{"component": "clause", "props": {"groups": [{"snippet_links": [{"key": "the-objectives", "type": "clause", "offset": [0, 14]}, {"key": "the-safety", "type": "clause", "offset": [48, 58]}, {"key": "high-risk", "type": "clause", "offset": [117, 126]}, {"key": "to-provide", "type": "clause", "offset": [160, 170]}, {"key": "in-order-to", "type": "clause", "offset": [188, 199]}, {"key": "pivotal-clinical-study", "type": "definition", "offset": [223, 245]}, {"key": "safety-and-efficacy", "type": "clause", "offset": [261, 280]}, {"key": "myocardial-infarction", "type": "clause", "offset": [326, 347]}], "snippet": "The objectives of this study are: \u00b7 to evaluate the safety of the BL-1040 myocardial implant in patients after MI at high risk for LV remodeling and CHF, and \u00b7 to provide feasibility data in order to initiate and conduct a pivotal clinical study evaluating the safety and efficacy of the BL-1040 implant in patients following myocardial infarction.", "size": 5, "samples": [{"hash": "aqqfj3FR3dp", "uri": "/contracts/aqqfj3FR3dp#study-objectives", "label": "License and Commercialization Agreement (Bellerophon Therapeutics, Inc.)", "score": 26.2429847717, "published": true}, {"hash": "eqgtMpj78Xc", "uri": "/contracts/eqgtMpj78Xc#study-objectives", "label": "License and Commercialization Agreement (Bellerophon Therapeutics LLC)", "score": 26.032169342, "published": true}, {"hash": "117iSGFYTmU", "uri": "/contracts/117iSGFYTmU#study-objectives", "label": "License and Commercialization Agreement (Bellerophon Therapeutics LLC)", "score": 25.3641338348, "published": true}], "hash": "1bbd120ba1c5ada4bb9449458027c44b", "id": 1}, {"snippet_links": [{"key": "primary-objective", "type": "definition", "offset": [4, 21]}, {"key": "standard-of-care", "type": "clause", "offset": [214, 230]}], "snippet": "The primary objective of this study is to demonstrate that mucous fistula refeeding between enterostomy creation and enterostomy closure reduces the time to full enteral feeds after enterostomy closure compared to standard of care.", "size": 5, "samples": [{"hash": "b0Hhss9ZaWL", "uri": "/contracts/b0Hhss9ZaWL#study-objectives", "label": "Study Protocol", "score": 30.0644397736, "published": true}, {"hash": "eiys2wvMbwx", "uri": "/contracts/eiys2wvMbwx#study-objectives", "label": "Study Protocol", "score": 28.687543869, "published": true}, {"hash": "8QuxqFEOqzc", "uri": "/contracts/8QuxqFEOqzc#study-objectives", "label": "Study Protocol", "score": 28.687543869, "published": true}], "hash": "335ad61a238c2b62cfdf5df5eec33e1b", "id": 2}, {"snippet_links": [{"key": "primary-objective", "type": "definition", "offset": [4, 21]}, {"key": "six-months", "type": "definition", "offset": [75, 85]}, {"key": "based-on", "type": "definition", "offset": [319, 327]}, {"key": "following-the", "type": "definition", "offset": [402, 415]}, {"key": "phase-of", "type": "clause", "offset": [516, 524]}, {"key": "the-study", "type": "definition", "offset": [525, 534]}, {"key": "to-receive", "type": "definition", "offset": [575, 585]}, {"key": "an-additional", "type": "clause", "offset": [612, 625]}, {"key": "specific-objectives", "type": "definition", "offset": [641, 660]}, {"key": "information-on", "type": "clause", "offset": [704, 718]}, {"key": "study-subjects", "type": "clause", "offset": [729, 743]}, {"key": "provide-information", "type": "clause", "offset": [861, 880]}, {"key": "associated-with", "type": "definition", "offset": [1114, 1129]}, {"key": "after-18-months", "type": "clause", "offset": [1362, 1377]}, {"key": "additional-analyses", "type": "clause", "offset": [1617, 1636]}, {"key": "details-of-the", "type": "clause", "offset": [1746, 1760]}, {"key": "statistical-procedures", "type": "clause", "offset": [1761, 1783]}, {"key": "statistical-analysis-plan", "type": "definition", "offset": [1819, 1844]}], "snippet": "The primary objective of this study is to evaluate data obtained following six months of treatment with alendronate, in subjects who have previously received 18 months of blinded Abaloparatide -SC/Placebo. Safety will be evaluated with clinical, laboratory and radiologic assessment. The analysis at six months will be based on the treatment that subjects were randomized to in the BA058-05-003 study. Following the initial six months of treatment in this study, subjects will then enter the long-term observational phase of the study