Cover Image

PAPERBACK
$34.00



View/Hide Left Panel

Appendixes



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 155
Review of the Fialuridine (FIAU) Clinical Trials Appendixes

OCR for page 155
Review of the Fialuridine (FIAU) Clinical Trials This page in the original is blank.

OCR for page 155
Review of the Fialuridine (FIAU) Clinical Trials A Chronology of FIAU/FIAC Clinical Trails 1989 July R89 Corey and Richman approached by Oclassen Pharmaceuticals about use of FIAC for treatment of CMV infection in HIV-positive persons. August-October R89 Protocol modified, approved by ACTG committees, CMV Study Group, Opportunistic Infection Committee, NIAID Medical Branch and University of Washington and UCSD's IRBs. October R89 12- Meeting between Oclassen and FDA. Decision to limit trial to 4 weeks, due to lack of 90-day toxological support studies. 31-FIAC protocol open to accrual. 10 patients enrolled at UCSD. 1990 February R89 8-Conference call between UCSD site, Oclassen, and FDA to review results to date. April R89 15- First patient (subject 105) dies 40 days after last dose of FIAC. Death attributed to bacterial pneumonia, unrelated to FIAC. R89 16- Protocol modified to include only patients with CD4 counts >200. May R89 18- Second patient (subject 110) dies 58 days after last dose of FIAC. Death attributed to underlying disease. R89 30- FIAC protocol discontinued due to lack of efficacy against CMV. R90 Drs. Richman, Corey, and Straus, and Dr. Johnson from Oclassen draft an FIAU protocol, a two-week tolerance and pharmacokinetic study.

OCR for page 155
Review of the Fialuridine (FIAU) Clinical Trials 1990 June R89 2- Third patient (subject 107), dies 63 days after last dose of FIAC. Death attributed to underlying disease. The PI concludes that demyelinating polyradiculoneuropathy was caused by progressive HIV infection (the patient's family did not permit an autopsy). (FDA 1993 Task Force identifies this death as possibly FIAC-related.) R90 Draft protocol revised through multiple correspondence both written and via telephone between UW, UCSD, NIH (Straus), Oclassen, ACTG members, and FDA. July R90 Protocol presented to UW: Human Subjects Research Committee (HSRC). August R90 10- Amendment No. 1 sent to PIs by Oclassen. This amendment calls for enrolling HBV infected persons after initial cohort of non-HBV infected persons recruited. It also changes AST criteria to up to five times normal, from one and a half to three times normal and calls for one- and four-week port-treatment follow-ups to look for post-treatment ''flare". September R90 10- The protocol is submitted to the NIAID IRB, after approval by the Chief, Laboratory of Clinical Investigations (LCI) and the Acting Clinical Director, NIAID. R90 19-UW HSRC application approved, "Tolerance of HIV Infected Patients to Oral Doses of FIAU". October R90 1- First patient enters study at UW (1 mg/kg/day). R90 31- The NIAID IRB approves the protocol after PI responds to 23 stipulations. November R90 26- The Acting Director, NIH Clinical Center approves of protocol. 1991 February R90 25- First patient enters study, at dose of 1.7 mg/kg/day. Fatigue and nausea are documented with this dose of FIAU. March R89 11- Fourth patient (subject 103) dies 13 months after last dose of FIAC. Death attributed to AIDS, CMV, and Kaposi's sarcoma. R90 18/19- When 3rd of 3 patients dosed at 1.7 mg/kg develops gastrointestinal symptoms etc., it is decided to enroll no more subjects at this dose or higher.

