serology was negative. The subject had been receiving drugs X and Y concomitantly on a chronic basis 41
for >2 years prior to enrolment. Neither drug was suspected of causing the elevation in transaminases. 42
Both were continued during the adverse event, making it very unlikely that they were the cause of the 43
transaminase elevations. Of note, subject 102-037 was found to have concentrations of drug Z (Cmax) 44
approximately 8-fold higher than the mean of the 50 mg cohort, suggesting an inability to metabolize 45
drug Z. This possibility remains under investigation. An additional 148 subjects were exposed to drug Z 46
in the Phase I program, and none exhibited transaminase elevations. 47
In light of the rat findings and the transaminase elevations in subject 102-037, more frequent 48
monitoring has been implemented for the Phase II study. Assessments at Weeks 4 and 16 have been 49
added, so that subjects now undergo assessment of ALT, AST, bilirubin, and alkaline phosphatase at 50
baseline, Weeks 1, 2, 4, 8, 16, and 24. The protocol, informed consent document, and Investigator’s 51
Brochure have been revised accordingly. 52
DSUR 2013 53
19 Summary of Important Risks 54
New or updated risks are denoted with an asterisk. 55
1. Nephrotoxicity* 56
Drug Z is a para-aminoglycolate, one of a class of drugs bearing structural similarities to 57
aminoglycosides, and known to be nephrotoxic. Two of 30 healthy volunteers (6.7%) in the Phase I 58
program who had received drug Z 100 mg PO qd developed transient increases in serum creatinine 59
associated with mild proteinuria (by dipstick), and the 100 mg dose was dropped from further 60
development. In the completed Phase II trial of drug Z in patients with coronary artery disease and 61
stable angina pectoris (Study 201), increases in creatinine >1.25 but <1.5 times baseline were
62
observed in 5 of 60 subjects (8.3%) in the 50 mg group, 5 of 62 subjects (8.1%) in the 25 mg group, 63
and 3 of 59 subjects (5.1%) in the 10 mg group, versus 6 of 61 subjects (10%) in the placebo group. 64
For all of these subjects, the study drug was continued (per protocol), and serum creatinine returned 65
to baseline within 2 weeks. Increases in creatinine >1.5 times baseline were observed in 1 of 60 66
subjects (1.7%) in the 50 mg group, 0 of 62 subjects in the 25 mg group, and 1 of 59 subjects (1.7%) 67
in the 10 mg group, versus 2 of 61 subjects (3.3%) in the placebo group. The study drug was 68
discontinued in all of these subjects (per protocol), and serum creatinine returned to baseline within 2 69
weeks. As explained in sections 8.2 and 18.1, the “recovery” of creatinine to normal (i.e., the slope of 70
the creatinine vs. time relationship) was the same in subjects who continued and discontinued the 71
study drug, suggesting that this was not a specific drug effect. Of note, 3 of the 4 drug Z-treated 72
subjects who developed creatinine elevations were taking concomitant diuretics. In ongoing studies 73
202 and 204, serum creatinine, eGFR, blood urea nitrogen, and urinalysis continue to be monitored at 74
baseline, Weeks 1, 2, 4, 12, 24, and 48. Twenty-four-hour urinary protein excretion is determined in 75
any subject who develops proteinuria by dipstick. 76
2. Hepatotoxicity* 77
Drug Z caused centrilobular necrosis at the highest dose tested (60 mg/kg/d) in rats (although there 78
was no evidence of liver damage at this dose in rabbits). One (1) of 149 subjects (0.7%) in the Phase I 79
program developed unexplained elevations of ALT and AST approximately 2.5 x the upper limit of 80
normal on Day 14; which resolved on discontinuation of the drug. Two drug Z-treated subjects in the 81
completed Phase II study #201 (2/181, 1.1%) had transaminase elevations (see section 8.2), but 82
these were mild and transient, and one subject in the placebo group (1/61, 1.6%) had more severe 83
elevations. Based on this information, the present monitoring plan seems appropriate, and no changes 84
have been made to the protocol, Investigator’s Brochure, or informed consent document. Of note, one 85
ICH guideline E2F on development safety update report
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