during which the subjects will continue to receive alendronate treatment for an additional 18 months. The specific objectives of this study are to: \u00b7 Provide additional information on safety in study subjects receiving six months of treatment with alendronate following 18 months of treatment with Abaloparatide-SC/Placebo. \u00b7 Provide information on the vertebral fracture rate in subjects receiving six months of treatment with alendronate following 18 months of treatment with Abaloparatide-SC/Placebo. \u00b7 Provide additional information on non-vertebral fractures and BMD change associated with six months of treatment with alendronate following 18 months of treatment with Abaloparatide-SC/Placebo. \u00b7 Provide additional information on BMD change and osteoporosis status associated with 24 months of treatment with alendronate after 18 months of Abaloparatide-SC/Placebo. The analysis performed at six months will be used as a follow-up to the 18 month fracture endpoint for Study BA058-05-003. Vertebral fractures based on radiologic assessments will also be analyzed at Month 24. Additional analyses for other endpoints will be conducted cumulatively at Months 12, 18, and 24 (i.e., Visits 4, 5, and 6). Full details of the statistical procedures to be used will be provided in the Statistical Analysis Plan.", "size": 4, "samples": [{"hash": "b8Xw4kE7XvU", "uri": "/contracts/b8Xw4kE7XvU#study-objectives", "label": "Clinical Trial Services Agreement (Radius Health, Inc.)", "score": 25.1492137909, "published": true}, {"hash": "9GjiQ2386lL", "uri": "/contracts/9GjiQ2386lL#study-objectives", "label": "Clinical Trial Services Agreement (Radius Health, Inc.)", "score": 24.3415470123, "published": true}], "hash": "6c560ee03ea2c495d250341d231e302d", "id": 3}, {"snippet_links": [{"key": "the-objectives", "type": "clause", "offset": [0, 14]}, {"key": "provide-a", "type": "definition", "offset": [60, 69]}, {"key": "selection-of-the", "type": "clause", "offset": [109, 125]}, {"key": "final-development", "type": "definition", "offset": [177, 194]}, {"key": "proof-of", "type": "clause", "offset": [212, 220]}, {"key": "reduction-in", "type": "definition", "offset": [247, 259]}, {"key": "frequency-and", "type": "definition", "offset": [260, 273]}, {"key": "determine-the", "type": "clause", "offset": [328, 341]}, {"key": "safety-and", "type": "clause", "offset": [609, 619]}], "snippet": "The objectives of this study are therefore as follows: \u00b7 To provide a clinical and statistical basis for the selection of the optimal dose of ER-306323 to be taken forward into final development \u00b7 To demonstrate proof of efficacy of ER-306323 for reduction in frequency and severity of hot flashes in postmenopausal women. \u00b7 To determine the pharmacodynamic. effects (i.e., effects on mineral metabolism and biochemical markers of bone formation and resorption) of [*] months of treatment with ER-306323. \u00b7 To determine the effects of [*] months of treatment with ER-306323 on BMD. \u00b7 To determine the overall safety and tolerability of ER-306323 after [*] months of dosing in postmenopausal women with vasomotor symptoms. \u00b7 To determine the uterine safety of ER-306323 after [*]months of dosing in postmenopausal women with vasomotor symptoms.", "size": 3, "samples": [{"hash": "9QQYQYlpXSg", "uri": "/contracts/9QQYQYlpXSg#study-objectives", "label": "License Agreement (Radius Health, Inc.)", "score": 20.8507862091, "published": true}, {"hash": "lADXuIafkRl", "uri": "/contracts/lADXuIafkRl#study-objectives", "label": "License Agreement (Radius Health, Inc.)", "score": 20.8097190857, "published": true}, {"hash": "4U5lWs2vv2W", "uri": "/contracts/4U5lWs2vv2W#study-objectives", "label": "License Agreement (Radius Health, Inc.)", "score": 20.7440109253, "published": true}], "hash": "d8e380d1c2d014a09c384fa488f3ad36", "id": 4}, {"snippet_links": [{"key": "the-objectives", "type": "clause", "offset": [0, 14]}, {"key": "to-provide", "type": "clause", "offset": [57, 67]}, {"key": "evidence-of", "type": "clause", "offset": [77, 88]}, {"key": "treatment-of", "type": "clause", "offset": [289, 301]}, {"key": "determine-the", "type": "clause", "offset": [466, 479]}, {"key": "safety-and", "type": "clause", "offset": [488, 498]}], "snippet": "The objectives of this study are therefore as follows: \u00b7 To provide clinical evidence of the long-term