OCR for page 155
Review of the Fialuridine (FIAU) Clinical Trials 1991 April R90 16- NIH enrolls their first HBV-infected patient at 1 mg/kg. Investigators feel that the 1.0 mg/kg 14-day dose is being well tolerated at other sites, with marked anti-HBV activity. Protocol reviewed by FDA and ACTG Viral Pathogens Working Group. It is agreed that the results deserve continued study. Amendment No. 2 initiates dose de-escalation to 0.5 mg/kg (1/2 the dose) to determine if drug active at lower doses. R90 19- First HBV-infected subject enrolled at UW site at 1.0 mg/kg dose. July-August R91 1- Drs. Hoofnagle and Straus submit a protocol entitled "A 4-week course of FIAU for chronic Hepatitis B" to the NIDDK IRB. This study would use different doses of FIAU (0.25, .50, or 1.0 mg/kg/day) in patients with HBV without HIV-infection. Oclassen would not agree to therapy for more than 28 days because animal toxicology data available only in support of short-term courses of treatment. This study was written to include a staggered entry of patients so efficacy and tolerance could be assessed before increasing dosage. R91 28- The NIDDK IRB reviewed the protocol, and approval was granted pending compliance with a number of stipulations. August R904- UW IRB approves Amendment No. 2—lowering dose to 0.5 mg/kg. R90 5- The NIAID IRB recommends approval pending compliance with 8 stipulations. R90 27-UW IRB approves revised consent form. September R89 2- Fifth patient (subject 101) dies months after last dose of FIAC. Death attributed to P. carinii pneumonia. R91 9- Protocol approved by the Acting Chair, NIDDK IRB and the Clinical Director, NIDDK as well as by the Acting Director, Clinical Center. R90 19- UW renewal application submitted to HSRC. Reports adverse reactions seen in FIAU among the 13 UW patients (gastrointestinal complications in 11, fatigue in 6, and elevated SGOT and CPK in 2). October R90 27- Amendment No. 3 proposed—to continue dose de-escalation to 0.1 mg/kg-as anti-HBV activity is present at both the 0.5 mg and 1 mg/kg. Detailed pharmacokinetic work is added. R90 31- The Chair of the IRB and the Clinical Director, NIAID approve continuation of the protocol.

OCR for page 155
Review of the Fialuridine (FIAU) Clinical Trials 1991 November R90 14- Dr. Straus requests approval from the Chair, NIAID IRB of annual report to the FDA on protocol 91-I-31 (R90-001). The report notes that one subject had received an overdose of FIAU, without adverse effect (NIH). R90 18- The NIAID IRB votes to recommend approval of the report to the FDA. R90 27- Dr. Straus writes the IRB Chair requesting approval of Amendment 3—lowering dose to 0.1 mg/kg. December R90 5- Investigators meet to discuss efficacy and toxicity data with initial HBV-infected enrollees. 10- Switch to 1 mg/ml syrup formulation. UW IRB notified. 15- Approved consent to Amendment No. 3 from UW IRB. 23- Approved consent to Amendment No. 3 from NIAID IRB, pending clarification of amount of blood drawn. 1992 February R91 Protocol R91-010 submitted to FDA. March R91 26- Approval received from the FDA subject to changes in consent form language, use of DNA polymerase activity rather than just HBV DNA as a means of monitoring therapy, and a change in doses. While waiting for FDA approval, more information becomes available from the study (R90-010) and the protocol is amended to use four lower dose levels (.05, 0.1, 0.25 and .50 mg/kg/day). Also, in the case of moderate toxicity, the drug would be stopped rather than reduced in dose. April R91 18-First patient dosed in study R91-010. May R90 16- Patient 408 (R90-001) dies of an esophageal hemorrhage and cirrhosis of the liver secondary to hepatitis B, C, and D, 6 months after completing a second 2 week course of FIAU. His death is not discovered by investigators until July 1993. (FDA 1993 Task Force identifies this death as possibly FIAU-related.) June R90 15- Last HIV+/HBV+ patient entered into 0.1 mg/kg dosage. R90 29- In total, 4 HIV+ patients enrolled at UCSD, 25 HIV+ at UW (12 non-HBV+ and 13 HBV+) and 14 HIV+ (all HBV+) at NIH clinical Center. R91 30- The Chair, NIDDK IRB approves continuation of protocol 91-DK-AI-213 (R91 study) for a second year. July R90 30- Patient 409 (R90 study) hospitalized with pancreatitis, 3 months after completing second 2-week course of FIAU. Pancreatitis attributed to current ddI use.

