RFA-DK-01-003: TYPE 1 DIABETES TRIALNET: CLINICAL CENTERS

Department of Health
and Human Services (HHS)

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TYPE 1 DIABETES TRIALNET: CLINICAL CENTERS Release Date: October 5, 2000 RFA: DK-01-003 National Institute of Diabetes and Digestive and Kidney Diseases (http://www.niddk.nih.gov) National Institute of Allergy and Infectious Diseases (http://www.niaid.nih.gov) National Institute of Child Health and Human Development (http://www.nichd.nih.gov) Letter of Intent Receipt Date: February 28, 2001 Application Receipt Date: March 29, 2001 PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), and the National Institute of Child Health and Human Development (NICHD) are seeking applications for clinical centers (and associated networks of recruitment and follow-up sites) to perform intervention studies to preserve pancreatic beta cell function and prevent type 1 diabetes. The Clinical Centers will complete the ongoing Diabetes Prevention Trial for Type 1 Diabetes (DPT-1) and participate in the design and execution of pilot and expanded studies of new agents to prevent or ameliorate type 1 diabetes, and in natural history and genetics studies in populations screened for or enrolled in these studies. The Clinical Centers selected to complete the ongoing DPT-1 and to participate in new studies, as well as core support facilities, will constitute a national diabetes trial network (Type 1 Diabetes TrialNet or TrialNet) of clinical research groups whose aim is to recruit patients and to support studies that may eventually result in an improved understanding of type 1 diabetes and the prevention of the disease. A complementary Request for Application (RFA)(DK-01-004) is being published to establish the Type 1 Diabetes TrialNet Operations Coordinating Center, Data Monitoring Unit, core laboratories, compounding pharmacy, central distribution pharmacy, and clinical cost reimbursement system. Institutions and investigators applying to become Clinical Centers may also apply for components of the TrialNet solicited under RFA DK-01-004. This RFA responds to recommendations of the Congressionally-established Diabetes Research Working Group (http://www.niddk.nih.gov/federal/dwg/dwgsummary.htm), which developed a strategic plan for research in diabetes. Among the extraordinary research opportunities mentioned in the plan were: the conduct of additional clinical trials of immunoprevention of type 1 diabetes using antigen- specific, cytokine- or antibody-based immunotherapy, and the establishment of a national diabetes trial network of cooperative clinical research groups to create the stable, high-quality infrastructure necessary for the conduct of effective and efficient clinical trials in diabetes. The actual studies to be performed, in addition to completion of DPT-1, will be determined by a steering committee (see Special Requirements, Study Organization below) composed of Principal Investigators of the Clinical Centers, Operations Coordinating Center, Data Monitoring Unit, Core Laboratories, and NIH Program Officers. Nonetheless, applicants wishing to participate in these studies should propose one intervention study of a new agent to prevent or ameliorate type 1 diabetes. Current DPT-1 Clinical Centers wishing only to complete DPT-1 and not to participate in future studies do not need to submit a proposal for a study of a new agent. It is anticipated that many of the pilot and expanded intervention studies of new agents to prevent or ameliorate type 1 diabetes that eventually will be performed in the TrialNet will be proposed through this RFA. However, after awards are made in response to this RFA, research proposals for pilot and expanded intervention studies requiring Type 1 Diabetes TrialNet resources may be submitted by non-members of the TrialNet (see Eligibility Requirements below). The mechanism for receiving and evaluating future proposals, and prioritizing studies, will be determined by the TrialNet Steering Committee. The Immune Tolerance Network (ITN), a program of the NIAID, NIDDK and Juvenile Diabetes Foundation International (JDF), also supports clinical trials to evaluate the safety and efficacy of tolerance induction strategies to prevent and ameliorate type 1 diabetes and other autoimmune diseases. Information on this program can be found at http://www.immunetolerance.org. The Type 1 Diabetes TrialNet and the ITN will provide an integrated approach to immunoprevention and amelioration of type 1 diabetes. Promising pilot studies initiated in the ITN may lead to larger clinical trials that could be conducted using TrialNet. In addition, TrialNet may use assays provided through the ITN to generate information on mechanisms by which interventions exert their effect. Investigators wishing to seek funding for ancillary studies, such as those identifying underlying mechanisms in immunoprevention, should consider other sources. These include investigator-initiated grants and the ITN mentioned above. Investigators interested in mechanistic studies involving patients and patient materials in the DPT-1 or Type 1 Diabetes TrialNet may also consider funding through the Hyperaccelerated Award/Mechanisms in Immunomodulation Trials (RFA AI-00-005). 