STUDY OF VIRAL RESISTANCE TO ANTIVIRAL THERAPY OF CHRONIC HEPATITIS C (VIRAHEP-C): CLINICAL CENTERS, DATA COORDINATING CENTER, ANCILLARY STUDIES Release Date: September 6, 2000 RFA: DK-01-007 National Institute of Diabetes and Digestive and Kidney Diseases (http://www.niddk.nih.gov/) Letter of Intent Receipt Date: November 15, 2000 Application Receipt Date: December 15, 2000 PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites cooperative agreement applications from investigators to design and implement a multicenter, clinical trial to study viral resistance to interferon alpha therapy in patients with chronic hepatitis C, specifically focusing upon African Americans among whom such viral resistance is common. The study will examine several issues surrounding viral resistance to interferon in hepatitis C, including the following specific clinical research questions: 1) What are the differences in sustained virological response rates to optimal combination antiviral therapy of hepatitis C among African Americans in comparison to non-Hispanic whites? 2) For both racial groups, what clinical, biochemical, or virological factors are most reliable in predicting a beneficial long-term response to antiviral therapy? 3) Does a sustained response correlate with the decrease in hepatitis C viral (HCV) RNA in serum that occurs within the first few days of antiviral therapy (viral kinetics)? 4) Can monitoring of HCV RNA levels reliably predict a lack of sustained virological response to interferon-based antiviral therapy? 5) What are the virological, cellular, immunological and genetic factors that underlie the response to antiviral therapy in hepatitis C? The Study of Viral Resistance to Antiviral Therapy of Chronic Hepatitis C (Virahep-C) is expected to recruit 400 patients at eight geographically distributed Clinical Centers over a one-year period with two additional years of treatment and follow-up. The 400 patients will include approximately equal numbers of African Americans and non- Hispanic whites all of whom have chronic hepatitis C and are infected with HCV genotype 1. Patients will undergo an extensive initial medical evaluation including liver biopsy. All patients will then receive what is judged to be the current optimal therapy of chronic hepatitis C. Special emphasis will be placed on determination of the viral kinetics of HCV RNA during the first four weeks of treatment and laboratory analysis of virological and host factors that might explain the diversity in clinical outcome of therapy of hepatitis C. The study will be coordinated by a Data Coordinating Center and will be complemented by three to four ancillary studies on the biological basis of antiviral resistance in hepatitis C. This RFA requests three separate types of applications: for a single Data Coordinating Center, for eight Clinical Centers, and for three to four ancillary studies on serum, tissue or cells from patients participating in this study. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Study of Viral Resistance to Antiviral Therapy of Chronic Hepatitis C (Virahep-C) is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/ ELIGIBILITY REQUIREMENTS Applications may be submitted by for-profit and non-profit domestic organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Foreign institutions are not eligible for this award. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. For Clinical Center applications, the expertise appropriate for this research program includes knowledge of the clinical and virological aspects of hepatitis C and liver disease, expertise in the conduct of clinical investigation, and experience in the conduct of multicenter clinical trials. Clinical centers must also have a demonstrated experience in enrolling and retaining African American subjects in clinical trials. For Data Coordinating Center applications, the expertise appropriate for this research program includes biostatistics, knowledge of the clinical and epidemiological aspects of hepatitis C and liver disease and expertise in data coordination and analysis for multi-center clinical trials. For Ancillary Studies applications, the expertise appropriate for this research program includes knowledge of the virology or immunology of hepatitis C or of cellular and molecular biology of liver disease or the interferon system. A single institution may apply for more than one component of the RFA, such as for a Clinical Center, the Data Coordinating Center and one or more Ancillary Study awards. However, separate applications are required for each component Center and for each separate Ancillary Study, if applying for more than one. In addition, a specific plan of how the independent operation of each unit will be maintained is required in each application. Each study should have a separate principal investigator and must be administratively and fiscally distinct. MECHANISM OF SUPPORT The administrative and funding mechanism to be used to undertake this project will be the cooperative agreement (U01), which is an assistance mechanism rather than an acquisition mechanism. Under the cooperative agreement, the NIDDK’s purpose is to support and/or stimulate the recipient’s activity by collaborating and otherwise working jointly with the award recipient in a partnership role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the tasks and activities in carrying out the studies will be shared among the awardees and the NIDDK Project Scientist. Details of the responsibilities, relationships and governance of this study funded under a cooperative agreement are discussed under the section Terms and Conditions of Award. Except as otherwise stated in this announcement, awards will be administered under NIH grants policy as stated in the NIH Grants Policy Statement. Applications from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources are encouraged and should identify the GCRC as a resource for conducting the proposed research. In such a case, a letter of agreement from either the GCRC program director or Principal Investigator should be included with the application. The total project period for applications submitted in response to this RFA will be five years. The first year will be used to design the trial and develop a detailed protocol and manual of operations for the study. Patients will be enrolled during the second year and treated for up to one year. A twelve month follow up period after therapy will be needed. There will then be a twelve month final period of data analysis and close out of the clinical trial. The anticipated award date is July 1, 2001. It is anticipated that the awards for the Clinical Centers will average approximately $150,000 in direct costs per year in Fiscal Year (FY) 2001 during the planning phase. Direct costs at the Clinical Centers are expected to gradually increase as the protocol is implemented, to a maximum of $250,000 per center (direct costs) by the end of recruitment. In post-treatment years, this level of effort is anticipated to decline to approximately $150,000 in direct costs, in keeping with reduced Clinical Center effort after treatment has been completed and patients are followed on no therapy. The award for the Data Coordinating Center is anticipated to be $700,000 (direct costs) during the planning phase. Direct costs are expected to gradually increase as the protocol is implemented to a maximum of approximately $1,000,000 (direct costs) per year for the Data Coordinating Center activities and another $500,000 in subcontracts for a serum repository and virological testing laboratory. In the final analysis year, the level of effort is anticipated to decline to approximately $700,000 in direct costs, in keeping with reduced effort after treatment and follow up have been completed. Funds to support the subcontract aspects of the trial will largely cease during the final year of closeout, data analysis, and reporting. The awards for the Ancillary Studies are anticipated to average approximately $100,000 in direct costs per year in Fiscal Year (FY) 2001, during the planning phase while the collaborations and protocol are being developed. Direct costs are expected to gradually increase as the protocol is implemented, to a maximum of $250,000 (direct costs) by the end of the enrollment and during the years of treatment and follow up. Because the nature and scope of the research proposed in Ancillary Studies in response to this RFA may vary, it is anticipated that the sizes of awards will vary also. Awards and level of support depend upon receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NIDDK, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated R01 applications and be reviewed according to the customary peer review procedures. FUNDS AVAILABLE For FY 2001, during planning of the trial, $4 million (total costs) will be committed to fund the Data Coordinating Center, the Clinical Centers, and the Ancillary Study applications submitted in response to this RFA. It is anticipated that one award will be made for the Data Coordinating Center, eight for Clinical Centers, and three to four for Ancillary Studies. NIDDK also has planned for the projected fiscal requirements of the study beyond FY 2001, consistent with the direct costs of Clinical Centers, the Data Coordinating Center and the Ancillary Studies as described above. The National Institute of Allergy and Infectious Diseases (NIAID) also funds research on therapy and viral resistance in hepatitis C and may provide funding for applications that are appropriate to areas of interest and focus to NIAID. Although this program is provided for in the financial plans of the NIDDK, the awards pursuant to this RFA are also contingent upon the availability of funds and receipt of a sufficient number of applications of outstanding scientific and technical merit. RESEARCH OBJECTIVES A. Background Population based studies indicate that 1.8% of the United States population have antibody to hepatitis C virus (anti-HCV) and that three-fourths of these or approximately 2.7 million Americans are