US 200200.52317A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0052317 A1 Itri et al. (43) Pub. Date: May 2, 2002

(54) ANTI-VIRAL AND ANTI-TUMOR Publication Classification CHEMOTHERAPY BY ADMINISTRATION OF ERYTHROPOETIN (51) Int. Cl." ...... A61K 38/21; A61K 31/522; A61K 38/17 (76) Inventors: Loretta Itri, Westfield, NJ (US); Peter (52) U.S. Cl...... 514/12; 424/85.5; 514/307; Bowers, Bedminster, NJ (US) 514/171; 514/263.36; 514/323 Correspondence Address: Philip S. Johnson, Esq. (57) ABSTRACT Johnson & Johnson The present invention provides methods using erythropoi One Johnson & Johnson Plaza etin to improve the tolerance of anti-viral and anti-tumor New Brunswick, NJ 08933-7003 (US) chemotherapeutic regimens containing interferon. The invention also described improved methods to treat chronic (21) Appl. No.: 09/921,516 HCV by adjusting the dose of ribavirin to tailor the active dose of the drug while Supporting the hemoglobin levels in (22)22) FileFilled: Aug.ll. 1,1, 2001 the patient with EPO. The present invention also provides Related U.S. Application Data anti-viral dosing regimens, particularly for chronic HCV comprising administration of an interferon containing anti (63) Non-provisional of provisional application No. Viral medicament, EPO, and a compound that reduces the 60/222,538, filed on Aug. 2, 2000. amount of active tumor necrosis factor in the Subject. Patent Application Publication May 2, 2002 Sheet 1 of 2 US 2002/0052317 A1 Figure 1

14.5 14

13.5 - PROCRT 13 -- Standard-of-Care Hemoglobin 12.5 (Hb) 12 11.5

10.5 10 Baseline Week 2 Week 4 Week 8 Week 12 Week 16 Patent Application Publication May 2, 2002 Sheet 2 of 2 US 2002/0052317 A1 Figure 2

1,200

1,000800 is --r- -

Hemoglobin(Hb) 600 Y PROCRT 400 Standard-of-Care

200

Baseline Week 2 Week 4 Week 8 Week 12 Week 16 US 2002/0052317 A1 May 2, 2002

ANTI-VIRAL AND ANT-TUMIOR alpha and INF-beta are secreted from different cell types in CHEMOTHERAPY BY ADMINISTRATION OF response to antigen Stimulation and both bind to the same ERYTHROPOETIN receptor, the type I INF receptor. Therefore these interferons are often called type I INF INF gamma binds to a second CROSS-REFERENCE TO RELATED receptor, called the type II INF receptor and is sometimes APPLICATION called type II INF. Several forms of type I INF are clinically 0001. This application claims the benefit of United States used in the treatment of Viral infections and as anti-tumor Provisional Application Serial No. 60/222,538, filed Aug. 2, agents due to the potent immunological response that type I 2OOO. INF induces in the subject. However the widespread use of these drugs has been limited due to the occurrence of FIELD OF THE INVENTION adverse events or Side effects associated with them. Simply put, the risks Sometimes outweigh the benefits of adminis 0002 The present invention provides, in one embodi tration of these drugs. There is a recognized unmet need to ment, methods to treat a Subject having hemolytic anemia by increasing the Supply of red blood cells using erythropoietin. minimize the adverse events of these drugs (Weiss (1998)). The present invention also provides methods to reduce the RebetronTM Side effects associated with administration of a Type I interferon by administration of an erythropoietin. The meth 0006 REBETRONTM is combination therapy of REBE ods of the present invention are particularly useful when TOL(R) (ribavirin or 1.f3-D-ribofuranosyl 1H-1,2,4-Triazole interferon is administered as a Single agent or as part of a 3-carboxamide), and INTRON ALPHACR, Interferon alpha combination therapy with an anti-Viral agent or anti-tumor 2b. REBETRON is indicated for the treatment of chronic agent. In one embodiment, concurrent administration of hepatitis C infection, particularly in patients that were not erythropoietin with a combination of the anti-Viral agent previously treated with Interferon alpha-2b monotherapy or ribavirin and interferon alpha-2b for chronic hepatitis C is who have suffered a relapse following Interferon alpha-2b provided that allows greater drug tolerance and fewer treat monotherapy. ment emergent adverse events. 0007. There are several side effects that are attributable to administration of REBETRON. A major contraindication for BACKGROUND OF THE INVENTION subjects treated with REBETRON is hemolytic anemia. Procrit(E) Anemia begins within 1 to 2 weeks following the first dose and is stabilized by week 4. Hemoglobin values returned to 0003 PROCRITE) is the brand name for the Epoetin alfa. pretreatment levels within 4-8 weeks of cessation of therapy In 1990, PROCRIT received market clearance by the FDA in most patients. Other Side effects are those associated with for the treatment of anemia in HIV-infected patients on the potent immunological effects of Interferon alpha-2b zidovudine (ZDV) therapy (sA200 mg/week) with endog including, but not limited to, neutropenia, exacerbation of enous serum erythropoietin levels s500 MU/mL. It is also autoimmune disease, exacerbation of psoriasis, flu-like approved for the treatment of anemia in patients with Symptoms, fatigue, nausea, anorexia, psychiatric disorders, non-myeloid malignancies receiving chemotherapy, in amenorrhea, Sexual dysfunction, and pulmonary disorders. A patients with chronic renal failure (pre-dialysis), and for use thorough Summary of contraindications is provided in the in elective noncardiac nonvascular Surgery to reduce the Physician's Desk Reference. Overall about 26% of patients need for allogeneic blood transfusion during high volume require a dose modification of REBETOL, either ribavirin, blood loSS procedures. In clinical trials to date, Epoetin alfa interferon, or both agents. The dose is modified based on has been evaluated in normal Subjects as well as in Subjects treatment emergent adverse events, including hemolytic with various anemic conditions. Epoetin alfa induces a brisk anemia. It is likely that a reduced dosing regimen results in haematological response in normal human Volunteers, pro less efficacious treatment of the chronic hepatitis C. Thus Vided that adequate Supplies of iron are available to Support there is an unmet need to develop a means to decrease the increased hemoglobin Synthesis. A majority of trials have onset of, or ameliorate the intensity of, adverse reactions due investigated the Safety and effectiveness of Epoetin alfa in to REBETRON or Interferon alpha-2b treatment. the treatment of chronic renal failure and of anemia in cancer. Other trials have evaluated Epoetin alfa for the PROCRITE(Epoetin alfa) Treatment for RBV/IFN treatment of anemia associated with rheumatoid arthritis, ASSociated Anemia in HCV Patients prematurity, AIDS, bone marrow transplantation, myelofi brosis, Sickle cell anemia, as a facilitator of presurgical 0008 Weisz, et al. (1998) evaluated the efficacy of autologous blood donation, and as a perisurgical adjuvant. r-HuBPO for treatment of anemia associated with interferon alfa/ribavirin therapy in HCV-infected, HIV-negative 0004 Erythropoietin is currently used to treat anemic patients. The authors concluded that r-HuBPO may be Subjects who are amenia as a result of insufficient levels of effective for treatment of anemia associated with interferon Erythropoietin or who demonstrate a blunted response to alfa/ribavirin therapy in HCV-infected, HIV-negative Erythropoietin. Erythropoietin is not currently used to treat patients. The problem with this Study was that it was a case hemolytic anemia or most form of anemia that results from study and not a controlled clinical trial. PROCRIT was only enhanced rate of clearance of the red blood cells, except for administered to the patients with the most Severe anemia, Sickle cell anemia and thalycemia. patients who were likely to have been dose modified to reduced levels of ribavirin. Thus the study introduced a bias Interferon into the results. The dose modifications of ribavirin were not 0005 Interferons are divided into three basic protein reported. Without this information, a physician could not families, the INF-alpha, INF-beta, and INF-gamma. INF understand the results that were reported, nor would the US 2002/0052317 A1 May 2, 2002

