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8
Eli Lilly Trial H3X-MC-PPPA

This study, under the sponsorship of Eli Lilly and Company, was carried out under investigational new drug (IND) application 34,973 after Lilly assumed IND responsibilities as part of a licensing agreement with Oclassen Pharmaceuticals. It involved a "pharmacokinetic/pharmacodynamic dosing regimen" to determine the safety and efficacy of FIAU in patients with compensated HBV disease. The study was planned to include 36 subjects and employ oral dosing of 0.10 or 0.25 mg/kg/day for 90 days. Half of the subjects in each dosage group were to receive the drug in two equal portions each day and half were to receive it in three equal doses. Patients were entered at two study centers: the University of Texas, Galveston, and Tufts New England Medical Center Hospital. A total of only five patients received FIAU between May 3 and June 26, 1993, when the trial was discontinued promptly upon receipt of information concerning adverse events in subjects in the H3X-MC-PPPC study that had commenced at the NIH in March 1993.

UNIVERSITY OF TEXAS, GALVESTON SITE

The principal investigator for this study was David P. Paar. He is a 1984 graduate of West Virginia University Medical School and, following residency in internal medicine at West Virginia University Hospitals, served an infectious disease fellowship in the Medical Virology Section of the Laboratory of Clinical Investigation at the National Institute of Allergy and Infectious Diseases (NIAID) from 1988 to 1991. Following an additional year (1991-1992) as a medical officer at the NIAID AIDS Research Clinic at NIH, he served as assistant professor of medicine/chief resident in the Department of Internal Medicine at West Virginia University Hospital. Currently he has an appointment as an assistant professor of medicine in the Infectious Disease Division at the Medical Branch, University of Texas, Galveston. He is board certified both in internal medicine (1987) and in the subspecialty of infectious diseases (1992). His publications deal with a variety of viral infections or their treatment or complications, coauthored with Stephen Straus, and several abstracts which concerned the effects of FIAC in HIV-infected patients and FIAU in patients chronic with HBV infection.

The three patients in the clinical trial at Galveston (see Appendix G for patient summaries) showed declines in serum HBV DNA levels to 2-33 percent of the levels observed at the time of study entry. FIAU was administered orally at doses of 0.05 or 0.125 mg/kg twice daily for periods of 16, 19, or 43 days. In one patient the AST and ALT levels remained



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Review of the Fialuridine (FIAU) Clinical Trials 8 Eli Lilly Trial H3X-MC-PPPA This study, under the sponsorship of Eli Lilly and Company, was carried out under investigational new drug (IND) application 34,973 after Lilly assumed IND responsibilities as part of a licensing agreement with Oclassen Pharmaceuticals. It involved a "pharmacokinetic/pharmacodynamic dosing regimen" to determine the safety and efficacy of FIAU in patients with compensated HBV disease. The study was planned to include 36 subjects and employ oral dosing of 0.10 or 0.25 mg/kg/day for 90 days. Half of the subjects in each dosage group were to receive the drug in two equal portions each day and half were to receive it in three equal doses. Patients were entered at two study centers: the University of Texas, Galveston, and Tufts New England Medical Center Hospital. A total of only five patients received FIAU between May 3 and June 26, 1993, when the trial was discontinued promptly upon receipt of information concerning adverse events in subjects in the H3X-MC-PPPC study that had commenced at the NIH in March 1993. UNIVERSITY OF TEXAS, GALVESTON SITE The principal investigator for this study was David P. Paar. He is a 1984 graduate of West Virginia University Medical School and, following residency in internal medicine at West Virginia University Hospitals, served an infectious disease fellowship in the Medical Virology Section of the Laboratory of Clinical Investigation at the National Institute of Allergy and Infectious Diseases (NIAID) from 1988 to 1991. Following an additional year (1991-1992) as a medical officer at the NIAID AIDS Research Clinic at NIH, he served as assistant professor of medicine/chief resident in the Department of Internal Medicine at West Virginia University Hospital. Currently he has an appointment as an assistant professor of medicine in the Infectious Disease Division at the Medical Branch, University of Texas, Galveston. He is board certified both in internal medicine (1987) and in the subspecialty of infectious diseases (1992). His publications deal with a variety of viral infections or their treatment or complications, coauthored with Stephen Straus, and several abstracts which concerned the effects of FIAC in HIV-infected patients and FIAU in patients chronic with HBV infection. The three patients in the clinical trial at Galveston (see Appendix G for patient summaries) showed declines in serum HBV DNA levels to 2-33 percent of the levels observed at the time of study entry. FIAU was administered orally at doses of 0.05 or 0.125 mg/kg twice daily for periods of 16, 19, or 43 days. In one patient the AST and ALT levels remained

