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The changes to the study protocol included the following:
According to the protocol, CLCR was determined at the screening visit and on the profile day
(00d). In the inclusion criteria (see Section 7.2.1), stable renal disease was defined as a
difference in CLCR of <20% between screening visit and profile day (00d). These 20%
correspond to 15 mL/min for a subject with mild renal impairment and a CLCR of 75 mL/min.
This was not clearly expressed in all parts of the protocol. Therefore, this non-substantial
amendment was intended to clarify this issue.
Several subjects enrolled in Study 15000 showed greater differences in CLCR than 15 mL/min
between the 2 measurements. This indicated that the degree of renal impairment was not
stable. This was also true for subjects with renal impairment who showed a CLCR value of
>90 mL/min on the profile day. The data of those subjects were not valid for
pharmacokinetic evaluation according to the protocol and the data had to be replaced.
In addition, the name of the responsible person at the laboratory for biomarkers and
pharmacogenetics was changed.
Therefore, this protocol amendment was non-substantial.    
A linear regression line was fitted to describe a possible relationship between the creatinine
clearance and each pharmacokinetic characteristic of interest. Sample size consideration was
based on AUCnorm for riociguat. The hypothesis of a zero slope was tested using the 2-sided
t-test at ?=0.05. A sample size of 32 subjects would haven had 80% power to detect a
difference between the null hypothesis regression slope of 0.00 and an alternative regression
slope of -279 g*h/L assuming that the standard deviation of the creatinine clearance was
39.4 mL/min and the standard deviation of the residuals was 21,486 g*h/L.
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FROM 122.236.16.*