conclusions be trusted or understood. Dieterich, et al. (1999) proteins, fusion proteins oligomers and multimers of the evaluated the impact of ribavirin administration with above, homologues of the above, glycosylation pattern Vari zidovudine (AZT) and stavudine (d4T) in patients co-in ants of the above, and muteins of the above, regardless of the fected with HIV and HCV. Of the 21 patients studied, 11 biological activity of Same, and further regardless of the received combination therapy with interferon alfa (3x106 U method of Synthesis or manufacture thereof including but thrice weekly (TIW) and ribavirin (1,000-1,200 mg/day), not limited to, recombinant whether produced from cDNA whereas ten started therapy with interferon alfa for three or genomic DNA, Synthetic, transgenic, and gene activated months, followed by combination therapy. Nineteen of the methods. Specific examples of erythropoietin include, Epo 21 patients were receiving highly-active antiretroviral etin alfa (EPREX(R), ERYPO(R, PROCRIT(R), Novel eryth therapy (HAART) including either AZT or d4T. During the ropoiesis stimulating protein (NESP) (a hyperglycosylated Six-month evaluation, both groups experienced decreases in analog of recombinant human erythropoietin (Epoetin) HCV RNA, CD4+ count, and HIV RNA values. Anemia described in European patent application EP640619), human occurred in 23.8% (n=5) of the patients. Treatment with erythropoietin analog-human Serum albumin fusion pro r-HuEPO (40,000 U once weekly OWI) increased hemo teins described in the international patent application globin (Hb) values (from 10 g/dL at initiation to 12.7 g/dL) WO9966054, erythropoietin mutants described in the inter after a median of four weeks. Among patients treated with national patent application WO9938890, erythropoietin r-HuEPO hemoglobin (Hb) values increased, subject to case omega, which may be produced from an Apa I restriction Study bias as described Supra. In addition to this abstract, a fragment of the human erythropoietin gene described in U.S. poster of this information was presented at the 39th Inter Pat. No. 5,688,679, altered glycosylated human erythropoi Science Conference on Antimicrobial Agents and Chemo etin described in the international patent application therapy (ICAAC) (Weisz, et al. 1999). WO9911781, PEG conjugated erythropoietin analogs described in WO9805363 or U.S. Pat. No. 5,643,575. Spe SUMMARY OF THE INVENTION cific examples of cell lines modified for expression of 0009. The present invention provides a method reduce endogenous human erythropoietin are described in interna the occurrence of the Side effects associated with adminis tional patent applications WO9905268 and WO9412650. tration of a Type I interferon comprising administering a Peptide mimetics of erythropoietin, abbreviated as “EMP interferon dosing regimen and administering a therapeuti herein, are described in pending U.S. patent application Ser. cally effective amount of erythropoietin (EPO) to the Sub No. 08/484135, filed on Jun. 7, 1995 by Zivin, et al, the ject, wherein the erythropoietin improves the ability of the contents of which are herein incorporated by reference. The Subject to maintain or increase the interferon dosing regi generally preferred form of EPO is purified, recombinant men. In another embodiment of the present invention, anti human EPO (rhEPO), distributed under the trademarks of Viral regimens are provided that comprises administration of EPREX(R), ERYPO(R), or PROCRITE). Epoetin alfa is a an anti-Viral interferon dosing regimen, EPO, and a com Sterile, clear, colorless, aqueous Solution for injection, which pound that inhibits the amount of tumor necrosis factor in is provided in prefilled, Single-use or multi-dose quantities. the patient. 0014) “Anemia' is a condition marked by decreases in 0.010 The present invention also provides a method to hemoglobin (Hb) levels defined herein as s 15.0 g/dL (9.30 dose adjust the amount of active ribavirin in a Subject by mmol/l) for male subjects and s 13.0 g/dL (8.06 mmol/l) for measuring the level of anemia in the Subject. The dose of female subjects. Mildly anemic conditions are defined ribavirin is adjusted until an acceptable level of hemolysis herein as Hb levelk 13.0 g/dL (8.06 mmol/1) for males and occurs in the Subject. Then the hemolytic anemia in the <12.0 g/dL (7.44 mmol/l) for females. Severely anemic Subject is treated with a therapeutically effective amount of conditions are defined herein for both sexes as Hbs 10.5 erythropoietin (EPO) to the subject, wherein the erythropoi g/dL, with further medical intervention, typically in the form etin improves the ability of the Subject to maintain or of blood transfusion, commonly administered at Hb<9 g/dL, increase the ribavirin dose. although transfusions are not common at hemoglobin levels above 9.0 g/dL. It is assumed that worsening anemia is a BRIEF DESCRIPTION OF THE DRAWINGS likely consequence of further anti-Viral therapy and/or the underlying disease. Concurrent dosing regimens of EPO 0011 FIG. 1: Concurrent administration of EPO and with another agent are conducted preferably when a Subject Ribavirin/INF-alpha increases hemoglobin levels. exhibits Severe anemia, more preferably when a Subject is 0012 FIG. 2: Concurrent administration of EPO and mildly anemic, and still more preferably when the Subject is Ribavirin/INF-alpha allows maintained dosing of Ribavirin/ at the low range of normal, about 15 g/dL for a male Subject INF-alpha. and about 13 g/dL for a female subject. Administration of EPO to a subject with > 10.5 g/dL provides a preferable response in relation to amelioration, or reversal of anemia in DETAILED DESCRIPTION OF THE Subjects receiving concurrent administration of an agent and INVENTION EPO. Early treatment with EPO can prevent worsening Definitions anemia requiring transfusion. Anemia can be caused by many different ways, including as a result of insufficient 0013 The erythropoietin is present in the compositions in levels of Erythropoietin, blunted response to Erythropoietin, therapeutically effective amounts. “Erythropoietin” shall hemolytic anemia, autoimmune hemolytic anemia, an include those polypeptides and proteins that have the bio enhanced rate of clearance of the red blood cells, or lack of logical activity of human erythropoietin, as well as eryth production of erythroid production of progenitor cells by ropoietin analogs, erythropoietin isoforms, erythropoietin bone marrow Suppression. Bone marrow Suppression can mimetics, erythropoietin fragments, hybrid erythropoietin occur by the effects of an infective agent, administration of US 2002/0052317 A1 May 2, 2002

Suppressive drugs, or alterations in the levels of inflamma hemoglobin levels remain within acceptable levels. Admin tory cytokines including IL-2, TNF, type I interferons, and istration of erythropoietin to a Subject who is concurrently type II interferons. The method of the present invention are receiving an interferon dosing regimen results in a higher particularly drawn to treating a human Subject who is quality of life, improved well being, and a reduction in anemic due to hemolytic anemia, autoimmune hemolytic treatment emergent Side effects of interferon. Quality of life anemia, enhanced clearance of red blood cells, bone marrow is usually affected by the underlying disease and/or the Suppression by Viral infections, or bone marrow Suppression effects of anti-viral therapy. The improved physical perfor by altered cytokine levels. The altered cytokine levels may mance and improved well being is provided to Subjects who be caused by altered endogenous production of the cytok exhibit at least a partial response to the EPO treatment as ines, for example increased TNF levels in HIV infected monitored by increased hemoglobin or hematocrit levels in individuals, or may be due to exogenous administration of a the blood. This results in better tolerability of the interferon cytokine therapeutic, for example IL-2, or an interferon. dosing regimen and allows maintenance of the regimen in 0.015 The term “concurrent as used herein, means that the Subject. a two or more therapeutically effective medicaments are 0019. The term “Interferon” as used herein refers to administered during the same period of time Such that the polypeptides or proteins that bind to the type I INF receptor patient receives the benefit of both agents alone and achieves and Stimulate Signal transduction. For example, but not by a Synergistic effect of the combination of the two agents. way of limitation, “interferon” includes Interferon alfa-2a Synergy refers to a combined pharmacological effect that (ROFERON-A(E), Interferon alfa-2b (INTRON ACE), and exceeds the anticipated result based on the amount of ALFERON NINJECTION(B), a recombinant, non-naturally administration of either Single agent. occurring type-I interferon INFERGENCR, Interferon beta 1a (AVONEX(R), and Interferon beta-1b (BETASERONGR). EPO Dosing Regimens Type I interferons are useful in the treatment of viral infections, including chronic Hepatitis C, and chronic Hepa 0016 EPO is administered by any suitable means, as titis B, Kaposi's Sarcoma, Hairy Cell Leukemia, Malignant would be apparent to one skilled in the art. AS used for Melanoma, Follicular Lymphoma, and Condylomata administration of EPO, the phrase “therapeutically effec Acuminata. tive' is from about 1 to 1000 I.U./kg, preferably from about 0020. The phrase “interferon dosing regimen” means 50 to 1000 I.U./kg, more preferably from about 50-600 administration of a therapeutically effective dose of an I.U./kg, and most preferably from 50 to 300 I.U./kg body interferon and optionally at least a Second agent. In one weight especially when erythropoietin is administered Sub embodiment of the present invention the interferon dosing cutaneously. The preferred methods of administration are regimen is one where an interferon is used as a Single intravenous (iv) and Subcutaneous (Sc), with Subcutaneous therapeutic agent. In a Second embodiment, the interferon being generally preferred. EPO is administered within the dosing regimen includes an interferon administered concur range of about 100-300 U/kg per dose, one to five times per rently with a nucleoside analog, preferably a nucleoside week, or at any other dosing regimen that provides the analog Selected from the group consisting of ribavirin, AZT desired therapeutic effect. A preferred initial dosing regimen (3'-azido-3'-deoxythymidine), 3TC (2R, cis)-4-amino-1-(2- is about 150 U/kg sc, three times per week, however it is hydroxymethyl-1,3-oxathiolan-5-yl-(1H)-pyrimidin-2-one, readily apparent to those skilled in the art that any EPO dose abacavir Sulfate ((1 S, cis )-4-2-amino-6-(cyclopropy or frequency of EPO administration that provides the thera lamino)-9 H-purin-9-yl)-2-cyclopentene-1-methanol sulfate peutic effect described herein is suitable for use in the (salt) (2:1)), stavudine (d4T or 2',3'-didehydro-3'-deoxythy present invention. For patients who show a blunted response midine), didanosine (dideoxyinosine or dd), Zalcitabine to a dosing regimen of 150 I.U./kg, the preferred dosing (2',3'-dideoxycytidine or ddC), Gemcitabine (2'-deoxy-2,2'- regimen is about 300 I.U./kg sc, three times per week. EPO difluorocytidine monohydrochloride (beta)-isomer), and administration is delayed or withheld if the patient, male or ganciclovir (9-2-hydroxy-1-(hydroxymethyl)ethoxyme female, exhibits a hemoglobin level in excess of about 15 thylguanine). The choice of a particular nucleoside analog g/dL. to treat a particular type of Viral infection is well known for 0017 For ease of operation it is advised that epoetin those skilled in the art. A particularly preferred embodiment treatment be Started at the beginning of the next therapy is a combination of ribavirin and interferon cycle. The traditional treatment for Severe anemia is blood (REBETRONTM), which is used to treat chronic hepatitis C transfusion. These are administered according to clinical infection. In yet another embodiment of the invention the need, although transfusions are not common or preferred at interferon dosing regimen includes an interferon adminis hemoglobin levels above 9.0 g/dL. Although subject to tered concurrently with an anti-tumor agent to facilitate extensive Screening, blood allogenic blood transfusion is not eradication of a malignancy. Preferred anti-tumor agents are without risk of acquired infections, primary concern is Selected from the group consisting of cladribine (2-chloro hepatitis (Dodd, R Y., N. Engl. J. Med. 192:327:419–421; 2'-deoxy-(beta)-D-adenosine), Chlorambucil (4-bis Waymack, J. P., Infections in Surgery (1990). July:41-47; (2-chlorethyl)amino benzenebutanoic acid), DTIC-Dome Busch, M.P., Lee, T., Heitman, J., Blood (1992) 80(8):2128 (5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide), 2135). platinum chemotherapeutics and non-platinum chemothera peutics. Platinum containing anti-tumor agents include, but Methods of Increasing the Tolerability of an are not limited to, cisplatin (cis-dichlorodiamineplatinum). Interferon Dosing Regimen Non-platinum containing anti-tumor agents include, but are not limited to, cyclophosphamide, fluorouracil, epirubicin, 0.018 Erythropoietin is administered to a subject in thera methotrexate, Vincristine, doxorubicin, bleomycin, and eto peutically effective amounts and is maintained So long as the poside. Each anti-tumor agent is administered within thera US 2002/0052317 A1 May 2, 2002