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Review of the Fialuridine (FIAU) Clinical Trials normal throughout the study; in a second patient, the levels were slightly elevated at baseline and did not change significantly during treatment, but they declined to normal during follow-up; in the third patient, the AST and ALT levels had almost doubled from the baseline values when FIAU treatment was discontinued after 16 days, and 3 months later they were 2-2.6 times higher than the baseline. One patient, who had a preexisting seizure disorder, had several seizures on his 21st day of FIAU therapy. The seizures were associated with subtherapeutic phenytoin levels, and no further seizures occurred after adequate phenytoin levels were obtained. In the second patient there was no clinical or laboratory evidence of hepatic or pancreatic toxicity or neurotoxicity related to FIAU administration during the short course of therapy or for 1 year after discontinuation of treatment with the drug. In the third patient an increase in his nausea over his baseline and lower-extremity weakness raised the investigator's suspicion of possible FIAU toxicity. However, these symptoms subsided after 1 day of hospitalization, there was no lactic acidosis, and a muscle biopsy showed no evidence of mitochondrial abnormalities—all of which were not supportive of the diagnosis of FIAU toxicity. Three months after discontinuation of FIAU liver treatment transaminase and serum HBV DNA levels began to rise; the investigator reasonably attributed these to reactivation of the chronic HBV-related hepatitis. An episode of hepatic decompensation occurring 6 months after receiving his last dose of FIAU was attributed to progression of the underlying active HBV-related hepatitis rather than to FIAU toxicity on the basis of the following: (1) a liver biopsy showed active inflammation and cirrhosis and only minimal microvesicular fat, (2) and there was no lactic acidosis. The committee feels that this interpretation is the most reasonable one considering the accumulated evidence. Thus, no toxicity clearly attributable to FIAU occurred in this clinical trial involving three patients. The informed consent document employed in this investigation (Appendix D) explained the details of the study and the known side effects of FIAU. Peripheral neuropathy was, however, not included as a known side-effect. Only one of the three study subjects interviewed 15 months later recalled being told about numbness or tingling of the toes and feet as a possible side effect. All three noted that Paar had personally talked to them about the informed consent form and had taken time to walk them through its contents. When interviewed, all three had expressed the opinion that Paar and staff had provided excellent care, and two stated that they would volunteer again for studies of new anti-HBV drugs. One of the three indicated that he was disappointed that he had not been informed of the deaths of prior patients and of the occurrence of neuropathy as a toxic side effect. For that reason he felt he would probably not consider volunteering for further studies of new anti-HBV drugs at Galveston or elsewhere. TUFTS NEW ENGLAND MEDICAL CENTER SITE The principal investigator was Marshall M. Kaplan, and coinvestigators were D. Greenblatt, Y. M. Lee, M. Nguyen, T. Sepe, G. Dickstein, A. Fribush, and D. Pratt. The principal investigator graduated from Harvard Medical School in 1960. He is board certified in internal medicine and gastroenterology. He is a professor of medicine at Tufts Medical School and is chief of Gastroenterology there and an associate editor of the New England