chronically infected with this virus. Rates of anti-HCV are higher among African Americans (3.2%) than among the non-Hispanic white population (1.8%). The major long-term consequences of hepatitis C are the development of chronic liver disease, cirrhosis and hepatocellular carcinoma. These complications of chronic hepatitis C are also more common among African Americans than Caucasians. At present, chronic hepatitis C is estimated to cause 10,000 deaths from end-stage liver disease yearly in the United States. Hepatitis C is also the single major reason for liver transplantation. Furthermore, HCV infection accounts for at least half of cases of liver cancer. Distressingly, the mortality rates for hepatitis C-related cirrhosis, the proportions of liver transplantations done for hepatitis C, and the incidence of hepatocellular carcinoma due to HCV all appear to be increasing, and these increases are expected to disproportionally affect African Americans. Mathematical models based upon the age-specific frequency of anti-HCV in the population and the natural history of the disease suggest that deaths from this disease may double or triple in the next decade. At present, therapies for hepatitis C are problematical. Alpha interferon was first shown to have beneficial effects in this disease in the middle 1980s and was approved for use as therapy of hepatitis C in the United States in 1991. Yet, a six- or twelve-month course of alpha interferon led to sustained remissions in only a minority of patients (6-16%). In 1998, several large randomized controlled trials showed that a 24- or 48-week course of the combination of alpha interferon with the oral antiviral agent ribavirin led to long-term sustained loss of hepatitis C viral (HCV) RNA from the serum and improvement in the underlying liver disease in 35-40% of patients. Combination therapy was approved for use in chronic hepatitis C in 1998. Despite its promise, combination therapy with interferon and ribavirin remains difficult and far from satisfactory. Therapy is expensive and associated with many side effects that often limit therapy and make therapy contraindicated in some patients. Furthermore, even the optimal regimen is effective in less than half of patients. Attempts have been made to identify factors that predict a response to interferon and ribavirin therapy. Retrospective analyses of trials have identified that the most important predictors of a higher rate of response are viral factors: HCV genotype (rates of response are higher with genotypes 2 and 3 than with genotype 1) and viral levels (rates of response are higher with lower initial levels of serum HCV RNA). Other, less reliable predictors of a higher rate of response are young age, female sex and absence of severe fibrosis on pre-treatment liver biopsy. Algorithms using these factors have been created to provide an estimate of a response to treatment for individual patients. Unfortunately, the large clinical trials of antiviral therapy in hepatitis C have been carried out largely in non-Hispanic white populations, and the applicability of these findings or any such algorithm to minority populations in the United States is unclear. Recently, retrospective analyses of large clinical trials have shown that rates of response to interferon differ by race or ethnicity. Thus, in virtually all clinical trials that have been analyzed, African American patients have had a lower rate of response to alpha interferon therapy than Caucasian, Hispanic white and Asian patients. Indeed, in several studies, the long-term response rate to interferon monotherapy among African American patients has been nil. The combination of alpha interferon with ribavirin led to higher response rates than monotherapy in African Americans, but the rates with combination therapy were still one-third to one-half those observed in Caucasians. The reasons for the relative lack of response to antiviral therapy among African Americans are not clear. Preliminary studies indicate that part of the poor response rate among African Americans relates to viral genotype. Patients infected with HCV genotype 1 (either 1a or 1b) typically have a two- to threefold lower rate of response to interferon or combination therapy than patients infected with genotypes 2 or 3. While genotype 1 accounts for 70% of HCV infections among Caucasians, it is found in over 90% of cases among African Americans. Nevertheless, genotype does not appear to account completely for the lack of response to antiviral therapy among African Americans. Controlling for genotype, African Americans still have a lower rate of response to interferon therapy than Caucasians with hepatitis C. Racial differences were most clearly evident from analyses of serial determinations of HCV RNA levels during antiviral therapy. African Americans often demonstrated minimal or no decrease in viral levels with interferon treatment, even when doses were escalated to maximally tolerated levels. These findings suggest that the viral strains of HCV that are commonly found among African Americans with hepatitis C are more resistant to antiviral therapy using interferon or the combination of interferon and ribavirin. While previous studies have indicated a lower response rate among African Americans with hepatitis C, these studies have had several shortcomings. The major problem was that virtually all large clinical trials of antiviral therapy in hepatitis C have included too few African Americans for meaningful analysis. Thus, African Americans who are estimated to represent 22% of persons with chronic hepatitis C, represented 5% or less of patients enrolled in many of these large published trials. The lack of sufficient numbers of African American patients makes it difficult to accurately estimate response rates and predictors of response in this population. Furthermore, the causes of the lack of response and relative resistance to interferon action cannot be adequately investigated without inclusion of these populations. B. Research Goal and Scope of the Activity The goal of this RFA is to select a Data Coordinating Center, eight Clinical Centers, and three to four Ancillary Studies to participate in planning and implementing a multicenter clinical trial and clinical investigation into combination antiviral therapy of patients with chronic hepatitis C infected with HCV genotype 1. The primary goal of this study will be to establish the response rates of optimal antiviral therapy among African Americans in comparison to non-Hispanic whites and to evaluate predictive factors of response. The results of this study should help in clinical management of patients, in providing accurate estimates of likelihood of response, as well as providing insights and reagents and materials for better investigation of the nature of resistance to interferon based antiviral therapy of hepatitis C. Several anticipated features of this study are cited below so that applicants have a common understanding of factors necessary for the collaborative effort. All patients will undergo a careful medical evaluation and liver biopsy before therapy along with extensive characterization of hepatitis C virology. Patients will then start therapy with what is considered at the time of this trial the optimal antiviral therapy for hepatitis C (genotype 1). While it is impossible to predict exactly what this regimen will be, it is likely to be the combination of alpha interferon (either regular or pegylated interferon) with ribavirin given for 48 weeks. Initially, patients will be followed with regular determinations of HCV RNA levels to characterize the early viral kinetics during therapy. Thereafter, patients will have at least monthly determinations of HCV RNA presence (qualitative assays) and/or level (quantitative assays). Symptoms and side effects will be carefully and objectively analyzed. After stopping therapy, patients will be followed for one year to establish whether responses were sustained. The exact details of the protocol will be established by the steering committee of this trial whose composition is defined below. A total of 400 patients will be enrolled into this trial, approximately 50 at each of 8 Clinical Centers. An equal number of African American and non-Hispanic whites will be enrolled averaged across all Centers. Thus, a total of 200 African Americans and 200 Caucasian patients will be enrolled. Applicants for the Clinical Centers and Data Coordinating Center should propose a detailed design that follows the outline given above. Applicants for the Ancillary Studies should propose a research plan that is based upon samples and data from the clinical study and that helps to elucidate underlying mechanisms of antiviral responses to therapy. This trial will aim to achieve the following five major research objectives. (1) Establish rates of sustained virological response to a 48-week course of combination antiviral therapy among African-Americans along with a comparable rate in non-Hispanic whites. The sample size of this trial is based upon this goal. The estimated rate of sustained virological response from previous trials of a 48 week course of combination therapy in Caucasian patients with genotype 1 is 30%. It is reasonable to estimate that the response rate among African Americans is 15%, approximately half of that among whites. To demonstrate a difference of 50% in African Americans with a p value of 0.05 and a power of 0.80 would require sample sizes of 176 per group. This study should also establish rates of end-of-treatment virological response as well as sustained and end-of-treatment biochemical responses. (2) Establish what factors are most predictive of a response to combination therapy in each of the two racial groups of patients infected with genotype 1 HCV. Thus, age, sex, hepatic fibrosis, viral level, duration of disease, and other factors have been identified as important predictors of a response in Caucasians with hepatitis C who are treated with alpha interferon based therapy. The reliability of these predictive factors in African American