peutically effective amounts, which are well known in the pharmacokinetic activity. Pentoxifylline inhibits TNF-C. art, and vary based on the agent used, the type of malig gene transcription (Doherty, et al., Surgery, St. Louis (1991) nancy, and other conditions. 110:192), while thalidomide enhances TNF-C. m-RNA deg radation (Moreira et al., 1993) and glucocorticoids such as Methods of Optimizing the Active Dose of dexamethasone inhibit TNF-C. m-RNA translation (Han, et Ribavirin in a Subject al., J. Exp. Med. (1990) 172:391). Infliximab and Etanercept 0021 Ribavirin is typically administered at a maximum act by reducing the amount of circulating, active TNFC. dose of 1200 mg/day for a subject with a body weight of >75 0024 Pentoxifylline (PENTOXILTM, Trental) decreases Kg or 1000 mg/day for a subject with a body weight of <75 circulating TNFC. at the Standard dose of 400 mg 3 times Kg. In each subject the amount of active ribavirin will vary daily. Pentoxifylline inhibits TNF-C. gene transcription based on many factors. Active ribavirin is ribavirin that is (Doherty et al., Surgery (St. Louis), 110:192, 1991). transported into the cell and is phosphorylated. One side effect of the accumulation of ribavirin in red blood cells is 0025) Glucocorticoids such as dexamethasone inhibit hemolytic anemia, possibly by premature clearance of the TNF-C. m-RNA translation. Dexamethasone is administered cells from the blood stream. Therefore by monitoring the orally, intramuscularly, or intravenously in the dose range of level of hemolysis, a physician can determine the relative 8-40 mg (pediatric dose: 0.25-0.5 mg/kg). If given intrave amount of active ribavirin in the subject. This allows the nously, dexamethasone should be given over 10-15 minutes, physician to alter the dose of ribavirin to a tailored dose for Since rapid administration may cause Sensations of gener the Subject. For patients that readily adsorb the ribavirin, the alized warmth, pharyngeal tingling or burning, or acute dose can be reduced. Patients that do not demonstrate transient perianal and/or rectal pain. Methylprednisolone is hemolysis at the maximum typical dose may receive higher also administered orally, intramuscularly, or intravenously at doses until the desired amount of hemolysis occurs. A doses and schedules that vary from 40-500 mg every 6-12 preferred range of hemolysis is a decrease in the hemoglobin hours for up to 20 doses. level of about 10 to 25%, preferably about 15 to 25%, and 0026 Thalidomide (N-phthalidoglutarimide) may act by particularly about 18 to 22%. The physician can then begin enhancing TNF-C. m-RNA degradation (Shannon, et al. administration of EPO to increase the hemoglobin levels (1990) Amer: Society for Microbiology Ann. Mtg., Abs. while maintaining the ribavirin dosing regimen. U53). Improved Methods of Treating Chronic HCV 0027. Thalidomide is given by oral administration in the Infection in a Subject range of about 30 mg to 1500 mg per 24 hours, preferably 200 to 500 mg per 24 hours for an adult human weighting 0022. The present invention also provides a dosing regi 70 kg. men for the treatment of chronic HCV comprising admin istration of an anti-Viral amount of an interferon with 0028) REMICADETM (Infliximab) is a monoclonal anti ribavirin, a therapeutically effective amount of EPO, and a body that blocks the biological activity of circulating TNFC. compound that inhibits the biological activity of tumor Infliximab does not neutralize TNFB (lymphotoxin C), a necrosis factor (TNF), called herein an “Anti-Tumor Necro related cytokine that utilizes the same receptors as TNFC. sis Factor Compound”. Modulation of TNF simultaneously Remicade is Supplied as a Sterile, white, lyophilized powder with EPO increases the effectiveness of EPO for increasing for intravenous infusion. Following reconstitution with 10 hemoglobin levels, ameliorating anemia, and counter acts mL of Sterile Water for Injection, USP, the resulting pH is the effects of bone marrow Suppression caused by the approximately 7.2. Each Single-use vial contains 100 mg chronic HCV infection, the interferon, and other drugs Infliximab, 500 mg sucrose, 0.5 mg polysorbate 80, 2.2 mg including, but not limited to, ribavirin. Therefore adminis monobasic Sodium phosphate and 6.1 mg dibasic Sodium tration of an anti-TNF compound further offsets the adverse phosphate. No preservatives are present. Data from a Study effects of the anti-Viral therapy while increasing the efficacy of Single intravenous infusions of 1, 5, 10 or 20 mg/kg Show of the EPO. a direct and linear relationship between the dose adminis tered and the maximum serum concentration (C) and area 0023 The term “Anti-Tumor Necrosis Factor Com under the concentration-time curve. The volume of distri pound” refers to drug products that decrease the amount of circulating, active TNFC. The compound may achieve this bution at Steady state (V), clearance and mean residence by decreasing the amount of cellular TNFC. mRNA tran time are independent of the administered dose. Infliximab scription, by decreasing mRNA translation into TNFC. pro has a prolonged terminal half-life and is predominantly tein, or by decreasing cellular secretion of TNFC. Roy A. distributed within the vascular compartment. A Single infu Black, et al., from ImmuneX Corporation, have discovered a Sion of the recommended dose of 5 mg/kg resulted in a compound that inhibits the enzyme that releases TNF from median C of 118 ug/mL, a median V equal to 3.0 liters cell surfaces (Nature, 370, 218(1994)). This compound, and a terminal half-life of 9.5 days. called TNF-C. protease enzyme inhibitor, curbs production 0029 ENBRELTM (Etanercept) is a dimeric fusion pro of soluble TNF. Other suitable anti-TNFC. compounds could tein consisting of the extracellular ligand-binding portion of work by increasing the rate of clearance or decreasing the the human 75 kilodalton (p75) tumor necrosis factor recep amount of functional TNFC. in circulation. Preferred anti tor (TNFR) linked to the Fc portion of human IgG1. The Fc TNFC. compounds are Thalidomide, Pentoxifylline, Inflix component of Etanercept contains the C2 domain, the C3 imab, glucocorticoids, and Etanercept. The anti-TNFC.com domain and hinge region, but not the C1 domain of IgG1. pounds may be administered as combinations in order to Etanercept is produced by recombinant DNA technology in maximize modulation of TNF Since these agents acts as a Chinese hamster ovary (CHO) mammalian cell expression TNFC. inhibitors at a different points in TNF synthesis and System. It consists of 934 amino acids and has an apparent US 2002/0052317 A1 May 2, 2002 molecular weight of approximately 150 kilodalton. Dosing ENBRELTM is supplied as a sterile, white, preservative-free, lyophilized powder for parenteral administration after 0035) 1. RIBAVIRIN reconstitution with 1 mL of the Supplied Sterile Bacterio 0036) Dose reductions of ribavirin will be determined by static Water for Injection, USP (containing 0.9% benzyl the individual clinician based on the RBV/IFN alfa-2b alcohol). Following reconstitution, the Solution of package insert or for patients receiving RBV/IFN alfa-2b on ENBRELTM is clear and colorless, with a pH of 7.4+0.3. protocol, as defined by guidelines recommended by the Each single-use vial of ENBRELTM contains 25 mg Etaner RBV/IFN alfa study protocol. cept, 40 mg mannitol, 10 mg Sucrose, and 1.2 mg tromethamine. ENBRELTM is administered as a single Sub 0037) 2. PROCRIT cutaneous (SC) injection. 0038 Patients will receive PROCRIT for up to 36 weeks at a dose of 40,000 Units qw by subcutaneous injection. If 0030 The following examples illustrate the present after 8 weeks of therapy, the hemoglobin has not invention without, however, limiting the same thereto. increased 21.0 g/dL from the nadir Hb value, PROCRIT therapy is to be discontinued. If the hemoglobin exceeds 14 EXAMPLE 1. g/dl for women and 16 g/dl for men, the dose of PROCRIT An Open-Label, Randomized, Parallel-Group Study should be withheld. PROCRIT should be resumed when the hemoglobin drops below 13 g/dl for women and 15 g/dl for Comparing the Effectiveness of Procrit(R) (Epoetin men. When PROCRIT is resumed the dose should be alfa) Administered Once Weekly Versus Standard reduced by 10,000 Units, then titrated, by increasing or of Care in Hepatitis C Patients Treated with decreasing the dose in 5,000-10,000 U increments or dec Combination Ribavirin/Interferon alfa-2b rements, (but not to exceed 40,000 Units total dose per Objective week) to maintain hemoglobin within the above specified limits. Following any increase in PROCRIT dose, patients 0.031) To determine the effectiveness of a weekly dosing should be monitored with weekly Hb and BP measurements regimen of PROCRIT in alleviating anemia and improving for 4 weeks before any additional increases. the quality of life, and minimizing ribavirin dose reductions in Hepatitis C virus (HCV) infected patients who are receiv 0039) 3. IRON ing combination Ribavirin/Interferon alfa-2b (RBV/IFN 0040. A potentially major efficacy-limiting factor for alfa-2b) treatment. normal erythropoiesis is functional and/or actual iron defi ciency. Patients may require Supplemental iron to avoid Overview of Study Design depletion of available iron Stores and to adequately Support 0032) Open-label, randomized, parallel group study using erythropoiesis stimulated by PROCRIT. The typical range PROCRIT 40,000 Units once a week or standard of care for Supplemental iron is approximately 150-200 mg elemen (i.e., no PROCRIT) in anemic HCV infected patients who tal iron per day. The appropriate formulation of iron will are receiving combination RBV/IFN alfa-2b treatment. The depend on patient and physician preference. The patient's study population includes HCV infected patients with iron status, including transferrin Saturation (serum iron Hbs 12 g/dL, and are evaluated during the first twenty four divided by iron binding capacity) and Serum ferritin, should weeks of treatment with combination RBV/IFN alfa-2b. be evaluated throughout the Study as clinically indicated. Patients randomized into the PROCRIT treatment arm will Patient Selection receive PROCRIT 40,000 Units once a week (qw) subcu taneously (s.c.) for up to 36 weeks. Patients randomized into Study Population the standard of care (SOC) arm will be treated according to the respective institution's SOC policy, however, not includ 0041 Approximately 60 HCV infected patients who ing PROCRIT treatment. meet the following criteria will be admitted into the study. Description of Study Inclusion Criteria 0042 1. Signed informed consent Design 0043. 2. Willing and able to complete Quality of 0033. This is a 36-week open-label study using PRO Life assessment tools (Modified SF-12 Health Sur CRIT qw. HCV-infected patients with Hbs 12 g/dL during vey Acute and Linear Analog Scale ASSessment) the first twenty four weeks of receiving combination RBV/ IFN alfa-2b therapy are eligible. Approximately sixty 0044) 3. HCV infected patients as confirmed by 1) patients will be enrolled from up to eight centers. Laboratory detectable HCV viremia by PCR, or branched DNA, results (hematocrit and hemoglobin), quality of life assess and 2) elevated ALT; or histological confirmation. ments, reduction in ribavirin dosage and transfusion infor 0045. 4. Current treatment with combination RBV/ mation will be obtained during the Study period as noted. IFN alfa-2b 0034. At the end of the 36-week treatment period with 0046) 5. Hb of s 12 g/dL during first 24 weeks of PROCRIT therapy, patients wishing to continue PROCRIT RBV/IFN alfa-2b treatment and in whom it is considered beneficial will have the option 0047 6. Male or female of receiving PROCRIT by prescription. Anyone eligible may participate in one of Ortho Biotech's financial assis 0048 7. Age 18-75 years inclusive tance programs. 0049 8. Life expectancy of >12 months US 2002/0052317 A1 May 2, 2002