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 RFA, Type 1 Diabetes TrialNet, is related to the priority area of Diabetes. Potential applicants may view a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by investigators from institutions in North America. This geographic constraint is necessary because of the need for close communication among members of the study group, the requirement for frequent Steering Committee meetings, and the anticipated need for site visits to ensure adequate recruitment, retention, and the use of standardized procedures across the studies. For-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government may apply. Applicants from racial/ethnic minority groups, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT The administrative and funding instrument to be used for this program will be the cooperative agreement (U01), an assistance mechanism (rather than an acquisition mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient"s activity by involvement in 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. Details of the responsibilities, relationships and governance of the study to be funded under cooperative agreement(s) are discussed later in this document under the sections titled Objectives and Scope , Special Requirements , and "Terms and Conditions of Award". The total project period for applications submitted in response to the present RFA should be 7 years. The anticipated award date is September 2001. Because the nature and scope of the research supported by the Type 1 Diabetes TrialNet may vary over time and by site, it is anticipated that the sizes of awards may also vary. After initiation of the TrialNet, awards in subsequent years will be determined by the requirements of the specific studies designed by the Steering Committee, the level of participation of individual sites, and the availability of funds. Awards and level of support depend on receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NIDDK/NIAID/NICHD, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or Principal Investigator should be included with the application. This RFA is a one-time solicitation. At this time, the NIDDK/NIAID/NICHD have not determined whether or how this solicitation will be continued beyond the present RFA. FUNDS AVAILABLE Approximately $4.6 million in total costs per year will be committed to provide personnel and supplies to the Clinical Centers in order to complete DPT-1 and initiate planning for future studies conducted within the Type 1 Diabetes TrialNet, with a cap of approximately $228,000 per clinical center per year in total costs. For Clinical Centers that previously participated in DPT-1, initial year funding will be allocated based on the success that Clinical Centers (and associated network sites) have had in recruitment and retention of DPT-1 participants and on numbers of network sites that Clinical Centers must administer. These costs do not include expenses for patient care, additional funds in the amount of approximately $725,000 per year will be provided to TrialNet Clinical Centers for patient care costs related to the screening, treatment, and follow-up of patients in the DPT-1. The funds allocated for patient care will be managed centrally by the clinical cost reimbursement system of the TrialNet’s core support facilities. Initial awards to the Clinical Centers will be in support of completion of DPT-1. Subsequently, as additional studies are developed by the TrialNet Steering Committee (see Special Requirements, Study Organization below), additional funds will be provided. Proposed budgets should include costs for personnel and supplies to support completion of the DPT-1. Proposed budgets should not include costs for patient care. In addition, proposed budgets should not include anticipated costs to support pilot and expanded studies because final design of these studies and allocation of costs will need to be determined by the Type 1 Diabetes TrialNet Steering Committee and the NIDDK. Ancillary studies will not be funded through this mechanism, however, interested investigators may seek funding through investigator-initiated grants and the ITN (www.immunetolerance.org). Investigators interested in mechanistic studies involving patients and patient materials in the DPT-1 or Type 1 Diabetes TrialNet may also consider funding through the Hyperaccelerated Award/Mechanisms in Immunomodulation Trials (RFA AI-00- 005). It is anticipated that up to 20 awards for Clinical Centers will be issued. Past participation in the DPT-1 is not a prerequisite for participation in the Type 1 Diabetes TrialNet. Nine clinical centers are currently supported for conduct of DPT-1 and are expected to compete for these awards. Institutions that have participated in the DPT-1 as Affiliates or Satellites of these Clinical Centers, Regional Recruitment Coordinating Centers, Minority Recruitment Centers, and other sites not previously participating in the DPT-1, may apply for Clinical Center awards. Institutions and investigators not participating in DPT-1 but with access to patient populations and with scientific expertise relevant to TrialNet are encouraged to apply in response to this solicitation. RESEARCH OBJECTIVES Background 1) Diabetes Prevention Trial for Type 1 Diabetes (DPT-1) 1.1) DPT-1 Objectives and Design Type 1 diabetes arises in genetically predisposed individuals as a consequence of immune-mediated destruction of the pancreatic islet insulin secreting beta cells. The onset of clinical symptoms of diabetes represents the endpoint of a chronic progressive decline in beta cell function, and occurs when the majority of beta cells have been lost. First-degree relatives of probands with type 1 diabetes have more than a tenfold risk of type 1 diabetes compared with the general population. Type 1 diabetes can be predicted with a high degree