Unlike any of the other FIAU studies reviewed in this report, the volunteers remained at the laboratory for the duration of the study. The laboratory is adjacent to the Wishard Memorial Hospital of the Indiana University Medical Center, where acute medical care is provided to any Lilly subjects who require it. The protocol was reviewed and approved by the Indiana University Medical Center IRB. According to Lilly, this inpatient arrangement not only facilitates control of diet and close monitoring of protocol compliance but also ensures complete data collection and follow-up on frequently unemployed and transient subjects.
Risks to subjects were described in the informed consent document (Appendix D) as including stomach pain, diarrhea, nausea, vomiting, headache, and muscle aches or fatigue. There was no mention of peripheral neuropathy, nor was there any description of symptoms like numbness or tingling in the arms and legs that might imply peripheral neuropathy. The form did note that changes in laboratory test values that measure liver, kidney, and muscle functions, and anemia (low blood count) had also occurred in prior studies. Decreases in sperm production and heart muscle damage "in animals given 3,500 to 14,000 times the dose planned for this study" were also reported, and subjects were warned that FIAU or the procedures used in the study might have other unknown effects. An extensive battery of hematology, blood and urine chemistry, and microscopic clinical laboratory tests was conducted 24 hours after the administration of each dose, but no explicit provision for grading toxicity or discontinuing subjects in the study was included in the protocol.
Pharmacokinetic measurements performed on blood and urine samples after the RIA were validated in June revealed more rapid absorption of FIAU in syrup than in tablet form, with food generally decreasing the rate of absorption, rapid distribution with all forms, and a very prolonged elimination phase with a terminal half-life of 28-30 hours (10 times the half-life previously estimated with the less sensitive HPLC method).
The adverse events that were noted included diarrhea, headache, transient myalgia, and in two cases, elevations in transaminase levels. Although both subjects with these elevations were asymptomatic, dosing was discontinued for one (subject 1203) after his serum ALT level rose to 92 units/liter (from 19 units/liter) and his AST level rose to 56 units/liter (from 17 units/liter) after dose 2. This subject was encouraged to stay at the laboratory despite being dropped from his dosage group, while the investigators worked him up for hepatitis and other possible causes of his ALT and AST elevations, which continued to rise to peaks of 137 and 60 units/liter, respectively, 1 week after receiving his last dose of FIAU. Lilly was later criticized for not promptly reporting this "hospitalization" to the FDA within the 10-day limit for serious adverse events. Lilly's records indicate that he was neither admitted (since he was already staying at the laboratory) nor given any acute medical treatment (since he remained asymptomatic). His transaminase levels returned to the baseline 5 weeks after receiving his second and last dose of FIAU.
The second subject (subject 508), who was also asymptomatic, also showed three- to five-fold increases in ALT and AST levels after receiving dose 2, but the levels of both enzymes decreased on each of the following 3 days and the subject was continued in the study. AST and ALT levels gradually returned to the baseline levels, despite the administration of three additional 5-mg doses of FIAU.