Exclusion Criteria 0070) 5. Physical examination including vital signs, 0050) 1. HIV-infected patients GI/liver exam 0.071) 6. Medication history, including RBV/IFN 0051 2. History of any primary hematologic disease alfa-2b (must be within first 12 weeks of initiating 0052 3. Presence or history of uncontrolled hyper RBV/IFN alfa-2b) tension (i.e., diastolic blood pressure>100 mmHg) 0.072 7. Hematocrit 0053 4. Uncontrolled seizure disorder 0.073 8. CBC with differential 0054 5. Anemia attributable to factors such as iron or folate deficiency, hemolysis or gastrointestinal 0074. 9. Transferrin Saturation, ferritin, and folate bleeding 0075) 10. Endogenous serum EPO level (must be before any transfusion is given or at least one month 0055 6. Life expectancy.<12 months following any transfusion) 0056 7. Current, active substance abuser 0076) 11. HCVLoad 0057 8. Pregnant or breast feeding 0077 12. Urinary pregnancy test if applicable 0058 9. Women of childbearing potential not taking 0078 13. ALT adequate birth control measures 0059 10. Patients with previous exposure to Epoetin Study Start/Day 1 alfa within 6 months prior to enrollment into the 0079 A hemoglobin result will need to be obtained Study within the two weeks prior to Study Start/Day One. This 0060) 11. Patients with known sensitivity to mam must be obtained prior to randomization. malian cell-derived products Upon Receipt and Review of all Outstanding 0061 12. Patients with known hypersensitivity to Clinical Laboratory Test Values in Regards to the human albumin Inclusion/Exclusion Criteria 0062) 13. Serum ferritin level-50 ng/mL 0080) 1. Quality of Life Assessment tools, (Attach ments 1 and 2), must be completed by the patient Overview before study-related assessments are done by a study health-care professional (nurse, physician, etc.) 0.063 Randomization will be used to avoid bias in the assignment of patients to treatment, to increase the likeli 0081 2. Confirm assigned patient number hood that known and unknown patient attributes (e.g., demo 0082) 3. Administer first dose of PROCRIT accord graphics and pretreatment characteristics) are evenly bal ing to protocol anced acroSS treatment groups, and to enhance the validity of Statistical comparisons acroSS treatment groupS and acroSS 0083 4. Review study timelines with patient Sites. This is a randomized, open-label, comparative Study of 0084 All Subsequent study visits should be scheduled PROCRIT therapy versus standard of care. according to this start date. Procedures Week 1 Up to Week 36 0.064 Patients will be assigned to one of two treatment 0085. The following should be taken on a weekly basis groups based on a computer-generated randomization Sched for at least the first four weeks of dosing with PROCRIT ule. The randomization will be balanced by using permuted 40,000 Units qw and weekly for four weeks after any dose blocks and will be stratified by center. In order to minimize change. bias, patients will be enrolled in numerical Sequence accord ing to the randomization Schedule. The treatment group 0086) Hb or HCT (PROCRIT or SOC), and the patient number will be assigned once the Subject has met the inclusion/exclusion 0087 Blood pressure criteria. 0088) Administer Study drug per protocol Study Procedures 0089 Monitor and collect adverse experiences and concomitant medications throughout the Study at Screening/Visit 1 each Visit 0065. The following procedures will be performed within Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36 or Early four weeks prior to study entry: Withdrawal Visits 0066 1. Signed consent form 0090 Administer study drug per protocol 0067 2. Demographic information 0091 Hb, Hct, and blood pressure 0068. 3. History of blood transfusion during the four 0092 Document all transfusions months prior to Study entry 0093. QoILassessments at Weeks 8, 16, 24, and 36 or 0069. 4. Medical history upon early withdrawal. The QoI assessments must US 2002/0052317 A1 May 2, 2002 7

be completed by the patient before consulting with a 0101 4. Any ALT elevation greater than or equal to health-care professional. The QoI assessment tools twice baseline should be repeated. must be checked immediately for thoroughness in completion. All attempts should be made to capture 0102 5. Inadequate hemoglobin response (Hb rise any missing QoL information within 3 days of patient's visit of <1.0 g/dl from nadir value, after 8 weeks of PROCRIT therapy) 0094. Adjust ribavirin dose as necessary 0103) 6. Patient request 0.095 ALT determinations at weeks 4, 8, 12, 16, 20, 24, 28, 32, and 36 0104 7. Physicians/Investigator's request

TABLE 1. Flow Chart of Study Procedures Weeks 16,20,24, Screening 28,32,36 Visit1. On Study Week Week 4 Week 8 Week 12 or Early Day 0 Day 1 Visit 2 Visit 3 Visit 4 Visit 5 Withdrawal Mod. SF-12 Health Surveys Xa Xa Xa and LASA Consent Form X Physical Exam & Vital X Signs History: Medical & Xb Medication Demographics X Blood Transfusion Xe Xe Xe Xe Xe Xe Information Endogenous Serum EPO X Level Hb, Hct, Blood Pressure' Xd Xd Xd Xd Xd Xd CBC with Differential X Serum Ferritin X Serum Folate X Pregnancy Test (if X Applicable) Administer PROCRIT Xe Xe Xe Xe Xe Xe Collect Adverse X X X X X X Experiences HCV Load Xf Xf Xf ALT X X X X X = QOL assessments to be performed at Day 1 and weeks 8, 16, 24, 36 and/or early withdrawal = Include combination treatment with ribavirin and interferon alfa-2b for HCV = At Screening/Visit 1: Capture history of blood transfusions of the past 4 months prior to enrollment = Hb or HCT and blood pressure should be monitored weekly for the first 4 weeks of dosing and subse quent 4 weeks following any dose adjustments = PROCRIT is to be administered weekly "= HCV to be performed at screening and at weeks 12, 24, 36 and/or early withdrawal

0096 HCV determinations at weeks 12, 24 and 36, STUDY SCHEDULE and/or early withdrawal Procrit Preparation Early Withdrawal from the Study 0105 PROCRIT 20,000 U/mL is formulated as a sterile, buffered Solution containing 2.5 mg/ml human Serum albu 0097 A Patient should be withdrawn prematurely from min. Each Single-use Vial will contain approximately 1.1 ml the Study for any of the following reasons (the reason must of PROCRIT. Two vials of PROCRIT 20,000 U/mL will be be clearly Stated on the case record form): used for each weekly dosing to achieve 40,000 Units qw. 0098 1. Development of a severe and alarming adverse reaction Effectiveness Parameters 0106 Effectiveness will be evaluated by change in hema 0099 2. Development of a clinically significant tologic parameters over time, transfusion utilization ribavi intercurrent illness rin dose changes, and viral load. 0100 3. HCV disease progression, as evidenced by a persistent, (elevated on two separate measure Concurrent Medication ments) 2-fold or greater elevation of ALT, as com 0107 All concurrent medications administered will be pared to baseline level measurements. recorded on the case report form and Source document. US 2002/0052317 A1 May 2, 2002