endometrial safety of ER-306323 in postmenopausal women with moderate and severe vasomotor symptoms. \u00b7 To confirm, clinically and statistically, the therapeutic benefit of ER-306323 for treatment of moderate and severe vasomotor symptoms in menopause \u00b7 To provide evidence of the long-term benefit of ER-306323 for prevention of postmenopausal osteoporosis. \u00b7 To determine the overall safety and tolerability of long-term treatment of ER-306323 in postmenopausal women with vasomotor symptoms.", "size": 3, "samples": [{"hash": "9QQYQYlpXSg", "uri": "/contracts/9QQYQYlpXSg#study-objectives", "label": "License Agreement (Radius Health, Inc.)", "score": 20.8507862091, "published": true}, {"hash": "lADXuIafkRl", "uri": "/contracts/lADXuIafkRl#study-objectives", "label": "License 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657]}, {"key": "determination-of-the", "type": "clause", "offset": [751, 771]}, {"key": "university-medical-center", "type": "definition", "offset": [857, 882]}, {"key": "detection-limit", "type": "definition", "offset": [1058, 1073]}, {"key": "completion-of-the-study", "type": "clause", "offset": [1278, 1301]}, {"key": "primary-treatment", "type": "definition", "offset": [1307, 1324]}, {"key": "treatment-group", "type": "definition", "offset": [1585, 1600]}, {"key": "baseline-data", "type": "clause", "offset": [1777, 1790]}, {"key": "effect-of", "type": "clause", "offset": [1895, 1904]}, {"key": "baseline-characteristics", "type": "clause", "offset": [1905, 1929]}, {"key": "changes-in", "type": "definition", "offset": [1953, 1963]}, {"key": "in-addition", "type": "clause", "offset": [2182, 2193]}, {"key": "other-parameters", "type": "clause", "offset": [2599, 2615]}], "snippet": "The primary endpoint of this sub-study was the change in CRP between 24 months and baseline. The relationship between CRP and MS score was a secondary endpoint. Patients returned to the study site after 12 hours fast at 3, 6, 12, 18 and 24 months when blinded lipid and safety measurements (creatinin kinase, ALT) were performed. CRP was measured at baseline and at 24 months. Lipid and safety measurements were performed at the Department of Clinical Chemistry and Hematology of the HAGA Hospital, according to ISO 15189 standard procedures. Blood samples were collected from the subjects after a 12 hour fast. EDTA tubes were used for the determination of HbA1c. Liver enzymes and lipids were measured in serum. A urine sample was collected for the determination of the albumin-to-creatinin ratio. The high sensitive CRP assay was performed in the Leiden University Medical Center with the Tina Quant C-reactive protein (latex) high sensitive assay from Roche using particle en- hanced immunoturbidimetry on a Roche Module P(Basel, Switzerland). The lower detection limit (analytical sensitivity) is 0.03 mg/L and the functional sensitivity 0.11 mg/L. The intra- assay CV is 1.34% at 0.55 mg/L and the inter-assay CV is 5.70% at 0.52 mg/L. All CRP assays were performed after completion of the study. The primary treatment comparison was between placebo and statin therapy in patients com- pleting the study, as on-treatment analysis. CRP values more than 15 mg/L were excluded. As CRP values were not normally distributed, logarithmic transformations were used. Changes within each treatment group were analyzed using Student\u2019s paired t-test. Comparisons of the effects between the treatment groups were performed using Student\u2019s independent samples t-test. Analysis of the baseline data was performed in all randomized patients. Step- wise regression techniques were used to investigate the effect of baseline characteristics on baseline CRP and on changes in CRP. ANOVA was used to investigate the relation between the MS score (1 point for every criterion (waist, triglycerides, HDL cholesterol and blood pres- sure) according to the NCEP/ATPIII criteria25) and baseline CRP. In addition, the effect of statin treatment on CRP was analyzed in a high-risk patient group with 3 or 4 additional MS criteria on top of their diabetes and LDL cholesterol levels > 2.6 mmol/L26. To test the equivalence of cerivastatin 0.4 mg and simvastatin 20 mg, LDL levels before and after the switch to simvas- tatin were compared using Student\u2019s paired t-test. Correlation between changes in CRP and changes in other parameters were evaluated with Pearson\u2019s