subjects needs to be assessed and how these factors differ from those among whites. Special attention will be focused upon the role of initial viral levels of HCV RNA and to developing a simple, clinically useful algorithm that could be used to advise patients on the likelihood of a response. (3) Establish the frequency of different patterns of viral kinetics in response to antiviral therapy in the two racial groups of patients. In preliminary analyses, measurements of HCV RNA levels after a few days, weeks or a month of therapy with combination alpha interferon and ribavirin clearly separates patients who will have a virological response by the end of treatment and possibly a high likelihood of a sustained virological response (that persists for at least six months after stopping all therapy). The frequency of different levels of response (log decreases in HCV RNA levels at different times) in different racial groups and the predictive factors for the different patterns of response require definition. This study should also define the minimal number and timing of points that will accurately reflect viral kinetic responses to therapy. (4) Establish whether early viral kinetics accurately reflect the eventual outcome of therapy and can be used clinically to guide management of individual patients being treated. Thus, lack of decrease or a minimal decrease in HCV RNA levels during the first weeks or month of therapy may reliably demonstrate that therapy is ineffective and futile and can be terminated early. A reliable guide to early termination of therapy would clearly be helpful in reducing costs and side effects of treatment in patients who have no chance for a beneficial response. The reliability of these measurements needs to be assessed in the two racial groups. These studies will help to define the clinical usefulness of measuring HCV RNA levels during antiviral therapy. (5) Develop and test research hypotheses regarding the viral or host factors that determine virological and biochemical responses to combination therapy of hepatitis C. This goal should be the major focus of the Ancillary Studies and need not be dealt with in detail in applications for the Data Coordinating Center or the Clinical Centers. Thus, the lack of a virological response to optimal antiviral therapy in hepatitis C requires investigation using virological, immunological, genetic and cellular biological methods. To aid in this goal, applications for Ancillary Studies on virological, immunological and host genetic factors are requested. 3. Study Components (a) Clinical Centers Clinical Centers in the Virahep-C trial will be expected to: o Design the study protocol and help write the manual of operations. o Develop operational plans for the Recruitment phase and the Treatment and Follow-up phase of the trial in close collaboration with the communities they serve. o Participate in a full-scale clinical trial. o Participate in ancillary studies of trial subjects, as appropriate. A Clinical Center is an institution that is actively involved in the recruitment, evaluation, treatment, and follow-up of study participants. For this trial it will consist of a core team of clinical investigators who are skilled in delivery of antiviral therapy of patients with chronic hepatitis C and have experience in collaborative clinical investigation. (b) Data Coordinating Center The Data Coordinating Center will participate with the Clinical Centers and Institute staff during the entire clinical trial. The Data Coordinating Center will have primary responsibility for the biostatistical analyses and data management aspects of the trial. It also will manage the central Virological Testing Laboratory and Serum/Tissue Repository of this trial through a subcontract. The Coordinating Center will also arrange and manage the interactions of the Ancillary Study investigators with the Clinical Centers. The Data Coordinating Center will also be responsible for arrangements made with industry or sponsors of the medications to be used and any virological testing reagents. The Coordinating Center will also be responsible for drug distribution and developing contracts to facilitate the shipping of specimens. Preparation of interim and final reports will be collaborative undertakings by all participating Centers, the Data Coordinating Center, and the NIDDK. The Data Coordinating Center will have a central role in statistical aspects of the trial, including sample size determination, estimates of event rates, interim analyses for quality control, analyses of trial outcomes, and full statistical oversight. The application should include a discussion of statistical issues and potential problems likely to arise in the design and conduct of this clinical trial. The Data Coordinating Center will provide the support and guidance necessary to maintain the scientific integrity of the trial through Coordinating Center staff or procurement of consultants as necessary. The Data Coordinating Center will have the primary responsibility for developing and implementing systems necessary for intra-study communications. The Center will facilitate the design and refinement of all protocols, manuals of operation, and forms. The Center will establish a system for electronic submission of data in a standard format from the clinical centers, process all data transmitted, monitor the quality of the data and the performance of the Clinical Centers in the implementation of the protocols, and prepare periodic reports to Clinical Centers on data quality problems identified. The Data Coordinating Center will be responsible for developing plans for the Data Monitoring Committee. The Center will perform analyses necessary for interim publications and presentations, and prepare appropriately detailed reports to the NIDDK, the Steering Committee, and to the Data Monitoring Committee at regular intervals and as dictated by the study needs. During Phase 4, the Data Coordinating Center will prepare outcome analyses of the data from the clinical trial and will collaborate with the investigators of the Clinical Centers and the NIDDK to prepare final reports of the study for publication. The Data Coordinating Center will be responsible for acquiring and administering subcontracts for a central Virological Testing Laboratory and Serum/Tissue Repository. The virological testing will be the routine and necessary assays for the clinical trial. Examples of the types of centralized routine virological testing required include HCV RNA testing by polymerase chain reaction, quantitation of HCV RNA in serum by polymerase chain reaction or other amplification methods, genotyping of HCV sequencing analysis, restriction fragment length polymorphism analysis or genotype specific hybridization. The Data Coordinating Center will be responsible for assuring the quality of the testing and justification of the methods used. The NIDDK also intends that a central Serum/Tissue Repository contracted by the Data Coordinating Center will store patient samples in a manner suitable for future DNA and molecular analyses particularly with the collaboration of the Principal Investigators of the ancillary studies. The contract for a Serum/Tissue Repository may be combined with or made a separate contract from the Virology Testing Laboratory. The Coordinating Center will also arrange for transport of samples to the Principal Investigators of the ancillary studies and arrange for integration of data from ancillary studies into the overall study data. A central laboratory supported by a subcontract from the Data Coordinating Center must adhere to all NIH policies and procedures governing consortium grants. Staff of the Data Coordinating Center will be required to travel to meetings during the planning phase for the development of study design, protocols, manuals, and forms. Phases 2 and 3 will require personnel to attend Steering committee meetings, to travel to the Clinical Centers as necessary to monitor quality control procedures, and to conduct training programs for clinic staff. Additionally, the Data Coordinating Center will be required to assist in managing the logistics of all committee and sub-committee meetings during the course of the trial and will be responsible for taking minutes of the various meetings. The Data Coordinating Center also will make logistical arrangements for meetings of the Data Monitoring Committee, but the NIDDK Project Scientist will serve as executive secretary of this group. The Data Coordinating Center will assist the NIDDK Project Scientist in written, telephone, and electronic communications with Clinical Centers and with various committees as requested. (c) Ancillary Studies Applicants for Ancillary Studies should propose a detailed research plan focused upon elucidation of the biological and virological basis for a lack of response to antiviral therapy in hepatitis C in the patient population studied in Virahep-C. Applicants should develop a research plan to test research hypotheses regarding the viral or host factors that determine virological and biochemical responses to combination therapy of hepatitis C. Thus, the lack of an on-treatment virological response to optimal antiviral therapy in hepatitis C occurs in 30-50% of Caucasians, but in 50-75% of African Americans with hepatitis C. The nature of this viral resistance requires investigation using virological, cellular, and molecular biological methods. These investigations will be based upon serum and peripheral blood mononuclear cells from patients participating in the Virahep-C trial on whom information from careful clinical characterization and viral kinetics in response to combination therapy will be available. Patients will be clearly identified with antiviral (largely interferon) resistant strains of HCV, and the degree of resistance will be carefully defined. In elucidating the nature and cause of antiviral resistance, at least four major areas of investigation are important: (1) virological, (2) immunological, (3) interferon pharmacokinetics, cell signaling and intracellular