Dropouts tion, median, minimum, maximum, range and interquar tiles). Categorical variables will be summarized by fre 0108 Reasons for Subject removal from this study may quency Statistics (frequencies, percentages and cumulative be completion of treatment; occurrence of a Serous adverse percentages). All data will be analyzed using SAS Software, event, Significant protocol Violation, the development of an Cary N.C. or an equivalent package. intercurrent illness, which would put the Subject at, increased risk or invalidates the results of the Study. If a Baseline ASSessment Subject's treatment is discontinued, the reason for discon tinuation will be documented on the case record form and 0115 Summary statistics will be used to present the Source document and all termination procedures will be baseline characteristics of the Study population. carried out. Dropouts will not be replaced. Planned Analyses Statistical Procedures 0116 Regression analysis (adjusted for baseline covari 0109) This open-label, randomized clinical trial is ates and comorbidities) is the anticipated methodology for designed to compare the effectiveness of PROCRIT 40,000 examining changes in hemoglobin, hematocrit and other Units once a week against Standard of care (SoC) in the hematopoietic indices as well as changes in QoL (Changes treatment of anemic (Hb<=12) hepatitis C infected patients will be calculated as the difference between final and base receiving Ribavirin-i-Interferon C-2b therapy. A time frame line assessment). In So far as possible, Subjects who meet the criteria for discontinuation of treatment will be followed-up of 36 weeks was chosen since it parallels the duration of the for all endpoints to the end of study. If follow-up is not standard treatment for hepatitis C (i.e. Ribavirin+Interferon possible, discontinued patients will have their last values C-2b). Efficacy will be assessed at study week 16. However, imputed using the last-value-carried-forward method for an patients will be treated according to this protocol for 36 intent-to-treat analysis. weeks. A Secondary analysis for efficacy will occur at end of study (week 36). 0117) 1. Primary Efficacy Variable 0118. The primary efficacy variable, the change in Hb (or Randomization changes in HCT) between baseline and week 16, will be 0110. Each subject will be randomly assigned to receive analyzed for the intent-to-treat and for the efficacy popula tions, where the intent-to-treat will be the main focus of the either PROCRIT or SoC in a 1:1 ratio balanced by using analysis. It is expected that Subjects in the PROCRIT arm randomly permuted blockS. will correct & maintain their Hb. Since HCT parallels Hb it can be evaluated to verify the results from the Hb analyses. Sample Size The Study is powered to detect changes in this endpoint with 0111) A sample size of 30 patients per arm (60 patients the following assumptions: (a) C=0.05(2-side), (b) f=0.20, total) was considered Sufficient based on the following (c) AHb=2 g/dL and (d) SD=2.5 g/dL. A sample size of 25 assumptions for the primary efficacy variable: (a) C=0.05(2- Subjects per arm was initially calculated but after adjusting side), (b) f=0.20, (c) AHb=2 g/dL and (d) SD=2.5 g/dL. An for an expected attrition of 20% (5 subjects) a sample size initial Sample size of 25 Subjects per arm was increased to of 30 patients per arm was obtained, for a total sample of 60 patients for the study. The change in Hb will be assessed 30 after adjusting for an expected attrition rate of 20% (5 through multiple linear regression analysis having as Ho: Subjects). The power associated with each efficacy variable “There is no difference in AHb between the two arms of the is discussed in the Planned Analyses Section. study”. The following equation will be used: AHb=f3+ Study Populations BHbo-BacoV+BacoV+BTX+e to test the null hypothesis. Patients who are lost-to-follow-up because of discontinua 0112 The intent-to-treat population will include all Sub tion at week 8 (of lack of response) will have their last values jects randomly assigned to a treatment group. The efficacy imputed using the last-value-carried-forward method for an population will include all subjects who will be in the study intent-to-treat analysis. Repeated measure ANOVA will be for longer than 8 weeks. The Safety population will include considered for efficacy population analyses. all Subjects randomly assigned to a treatment group who 0119 2. Secondary Efficacy Variable received at least one dose of PROCRIT and for whom safety 0120) The secondary efficacy variable is the difference in information was available. transfusion rates between the two arms. The analysis to test the Ho: “There is no difference between the transfusion rates Disposition of Patients in the two arms' will be carried out using the following 0113. The disposition of all patients over the course of the logistic regression equation: Txf (Y/N)=f30+B cov+ trial will be presented in a table listing each Site individually. BacoV+BTX--e. The original Sample Size of 25 will provide This presentation will include the number of patients who a power of 0.8 for this analysis assuming (a) C=0.05 completed the Study, the number who were discontinued, the (1-side), (b) p=0.70 (c) p=0.35. Since this is a secondary cumulative number of discontinued patients as well as the endpoint adjustments for multiple comparisons are not nec reason for discontinuing the Study. eSSary. Summary Statistics 0121 3. Tertiary Efficacy Variable 0114 Continuous variables will be summarized by 0.122 The tertiary efficacy variable will be the difference descriptive statistics (sample size N mean, Standard devia between the two arms in the number of units transfused. The US 2002/0052317 A1 May 2, 2002 analysis will test the null hypothesis Ho: “There is no difference between the number of units of blood transfused TABLE 4 in the two arms' through a Student t-test. Time Point PROCRT in SOC in 0123 4. Additional Analyses Baseline 25 19 Week 2 19 17 0124 A) The Change in Ribavirin+Interferon C-2b Dos Week 4 2O 13 age Week 6 15 13 0.125. This analysis is a parallel to the “secondary efficacy Week 12 14 8 variable' analysis outlined above because patients who Week 16 12 9 correct their anemia do not need transfusions and are able to withstand the original dosage for the Ribavirin+Interferon 0133. The results demonstrate that anemic patients, due C-2b combination. The following logistic regression equa to prior administration of Ribavirin/INF-alpha and/or the tion will be used to test the Ho: There is no difference between the rates of Ribavirin+Interferon C-2b (RBV+ underlying disease, that are treated with EPO (PROCRIT) IFNC-2b) dose reduction in the two arms: RBV+IFNC-2b increase their hemoglobin levels to near normal levels. dose reduction (Y/N)=f3+fcov+B.coV-Tx+e. Alternatively patients receiving Standard care remain ane mic, but their anemia did not worsen during the observed 0126 B) Quality of Life (SF-12+3 Questions from time period. SF-36) 0134) Patients treated with EPO (PROCRITOR) demon 0127. The sample size (25 subjects per arm) provides Strated an increased ability to maintain Ribavirin dosing only 21% power to detect an effect size of 0.33 (C=0.05(2- throughout the study period as demonstrated in FIG. 2. The Side)). However, an analysis for trend may provide useful number of patients used to determine these data are as information. follows: 0128 C) The Response to PROCRIT in Hematopoietic Indices at 16 Weeks TABLE 5 0129. The interest in analyzing this endpoint is to evalu Time Point PROCRT in SOC in ate the response to PROCRIT in patients with hepatitis C for Baseline 25 19 Week 2 17 15 the entire duration of treatment with Ribavirin-i-Interferon Week 4 2O 13 C-2b. Week 6 14 12 Week 12 13 8 0130) RESULTS: Analysis of Patients after 16 weeks of Week 16 11 9 treatment

TABLE 2 0.135 These results demonstrate that concurrent admin istration of EPO allows the physician to administer higher Baseline Demographics doses of antiviral agents to a patient during the course of the anti-viral regimen. The ability to maintain higher doses of Patient Group (n) Mean Age # Female (%) # Male (%) anti-viral agents does not correlate with worsening anemia All Patients (n = 44) 49.1 yrs. 13 (29.5%) 31 (70.5%) in the patient population, as Seen by comparing the "Stan PROCRIT (n = 25) 49.7 yrs. 9 (36%) 16 (64%) dard of Care’ curves of both FIG. 1 and FIG. 2. SOC (n = 19) 48.3 yrs. 4 (21.2%) 15 (78.9% Patient Well Being 0136 Patients receiving EPO reported “feeling better” 0131 Patients treated with EPO (PROCRIT(R) demon and demonstrated better well being even before the levels of Strated an increase in hemoglobin levels as demonstrated in hemoglobin improved in these patients. It is possible that the following table and in FIG. 1: this represents a reduction in CNS related treatment emer gent adverse events due to the interferon. Regardless the TABLE 3 increase in well being helps maintain the patient on the Change anti-viral dosing regimen and should increase patient com Mean Mean Hb pliance with Self dosing of the medications. Time Hb Hb Range change Hb Range Population N point (g/dL) (g/dL) (g/dL) (g/dL) EXAMPLE 2 PROCRIT 25 baseline 11 9.1-12.0 infa infa An Open-label, Randomized, Parallel-group Study SOC 19 baseline 11.2 9.6-12.O infa infa PROCRT 22 Last 13.5 7.7-16.8 2.4 -1.4-6.2 Comparing the effectiveness of Procrit (Epoetin available Alfa) Administered Once Weekly Versus Standard SOC 17 Last 11.5 9.3-13.3 O.3 -1.0-1.9 of Care In Heratitis C/Hiv Co-Infected Patients available Treated with Combination Ribavirin/Interferon Objective 0132) The number of patients used to determine these 0.137 To determine the effectiveness of a weekly dosing data for FIG. 1 are as follows: regimen of PROCRIT in alleviating anemia, improving the US 2002/0052317 A1 May 2, 2002

quality of life, and minimizing ribavirin dose reductions in tigator considers PROCRIT beneficial can commence PRO Hepatitis C/HIV co-infected patients who are receiving CRIT therapy for the remaining study period (total 48 combination Ribavirin/Interferon (RBV/IFN) treatment. weeks). All patients on PROCRIT will be followed for the Overview of Study Design duration of the PROCRIT therapy for safety assessments. 0138 Open-label, randomized, parallel group study using Dosing PROCRIT 40,000-60,000 Units once a week or standard of care (i.e., no PROCRIT) in anemic HCV/HIV co-infected 0146) 1. Ribavirin patients who are receiving combination RBV/IFN treatment. 0147 For patients receiving RBV/IFN by prescription, dose reductions of ribavirin will be determined by the Study Population individual clinician based on the RBV/IFN alfa-2b package 0139 80 HCV/HIV co-infected patients receiving Rib insert. For patients receiving RBV/IFN as part of a clinical avirin and Interferon treatment who either: Study, dose reductions will be defined by guidelines recom 0140) 1) have Hemoglobin (Hb)s 12 g/dL, or mended by the particular clinical Study protocol. 0141) 2) have experienced a decrease in hemoglobin 0148 2. Procrit (Epoetin alfa) of >2 g/dL compared to the patient's baseline hemo 0149 Patients will receive PROCRIT for up to 48 weeks globin prior to the start of RBV/IFN therapy. beginning with a dose of 40,000 Units qw by Subcutaneous injection. If after 4 weeks of therapy, the hemoglobin does Dosage and Administration not return to the patient's baseline Hb prior to commencing 0142 Patients randomized into the PROCRIT treatment RBV/IFN, the PROCRIT dosage should be increased to arm will receive PROCRIT 40,000 Units once a week (qw) 60,000 Units qw s.c. If after an additional 4 weeks of therapy subcutaneously (s.c.) for up to 48 weeks. PROCRIT dosage at 60,000 Units qw, the hemoglobin has not increasedd 1.0 should be increased to 60,000 units qw s.c. after 4 weeks of g/dL from the nadir Hb value, PROCRIT therapy is to be therapy if hemoglobin level does not return to patient's discontinued. The patient should be withdrawn from the baseline hemoglobin, prior to commencing RBV/IFN. Study. The reason for termination should be documented on Patients randomized into the standard of care (SOC) arm the case record form and Source documents. All termination will be treated according to the respective institution's SOC procedures should be completed. If the hemoglobin exceeds policy, however, not including PROCRIT treatment. 14 g/dL for women and 16 g/dL for men, the dose of PROCRIT Should be withheld. PROCRIT Should be Efficacy Evaluations resumed when the hemoglobin drops below 13 g/dL for 0143 Laboratory results (hematocrit and hemoglobin), women and 15 g/dL for men. When PROCRIT is resumed quality of life assessments, change in ribavirin dosage and the dose should be reduced by 10,000 Units, then titrated, by transfusion utilization will be obtained. increasing or decreasing the dose in 5,000-10,000 U incre ments or decrements, (but not to exceed 60,000 Units total Description of Study dose per week) to maintain hemoglobin within the above specified limits. Following any increase in PROCRIT dose, Design patients should be monitored with weekly Hb and BP 0144. This is an open-label, randomized study comparing measurements for 4 weeks before any additional increases. PROCRIT qw to SOC in anemic HCV/HIV co-infected 0150. After the initial 16 week period, patients random patients receiving RBV/IFN. To be eligible, patients must ized to the SOC group for whom the investigator considers have an anticipated duration of at least 16 weeks of therapy PROCRIT beneficial are eligible to receive PROCRIT with RBV/IFN, and have a Hbs 12 dL, or have experienced therapy for the remainder of the study. These patients will a decrease in hemoglobin of 22 g/dL compared to the continue to be evaluated per protocol. patient's baseline hemoglobin prior to the start of RBV/IFN therapy. Eighty patients will be enrolled. Laboratory results 0151. 3. Iron (hematocrit and hemoglobin), quality of life assessments, 0152 A potentially major efficacy-limiting factor for reduction in ribavirin dosage and transfusion information normal erythropoiesis is functional and/or actual iron defi will be obtained during the study period as noted. Patients in ciency. Patients may require Supplemental iron to avoid the study may receive PROCRIT for as long as 48 weeks, or depletion of available iron Stores and to adequately Support for the duration of RBV/IFN therapy, whichever is earlier. erythropoiesis stimulated by PROCRIT. The typical range 0145 At the end of week 16 post-randomization, patients for supplemental iron is approximately 150-200 mg of randomized in the PROCRIT group wishing to continue elemental iron per day. The appropriate formulation of iron PROCRIT and in whom it is considered beneficial will have will depend on patient and physician preference. The the option of continuing PROCRIT for the duration of their patient’s iron Status, including transferrin Saturation (serum RBV/IFN therapy. Likewise, at or after week 16 post iron divided by total iron binding capacity) and Serum randomization and after all week 16 study procedures are ferritin, should be evaluated throughout the Study as clini completed, patients in the SOC group for whom the inves cally indicated. US 2002/0052317 A1 May 2, 2002

