6, 12, 18, and 24 months, when blinded lipid and safety measurements (creatinine kinase and ALT) were performed. Carotid IMT was measured at baseline, 12 months, and 24 months. Femoral IMT was performed at baseline and 24 months. Two-year follow-up for clinical events was performed for all 250 patients. Ultrasound imaging was performed with an Acuson Aspen scanner with a linear array 7.5- MHz probe. All images were recorded digitally and on a S-VHS videotape for off-line, blinded analysis by an independent core laboratory (Heartcore, Leiden, the Netherlands). During the study, all measurements were performed by the same two certified ultrasonographers. In the supine position, the left and right carotid arteries, near and far walls, were examined longitudinally at the angle that resulted in an optimal and maximal IMT (while avoiding plaques) for each segment. The segments scanned were the distal 1.0 cm of the common carotid artery, the carotid bifurcation, and the proximal 1.0 cm of the internal carotid artery. The optimal angle was used for follow- up. The same procedure was done for the common femoral artery and superficial femoral artery. For each segment, three R wave– triggered images were stored. Mean and maximal IMT were measured, when possible, over the entire 1 cm of the vessel segment. The three IMT measurements were averaged. To obtain mean and maximal IMT per vessel segment, far and near wall, left and right values were averaged. During the first year of the study, a reproducibility investigation was performed for the two ultrasonographers in 16 subjects. For the common carotid artery, interobserver variability (expressed as mean difference ± SD) was 0.0082 ± 0.050 mm and intraobserver variability was 0.0067 ± 0.049 and 0.00036 ± 0.058 mm for the two observers. For the common femoral artery, interobserver variability was 0.039 ± 0.11 mm and intraobserver variability was 0.0085 ± 0.10 and 0.060 mm ± 0.078 mm for the two observers. All laboratory measurements were performed at the Department of Clinical Chemistry and Hematology of the Leyenburg Hospital, according to ISO 15189 standard procedures. When this study was designed, no data were available on IMT progression in type 2 diabetes. From clinical studies in patients with CAD, we assumed a progression rate of 0.03 mm per 2 years for the common carotid artery IMT. The number of patients needed to detect a differ- ence in mean common carotid artery IMT of 0.04 mm after 2 years (expected SD 0.10) with a power of 80% (α = 0.05) was 100 patients in each group. To allow for a 20% drop-out rate, the total number of patients randomized would be 250. The primary treatment comparison is between placebo and statin therapy in patients completing the study (on-treatment analysis). Changes from baseline within each treatment group were analyzed using Student’s paired t test. Comparisons of the effects between the treatment groups were performed using Student’s independent samples t test. Mixed-model analysis was used as a sensitivity analysis to assess the influence of missing values on the results, under the assumption of “missing at random” 20, and to investigate systematic differ- ences between replications, positions, and between far and near wall. Stepwise regression techniques were used to investigate the effect on baseline IMT and on changes in IMT of sex, age, smoking habits, ethnicity, blood pressure, anthropometric param- eters, and duration of cerivastatin versus simvastatin use. To test the equivalence of 0.4 mg cerivastatin and 20 mg simvastatin, LDL levels before and after the switch to simvastatin were compared using Student’s paired t test. Correlation between changes in IMT and changes in lipid levels were evaluated by calculating ▇▇▇▇▇▇▇’▇ correlation coefficients. The occurrence of clinical events was expressed as a proportion and evaluated using Chi-squared test or ▇▇▇▇▇▇’▇ exact test as appropriate. All analyses were two sided with a level of significance of α = 0.05.