effects, and (4) host genetic biology. It is expected that one ancillary study will be awarded in each of these areas. Each ancillary study should focus on only one of these areas. Investigations appropriate to this RFA include (but are not limited to) comparison of different cohorts of patients or interferon-sensitive versus interferon-resistant patients for: o Characterization of major circulating strains of HCV Nucleotide sequences of HCV RNA of these strains o Phylogenetic analyses of different strains and inter-isolate comparisons o Quasispecies complexity and diversity of circulating HCV o Changes in quasispecies complexity and diversity with therapy o Enzymatic and replicative activity of predominant circulating virus strain o Binding of intracellular proteins of expressed antigens from different HCV strains o Inhibition of constitutively expressed as well as interferon-induced proteins by HCV antigens from different isolates and strains o Levels of serum antibodies to different components of HCV and change of antibody levels with treatment o T cell immune responses to different areas of the genome from lymphocytes taken before and at different times during therapy o T cell immune responses to specific epitopes identified from resistant and sensitive HCV RNA strains o Innate immunity and non-specific immune reactivity Pharmacokinetics of interferon and time course of appearance and disappearance of serum interferon levels o Kinetics of cellular expression of interferon induced genes o Cell signaling pathways in response to interferon o Polymorphisms of interferon responsive gene products o Cytokine levels and changes in expression before and during interferon therapy o Differences in numbers and proportions of CD4 and CD8 cells and circulating lymphocyte subpopulations before and during therapy o In vitro response of peripheral blood monocytes to interferon actions o Polymorphisms of major immune response and cytokine genes Changes in gene expression during interferon therapy as assessed by microassay technology. A liver biopsy will be required on all patients before initiation of therapy. However, it is unlikely that liver tissue will be available for virological and immunological studies from most patients. Thus, Ancillary Studies should focus more on serum, plasma and peripheral blood mononuclear cell studies rather than analyses of liver tissue. 4. Study Phases Phase 1 (Planning phase, 12 months: Year 1): This phase will encompass collaborative development of the protocol and the manual of operations by a Steering Committee composed of the Principal Investigators of the Clinical Centers, the Chairperson of the study, the Principal Investigators of the Ancillary Studies, the Principal Investigator of the Data Coordinating Center, and the NIDDK Project Scientist. The Steering Committee-approved protocol and manual of operations will be subject to review by an NIDDK-appointed group of non-federal experts, the Data Monitoring Committee, that will serve to advise the Institute on subject safety, data quality and other issues. The Data Coordinating Center will solicit and award a subcontract for a virology testing laboratory and for a serum/tissue repository either as a combined or separate contract. The Steering Committee will choose a central pathologist for the trial during the planning phase. The pathologist may be a member of one of the clinical centers or be located at another institution. The pathologist will be funded through the Data Coordinating Center. The study will move into its operational phase only following the recommendation of the Data Monitoring Committee and the final approval of the NIDDK. Phase 2 (Enrollment phase, 12 months: Year 2): The protocol for the study will be initiated in Phase Two. Each Clinical Center will recruit and enroll 50 participants over this period, implement the protocol according to the manual of operations, collect the outcome data specified in the protocol, and provide study data to the Data Coordinating Center. Clinical Centers also will be responsible for collecting and shipping patient specimens to central facilities for evaluation and collaborating with the Principal Investigators of the ancillary studies in elucidating the nature of viral resistance in the treated patients. The Data Coordinating Center will coordinate these activities, and will manage the collection, editing, storage and analysis of data. During this phase, the Ancillary Studies will begin evaluation of serum, DNA and peripheral blood mononuclear cells from patients receiving antiviral therapy as designated in the protocol developed during phase 1. Phase 3 (Treatment and Follow-up phase, 24 months: Years 3 and 4): Clinical Centers will no longer recruit patients, but will continue to implement the protocol, collect outcome data, ship specimens, and provide study data to the Data Coordinating Center during this period. Patients will be treated for 48 weeks, and all will be followed off of therapy for another 48 weeks. Thus, follow up will conclude 96 weeks after enrollment of all patients. During this period, the Data Coordinating Center will continue to coordinate these activities, and will manage the collection, editing, storage and analysis of data. Ancillary Studies will continue during this phase. Phase 4 (Analysis phase, 12 months: Year 5): The final phase of the study will be for close-out of Clinical Center activities, final data analysis, and reporting of results. Ancillary Studies are likely to need to be continued at reduced activity during this phase and results of these studies added to the clinical database. SPECIAL REQUIREMENTS 1. Participation in a Collaborative Program To promote the development of a collaborative program among the awardees, the applicant should present evidence of experience in working cooperatively with other Clinical, Ancillary Study and Data Coordinating Centers and of ability to follow common protocols that are collaboratively developed. (a) Clinical Centers will be expected to communicate with the Data Coordinating Center and the NIDDK Project Scientist on a regular basis and work closely with the Principal Investigators on the Ancillary Studies. All Clinical Centers in the Virahep-C trial must agree to implement the protocol and manual of operations that will be developed cooperatively during Phase 1 and agree to electronically transmit all study data in a timely fashion to a central Data Coordinating Center for combination and analysis. An explicit statement of willingness to participate in a collaborative program should be included in the application. (b) The Data Coordinating Center will be involved in collaborations with the NIDDK, the ancillary studies and the Clinical Centers during all phases of the trial. Thus, the applicant is expected to demonstrate experience in working cooperatively with Clinical Centers and sponsoring organizations in a multicenter trial and in overseeing the implementation of and adherence to a common protocol, as well as assuring quality control of the data collected. In addition to organizing and attending regular meetings, the Data Coordinating Center will be expected to maintain close communications with the NIDDK Project Scientist, the Principal Investigators of the Ancillary Studies, and the Clinical Centers. (c) Principal Investigators of the Ancillary Studies will be expected to communicate with the Data Coordinating Center and the NIDDK Project Scientist on a regular basis. All Principal Investigators must agree to implement the protocol and manual of operations that will be developed cooperatively during Phase 1 and agree to electronically transmit all study data to the central Data Coordinating Center for combination and analysis. These ancillary studies will address virological, immunological, pharmacological and host genetic factors that might explain the nature and cause of viral resistance in chronic hepatitis C. The Principal Investigators on these ancillary studies will participate in the protocol design and set up the important collaborations and arrangements with the Clinical Centers that will be needed to carry out the analyses of viral and host factors that correlate with response and lack of response to interferon-based therapy of hepatitis C. Principal Investigators on the Ancillary Studies will be expected to perform hypothesis-driven laboratory research on serum and/or tissue samples from patients participating in the Virahep-C trial. The Investigators will direct all technical help and participate in the completion of planned experiments focusing on the mechanism of antiviral action of combination therapy against HCV and the possible mechanisms of antiviral resistance. The Investigator will be expected to report results regularly and provide results to the Data Coordinating Center for analysis in respect to the clinical and other virological features of individual patients. The Principal Investigators of the Ancillary Studies are expected to complete the planned experiments in a timely fashion and help analyze and prepare the findings for publication. (d) Steering Committee. The primary governing body of the study will be the Steering Committee, which will have responsibility for overall study design and policy decisions (described in more detail under Terms and Conditions). (e) Executive Committee. An Executive Committee also will be convened to facilitate the monitoring and conduct of the study between meetings of the Steering Committee (described in more detail under Terms and Conditions). (f) Data Monitoring Committee. An independent committee will be established by the Director, NIDDK, to review the progress of the study on a regular basis (described in more detail under Terms and Conditions). (g) NIDDK Project Scientist. The NIDDK will name an NIDDK Project Scientist whose function will be to assist the components as appropriate in all aspects of the study (described in more detail under Terms and Conditions). 