Patient Selection Randomization Study Population Overview 0153. Eighty HCV, HIV co-infected patients who meet 0176 Randomization will be used to avoid bias in the the following criteria will be admitted into the study. assignment of patients to treatment, to increase the likeli hood that known and unknown patient attributes (e.g., demo Inclusion Criteria graphics and pretreatment characteristics) are evenly bal 0154) 1. Signed informed consent anced acroSS treatment groups, and to enhance the validity of Statistical comparisons acroSS treatment groups and acroSS 0155 2. Willing and able to complete Quality of Sites. This is a randomized, open-label, comparative Study of Life assessment tools (Modified SF-12 Health Sur PROCRIT therapy versus standard of care, not including vey Acute), Please See Attachment 2 PROCRIT therapy. 0156 3. HIV infected patients as confirmed by branched DNA or PCR Procedures O157 4. HCV infected patients as confirmed by: a) 0177 Patients will be assigned to one of two treatment detectable HCV viremia by PCR, or branched DNA, groups based on a computer-generated randomization Sched or b) Histology. ule. The randomization will be balanced by using permuted blocks and will be stratified by center. In order to minimize 0158 5. Current treatment with combination RBV/ bias, patients will be enrolled in numerical Sequence accord IFN for an anticipated period of at least 16 weeks. ing to the randomization Schedule. The treatment group 0159) 6. Hb of s 12 g/dL or a 22 g/dL drop in (PROCRIT or SOC), and the patient number will be hemoglobin compared to baseline hemoglobin prior assigned once the patient has met the inclusion/exclusion to the start of RBV/IFN therapy criteria. 0160 7. Male or female Study Procedures 0.161 8. Age 18-75 years inclusive Screening/Visit 1 0162 9. Life expectancy of 212 months 0178 The following procedures will be performed within Exclusion Criteria four weeks prior to Study entry: 0163 1. History of any primary hematologic disease 0179 1. Signed consent form 0164. 2. Presence or history of uncontrolled hyper 0180 2. Demographic information tension (i.e., diastolic blood pressure>100 mmHg) 0181 3. History of blood transfusion during the four 0.165 3. Uncontrolled seizure disorder months prior to Study entry 0166 4. Anemia attributable to factors such as iron 0182 4. Medical history or folate deficiency, hemolysis or gastrointestinal bleeding 0183) 5. Physical examination including vital signs, GI/liver exam 0.167 5. Life expectancy C.12 months 0184 6. Medication history, including RBV/IFN 0168 6. Current, active substance abuser and antiretroviral therapy within past 3 months 0169. 7. Pregnant or breast feeding 0185 7. CBC (including Hemoglobin and Hema 0170 8. Women of childbearing potential not taking tocrit) with differential adequate birth control measures 0186 8. Transferrin Saturation, ferritin, and folate O171 9.. PatientSPat WIthith previpreviOuS eXDOSurep to EpoetiEDOetin 0187 9. Endogenous serum EPO level (must be alfa or any Epoetin formulations, within 3 months before any transfusion is given or at least one month prior to enrollment into the Study following any transfusion) 0172 10. Patients with known sensitivity to mam 0188 10. HCV Load malian cell-derived products 0189 11. Urinary pregnancy test if applicable 0173 11. Patients with known hypersensitivity to human albumin O190) 12. ALT 0174 12. Serum ferritin level-50 ng/mL 0191) 13. HIV Viral load 0.175 13. Any patients with contraindications to 0192] 14. CD4 Count ribavirin, Such as a history of Significant atheroscle (* Hemoglobin must be performed within two weeks prior to study rotic heart disease, are excluded from the Study. entry) US 2002/0052317 A1 May 2, 2002 12

Study Start/Day 1 in completion. All attempts should be made to cap ture any missing QoI information within 3 days of 0193 A hemoglobin result will need to be obtained patient's visit within the two weeks prior to Study Start/Day One. This must be obtained prior to randomization. 0211 Adjust ribavirin dose as necessary 0212 For all patients at weeks 8, 16 and 48 or upon Upon Receipt and Review of all Outstanding early withdrawal, 20 ml of whole blood to be Clinical Laboratory Test Values in Regards to the obtained and the Serum Stored for future analyses. Inclusion/Exclusion Criteria 0213 For patients randomized to the standard of care 0194 1. Quality of Life Assessment tools must be group who receive PROCRIT at or after week 16, prior to completed by all patients before Study-related initial PROCRIT administration, 20 ml of whole blood must assessments are done by a study health-care profes be obtained and the Serum Stored for future analyses. Sional (nurse, physician, etc.) 0214. The 20 ml of whole blood is to be obtained again 0.195 2. Confirm assigned patient Number at 8 and 16 weeks after the initial administration of PRO 0196) 3. Prior to study drug administration obtain 20 CRIT, if patients are within the study period (48 weeks from ml of whole blood. The serum will be stored for Day 1), and at the end of the study or upon early withdrawal. future analyses. Specific laboratory instructions for 0215 ALT determinations at weeks 4, 8, 12, 16, 20, handling, labeling and Storage will be provided. 24, 28, 32, 36, 48, and 52 0197) 4. Administer first dose of PROCRIT accord 0216 HCV determinations at weeks 12, 24, 36, 48, ing to protocol 52 and/or early withdrawal 0198 5. Review study timelines with patient 0217 HIV Viral load and CD4 count determinations at week 16, 48 and week 52 0199 6. Collect all adverse experiences and con 0218. Physical exam with vital signs and CBC with comitant medications differential is to be performed at week 52 0200 All Subsequent study visits should be scheduled 0219 6 Month Follow-Up according to this start date. 0220. The following procedures should be completed for Week 1 Up to Week 48 all patients 6 months after the last visit: 0201 The following should be taken on a weekly basis 0221 ALT determination for at least the first four weeks of dosing with PROCRIT 40,000 Units qw and weekly for four weeks after any dose 0222 HCV determination change. 0223) HIV viral load 0202) Hb and HCT 0224) CD4 count 0203 Blood pressure 0225, 20 ml of whole blood to be obtained and the Serum Stored for future analyses on all patients 0204 Administer study drug per protocol Early Withdrawal from the Study 0205 Monitor and collect adverse experiences and concomitant medications throughout the Study at 0226. A patient should be withdrawn prematurely from each Visit the Study for any of the following reasons (the reason must be clearly Stated on the case record form): Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 48, 52 or 0227 Development of a severe and alarming Early Withdrawal Visits adverse reaction 0206. The following procedures should be completed for 0228 Development of a clinically significant inter all patients: current illness 0207 Administer study drug per protocol (except 0229 HCV disease progression, as evidenced by a week 52) persistent, (elevated on two separate measurements) 0208 Hb, Hct, and blood pressure to be monitored 2 fold or greater elevation of ALT, as compared to weekly for the first 4 weeks of dosing and Subse baseline level measurements. Any ALT elevation quent 4 weeks following any dose adjustments greater than or equal to twice baseline should be repeated within one week. 0209 Document all transfusions 0230 Inadequate hemoglobin response (Hb rise of 0210 QoI assessments at Weeks 8, 16, 24, 36, and <1.0 g/dL from nadir value, after 8 weeks of PRO 48 or upon early withdrawal. The QoI assessments CRIT therapy) must be completed by the patient before consulting with a health-care professional. The QoI assessment 0231. Patient request tools must be checked immediately for thoroughness 0232 Physicians/Investigator's request US 2002/0052317 A1 May 2, 2002

TABLE 6 Flow Chart of Study Procedures Weeks 16.20,24,28, 6 Mo. Screening 32,36.48 or after Visit 1 Study Week Week Week Week Week Week Early Week Last Day 0 Day 1 1. 2 3 4 8 12 Withdrawal 52 Visit Mod. SF-12 Xa Xa Xa Health Surveys Consent Form X Physical Exam & X Vital Signs History: Medical X & Medication Demographics X Blood Xe Transfusion Information Endogenous X Serum EPO Level Hb, Hct, Blood Xd Pressure' CBC with X Differential Serum Ferritin X and Transfenin Saturation Serum Folate X 2O mls of blood Xh obtained and serum stored for future analysis Pregnancy Test X (if Applicable) Administer Xe Xe Xe Xe Xe Xe Xe Xe PROCRITe Collect Adverse X Experiences and Concomitant Medications HCV Load Xf ALT X HIV Load and X s s CD4 Count = QOL assessments to be performed at Day 1 and weeks 8, 16, 24, 36, 48, and/or early withdrawal = Include combination treatment with ribavirin and interferon alfa-2b for HCV = At Screening/Visit 1: Capture history of blood transfusions of the past 4 months prior to enrollment. = Hb and HCT and blood pressure should be monitored weekly for the first 4 weeks of dosing and subsequent 4 weeks following any dose adjustments. = PROCRIT is to be administered weekly "= HCV to be performed at screening and at weeks 12, 24, 36, 48, and/or early withdrawal = HIV and CD4 count at week 16 and 48 "= To be obtained for all patients in SOC or PROCRIT group. = To be obtained at week 16 and 48 or upon early withdrawal for all patients. For patients randomized in the SOC group who receive PROCRIT at or after week 16, 20 ml of blood to be obtained prior to initial PROCRIT adminis tration. Also, 8 and 16 weeks after initial PROCRIT administration, if study time permits, and at the end of study or upon early withdrawal.

