Statistical Review and Evaluation
NDA #: 21321
Related IND #: 51,898
Applicant: Baxter Healthcare Corporation
Name of Drug: Extraneal^{TM} (Icodextrin)
Indication: Treatment
of chronic renal failure
Document reviewed: Volume 1155
Date of submission: December 22, 2000
Statistical Reviewer: John Lawrence, Ph.D. (HFD–710)
Medical Reviewer: Stephen Fredd, M.D. (HFD–110)
1. Introduction
On October 19, 2000, a closed session of the CardioRenal Advisory Committee was held and the 12month safety study RD97CA131 was discussed. The protocol had required only 30day followup for patients who had withdrawn from the study. The committee asked to see the results of the mortality analysis for the 12month intended duration of treatment and for 30 days thereafter. The document under review here relates to this analysis in the addendum to the clinical report for this study.
2. Study Design
Study RD97CA131 was a 52week prospective, doubleblind, randomized, activecontrolled, parallel group study comparing the safety of Extraneal with dextrose for the long dwell in Continuous Ambulatory Peritoneal Dialysis (CAPD) and Automated Peritoneal Dialysis (APD) patients. 287 patients (112 control and 175 Extraneal) were enrolled in the study.
3. Planned
Statistical Analysis
The original analysis of mortality required 30day followup for patients who had withdrawn or completed the study. Based on the comments from the Advisory Committee, patients' status for the intended 12month duration of the study plus 30 days thereafter was analyzed.
4. Results
The mortality status of 17 patients was not known after 360 days from the start of the study (6 control and 11 Extraneal). The status of 161 patients was not known 375 days from the start of the study (59 control and 102 Extraneal). The status of 168 patients was not known 395 days from the start of the study (63 control and 105 Extraneal). The KaplanMeier estimates of the probability of having followup at each time point for each group appears in the appendix.
Using the mortality data for the 12month intended treatment period plus 1 month additional followup, a total of 29 patients died. This includes 20 patients from the Extraneal group (20/175 = 11.4%) and 9 patients from the control group (9/118 = 8.0%). The KaplanMeier estimates of the survival curves appear in Figure 4.1.
Figure 4.1 KaplanMeier estimates of survival curves using available data with
13months of followup.
The value of the logrank statistic is not significant (p=0.305). However, insufficient evidence to rule out equality of the two curves is not the same thing as proving that there is no difference in the curves. Numerically, the estimated hazard ratio for mortality in the Extraneal group relative to the control group was 1.51 with a 95% confidence interval of (0.686, 3.30). This estimate is from a Cox regression model with one term for treatment group. In order to subjectively evaluate the two survival curves, the Medical Officer wanted to examine the 80% confidence intervals for mortality rates at each month. The choice of 80% was prespecified according to the Medical Officer. The point estimates and lower and upper bounds of the 80% confidence intervals for each group are in Table 4.1.
Table 4.1 Point estimates and 80% confidence interval for survival in each group.
Month 
Extraneal 
Control 

Lower bound 
Point estimate 
Upper bound 
Lower bound 
Point estimate 
Upper bound 