2. Terms and Conditions of Award The following special terms of award (1-4) are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92, and other HHS and NIH grant administration policies. The administrative and funding mechanism to be used to undertake this project will be the cooperative agreement (U01), which is an assistance mechanism (rather than an acquisition mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activity. Under the cooperative agreement, the NIDDK’s purpose is to support and/or stimulate the recipient’s activity by collaborating and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the tasks and activities in carrying out the studies will be shared among the awardees, the Principal Investigators of the Clinical Centers, the Ancillary Studies, the Data Coordinating Center, and the NIDDK Project Scientist. (a) Awardee Rights and Responsibilities. The tasks or activities in which awardees for the Clinical Centers, the Ancillary Studies and the Data Coordinating Center of the Virahep-C trial will have substantial and lead responsibilities include protocol development, patient recruitment and follow-up, data collection, quality control, investigation of patient samples, final data analysis and interpretation, and preparation of publications. The awardee agrees to work cooperatively with the other Clinical Centers, other Ancillary Study investigators and the Data Coordinating Center and agrees to follow the common protocol and manual of operations developed in Phase 1 of the study by the Steering Committee. Awardees will retain custody of and have primary rights to their data developed under these awards, subject to Government policies regarding rights of access. (b) NIDDK Staff Responsibilities. The NIDDK will name the Project Scientist. The Project Scientist’s function will be to provide technical assistance to the Steering Committee, Executive Committee, Data Monitoring Committee, and other subcommittees in carrying out the study, including quality control, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and coordination and performance monitoring. The NIDDK Project Scientist will have voting membership on the Steering Committee, the Executive Committee, and, as appropriate, other subcommittees of the Steering Committee. The NIDDK Project Scientist also will serve as executive secretary of the independent Data Monitoring Committee. Other NIDDK scientists may, as appropriate, serve on study committees and work with awardees on issues coming before the Steering Committee or its subcommittees, however, in all cases, the NIDDK will have only a single vote on study committees, either of the whole or on subcommittees. In addition, the NIDDK may invite non-voting representatives from other sponsoring Institutes and agencies, as appropriate, to attend meetings. The NIDDK will name a Program Officer, separate from the Program Scientist, who will be responsible for administering the awards. The NIDDK reserves the right to terminate or curtail the study (or an individual award) in the event of (a) a major breach in the protocol or substantial changes in the agreed-upon protocol with which the Institute does not agree or (b) human subject ethical issues that may dictate a premature termination or (c) substantial shortfall in recruitment and/or retention of subjects. (c) Collaborative Responsibilities and Governance. (1) The Steering Committee, comprised of each of the Principal Investigators of the Clinical Centers, the Study Chairperson, the Principal Investigators of each of the Ancillary Studies, the Principal Investigator of the Data Coordinating Center, and the NIDDK Project Scientist, will have primary responsibility for developing common clinical protocols, facilitating the conduct and monitoring of the studies, and reporting the study results. Each member of the Steering Committee will have one vote, and all major scientific decisions will be determined by majority vote of the Steering Committee. A Chairperson will be chosen from among the Principal Investigators of the Clinical Centers. Subcommittees appointed by the Steering Committee and comprised of Principal Investigators and appropriate staff from the Clinical Centers, the Ancillary Studies and the Data Coordinating Center will be involved in design of the protocol and the manual of operations, and in ongoing functions of the trial, such as review of ancillary studies and preparation of publications. Not all Clinical Centers will necessarily be represented on all subcommittees. (2) An Executive Committee comprised of the Study Chairperson, the Principal Investigator of the Data Coordinating Center and the NIDDK Project Scientist also will be convened to effect management decisions required between Steering Committee meetings, as needed for efficient progress of the trial. The Executive Committee will report its actions to the Steering Committee on a regular basis. Meetings of the Executive Committee will generally be held in the Washington, D.C. metropolitan area or by conference call. (3) An independent Data Monitoring Committee will be appointed by the Director, NIDDK, to review periodically the progress of the Virahep-C trial. It will be comprised of experts in relevant medical, statistical, operational, and bioethical fields who are not otherwise involved in the study. The Data Monitoring Committee will oversee participant safety, evaluate results, monitor data quality, and provide operational and policy advice to the Steering Committee and to the NIDDK regarding the status of the study. The Principal Investigator of the Data Coordinating Center, the NIDDK Project Scientist, and the Director of the Division of Digestive Diseases and Nutrition (or representative) may participate as ex-officio, non-voting members of the Committee. The NIDDK Project Scientist will serve as executive secretary of the Data Monitoring Committee. The Data Monitoring Committee will review progress and report to the NIDDK at least once per year. (d) Arbitration. Any disagreement that may arise in scientific- programmatic matters (within the scope of the award) between award recipients and NIDDK may be brought to arbitration. An arbitration panel will be composed of three members: one selected by the Steering Committee (with the NIDDK member not voting) or by the individual awardees in the event of an individual disagreement, a second member selected by NIDDK, and a third member selected by the two prior selected members. The special arbitration procedure in no way affects the awardee’s right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulations at 45 CFR Part 16. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. This study will recruit equal numbers of African American and non- Hispanic white patients. The focus of the study is on African Americans who have a high rate of resistance to antiviral therapy with alpha interferon. The non-Hispanic whites are to be used as a control and reference group to analyze response rates by racial group to alpha interferon therapy and viral kinetics. Other minority groups such as Asians, Hispanic whites and native Americans will not be included in this trial. Asian Americans will not be included because hepatitis C appears to be less frequent in this group than in whites, and because data from the United States as well as Asian countries indicate that the sustained virological response rates to alpha interferon therapy are equal or higher in Asians compared to Caucasians. Hispanic whites will not be included in this trial because response rates to antiviral therapy in this group has been similar to that among non-Hispanic whites. Furthermore, studies from Spain report response rates that are similar to those from other European countries. Thus, viral resistance does not appear to be common in the Hispanic groups enrolled in published clinical trials. Native Americans have not been included in this trial because there is little or no information on the frequency of hepatitis C in this group and no data on the frequency of response to antiviral therapy. Most studies indicate that hepatitis C is not common in Native American populations. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applicants are asked to submit, by November 15, 2000, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted, and whether the application is for a Clinical Center, Data Coordinating Center or Ancillary Study. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIDDK staff to estimate the potential review workload and to plan the review. The letter of intent is to be sent to: Ann A. Hagan, Ph.D. Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Rm. 653 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8885 FAX: (301) 480-3505 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: GrantsInfo@nih.gov. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2a of the face page of the application form, and the YES box must be marked. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC-7710 Bethesda, MD 20892-7710 (for express/courier service: Bethesda, MD 20817) At time of submission, two additional copies of the application must be sent to: Ann A. Hagan, Ph.D. Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Rm. 653 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8885 FAX: (301) 480-3505 Applications must be received by December 15, 2000. