Review of the Fialuridine (FIAU) Clinical Trials (1995) / Chapter Skim
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Eli Lilly Trial H3X-MC-PPPC (NIH Protocol 93-DK-0031)
Eli Lilly Trial H3X-MC-PPPC (NIH Protocol 93-DK-0031)
Pages 73-89
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From page 73... ...
Testimony to his stature in the field of hepatology is that he is recent Past-President of the American Association for the Study of Liver Diseases, the foremost hepatology association in the world. Rationale for the study came from the lack of available effective therapy for chronic HBV infection, the lack of major toxicity of FTAU in preclinical animal toxicology studies, and the promise of this compound as an anti-HBV drug in earlier human trials.
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From page 74... ...
The rationale behind the final NIH FIAU study was that retreatment of approximately 20 patients with chronic HBV infection for 24 weeks would result in short-term inhibition of viral replication, normalization of serum aminotransferase levels, and potentially long-term virologic remission. The protocol was written in September 1992, before completion of the R91 study.
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From page 75... ...
This was associated with a rise in liver enzyme levels in eight of the nine patients. Subsequently, ALT levels returned to normal or near normal in all patients.
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From page 76... ...
Included in the protocol was discussion of peripheral neuropathy and the death of patient 4D from protocol R91. Other adverse events summarized included the elevations in ALT level seen in protocol R91 (patients 6A and 3B seen in association with the inhibition of viral replication and interpreted as a delayed flare of hepatitis)
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From page 77... ...
PATIENT SELECTION AND ENROLLMENT All patients in the PPPC trial had chronic HBV infection with active viral replication (HBeAg and HBV DNA positive)
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From page 78... ...
potential severe side effects that were not clearly related to FlAU, including one patient who died following laparoscopic cholecystectomy and two patients who developed a peripheral neuropathy after FTAU was stopped; mention was made of a single patient with an elevated CPK level that resolved on therapy and two additional patients with fatigue and irritability that resolved after FlAU was stopped; (5) Possible toxic effects, which included neuromuscular damage and bone marrow suppression; and (6)
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From page 79... ...
Documentation of the quality of care is apparent from the frequent patient monitoring visits and the frequent telephone contacts. There is no evidence of errors in clinical judgment related to interpretation of clinical or biochemical adverse events that would have predicted the fatal toxic events that occurred.
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From page 80... ...
Deaths Patient 2 This 42-year-old man was diagnosed with HBV infection in 1981. A liver biopsy in 1984 revealed chronic active hepatitis.
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From page 81... ...
Autopsy revealed hemorrhagic pancreatitis, glomerulonephritis, esophageal varices, and pneumonia. Histology of the liver explant showed micro- and macrovesicular steatosis, chronic active hepatitis with fibrosis, and cholestasis.
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From page 82... ...
Liver histology revealed fibrosis, cholestasis, and severe micro- and macrovesicular steatosis. Patient 4 This 52-year-old man was diagnosed with chronic HBV infection in May 1989, at which time a liver biopsy showed chronic active hepatitis with cirrhosis.
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From page 83... ...
There was hemorrhagic pancreatitis. Patient 6 This 37-year-old woman was diagnosed with HBV infection in March 1990, and a liver biopsy in October 1990 showed chronic active hepatitis.
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From page 84... ...
A liver biopsy in May 1991 showed mild chronic active hepatitis. He was enrolled in the ribavirin protocol in June 1991 without response and was therefore evaluated for and enrolled in the R91 FlAU protocol.
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From page 85... ...
Patient 3 This 57-year-old man with chronic HBV infection had previously been enrolled in a ribavirin protocol at NTH. A liver biopsy before therapy reportedly showed chronic active hepatitis.
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From page 86... ...
He had persistent neuropathy following liver transplantation. Other NonIethal Adverse Events In early June 1993 it became apparent that the 10 retreatment patients were having significant side effects, particularly nausea and peripheral neuropathy.
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From page 87... ...
Despite the mean fall in ALT levels in these patients while they were on therapy, microvesicular steatosis indicative of FIAU toxicity was present on liver biopsies performed subsequent to June 1993 in all three. Peripheral Neuropathy/Myopathy Several patients developed symptoms of a peripheral neuropathy while on FIAU therapy, but nerve conduction studies were normal or near normal.
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From page 88... ...
Accurate association between the drug and the toxic events was confounded by liver abnormalities associated with chronic HBV infection, rises in liver enzyme levels that were interpreted as a positive response to the drug (the flare) , and confounding variables including treatment in previous FIAU/FIAC trials and with other nucleoside analogs known to cause neuropathies and pancreatitis (ddC and ddI)
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From page 89... ...
He is receiving long-term hepatitis B immunoprophylaxis and remains HBsAg and HBV DNA negative. He has physical signs of an ongoing peripheral neuropathy, confirmed by nerve conduction studies.
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