correlation coefficients. Analyses were performed using SPSS 11.0 for Windows software. All analyses were 2-sided, with a level of significance of \u03b1 = 0.05.", "size": 3, "samples": [{"hash": "lxZNDKVUKqY", "uri": "/contracts/lxZNDKVUKqY#study-objectives", "label": "Doctoral Thesis", "score": 18.0, "published": true}, {"hash": "lHXpfmBJwsh", "uri": "/contracts/lHXpfmBJwsh#study-objectives", "label": "Doctoral Thesis", "score": 18.0, "published": true}, {"hash": "7vWqpqmKvz2", "uri": "/contracts/7vWqpqmKvz2#study-objectives", "label": "Doctoral Thesis", "score": 18.0, "published": true}], "hash": "bc8e7c2ae51fc73ce2b06c1a3f8334c3", "id": 6}, {"snippet_links": [{"key": "primary-endpoint", "type": "clause", "offset": [4, 20]}, {"key": "change-in", "type": "clause", "offset": [42, 51]}, {"key": "secondary-endpoints", "type": "clause", "offset": [88, 107]}, {"key": "maximum-values", "type": "clause", "offset": [426, 440]}, {"key": "study-site", "type": "definition", "offset": [542, 552]}, {"key": "and-safety", "type": "clause", "offset": [624, 634]}, {"key": "two-years", "type": "clause", "offset": [754, 763]}, {"key": "an-independent", "type": "clause", "offset": [997, 1011]}, {"key": "the-netherlands", "type": "clause", "offset": [1049, 1064]}, {"key": "during-the-study", "type": "clause", "offset": [1066, 1082]}, {"key": "performed-by", "type": "clause", "offset": [1106, 1118]}, {"key": "the-vessel", "type": "definition", "offset": [1701, 1711]}, {"key": "the-right", "type": "clause", "offset": [1816, 1825]}, {"key": "blood-pressure", "type": "definition", "offset": [2316, 2330]}, {"key": "the-media", "type": "clause", "offset": [2753, 2762]}, {"key": "detection-system", "type": "definition", "offset": [2834, 2850]}, {"key": "percentage-increase", "type": "definition", "offset": [2966, 2985]}, {"key": "department-of", "type": "clause", "offset": [3532, 3545]}, {"key": "according-to", "type": "definition", "offset": [3607, 3619]}, {"key": "standard-procedures", "type": "definition", "offset": [3630, 3649]}, {"key": "blood-samples", "type": "clause", "offset": [3651, 3664]}, {"key": "the-determination-of", "type": "definition", "offset": [3745, 3765]}, {"key": "determination-of-the", "type": "clause", "offset": [3859, 3879]}, {"key": "beckman-coulter", "type": "definition", "offset": [4107, 4122]}, {"key": "measurement-of", "type": "clause", "offset": [4724, 4738]}, {"key": "number-of-patients", "type": "clause", "offset": [4832, 4850]}, {"key": "power-of", "type": "clause", "offset": [4932, 4940]}, {"key": "primary-treatment", "type": "definition", "offset": [4992, 5009]}, {"key": "treatment-group", "type": "definition", "offset": [5154, 5169]}, {"key": "changes-in", "type": "definition", "offset": [5420, 5430]}, {"key": "duration-of", "type": "definition", "offset": [5482, 5493]}, {"key": "standard-methods", "type": "definition", "offset": [5876, 5892]}, {"key": "the-student", "type": "clause", "offset": [5913, 5924]}], "snippet": "The primary endpoint of the study was the change in FMD between 24 months and baseline. Secondary endpoints were the change in absolute diameter (Dmax-D), the time to peak (Tmax), the change in Nitroglycerin Mediated Dilation (NMD) and the FMD-to-NMD ratio(FMD/NMD). Comparisons between standard measurements for FMD at 1 minute after cuff deflation and for NMD at 3,4 or 5 minutes after Nitroglycerin administration and real maximum values obtained by beat-to-beat analysis were analyzed as an exploratory endpoint. Patients returned to the study site after a 12 hours fast at 3, 6, 12, 18 and 24 months when blinded lipid and safety measurements (creatinin kinase, ALT) were performed. Ultrasound measurements were performed at baseline and 24 months. Two years 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 for off-line, blinded, analysis by an independent core laboratory, Heart Core, Leiden, the Netherlands. During the study, all measurements were performed by the same two, certified, ultrasonographers. Fasting subjects were examined in the supine position. Heart rate was continuously moni- tored by three-lead ECG. Mean common carotid artery Intima-Media Thickness (CCA IMT) was measured as reported earlier 27. Briefly, the left and right distal 1.0 cm of the common carotid arteries, near and far walls, were examined longitudinally in the angle resulting in an optimal and maximal IMT (while