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications previously reviewed, but such applications must include an introduction addressing the previous critique. Instructions to Prospective Applicants (1) Clinical Centers The applicants for the Clinical Centers should discuss the important design considerations for a clinical trial to investigate viral resistance to antiviral therapy of chronic hepatitis C. While the final design for the Virahep-C trial will be determined by the Steering Committee, applicants should address the potential requirements of the study by providing a description of projected tasks likely to be performed by the Clinical Centers. Solutions should be suggested for likely problems. The applicant"s study design should propose eligibility requirements for study participation, including patient age, gender, and racial/ethnic background. In addition, exclusion criteria should be specified, along with a rationale. Applicants should provide a justification for the subject selection criteria, including discussion of statistical considerations, an estimate of the number of subjects in the source population, and projected necessary time for recruitment. The overall racial composition of the recruited patient populations in this study will be equally divided between African Americans and non- Hispanic whites. Plans should include methods and criteria for assigning racial and ethnic background. Plans should include racially and ethnically sensitive strategies for recruitment, screening, enrollment and retention in the study protocol. Each applicant should propose the study design he or she believes best addresses the objectives of this project as described in RESEARCH OBJECTIVES and is most appropriate to the proposed patient population. The potential differential effectiveness of antiviral therapy with respect to racial/ethnic background of study participants should be discussed. The applicant should propose one specific antiviral therapy (not a comparison of two treatments) that would be considered optimal therapy for genotype 1 infected patients with hepatitis C. The applicant should discuss the components of the initial evaluation, inclusion and exclusion criteria. The applicant should propose a schedule of evaluations during therapy with a table showing timing of evaluations and assessments and tests to be applied at each point before, during and after therapy. In addition to the primary and secondary outcome measures listed in RESEARCH OBJECTIVES, which should be included in the study design, applicants should indicate other outcome measures proposed for assessment (e.g., quality of life instruments, symptom scales and measurements, virological assays, other measures of liver function) identifying those they consider the highest priority that can be accommodated within the funds available. The applicant should clearly define endpoints of therapy (virological and biochemical). Methods to monitor and encourage patient adherence to the trial protocol should be clearly defined. Plans for collection and handling of data and samples should be discussed. Part of the proposed study design also should address the means for communicating results of patient laboratory tests and guidelines for treatment of comorbidities to primary care physicians. Clinical Centers should describe their experience in recruiting and studying patients with liver disease, and in minimizing losses of patients to follow-up during long-term clinical studies. The Clinical Center should include a pathologist with experience in reading hepatic pathology who will read liver biopsies from patients in the trial. Clinical Centers also should document prior involvement in multi-center clinical trials and success in recruiting from minority populations. Applicants should provide evidence that the Clinical Center will be capable of recruiting a sufficient number of patients with hepatitis C with the proposed inclusion criteria. The NIDDK expects that the average number of patients per center will be approximately 50 and that half of the patients will be African Americans and half non-Hispanic whites. An organizational structure for the Clinical Center should be provided in the application, delineating lines of authority and responsibility for dealing with problems in all general areas. There should be evidence of strong institutional support for the Clinical Center, including documentation of adequate space in which to conduct clinic activities and office space for staff. Personnel: The application for a Clinical Center must describe the expertise of key scientific, technical and administrative personnel and include a mechanism for replacing key professional or technical personnel should the need arise. Overall, the staff of a Clinical Center should include expertise in liver disease and clinical investigation. The study team is anticipated to include members who perform in roles similar to those cited below. Members may be full or part-time and may serve in more than one capacity, as appropriate. The following suggested roles are intended to be illustrative, not prescriptive: o Principal Investigator to provide overall scientific guidance. o Project Coordinator who can provide full-time attention to administration and management of the trial. o Physician(s) with expertise in the clinical management of hepatitis C and liver disease to help enroll and maintain the patients in this study and to oversee the use of antiviral therapy. o Pathologist with expertise in liver histology and interpretation of liver histology in chronic hepatitis. o Research nurse(s) or other allied health professional(s) to assist in case management and data collection procedures (e.g., phlebotomy, and patient assessments). o Individual(s) for clerical and technical support, including administrative tasks, data entry, laboratory sample handling, assistance with recruitment and other tasks. Budget: Applicants for a Clinical Center should submit adequately justified budgets for each 12-month period of the trial, reflecting the major changes in proposed activities projected to occur as the trial progresses through its phases. During Phase 1 (Year 1), the budget will be for development of the protocol and manual of operations, staff recruitment and training, and staff certification. The travel budget for Phase 1 should be estimated on the basis of six meetings at regular intervals during the first year of award. During Phase 2 (Year 2), the budget should reflect subject recruitment and randomization, implementation of the proposed interventions, collection of outcome data proposed by the applicant, and provision of study data to the Data Coordinating Center. Phase 2 budgets should include three meetings per year. During Phase 3 (Years 3 and 4), the budget should reflect the end of recruitment and the continued implementation of the proposed interventions, collection of proposed outcome data, and provision of study data to the Data Coordinating Center. Phase 3 budgets should include three meetings per year. The Phase 4 budget (Year 5) will be concerned with study close-out, analysis of study data, and reporting of results. Phase 4 budgets should include three meetings. NOTE: o Detailed budget estimates for years in Phases 2, 3, and 4 should be based on the applicant"s proposed plan. Actual budgets for these phases will be based on the final protocol developed collaboratively during Phase 1. o It is the intention of the NIDDK that the Data Coordinating Center will establish central resource units for the standardized performance of key laboratory and clinical parameters. These costs will be included in the Data Coordinating Center funding and should not be budgeted by the Clinical Centers. Clinical Center budgets should also not include costs for medications, drug distribution or specimen shipping costs. o Budgets should allow travel and lodging costs for approximately two persons, including the Principal Investigator, to attend Steering Committee and Subcommittee meetings. Since actual meeting locations have not been selected, each meeting may be assumed to cost $1500 per person for budget purposes. It is anticipated that about one-half of the meetings will be held in the Washington, DC area or Bethesda, MD. (2) Data Coordinating Center Applicants for the Data Coordinating Center should address the potential requirements of the study by providing a description of projected tasks likely to be performed by the Data Coordinating Center and the centralized facilities, consistent with resources projected to be available for this study. The application should be structured around the requirements of a projected study design that addresses likely outcomes to be determined and likely eligibility requirements for study participation, including patient age, gender, and exclusion criteria. Plans for collection and handling of data and samples consistent with the projected needs of the study should be discussed. Part of the proposed study design also should address the means for communicating results of patient laboratory tests. Plans for integration of results from the Clinical Centers and the Ancillary Studies should be discussed. Plans for ensuring data integrity and quality control should be discussed. Personnel: The application for the Data Coordinating Center must describe the expertise of key scientific, technical and administrative personnel and include a mechanism for replacing key professional or technical personnel should the need arise. A Director and a Deputy Director for the Data Coordinating Center must be designated. The Director of the Data Coordinating Center should be a biostatistician, epidemiologist, or other professional with experience in directing a coordinating center for a large scale collaborative multicenter clinical trial or other large scale epidemiological research project involving multiple institutions. The Deputy Director should be fully qualified to carry out the responsibilities of the Director. Staff needs may be modified as the trial progresses, however, adequate support staff should be designated to manage routine tasks. It is expected that senior statistical staff will devote time to developing data analysis methods for use in the trial. o Director of Data Coordinating Center to provide overall scientific and biostatistical guidance. o Deputy Director qualified to replace the Director. o Project Manager to attend to day-to-day details of the trial and communicate necessary information to clinical centers, repository, virology testing laboratory and ancillary studies sites. Staff training is also a responsibility of the Project Manager. o Statisticians to help in data analysis. o System analysts to help with developing and managing the database programs. o Computer programmers to develop computer database. o Clerks and administrative assistants to help in administrative work and data