I’m not sure the higher dose group were doing better.
Page 99:
"Appropriateness of Test Models
The sponsor chose empagliflozin doses of 0, 0, 100, 300 and 1000 mg/kg/day based on the recommendations of the ECAC. Overall treatment was well tolerated and the results showed no dose-limiting toxicity, except for excess mortality in the high dose male group which was terminated at week 97. As all high dose males and females were terminated at weeks 97 and 102, respectively, the high dose was considered adequate for tumor assessment and statistical evaluation. Exposure at the high dose (700 mg/kg) provided approximately 45x and 62x the maximum recommended human dose (MRHD) in males and females, respectively, based on total exposure (AUC0-24h)."
Page 100:
"Mortality
Decreased survival was observed in the 1000 mg/kg males that resulted in early termination for this group at week 97 (see sponsor’s figure below). At study termination 16 males and 17 females were present in the high dose (HD) group. Although, a submission to the Division and ECAC was not made to request early termination of the HD male group, it is likely ECAC would have concurred if the number of survivors had reached 15 or less, prior to week 100 of the study. increased mortality observed for the HD male group was due to urinary tract dilatation. Given that all HD males and females were terminated at week 97 and 102, respectively, the HD group is considered adequate for tumor assessment and statistical evaluation."
Page 101:
“In the males the most common non-neoplastic cause of death was attributed to urinary tract dilatation that showed a treatment-related increase in the low, mid and high dose males (see sponsor’s table below). These lesions account for the early termination of the HD male group, and were described as dilated renal pelves, distended urinary bladder and/or uteral dilatation and renal tubular cysts that were observed macroscopically with renal/uretal dilatation and chronic progressive nephropathy. All other causes of death were not dose related (sponsor’s table below).”
Also, the bodyweight story was more complicated and sex dependent. Page 102:
"Body Weights
Treatment with empagliflozin had no effect on the mean body weight in both males and females at the end of treatment (see table below). Mean body weights were, however, statistically significantly (ss) reduced in all empagliflozin-treated males for weeks 12 to 78, and did not correlate with the observed increased food consumption (vehicle 1 and 2 were combined for the analysis). The reduced mean body weight ranged from 5-10% and was not dose-dependent. Mean body weights were also ss reduced 3-7% in the 100 and 300 mg/kg males from weeks 86-94, respectively. Similar final body weight at the end of the study appears due to a downward trend in body weight of both control groups, rather than a change in the dosed groups.
In contrast, there was a statistically significant increase in body weight at weeks 2-26 in the 1000 mg/kg females (data not shown but see sponsor’s figure below). The increase in body weight ranged from 5-12% and was associated with increased food consumption. However, overall body weight for the duration of the study was not statistically significantly increased. Mean body weight was also ss increased at weeks 4-13 and week 18 in the 300 mg/kg females. The increase in body weight was of a lower magnitude compared to the high dose females and ranged from 3-7%."