OCR for page 155
Review of the Fialuridine (FIAU) Clinical Trials 1992 August R90 11- Patient 406 (R90 study) dies 2 months after completing 2nd 2-week course of FIAU. Death attributed to ddI-induced pancreatitis. (FDA 1993 Task Force suggests this death FIAU related, although interpretation of FIAU toxicity is complicated by concurrent administration of ddI). R91 15- Status report on 24 subjects shows FIAU administration led to an immediate and profound inhibition of serum hepatitis B virus levels. All dose levels were well tolerated and the only toxicities reported were minor degrees of irritability and gastrointestinal upset at the highest dose level, with no patients requiring modification of dosage. September R91 10- Last R91-010 patient receives last does of FIAU. PPPC 16- Dr. Hoofnagle submits a 6-month course of FIAU protocol (PPPC) to the NIDDK IRB. The protocol is initially designed as a retreatment for patients who had not responded to therapy in the 28-day study. They would be eligible for enrollment five months after completion of the 28-day course. October R90 18- Patient 401 (R90 study) dies 4 months after completing second 2-week course of FIAU. Death attributed to liver failure due to cirrhosis. (FDA 1993 Task Force suggests this death possibly FIAU related, but notes that the presence of multiple hepatitis virus infections limits possible conclusions about FIAU toxicity.) PPPC 21- Lilly summarizes results of R90, R91 trials at meeting with FDA, lays out future plans. PPPC 24- Dr. Hoofnagle writes to the Chair, NIDDK IRB responding to the stipulations required by the NIDDK IRB. PPPC30- The Chair of the NIDDK IRB approves the protocol. November-December R90 Last of 4 patients retreated at NIH, finishes study. One of the 4 developed neuropathy. Protocol terminated. 1993 January R91 7- Death of patient 004D from this FIAU study (R91 study), 4 months after completing 1 month course of FIAU. Death was attributed to post-surgical complications of gall bladder removal (against the advice of PIs). In retrospect, the presence of lactic acidosis and the absence of elevated liver enzymes raise real suspicion that this patient may have had FIAU toxicity. (FDA 1993 Task Force suggests this death FIAU toxicity related.)

OCR for page 155
Review of the Fialuridine (FIAU) Clinical Trials 1993 February PPPC 12- Dr. Hoofnagle writes to the Chair, NIDDK IRB requesting two amendments to 93-DK-0031 (PPPC): 1) provision to include additional patients who have not previously received FIAU and 2) provision to do nerve conduction tests on patients before starting therapy and again after 3 months of therapy. The memo includes a discussion of the death of a subject and the appearance of peripheral neuropathies in two subjects who had participated in R91-010 (28 days). PPPC 19- Lilly provides Dr. Hoofnagle a copy of the newly revised FIAU Clinical Investigators's Brochure that includes the FDA's modifications in the informed consent documents. March PPPC 5- After the PI responds to the IRB's stipulations, the Chair, NIDDK IRB approves the amended protocol. PPPG 19- Sixteen healthy volunteers begin series of 5 doses of FIAU in different formulations at Lilly Laboratory of Clinical Research in Indianapolis, where subjects reside for duration of study. PPPC 24- First patient dosed in PPPC protocol. PPPG 25- Subject 1203 dropped from Indianapolis study due to elevated AST/ALT measures after 2nd dose of FIAU. April PPPG 12- Fifteen subjects receive fifth and last doses of FIAU. May PPPA 3- First patient dosed in PPPA trial at New England Medical Center. PPPG 5- Sixteenth subject receives final dose at Indianapolis. PPPA 14- First patient dosed in PPPA trial at Galveston. June PPPC 7- The PI writes to the Chair, NIDDK requesting approval of an amendment permitting the dosing of subjects twice daily rather than three times per day as specified in the protocol. PPPC 8- The Chair, NIDDK IRB approves the amendment—dosing two times daily rather than three. PPPC 15- Patient #6C telephones to report symptoms of nausea, vomiting, diarrhea, and fatigue. PPPC 25- Patient #2B admitted to a Virginia emergency room with lactic acidosis. PPPC 26- All subjects who ha received FIAU in either the 28 day or the 6 month study were recalled to NIH for examination and possible treatment of FIAU toxicity. PPPA 26- Last patient (total of 3) dosed in PPPA trial at Galveston.