entry. Budget: Applicants for the Data Coordinating Center should submit adequately justified budgets for each 12-month period of the trial, reflecting the major changes in proposed activities that occur as the trial progresses through its phases. NOTE: Budgets for this application should be based on the applicant"s best judgment of likely activities projected to be included in a final protocol. Final budgets will be determined following the design of the study protocol and writing of the manual of operations during Phase 1. The Phase 1 budget (Year 1) should include costs of establishing the Data Coordinating Center staff, as required to carry out the Coordinating Center"s functions. Phase 1 also will involve development of the protocol and manual of operations in conjunction with the Steering Committee for the study and creation of a database for the trial. During this phase, the collaborating centralized Virological Testing Laboratory and a Serum/Tissue Repository will be identified. Coordination will be established with the ancillary studies investigators to obtain serum and tissue specimens. Budgets should include the costs of organizing six Steering Committee meetings and providing for attendance of necessary Data Coordinating Center staff. During Phase 2 and 3 (Years 2, 3, and 4), the budgets should include projected data handling costs, reporting functions, meetings and other communications costs, and the projected expense of performing interim analyses requested by the Data Monitoring Committee. The applicant also should address the potential requirements of the study by budgeting for tasks likely to be performed by the central virological testing facility. These should include development of a repository to store patient samples. It should, however, be understood that the specific centralized facilities required and their final budgets will be determined following the design of the study protocol and the writing of the manual of operations by the Steering Committee. The Budget should include funding for a central hepatic pathologist for reading liver biopsies for the study. Budgets should include costs of organizing three Steering Committee meetings per year and providing for attendance of necessary Data Coordinating Center staff. The Phase 4 budget (Year 5) should be concerned with study close-out, analysis of study data, and reporting of results in collaboration with the Clinical Centers. Budgets should include the costs of organizing three meetings of the Steering Committee and providing for attendance of necessary Data Coordinating Center staff. NOTE: Since actual meeting locations have not been selected, each meeting may be assumed to cost $1,500 per person. Each Clinical Center will budget for the travel of its own staff members. It is estimated that approximately one-third of the meetings will be held in the Washington D.C. area. The Data Coordinating Center also will be responsible for organizing meetings of the Data Monitoring Committee at least once a year and for supporting the travel of these individuals to meeting sites and their lodging. These costs should be included in the budget. (3) Ancillary Studies The applicants for an Ancillary Study should discuss how their proposal would be integrated into the design of the clinical trial and relate to the trial protocol. These applications need to discuss the design considerations for the clinical trial only in relationship to the laboratory investigations that are planned. Thus, if repeated measures of virological, immunological or interferon-related responses are necessary, it would be important to define the time points necessary and what special therapy, data or provisions would be necessary to collect the specimens and clinical information. The plan should also discuss any deviation from standard medical practice that would be needed for the investigations, such as extra blood drawings, lymphopheresis or special procedures. The investigator should be careful not to propose studies that would interfere significantly with the recruitment and retention of patients or the course of optimal therapy of hepatitis C or interfere with the primary goals of this study detailed above under research objectives #1-4. Personnel: The application for an Ancillary Study must describe the expertise of key scientific, technical and administrative personnel and include a mechanism for replacing key professional or technical personnel should the need arise. o Principal Investigator to provide overall scientific guidance. o Laboratory technicians with expertise in the laboratory investigations that are planned. o Post-doctoral or other professionals to help direct and conduct the laboratory investigations. Budget: Applicants for an Ancillary Study should submit adequately justified budgets for each 12-month period of the trial, reflecting the major changes in proposed activities projected to occur as the trial progresses through its phases. During Phase 1 (Year 1), the budget will be for development of research protocol along with techniques and reagents, and staff recruitment and training. The travel budget for Phase 1 should be estimated on the basis of six meetings at regular intervals during the first year of award. During Phase 2 (Year 2), the budget should reflect full implementation of the research project. Phase 2 budgets should include three meetings per year. During Phase 3 (Years 3 and 4), the budget should reflect the end of recruitment and the continued implementation of the proposed interventions, collection of samples and testing, and provision of study data to the Data Coordinating Center. Phase 3 budgets should include three meetings per year. The Phase 4 budget (Year 5) will be concerned with completing final studies on patients at the end of the trial, study close-out, analysis of study data, and reporting of results. Phase 4 budgets should include three meetings. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIDDK in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Diabetes and Digestive and Kidney Diseases Advisory Council. Review Criteria Applicants are encouraged to submit and describe their own ideas about how best to meet the goals of the cooperative study as outlined in this RFA and are expected to address the points discussed under SPECIAL REQUIREMENTS. In the written comments reviewers will be asked to evaluate the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score and will be weighted as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. Furthermore, the focus of these criteria will depend upon whether the application is for a Clinical Center, Data Coordinating Center or Ancillary Study. (1) For the Clinical Centers of the Virahep-C trial, review will focus on the following issues which are listed under the five major review criteria: o Significance: Does this study address an important problem? If the aims of the applications are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? The final study design will be developed collaboratively by the Steering Committee for the trial. In assessing applications for Clinical Centers, the peer review group will focus on evidence that the applicant recognizes the significance of the issues involved and possesses the knowledge necessary to contribute meaningfully to the final design, including understanding of the scientific, ethical, and practical issues underlying the proposed study. o Approach: Are the conceptual framework, design, and methods adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Does the proposed approach in managing the clinical requirements of the study as outlined in the RFA have scientific and technical merit? Has the Principal Investigator proposed an adequate and practical plan to recruit, evaluate, enroll, and monitor patients, particularly African American subjects? Does the application provide evidence of successful experience in recruitment and retention of research subjects in multicenter clinical trials, and particularly experience in the recruitment and retention of African American individuals with chronic hepatitis C or other liver diseases? Does the application include documentation of access to an adequate patient population from which to recruit 50 eligible patients over a one-year period? At least half of patients (25) should be African American. o Innovation: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? The final protocol will be developed by the Steering Committee. Does the Principal Investigator offer innovative ideas on means to achieve the goals of the study in its design and clinical components? Does the proposal address problems that may arise during the study and provide innovative solutions to such problems? o Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? Does the Principal Investigator have demonstrated knowledge of clinical and epidemiological aspects of liver disease and hepatitis C, particularly among African American patients? Does the investigator have documented expertise in management and monitoring of therapy of patients with hepatitis C? Does the other professional, technical, and administrative staff have specific competence and previous experience relevant to the operation of a Clinical Center in the proposed study? o Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies take advantage of unique features of the scientific environment or employ useful collaborative agreements? Is there evidence of institutional support and commitment for the proposed program? Has the applicant provided evidence for adequacy of the proposed facility, space, and resources for the work proposed? This includes evidence of an appropriate organizational structure and institutional support for the Clinical Center. For those applications that propose collaborative efforts between two applicants to form a single Clinical Center, additional factors to be considered would include the advantages of the collaboration in terms of cost, recruitment, or facilities, the commitment of the participants to the collaboration, and the adequacy of plans to coordinate