avoiding plaques). For each segment, three R-wave trig- gered images were stored. Mean IMT was measured, when possible, over the entire 1 cm of the vessel segment. CCA IMT was obtained by averaging the mean IMT\u2019s of far and near wall, left and right. For FMD the right arm was placed in extension in the elbow, hand in supination, wrist and elbow supported by foam cushions. An optimal longitudinal image of the brachial artery at, or just above the elbow, was established and kept stable using a specially designed fixative. To obtain clearer images, a water bag was placed between the transducer and the skin. At baseline, 15 consecutive R-wave triggered beats were stored. A cuff placed just distally from the elbow was inflated to 50 mm Hg above systolic blood pressure (up to a maximum of 230 mm Hg) for four minutes. After deflation, R-wave frozen images were recorded for every beat, during 5 minutes. After 10 minutes rest again 15 R-wave triggered beats were stored. Subsequently two puffs of nitroglycerin (0.8 mg) spray were given sublingually, upon which again R-wave frozen images were recorded for every beat during 5 minutes. Lumen diameter (D) was defined as the distance between the media-adventitia interfaces of far and near wall. Using an automated contour detection system, D was measured semi- automatically by placing a cursor on the media-adventitia interfaces. FMD was defined as the percentage increase in brachial artery diameter within 30 to 120 seconds after ischemia ((Dmax-D)/ D). NMD is defined as the percentage increase within five minutes after nitroglyc- erin. Earlier studies in our institute reported reliability coefficients of 99%, 99% and 67% for baseline diameter, peak diameter and FMD respectively 28. In a recent report on variability of FMD (using a continuous method like we did) in DM2, CVs for baseline diameter, peak diameter and FMD were 2.7, 2.5 and 29.7%, respectively29. All laboratory measurements were performed at the Department of Clinical Chemistry and Hematology of the Leyenburg Hospital, according to ISO 15189 standard procedures. Blood samples were collected from the subjects after a 12 hour fast. EDTA tubes were used for the determination of HbA1c. Liver enzymes and lipids were measured in serum. A urine sample was collected for the determination of the albumin-to-creatinin ratio. Serum or plasma was isolated by centrifugation at 1700 g (2900 rpm) for 5 minutes. Serum levels of total cholesterol and triglycerides were measured by enzymatic methods on a Synchron LX20-analyzer (Beckman Coulter, Brea, USA). LDL cholesterol was calculated according to the Friedewald formula. If triglycerides were > 4.5 mmol/l, LDL cholesterol was measured directly with the use of a reagent kit (Genzyme Diagnostics). HDL cholesterol levels were determined after dextran sulfate-magnesium precipitation of apolipoprotein B-containing lipoproteins. Creatinin kinase and ALT were measured by an enzymatic rate method on a Synchron LX20 multichannel chemistry analyzer, according to IFCC-methods. HbA1c was measured by HPLC on a Variant II (BioRad, USA). For the urine sample, a Jaff\u00e9 rate method was used for the measurement of creatinine on a Synchron LX20-analyzer, while albumin was measured by rate nephelometry. The number of patients needed to detect a difference in FMD of 2% after 2 years (expected SD 4%) with a power of 80 % (\u03b1 = 0.05) was 63 patients in each group. The primary treatment comparison was between placebo and statin therapy in patients completing the study, as on-treatment analysis. Changes from baseline within each treatment group were analyzed using Student\u2019s paired t-test. Comparisons of the effects between the treatment groups were performed using Student\u2019s independent samples t-test. Stepwise regression techniques were used to investigate the effect on baseline FMD and on changes in FMD of baseline character- istics, carotid IMT and duration of cerivastatin versus simvastatin use. To test the equivalence of cerivastatin 0.4 mg and simvastatin 20 mg, LDL levels before and after the switch to sim- vastatin were compared using Student\u2019s paired t-test. Correlation between changes in FMD and changes in lipid levels were evaluated by calculating Pearson\u2019s correlation coefficients. Comparison between beat-to-beat analysis and standard methods was performed using the