OCR for page 155
Review of the Fialuridine (FIAU) Clinical Trials 1993 June cont. PPPC 28- Dr. Hoofnagle calls the Acting Director, Clinical Center to report that two subjects receiving FIAU on protocol 93-DK-31 had been admitted with catastrophic illness and that all subjects had been contacted and told to stop taking FIAU on June 26. PPPA 28- Last patient dosed (total of 2) at New England Medical Center. PPPC 29- The PI writes to the Chair, NIDDK IRB reporting the complications during the protocol with two subjects. At a regularly scheduled meeting of the NIDDK IRB, Dr. Hoofnagle provides patient updates and reports on the death of the subject who had participated in protocol 91-DK-213. The IRB minutes reflect discussion of attempts to ''rescue" subjects from the toxic effects of FIAU. The IRB approves a consent document to be used for their treatment. PPPC 30- A meeting on FIAU toxicity is held at NIH. Attendees include staff from NIDDK, NIAID, the NIH Clinical Center, FDA, Lilly, Yale University, University of Alabama at Birmingham, Tufts University (Clinical Investigator on FIAU) and University of Texas at Galveston (Clinical Investigator on FIAU). On this day, the Director, OHSR reports the complications occurring on NIH protocol 93-DK-31 (PPPC) to the Office for Protection from Research Risks. July PPPC At this time, NIH investigators learn of the death of patient 408 (R90) on May 16, 1992. This patient had been treated with FIAU for 12 days in November of 1991 and retreated for 14 days in January of 1992. PPPC 2- A second meeting was held on FIAU toxicity at NIH. PPPC 5- Patient #3D (Lilly #001-2002) dies of Lactic acidosis and cardiovascular collapse one day after an unsuccessful liver transplantation. PPPC 6- Patient #2B (Lilly #001-3004) dies of lactic acidosis and cardiovascular collapse two days after an unsuccessful liver transplantation. PPPC 9- Patient #6C (Lilly #001-6003) receives a liver transplant. PPPC 12- A meeting of the Senior Clinical Staff, NIDDK was held and protocol 93-DK-3l's severe complications were reviewed. PPPC 27- At a regularly scheduled meeting of the NIDDK IRB, patient updates were given, and the committee commended the group for their immediate reaction to the new FIAU side effects and diligent follow-up. It was noted that all patients had been informed in advance of the earlier death of a FIAU patient, and this had been documented in the patient charts. PPPC 30- Patient #3A (Lilly #001-3001) dies of sever pancreatitis and relentless lactic acidosis.

OCR for page 155
Review of the Fialuridine (FIAU) Clinical Trials 1993 August PPPC 4- Patient #1C (Lilly #001-1003) undergoes a successful liver transplantation. PPPC 13- Patient #6C (Lilly #001-6003) undergoes a second liver transplantation. PPPC 31- Patient #6C dies of multiorgan failure. September PPPC 22- The Director, OHSR wrote to OPRR providing all available documentation regarding the protocol and informing that office that review of the materials indicated that the protocol had been conducted in accord with the terms and conditions of the NIH Multiple Project Assurance.