efforts. Is there evidence of successful collaborative interactions with other investigators under a common protocol in a multicenter clinical trial? (2) Review of applications for the Data Coordinating Center will be based on the following specific issues which are listed under the five major review criteria: o Significance: Does this study address an important problem? If the aims of the applications are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? The final study design will be developed collaboratively by the Steering Committee for the trial. In assessing applications for a Data Coordinating Center, the peer review group will focus on whether the applicant recognizes the significance of the issues involved and possesses the knowledge necessary to contribute meaningfully to the final design, including understanding of the scientific, ethical, and practical issues underlying the proposed study. o Approach: Are the conceptual framework, design, and methods adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Does the proposed approach in managing the data coordination and conduct of the study as outlined in the RFA have scientific and technical merit? Are the proposed plans and experience relating to data collection, management, editing, processing, analysis, and reporting adequate? Is there a demonstrated ability to identify, enlist, recruit and coordinate the efforts of central Virological Testing Laboratory and Serum/Tissue Repository? Are the plans for management of biological samples and coordination with the Ancillary Study investigators adequate? Is the approach to developing a cooperative relationship among the participating clinical centers and principal investigators on the ancillary studies adequate? Are the plans for exercising appropriate leadership in matters of study design, data acquisition, data management, and data analysis demonstrated? o Innovation: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? The final protocol will be developed by the Steering Committee. Does the applicant for the Data Coordinating Center offer innovative ideas on how to achieve the goals of the study in its design and administration? Does the proposal address problems that may arise during the study and provide innovative solutions to such problems? o Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? Does the application provide evidence of specific competence and relevant experience of professional, technical, and administrative staff pertinent to the operation of a Data Coordinating Center for a collaborative clinical trial? Prior experience collecting data and patient specimens from multiple clinical sites, monitoring the data quality, and developing and utilizing statistical methods for analysis of data should be demonstrated. Is there evidence of experience in and willingness to participate appropriately in a collaborative study as described in this RFA? Are there adequate assurances that Data Center personnel have experience in utilizing procedures that insure the safety and confidentiality of medical records? o Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies take advantage of unique features of the scientific environment or employ useful collaborative agreements? Is there evidence of institutional support and commitment for the proposed program? Has the application documented the adequacy of the proposed facility, technical hardware, and space for the Data Coordinating Center? Is there an appropriate organizational and administrative structure to the Center? Evidence of institutional support and commitment for the proposed program should be provided. (3) Review of applications for Ancillary Study awards will be based on the following specific questions which are listed under the five major review criteria: o Significance: Does this study address an important problem? If the aims of the applications are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? The final study design will be developed collaboratively by the Steering Committee for the trial. In assessing applications for an Ancillary Study, the peer review group will address whether the application addresses an important and relevant issue in regard to viral resistance and possible genetic, host or environmental determinants of response to antiviral therapy. Will the findings from the studies add to understanding of the pathogenesis of hepatitis C and the determinants of outcome of therapy? Will the results ultimately be applicable to clinical management of patients? o Approach: Are the conceptual framework, design, and methods adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Does the application have scientific and technical merit and relevance to the research objective of elucidating the mechanisms of antiviral effects of alpha interferon and other antivirals in hepatitis C or in possible racial or ethnic differences in antiviral responses? Has the investigator adequately demonstrated the plan and methods of the laboratory studies and integrated these studies into the general design of the clinical study? Does the applicant recognize the practical problems in acquiring the required samples from the patients in the trial and propose means of correcting these problems? Does the applicant recognize problems in the laboratory results and their interpretation and provide possible solutions? o Innovation: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? Does the project suggest novel mechanisms and offer new insights into the activity of antiviral agents in hepatitis C? Does the project suggest new approaches to analysis and understanding of clinical responses to treatment in hepatitis C and possible racial or ethnic differences in these responses? o Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? Does the investigator and supporting research staff have adequate training and experience in laboratory investigation of virology or immunology of hepatitis C or the cellular biological and antiviral activity of interferon or in host genetic markers of disease outcome? Is there evidence of prior experience and willingness in working collaboratively in carrying out a developed study protocol and sharing data? o Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies take advantage of unique features of the scientific environment or employ useful collaborative agreements? Is there evidence of institutional support and commitment for the proposed program? Is the adequacy of the proposed facility, space, and resources for the work proposed documented in the application? This includes evidence of an appropriate organizational structure and institutional support. In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research o The adequacy of the proposed protection for humans or the environment, to the extent they may be adversely affected by the project proposed in the application. The initial review group will also examine the safety of the research environment. Schedule Letter of Intent Receipt Date: November 15, 2000. Application Receipt Date: December 15, 2000. Peer Review Date: March-April, 2001. Council Review: May 2001. Earliest Anticipated Start Date: July 1, 2001. AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific and technical merit of the application for a Clinical Center, Data Coordinating Center or Ancillary Study o Availability of funds o Cost o Availability of appropriate study populations and especially the racial and ethnic balance among the populations to be accessed by the potential awardees o Geographical distribution of the applicant organizations o Program balance, including, in this instance, sufficient compatibility of features to make a successful collaborative program a reasonable likelihood. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. The NIDDK will host a meeting of potential applicants for the Virahep-C study at the time of the Annual Meeting of the American Association for the Study of Liver Disease in Dallas, Texas October 27, 2000. At that time NIDDK staff will be available to discuss the proposal and answer questions from applicants. For the exact time and place of the meeting and for other inquires regarding programmatic issues that are not addressed in this announcement, contact: Tommie Tralka Director, Clinical Trials Program Division of Digestive Diseases and Nutrition 6707 Democracy Boulevard, Room 675 Bethesda, MD 20892 Telephone: (301) 594-8879 FAX: (301) 480-8300 Email: TralkaT@extra.niddk.nih.gov Direct inquiries regarding fiscal and administrative matters to: George Tucker Division of Extramural Activities 6707 Democracy Boulevard, Room 635 Bethesda, MD 20892 Telephone: (301) 594-8853 FAX: (301) 480-3504 E-mail: tuckerg@extra.niddk.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847 and 93.848. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. REFERENCES Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao FX, Moyer LA, Kaslow RA, Margolis HS. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999,341:556-62. Liang TJ, Rehermann B, Seeff LB, Hoofnagle JH. Hepatitis C. Ann Intern Med 2000, 132: 296-305. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. Interferon alfa-2b alone or in combination with riabvrin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 1998,339:1485-92. Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. Randomised trial of itnerferon alpha-2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International hepatitis Interventional Therapy Group. Lancet 1998,352:1426-32. Reddy KR, Hoofnagle JH, Tong MJ, Lee WM, Pockros P, Heathcote EJ, Albert D, John T, Consensus Interferon Study Group. Racial differences in responses to therapy with interferon in chronic hepatitis C. Hepatology 1999,30:787-93. Howell C, Jeffers L, Hoofnagle JH. Hepatitis C in African Americans. Summary of a Workshop. Gastroenterology 2000, 119: in press. Newman AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ, et al. Hepatitis C viral dynamics in vivo and the antiviral effiacy of interferon-alpha therapy. Science 1998,282:103-7.


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