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Review of the Fialuridine (FIAU) Clinical Trials Journal of Medicine. In the area of gastroenterology his interest is particularly in hepatology. His publications have dealt with various forms of liver disease, and he has been involved in multicenter clinical drug trials, especially in the treatment of primary biliary cirrhosis. Ten patients entered the screening phase of this trial. Four were subsequently excluded because they did not meet the entrance requirements. Four had not yet begun treatment when the study was discontinued on June 28, 1993, and two patients actually received FIAU. Both of these patients (see Appendix G for details) showed declines in serum HBV DNA levels to less than 5 percent of the levels observed at the time of entry in to the study. This represents a clear response of the infection and, in view of its coincidence with FIAU treatment, is unlikely to have represented a spontaneous fluctuation in HBV infection. FIAU was administered at dosages of 0.05 or 0.125 mg/kg twice daily for periods of 28 or 55 days. In one patient, the ALT levels rose to 1.9-fold the baseline levels at the end of 4 weeks of therapy; it then peaked at 3.2-fold the baseline level 1 week later, dropping to 35 percent of the baseline level at 5 months after starting treatment and then rising to 3.2-fold the baseline level at the end of 7 months. In the second patient, ALT levels rose to 1.8-fold the baseline at the time of cessation of FIAU therapy, peaked at 2.7-fold the baseline level 2.5 weeks later, and then gradually fell to below the baseline level of 88 units/liter at 8 months after the start of therapy. The rises in ALT level may have represented a flare in ALT levels associated with a reduction in circulating HBV DNA levels or may have been a fluctuation in the course of the underlying hepatitis. Although this may have represented a manifestation of FIAU hepatotoxicity, the committee believes that this is less likely in view of the type of hepatotoxicity associated with FIAU and in view of the fluctuations in ALT levels observed over the 6-month period of observation. One patient noted leg pain and numbness beginning 3-4 months after stopping FIAU therapy. Evidence of a primary sensory neuropathy was found on neurologic consultation, and electrophysiologic studies identified the presence of an axonal neuropathy, primarily sensory, but some motor involvement as well. Unfortunately, there are no antecedent nerve conduction studies that can be used to objectively evaluate whether this condition predated the administration of FIAU, and it may have been related to his previous alcohol and parenteral drug abuse. Over the next 8 months there were no significant changes on neurologic examination or on nerve conduction studies, but subjectively the patient felt that his symptoms had worsened. His total dose of FIAU was two-thirds that of a patient in another study who also had a past history of alcohol abuse and who developed peripheral neuropathy 4 months after stopping FIAU therapy in a 28-day trial. The committee feels that although this patient may possibly have been predisposed by virtue of his prior history of alcohol abuse, his documented peripheral neuropathy should be considered a neurotoxic effect of FIAU. The informed consent document (Appendix D) explained the details of the study and the known side effects of FIAU. Peripheral neuropathy (numbness, tingling) was, however, not included as a possible side effect, although mention of possible muscle aches was mentioned. A statement to the effect that "other unpredictable bad effects due to the study drug may occur" was included in the consent form. Neither of the two subjects interviewed 14 months later recalled being told about numbness or tingling of the toes and feet. Both recalled being counseled about the informed consent forms by study nurses, and one of the two subjects remembered the study nurse walking him through its contents. The committee has reviewed

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Review of the Fialuridine (FIAU) Clinical Trials the informed consent form and finds it to be of generally high quality, but noted that it did not include specific reference to the clinical manifestations of peripheral neuropathy. The patient who developed peripheral neuropathy recalled that during the last or penultimate scheduled visit he happened to mention to the study nurse numbness in his toes, which he attributed to wearing ''flip-flops.'' She insisted on setting up an appointment with a neurologist to evaluate this symptom. Neither subject would consider volunteering for further studies of new hepatitis drugs, but one indicated that it was because he could not take time off from work.