Endpoints secondary

Direct Fibrinolytics Alfimeprase is a recombinant tmncated form of fibrolase, a fibrinolytic zinc metalloproteinase isolated from the venom of the Southern copperhead snake. It degrades fibrin directly and achieves thrombolysis independent of plasmin formation. This may result in faster recanalization and a decreased risk of hemorrhagic conversion. The initial data on the safety and efficacy of alfimeprase in peripheral arterial occlusion disease appeared very promising, but recent communication from the sponsor revealed that the phase III trials of the drug in peripheral arterial disease and catheter obstruction (NAPA-2 and SONOMA-2) failed to meet their primary and key secondary endpoints of revascularization. A trial for I AT in acute stroke (CARNEROS-1) is planned to begin soon. 

Level II Intermediate level of evidence. Small randomized trials or predefined secondary endpoints of large RCTs. 

HY-10275 (no structure reported), having such a dual mechanism, has been recently reported to meet the primary and secondary endpoints in the initial phase II trial at doses of 1 and 3 mg in adults with transient insomnia [93]. 

Primary endpoints Secondary endpoints In vivo model selection Species-specific effects Effects independent of species Animal model of disease... 

There are several inherent weaknesses in observational trials, hi controlled clinical trials, every effort is made to select patient populations in a way that excludes as many variables as possible between the placebo- and drug-treated groups, leaving drug treatment as the only variable. This ideal cannot be strictly realized in practice but experienced investigators come pretty close. Beyond that, controlled clinical trials state upfront what the primary and secondary endpoints... 

Clinical trials generate vast quantities of data, most of which are processed by the sponsor. Assessments should be kept to the minimum that is compatible with the safety and comfort of the subject. Highest priority needs to be given to assessment and recording of primary endpoints, as these will determine the main outcome of the study. The power calculation for sample size should be based on the primary critical endpoint. Quite frequently, trials have two or more evaluable endpoints. It must be stated clearly in the protocol whether the secondary endpoints are to be statistically evaluated, in which case power statements will need to be given, or are simply... 

The analysis plan should also specify the hypothesis and objectives of the study, define the primary and secondary endpoints, and describe how the endpoints will be constructed (e.g., multiplying resource counts measured in the trial times a set of unit costs measured outside the trial). In addition, the analysis plan should identify the potential covariables that will be used in the analysis and specify the time periods of interest (e.g., costs and clinical outcomes at... 

These ambitious primary and secondary endpoints can only be obtained depending on the grades of erosion and on naivety to SBC-5-IMNs. Similar primary and secondary endpoints are reached in DMARDs and SBC-5-IMNs refractory RA with the combination of SBC-5-IMNs -f 100 mg infliximab at week 0, 2 and 6. 

The 4 phases of SBC-5-IMNs can achieve primary and secondary endpoints of ASAS 20, ASAS 50 and ASAS 70 in circa 80% of the patients. 

Secondary variables may be defined which support a more detailed evaluation of the primary endpoints or alternatively such endpoints may relate to secondary objectives. These variables may not be critical to a claim but may help in understanding the nature of the way the treatment works. In addition, data on secondary endpoints may help to embellish a marketing position for the new treatment. 

If the primary endpoint gives a negative result then the secondary endpoints cannot generally recover a claim. If, however, the primary endpoint has given a positive result, then additional claims can be based on the secondary endpoints provided these have been structured correctly within the confirmatory strategy. In Chapter 10 we will discuss hierarchical testing as a basis for such a strategy. 

These ideas can also be considered as a way of dealing with secondary endpoints which might be considered for inclusion in a claim. In many cases secondary endpoints are simply primary endpoints lower down in the hierarchy. 

There is also the possibility of mixing hierarchical considerations with adjustment. For example, in the case of a single primary endpoint and two secondary endpoints, of equal importance to each other, the primary endpoint would be evaluated at a = 0.05 while each of the secondary endpoints would use a = 0.025. Claims could only be considered for the secondary endpoints if the primary endpoint gave p < 0.05, but then additional claims could be made on whichever of the secondary endpoints gives p < 0.025. In theory the use of both a hierarchy and Bonferroni-type adjustments could move beyond a second level, all that is needed is that 0.05 is assigned to each level of the hierarchy. For example, there could be a single endpoint at the first level, two endpoints at the second level (with a Bonferroni adjustment) and finally a single endpoint at the third level. 

Combining studies can also very effectively increase power for primary or secondary endpoints or for particular subgroups. Individual studies are unlikely to be powered for secondary endpoints and subgroups, and meta-analysis can be... 

How can we choose primary and secondary endpoints in line with the clinical objectives for the trial ... 

At both the trial level and the development plan level, statisticians should take time to review the case report forms (CRFs) to make sure, in particular, that the data being collected will be appropriate for the precise, unambiguous and unbiased measurement of primary and secondary endpoints. Other aspects of the data being collected should also be reviewed in light of the way they will be used in the analysis. For example, baseline data will form the basis of covariates to be used in any adjusted analyses, intermediate visit data may be needed for the use of... 

Clear definition and delineation of the primary and secondary endpoints and how these link with the objectives of the trial... 

Overview of statistical methods for the analysis of secondary endpoints... 

Secondary endpoints Binary restenosis at 4 months follow-up (defined as > 50% diameter stenosis by QCA) Quantitative coronary angiography endpoints including late loss, loss index, late absolute MLD at 4 months Incidence of (sub)acute stent thrombosis (SAT) to 30 day follow-up, MACE at 4 and 9 months... 

Secondary endpoints MACE at 30 days + 1 year, vascular complications, TLR, TVF, TVR... 

Ref. (61)]. The interim results confirmed the feasibility and safety of using E2F-I decoy. Analysis of the secondary endpoints using quantitative coronary angiography and three-dimensional intravascular ultrasound demonstrated increased patency and adaptive vessel remodeling characterized by reduction in neointimal size and volume in the treated group one year after treatment, leading to 40% reduction in critical stenosis. These results will now need to be confirmed in adequately sampled and powered phase III studies in patients with coronary and peripheral vessel disease in order to further... 

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