1 
0.987 
0.994 
1.000 

1.000 

2 
0.970 
0.983 
0.995 

1.000 

3 
0.963 
0.977 
0.992 

1.000 

4 
0.963 
0.977 
0.992 
0.980 
0.991 
1.000 
5 
0.941 
0.960 
0.979 
0.980 
0.991 
1.000 
6 
0.913 
0.936 
0.960 
0.954 
0.973 
0.993 
7 
0.906 
0.930 
0.956 
0.954 
0.973 
0.993 
8 
0.893 
0.919 
0.946 
0.942 
0.964 
0.987 
9 
0.886 
0.913 
0.941 
0.942 
0.964 
0.987 
10 
0.873 
0.901 
0.931 
0.931 
0.955 
0.981 
11 
0.866 
0.896 
0.926 
0.919 
0.946 
0.974 
12 
0.852 
0.883 
0.915 
0.896 
0.928 
0.960 
The 80% confidence intervals overlap except at months 5 and 9 where the upper limit of the confidence interval for the Extraneal group is 0.001 below the lower limit for the control group. The standard error (and consequently, the confidence limits) could not be estimated for the first three months in the control group because all patients survived at least 3 months in that group.
The amendment to the study report states that exploratory analyses (Cox regression models) were done to determine whether any baseline characteristics could explain the numerical difference in mortality between the two groups. The covariates that were studied included: age, race, gender, diabetes, time on chronic dialysis therapy, and serum albumin. The report indicates that although there was a significant relationship between some of these covariates and mortality, there was no significant treatment by covariate interaction that would help explain the numerical difference in mortality rates. This reviewer believes the purpose of the amendment is to answer a narrower question regarding mortality, viz. is there an overall difference in the mortality rates between the two groups. Also, there doesn't seem to be an adequate amount of information to answer questions about the treatment by covariate interactions. For these reasons, this will not be investigated in further depth in this review.
5. Conclusions
Since the mortality status of over half (161/289) of the patients was not known 375 days from the start of the study, this reviewer doubts that the questions raised by the Advisory Committee can be answered from the data provided. The data provided seems to indicate that there is insufficient evidence to rule out the equality of the two survival curves. Numerically, the estimated hazard ratio for mortality in the Extraneal group relative to the control group was 1.51 with a 95% confidence interval of (0.686, 3.30). Moreover, the rate of loss to followup in the last month is high and the Extraneal group has more patients lost to followup. This might induce bias in favor of the Extraneal group. Hence, the excess risk could be much higher than observed.
Appendix
This reviewer estimated the proportion of patients in each group that survive and the mortality status is known to the investigator at each time point. In this analysis, a month is defined as (#days from start of study)*12/365. A patient who was known to be alive x number of days from the start of the study (with no further followup) is counted as having an event at that time. A patient who died is counted as censored at the time of death. Figure A1 shows the resulting KaplanMeier estimates and Table A1 shows the actual numerical estimates for each group. Both the figure and the table illustrate that a relatively high number of patients in each group did not have followup for the intended 13month period. Roughly 40% in the control group and 32% in the Extraneal group did have complete followup for this period of time.
Figure A1. KaplanMeier estimates of probability of remaining in study over time. Patients who died are counted as censored in this analysis. Months = Days*12/365.
Table A1. KaplanMeier estimates of proportion of patients who survive and the mortality status is known by the investigator.
Control group 

Months from start of study 
# at risk 
# of events 
Survival 
8.88 
108 
1 
0.991 
11.08 
105 
1 
0.981 
11.74 
104 
2 
0.962 
11.80 
102 
1 
0.953 
11.84 
100 
1 
0.943 
11.87 
99 
1 
0.934 
11.93 
97 
9 
0.847 
11.97 
88 
4 
0.809 
12.00 
84 
11 
0.703 
12.03 
73 
11 
0.597 
12.07 
62 
5 
0.549 
12.10 
57 
1 
0.539 
12.16 
56 
2 
0.520 
12.20 
54 
3 
0.491 
12.23 
51 
2 
0.472 
12.26 
49 
2 
0.453 
12.30 
47 
1 
0.443 
12.33 
46 
1 
0.433 
12.36 
45 
1 
0.424 
12.43 
44 
1 
0.414 
12.46 
43 
1 
0.404 
12.72 
42 
1 
0.395 
13.02 
40 
40 
0.000 
Table A1 (continued).
Extraneal group 

Months from start of study 
# at risk 
# of events 
Survival 
0.329 
175 
1 
0.99429 
3.058 
170 
1 
0.98844 
3.682 
169 
1 
0.98259 
11.507 
154 
1 
0.97621 
11.540 
153 
1 
0.96983 
11.704 
152 
1 
0.96345 
11.770 
151 
2 
0.95069 
11.803 
149 
1 
0.94431 
11.836 
148 
2 
0.93154 
11.901 
146 
1 
0.92516 
11.934 
145 
8 
0.87412 
11.967 
136 
9 
0.81627 
12.000 
126 
18 
0.69966 
12.033 
108 
14 
0.60897 
12.066 
94 
8 
0.55714 
12.099 
86 
8 
0.50531 
12.132 
78 
4 
0.47940 
12.164 
74 
5 
0.44701 
12.197 
69 
3 
0.42757 
12.230 
66 
10 
0.36279 
12.263 
56 
1 
0.35631 
12.296 
55 
2 
0.34335 
12.460 
53 
1 
0.33688 
12.592 
52 
1 
0.33040 
12.658 
51 
1 
0.32392 
13.019 
50 
46 
0.02591 
13.151 
4 
1 
0.01944 
13.381 
3 
1 
0.01296 
13.512 
2 
1 
0.00648 
13.644 
1 
1 
0.00000 
_________________________
John Lawrence, Ph.D.
Mathematical Statistician
This review consists of 1 pages of text, tables, and figures.
Concur: James Hung, Ph.D.
Acting Team Leader, Biometrics I
George Chi, Ph.D.
Division Director, Biometrics I
cc: NDA #
21321
HFD110/Dr.
Lipicky
HFD110/Dr.
Fredd
HFD110/Mr.
Guzman
HFD700/Dr.
Anello
HFD710/Dr.
Chi
HFD710/Dr. Hung
HFD–710/chron
LAWRENCEJ/594–5375/report.doc/4/23/2003