Student\u2019s paired t-test and Bland Altman analysis30. Analyses were performed using SPSS 11.0 for Windows software. All analyses were 2-sided, with a level of significance of \u03b1 = 0.05.", "size": 3, "samples": [{"hash": "lxZNDKVUKqY", "uri": "/contracts/lxZNDKVUKqY#study-objectives", "label": "Doctoral Thesis", "score": 18.0, "published": true}, {"hash": "lHXpfmBJwsh", "uri": "/contracts/lHXpfmBJwsh#study-objectives", "label": "Doctoral Thesis", "score": 18.0, "published": true}, {"hash": "7vWqpqmKvz2", "uri": "/contracts/7vWqpqmKvz2#study-objectives", "label": "Doctoral Thesis", "score": 18.0, "published": true}], "hash": "abc215f3b1380b5c0297b4bba9cab5f8", "id": 7}, {"snippet_links": [{"key": "the-objectives", "type": "clause", "offset": [0, 14]}, {"key": "to-provide", "type": "clause", "offset": [57, 67]}, {"key": "evidence-of", "type": "clause", "offset": [93, 104]}, {"key": "reduction-in", "type": "definition", "offset": [105, 117]}, {"key": "determine-the", "type": "clause", "offset": [240, 253]}, {"key": "safety-and", "type": "clause", "offset": [262, 272]}, {"key": "treatment-of", "type": "clause", "offset": [299, 311]}, {"key": "at-risk", "type": "definition", "offset": [372, 379]}], "snippet": "The objectives of this study are therefore as follows: \u00b7 To provide clinical and statistical evidence of reduction in bone loss and to provide evidence of a trend towards prevention of fractures with long-term treatment with ER-306323 \u00b7 To determine the overall safety and tolerability of long-term treatment of ER-306323 in postmenopausal women with osteoporosis who are at risk of fracture.", "size": 3, "samples": [{"hash": "9QQYQYlpXSg", "uri": "/contracts/9QQYQYlpXSg#study-objectives", "label": "License Agreement (Radius Health, Inc.)", "score": 20.8507862091, "published": true}, {"hash": "lADXuIafkRl", "uri": "/contracts/lADXuIafkRl#study-objectives", "label": "License Agreement (Radius Health, Inc.)", "score": 20.8097190857, "published": true}, {"hash": "4U5lWs2vv2W", "uri": "/contracts/4U5lWs2vv2W#study-objectives", "label": "License Agreement (Radius 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"offset": [4529, 4536]}, {"key": "type-2-diabetes", "type": "definition", "offset": [4574, 4589]}, {"key": "clinical-studies", "type": "definition", "offset": [4596, 4612]}, {"key": "rate-of", "type": "clause", "offset": [4660, 4667]}, {"key": "number-of-patients", "type": "clause", "offset": [4727, 4745]}, {"key": "power-of", "type": "clause", "offset": [4863, 4871]}, {"key": "total-number-of", "type": "definition", "offset": [4957, 4972]}, {"key": "primary-treatment", "type": "definition", "offset": [5011, 5028]}, {"key": "treatment-group", "type": "definition", "offset": [5170, 5185]}, {"key": "model-analysis", "type": "clause", "offset": [5352, 5366]}, {"key": "sensitivity-analysis", "type": "definition", "offset": [5381, 5401]}, {"key": "the-assumption", "type": "clause", "offset": [5466, 5480]}, {"key": "blood-pressure", "type": "definition", "offset": [5761, 5775]}, {"key": "duration-of", "type": "definition", "offset": [5810, 5821]}], "snippet": "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\u201323). 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\u2013 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 \u00b1 SD) was 0.0082 \u00b1 0.050 mm and intraobserver variability was 0.0067 \u00b1 0.049 and 0.00036 \u00b1 0.058 mm for the two observers. For the common femoral artery, interobserver variability was 0.039 \u00b1 0.11 mm and intraobserver variability was 0.0085 \u00b1 0.10 and 0.060 mm \u00b1 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% (\u03b1 = 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\u2019s paired t test. Comparisons of the effects between the treatment groups were performed using Student\u2019s 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 \u201cmissing at random\u201d 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\u2019s paired t test. Correlation between changes in IMT and changes in lipid levels were evaluated by calculating \u2587\u2587\u2587\u2587\u2587\u2587\u2587\u2019\u2587 correlation coefficients. The occurrence of clinical events was expressed as a proportion and evaluated using Chi-squared test or \u2587\u2587\u2587\u2587\u2587\u2587\u2019\u2587 exact test as appropriate. 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