STUDY SCHEDULE Effectiveness Parameters Materials and Supplies 0234 Effectiveness will be evaluated by change in hema tologic parameters over time, transfusion utilization and Procrit Preparation ribavirin dose changes. 0233 PROCRIT 40,000 U/mL is formulated as a sterile, Study Management buffered Solution containing 2.5 mg/mL human Serum albu min. Each Single-use Vial will contain approximately 1.1 Departure from Protocol ImL of PROCRIT PROCRIT dosage should be increased to 0235 Any departure from the protocol should be docu 60,000 units once a week (qw) subcutaneously (s.c.) after 4 mented in the Source document and case record form as weeks of therapy if hemoglobin level does not return to applicable. If an exemption has been granted, the protocol patient's baseline hemoglobin prior to commencing RBV/ exemptions will be documented in the CRF and source IFN. documents. US 2002/0052317 A1 May 2, 2002

Concurrent Medication Main Analyses 0242 1. Difference in Average Hemoglobin Change 0236 All concurrent medications administered will be Between two Arms recorded on the case report form and Source document. 0243 Difference between average hemoglobin change Dropouts (delta) will be compared using 't test. If there is evidence of departure from a normal distribution, the nonparametric 0237 Reasons for patient termination from this study Wilcoxon-Mann-Whitney test will be used to compare the may be permanent discontinuation of Ribavirin treatment; two study groups. occurrence of a Serious adverse event, Significant protocol 0244 2. Dose Reduction Violation, the development of an intercurrent illness, which 0245 RBV dosing adjustments will be assessed as fol would put the Subject at, increased risk or invalidates the lows: For each patient in each group who requires a reduc results of the Study. If a patient's treatment is discontinued, tion in RBV dose the time from randomization to dose the reason for discontinuation will be documented on the reduction will be recorded and methods of Survival analysis case record form and Source document and all termination will be employed to compare the pattern of timing of dose reductions in the two groups. Specifically, Kaplan-Meier procedures will be carried out. Dropouts will not be Survival plots (i.e. time to dose-reduction) will be generated replaced. and the two groups will be compared with the logrank test. In addition, Cox proportional regression models will be Statistical Procedures employed to assess the effects of baseline variables on time to dose-reduction. Further analyses will be conducted on the Study Objectives Subgroups that have dose-reductions during the Study to assess and compare the magnitude of Such reductions. This 0238. This open-label, randomized, parallel group study Subgroup analysis will employ comparisons based on stu is designed to compare the effectiveness of once weekly dent's t-test and/or the nonparametric Wilcoxon-Mann (qw) dosing of PROCRIT versus Standard-of-Care (SOC) Whitney test. for Hepatitis C/HIV co-infected patients. All patients will be 0246 3. Quality of Life (assessed by modified SF-12 treated with RBV/IFN. The variable of interest is hemoglo Health Survey-Acute) bin change from baseline to 16 weeks post-randomiza tion.(A=Ye-weeks-Y) readings. The primary endpoint is 0247 Mean change in quality of life scores between the to compare the average hemoglobin change between the two arms will be compared using a t-test or a Wilcoxon PROCRIT group and the SOC group. The secondary end Mann-Whitney test (if there is a departure from normally point will be to compare Ribavirin dosing, quality of life and distributed data). transfusion. 0248 4. Transfusion 0249 Change from baseline and month 1, 2, 3 and 4 of Sample Size Calculation percent patients transfused will be analyzed using McNe mar S X2 test. 0239 Previous studies in HIV have suggested that a 2 g/dL change in Hb is considered meaningful (Data on file: 0250) 5 Dropouts 0251 All analyses described in this section will be, Ortho Biotech, NJ 1999). The standard deviation for change insofar as possible, on an intention-to-treat basis, i.e. in hemoglobin, in the PROCRIT arm is between 1.9 and 2.1 analyzed on the basis of the group to which the patient was g/dL. ASSuming a 2 g/dL average difference and a Standard randomly assigned, regardless of whether the designated deviation of 2.0 g/dL, with type I error (alpha)=0.05 and treatment was received. If there are Substantial missing data power=0.90, a Sample size of 23 per arm is calculated. because of withdrawals and drop-outs, Standard methods Allowing for a 20% attrition rate, a Sample size approxi will be employed to account for Such occurrences Such as mately 29 patients per arm is estimated. This calculation also imputation, last-observation-carried-forward and the poS assumes that HgbA is normally distributed. Because of the Sible use of propensity Scores. possibility of non-normality and to ensure adequate power should a nonparametric test be used, Sample size could be Interim ASSessment increased to 40 per arm. 0252) When half the patients (i.e. 40) have been random ized and have completed their 16-week post-randomization Summary Statistics follow-up, there will be an interim analysis to assess the validity of the assumptions underlying the Sample size 0240 Continuous variables will be summarized by calculation. In particular, the Standard deviations of the descriptive statistics (i.e. sample size N mean, median, difference between baseline and 16-week Hbs will be cal Standard deviation.) Categorical variables will be Summa culated in each of the two study groups. If these Standard rized by frequency statistics (i.e. frequencies, percentages deviations depart substantially from the 2.0 assumed in the and cumulative percentages). All data will be analyzed using Sample size calculation (see Section X. A. Sample Size SAS Software, Cary N.C. or an equivalent Statistical pack Calculation), the Sample size will be recalculated with age. appropriate Statistical adjustments to retain the Specified 90% power to detect a 2.0 g/dL difference in change between Baseline ASSessment the two study groups. 0241 Summary Statistics (i.e. mean, median, Standard References deviation) will be used to present and compare the baseline 0253) 1. Henry D. H., Beall G. N., et al. “Recombinant characteristics of the two study groups. Human Erythropoietin in the Treatment of Anemia US 2002/0052317 A1 May 2, 2002

Associated with Human Immunodeficiency Virus 0265 13. Davis, G. L., Esteban-Mur, RustgiV., et al. (HIV) Infection and Zidovudine Therapy Annals of “Retreatement of Relapse After Interferon Therapy for Internal Medicine (1992) 117:739-748. Chronic Hepatitic C: An International Randomized Controlled Trial of Interferon Plus Ribavirin VS. Inter 0254 2. Danna, R. P., Rudnick, S. A., Abels, R. I., “Erythropoietin Therapy for the Anemia Associated feron Alone'Hepatology (1997) 26(4):247A. with AIDS and AIDS Therapy and Cancer”. Erythro 0266 14. McHutchinson, J. G., Cralon, S.C., Schiffer, poietin in Clinical Applications- An International Per et al. “Interferon alfa-2-b Alone or in Combination with spective. (1990) 301-324. Ribavirin as Initial Treatment for Chronic Hepatitis as Initial Treatment for Chronic Hepatitis'C.N. Engl. J. 0255 3. Cella, David F. “Functional Assessment of Med. (1998) 339:1485-92. Cancer Therapy (FACT) Scales and the Functional Assessment of HIV Infection (FAHI) Scale Version 3” 0267 15. Dieterich, D., Weisz, K., Goldman, D., et al. (Sep. 1, 1994) (prepared with Amy E. Bonomi) Rush “Interferon (IFN) and Ribavirin (RBV) Therapy for Presbyterian-St. Lukes Medical Center, Chicago, Ill. Hepatitis C (HCV) in HIV-Co-Infected Patients Ab stract"Proceedings of the 39" Interscience Conference 0256 4. Schvarcz, R., Ando, Y., Sonnerborg, A., and On Antimicrobial Agents and Chemotherapy; (Sep. Weiland, O. "Combination Treatment with Interferon 26-29, 1999) San Francisco, Calif. alfa-2b and Ribavirin for Chronic Hepatitis C in Patients Who Have Failed to Achieve Sustained 0268 16. Goldberg, M. A., McCutchen, J. W., Jove, Response to Interferon Alone: Swedish Experience'J. M., et al. “A Safety and Efficacy Comparison Study of Two Dosing Regimens of Epoetin Alfa in Patients Hepatol. (1995) 23(Sup. 2):17-21. Undergoing Major Orthopedic Surgery'The American 0257 5. Reichard, O., Norkans, G., Fryden, A., et al. Journal of Orthopedics (1996) 544-552. "Randomized Double-Blind, Placebo-Controlled Trial of Interferon alfa-2b with and without Ribavirin for 0269) 17. Cheung, W. C., Goon, B. L., Guilfoyle, M. C., et al. “Pharmacokinetics and Pharmacodynamics of Chronic Hepatitis C"Lancet (1998) 351:83-87. Recombinant Human Erythropoietin After Single and 0258 6. Goldberg, M.A., McCutchen, J. W., Jove, M., Multiple Subcutaneous Doses to Healthy Sub et al. “A Safety and Efficacy Comparison Study of Two jects'Clinical Pharmacology & Therapeutics (1998) Dosing Regimens of Epoetin Alfa in Patients Under 64(4) 412–423. going Major Orthopedic Surgery'The American Jour 0270 18. Gillings and Koch, “The Application of the nal of Orthopedics (1996) 544-552. Principle of Intention-to-Treat in the Analysis of Clini 0259 7. Cheung, W. C., Wacholtz, M. C., Young, D. cal Trials'Drug Information (1991) 25:411-424. C., “Pharmacokinetics (PK) and Pharmacodynamics (PD) of Weekly and T.I.W. Subcutaneous Doses of 0271) 19. Weiss, Karen, “Safety Profile of Interferon-C. Recombinant Human Erythropoietin in Healthy Sub Therapy"Semin. Oncol. (1998) 25 (1 Sup. 1) 9-13. jects'Blood. (1997) 90 (sup.1, pt. 2)183b Abstract. What is claimed is: 1. A method comprising the Steps in any order: 0260) 8. Weisz, K., Hau, T., Keiswirth, S., et al. “Eryth ropoietin Use for Ribavirin/Interferon Induced Anemia (a) administering an interferon dosing regimen to a Sub in Patients with Hepatitis C" 38" Interscience Confer ject in need thereof, and ence on Antimicrobial Agents and Chemotherapy (b) administering a therapeutically effective amount of (1998) poster presentation. erythropoietin (EPO) to the subject; 0261) 9. Revicki, D. A., Brown, R. E., Henry, D. H., et wherein the erythropoietin improves the ability of the al. “Recombinant Human Erythropoietin and Health Subject to maintain or increase the interferon dosing Related Quality of Life of AIDS Patients with Ane regimen. mia'J. Acq. Immunie. Defic. Syn. (1994) 7:474-484. 2. The method of claim 1 wherein the interferon dosing 0262 10. Glaspy, J., Bukowski, R., Steinberg, D., et al. regimen is administered as a Single therapeutic agent. “Impact of Therapy with Epoetin alfa on Clinical 3. The method of claim 1 wherein the interferon dosing Outcomes in Patients with Non-myeloid Malignancies regimen comprises administration of an interferon concur During Cancer Chemotherapy in Community Oncol rently with a nucleoside analog. 4. The method of claim 3 wherein the nucleoside analog ogy Practice'J. Clin. Oncol. (1997) 15:1218-1234. is Selected from the group consisting of: 0263. 11. Demetri, G., Kris, M., Wade, J., et al. “Oual ity of Life Benefit in Chemotherapy Patients Treated a) ribavirin (1-3-D-ribofuranosyl 1H-1,2,4-Triazole-3- with Epoetin alfa is Independent of Disease Response carboxamide); or Tumor Type: Results from a Prospective Community b) AZT (3'-azido-3'-deoxythymidine); Oncology Study'J. Clin. Oncol. (1998) 16:3412-3425. c) 3TC (2R, cis)-4-amino-1-(2-hydroxymethyl-1,3-ox 0264. 12. Abrams, D., Steinhart, C., Frascino, R., athiolan-5-yl-(1H)-pyrimidin-2-one; “Epoetin alfa Improves the Quality of Life (QoI) in HIV+Patients with Anemia"Blood; 92(10 Sup. 1, Pt. d) abacavir Sulfate ((1S, cis)-4-2-amino-6-(cyclopropy 2): 10b(abs 3020) (1998) 40" Annual Meeting of the lamino)-9-H-purin-9-yl)-2-cyclopentene-1-methanol American Society of Hematology, Miami Beach, Fla., Sulfate (salt) (2:1)); (Dec. 4-8, 1998). e) stavudine (d4T or 2',3'-didehydro-3'-deoxythymidine); US 2002/0052317 A1 May 2, 2002

