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• Group 1 is a control group of 40 subjects, 20 male and 20 female, dosed with vehicle once per day for 30 days. Of this group, 10 males and 10 females will be fed ad libitum, while the remainder will be subject to a restricted diet. Half of the subjects will be terminated after 30 days, while the other half will be subject to a 14-day recovery period; the subjects selected for recovery will be divided equally among animals fed ad libitum and those subject to restricted feeding (i.e., 5 males and 5 females with ad libitum feeding will move to recovery, and 5 males and 5 females with restricted diet will also move to recovery).
• Group 2 is a low-dose group of 40 subjects, 20 male and 20 female, dosed at 5 mg/kg once per day for 30 days. Of this group, 10 males and 10 females will be fed ad libitum, while the remainder will be subject to a restricted diet. Three subjects of each sex and feeding pattern will be subject to blood sampling for the purpose of TK analysis (i.e., 3 males and 3 females from those fed ad libitum and 3 males and 3 females from those receiving a restricted diet)
• Group 3 is a high-dose group of 40 subjects, 20 male and 20 female, dosed at 100 mg/kg once per day for 30 days. Of this group, 10 males and 10 females will be fed ad libitum, while the remainder will be subject to a restricted diet. Of those subjects fed ad libitum, 3 males and 3 females will be subject to blood sampling for the purpose of TK analysis and terminated on day 30; 3 males and 3 females (other than those selected for TK analysis) will be subject to a 14-day recovery period, and the remaining subjects will be terminated on day 30. of the subjects given a restricted diet, 6 males and 6 females will be subject to blood sampling for the purpose of TK analysis; half of these subjects will be terminated on day 30 while the others are subject to a 14-day recovery period before termination. The balance of the subjects receiving a restricted diet will be terminated at the end of the treatment dosing period (day 30).

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The variety of feeding and TK analysis factors do not affect the TE dataset, which deals only with treatmentsdosing. The fact that only some of the treatment dosing elements are combined with the recovery element is only captured in the TA dataset.

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Despite the complex description in the study protocol, there are only 5 trial arms in this study. All subjects experience a screening element. Based upon the result of randomization, they then receive 1 of 3 different treatmentsexposure levelsexp; some of the subjects receiving the vehicle control or the medium high dose are subject to a recovery period post-treatment.

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In this study there are multiple experimental factors of interest: the treatment dosing level given during the treatment exposure epoch (3 levels), the feeding regimen of the subjects (ad libitum vs. restricted feeding), whether the subjects are to be used for TK analysis, and whether the subjects will be terminated at the end of the dosing period or experience a recovery period. The combination of these factors (3x2x2x2) could lead to up to 24 possible combinations or sets; however, upon careful reading of the description there are 14 sets that will actually be part of the study:

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