f) didanosine (dideoxyinosine or dd); k) bleomycin; and g) Zalcitabine (2',3'-dideoxycytidine or ddC) l) etoposide ((5R,5aR,8aR.9S)-9-4,6-O-( 1R)-eth ylidene-b-D -glucopyranosyl oxy-5,8,8a,9-tetrahy h) Gemcitabine (2'-deoxy-2,2'-difluorocytidine monohy dro-5-(4-hydroxy-3,5-dimethoxyphenyl)-Furo 3',4':6, drochloride (beta)-isomer); and 7 naphtho2,3-d-1,3-dioxol-6(5aH)-one). i) ganciclovir(9-2-hydroxy-1-hydroxymethyl)ethoxy 11. The method of claim 9 wherein the anti-tumor agent methylguanine). is fluorouracil and wherein the interferon dosing regimen is 5. The method of claim 4 wherein the nucleoside analog administered to a Subject for treatment of colorectal cancer. is ribavirin and where the interferon dosing regimen is 12. The method of claim 9 wherein the anti-tumor agent administered to a Subject with chronic hepatitis C. is cladribine and wherein the interferon dosing regimen is 6. The method of claim 4 wherein the nucleoside analog administered to a subject for treatment of Hairy Cell Leu is ribavirin and where the interferon dosing regimen is kemia. administered to a Subject for treatment of chronic hepatitis 13. The method of claim 9 wherein the anti-tumor agent C (HCV) and the subject also in infected with human is cladribine and wherein the interferon dosing regimen is immunodeficiency virus (HIV). administered to a subject for treatment of Multiple Sclerosis. 7. The method of claim 1 wherein the interferon dosing 14. The method of claim 9 wherein the anti-tumor agent regimen comprises an administration of an interferon con is Chlorambucil and wherein the interferon dosing regimen currently with a protease inhibitor. is administered to a Subject for treatment of Lymphoma. 8. The method of claim 7 wherein the protease inhibitor 15. The method of claim 9 wherein the anti-tumor agent is Selected from the group consisting of: is Cisplatin and wherein the interferon dosing regimen is administered to a Subject for treatment of Solid tumors. a) aquinavir (N-tert-butyl-decahydro-2-2(R)-hydroxy-4- 16. The method of claim 9 wherein the anti-tumor agent phenyl-3(S)-N-(2-quinolylcarbonyl)-L-asparaginyl is cyclophosphamide and wherein the interferon dosing aminobutyl-(4aS,8aS)- isoquinoline-3 (S)-carboxam regimen is administered to a Subject for treatment of Hema ide methaneSulfonate); tological malignancies. b) itonavir (10-hydroxy-2-methyl-5-(1-methylethyl)-1- 17. The method of claim 9 wherein the anti-tumor agent 2-(1-methylethyl)-4-thiazolyl)-3,6-dioxo-8,11-bis is epirubicin and wherein the interferon dosing regimen is (phenylmethyl)-, 5-thiazolylmethyl ester, (5S,8S, 10S, used in a Subject for the treatment of bladder cancer. 18. The method of claim 9 wherein the anti-tumor agent 11S)-2,4,7,12-Tetraazatridecan-13-oic acid); and is epirubicin and wherein the interferon dosing regimen is c) indinavir (2,3,5-trideoxy-N-(1S,2R)-2,3-dihydro-2- administered to a Subject for treatment of renal cancer. hydroxy-1H-inden-1-yl)-5-[(2S)-2-(1,1-dimethyl 19. The method of claim 9 wherein the anti-tumor agent ethyl) aminocarbonyl)-4-(3-pyridinylmethyl)-1-piper is epirubicin and wherein the interferon dosing regimen is azinyl)-2-(phenylmethyl)-D-erythro-Pentonamide) and administered to a Subject for treatment of ovarian cancer. d) wherein the interferon dosing regimen is used in a 20. A method comprising the Steps in any order: Subject for the treatment of HIV. a) administering an anti-viral regimen comprising an 9. The method of claim 1 wherein the interferon dosing interferon and ribavirin to a Subject in need thereof; regimen comprises administration of an interferon concur rently with an anti-tumor agent. b) measuring hemolysis of Said Subjects red blood cells; 10. The method of claim 9 wherein the anti-tumor agent c) adjusting the amount of ribavirin provided to the is Selected from the group consisting of: Subject Such that a desired amount of hemolysis occurs, a) cladribine (2-chloro-2'-deoxy-(beta)-D-adenosine); and d) administering a therapeutically effective amount of b) Chlorambucil (4-bis(2-chlorethyl)aminobenzenebu erythropoietin (EPO) to the subject, wherein the eryth tanoic acid); ropoietin improves an ability of the Subject to maintain c) DTIC-Dome (5-(3,3-dimethyl-1-triazeno)-imidazole or increase the ribavirin dose. 4-carboxamide); 21. The method of claim 20 wherein the desired amount of hemolysis is a reduction in the hemoglobin levels by d) cisplatin (cis-dichlorodiamineplatinum); about 20% within about one week of ribavirin administra e) cyclophosphamide (2-oxide N,N-bis (2-chloroethyl) tion. tetrahydro-2H-1,3,2-OxaZaphosphorin-2-amine); 22. The method of claim 20 wherein the amount of ribavirin administered is greater than 1200 mg/day for a f) fluorouracil (5-fluoro-2,4 (1H.3H)-Pyrimidinedione); Subject weighing greater than 75 Kg or greater than 1000 g) epirubicin (5,12-Naphthacenedione); mg/day for a Subject weighing less than 75 Kg. h) methotrexate (N-4-(2,4-diamino-6-pteridinyl)m- 23. A method comprising the Steps in any order; ethyl methylamino benzoyl-L-Glutamic acid); a) administering an interferon dosing regimen to a Subject i) Vincristine (22-oxo-Vincaleukoblastine); with a chronic viral infection; j) doxorubicin (10- (3-amino-2,3,6-trideoxy-a-L-lyxo b) administering a therapeutically effective amount of -hexopyranosyl)oxy-7,8,9,10-tetrahydro-6,8,11-trihy erythropoietin (EPO) to the subject; and droxy-8-(hydroxyacetyl)-1-methoxy 5.1 2-Naph c) administering a therapeutically effective amount of an thacenedione); anti-tumor necrosis factor compound to the Subject; and US 2002/0052317 A1 May 2, 2002

d) wherein the administration of the erythropoietin and d) wherein the administration of the erythropoietin and the anti-tumor necrosis compound improves the ability the anti-tumor necrosis compound improves the ability of the Subject to maintain or increase the interferon of the Subject to maintain or increase the interferon dosing regimen. dosing regimen. 24. The method of claim 23, wherein the anti-tumor 26. The method of claim 25 wherein the interferon dosing necrosis factor compound is Selected from the group con regimen comprises administration of interferon concurrently sisting of THALIDOMIDE, PENTOXIFYLLIN, INFLIX with ribavirin. IMAB, glucocorticoids, and ETANERCEPT. 27. The method of claim 26, wherein the anti-tumor 25. A method comprising the Steps in any order; necrosis factor compound is Selected from the group con sisting of THALIDOMIDE, PENTOXIFYLLIN, INFLIX a) administering a interferon dosing regimen to a Subject IMAB, glucocorticoids, and ETANERCEPT. with chronic HCV; 28. The method of claim 25, wherein the anti-tumor b) administering a therapeutically effective amount of necrosis factor compound is Selected from the group con erythropoietin (EPO) to the subject; and sisting of THALIDOMIDE, PENTOXIFYLLIN, INFLIX c) administering a therapeutically effective amount of an IMAB, glucocorticoids, and ETANERCEPT. anti-tumor necrosis factor compound k k k k k