of accuracy in relatives of patients with type 1 diabetes by the presence of autoantibodies and evidence of pancreatic beta-cell dysfunction. The major objective of the ongoing DPT-1 is to determine whether early intervention using antigen-based therapies (parenteral or oral insulin) in nondiabetic relatives of persons with type 1 diabetes can delay the development of type 1 diabetes as a clinical disease. The rationale for initiating the DPT-1 was based on several lines of evidence. Parenteral insulin had been successfully used to prevent diabetes in animal models of spontaneous diabetes (e.g., BB rat, NOD mouse). In humans, intensive insulin therapy in newly-diagnosed diabetic patients had preserved beta- cell function, and small pilot studies of prediabetic patients suggested that insulin treatment may delay development of type 1 diabetes. In these studies, it was thought that exogenous insulin may be serving as an immune modulator or may be decreasing the expression of secretory granule-associated antigens from the beta-cells, making them less susceptible to immune attack. Oral insulin had been studied in the NOD mouse model of type 1 diabetes, these studies demonstrated that oral administration of islet cell autoantigens was effective in delaying the onset of type 1 diabetes. In addition, ingestion of glutamic acid decarboxylase (GAD), a beta-cell antigen, by NOD mice also inhibited the development of diabetes. These results suggested that tolerance provoked by presentation of oral insulin or GAD to the immune system via the intestinal mucosa could attenuate pancreatic islet autoimmunity, leading to a delay in the onset of type 1 diabetes. Initial screening for DPT-1 is being conducted by determining the presence of islet cell autoantibodies (ICA) in nondiabetic relatives of individuals with type 1 diabetes. Those individuals found to have ICA are then staged into different categories of risk for type 1 diabetes, depending on their point in the progression to clinical disease. This further assessment of risk of type 1 diabetes in nondiabetic relatives is based on a number of factors, including: genetic susceptibility, the presence of insulin autoantibodies (IAA), and the degree of loss of first phase plasma insulin response (FPIR) during an intravenous glucose tolerance test. Individuals with a protective HLA haplotype are excluded from study. High risk relatives are those who have been predicted to have a greater than 50% probability of developing type 1 diabetes within the next 5 years based on being positive for ICA and having a low FPIR. Intermediate Risk relatives are those who have been predicted to have a 25-50% risk of type 1 diabetes during the next 5 years based on being positive for ICA and also for IAA, but not having a low FPIR. Relatives at lower risk lack IAA and do not have a low FPIR. Subjects were divided into predictive risk groups to permit different intervention strategies to be applied based on their stage in the progression of the disease. The more invasive therapeutic approach with parenteral administration was tested in the group with the higher estimated risk of type 1 diabetes. In the High Risk group, the protocol is designed to determine whether parenteral insulin therapy, consisting of daily subcutaneous insulin injections with an accompanying annual course of continuous intravenous insulin, will delay the expected development of clinical type 1 diabetes. Subjects are being randomized to either the experimental treatment group or closely monitored (control) group who will be carefully assessed and offered treatment at the earliest sign of clinical diabetes. The intervention protocol for the Intermediate Risk group is designed to determine whether orally-ingested insulin can induce immunological tolerance, thereby delaying the development of type 1 diabetes. Subjects are being randomized to either the experimental treatment group or placebo-controlled group. Randomized participants are followed at six- month intervals. Subjects who are ICA positive but who are at lower risk of type 1 diabetes are not being enrolled in the study but are being followed for progression to intermediate or high risk with the opportunity for enrollment at that stage. The design of DPT-1 requires the enrollment of 340 High Risk and 490 Intermediate Risk subjects. Screening for the trial began in September 1993. Subjects were first randomized to the High Risk protocol in December 1994 and to the Intermediate Risk protocol in September 1996. Participants are to be followed for at least two years and up to approximately 6 years. As of July 2000, the recruitment for the High Risk protocol is approximately 95% complete and for the Intermediate Risk protocol is approximately 55% complete. Recruitment is expected to be completed by the end of 2002. 1.2) DPT-1 Clinical Centers and Networks, Core Support Facilities Nine parent Clinical Centers are participating in the DPT-1. Parent Clinical Centers are involved in screening, staging, enrolling, and following study participants. Each Clinical Center provides administrative support for its own network of Affiliates and Satellites. In total, there are approximately 350 Affiliates and Satellites participating in DPT-1 across the United States, Canada, and Puerto Rico. Affiliates screen, stage and follow participants, while Satellites are involved only in screening. In addition, there are designated regional recruitment coordinating centers which provide local outreach to underserved geographic areas of the country to enhance recruitment, as well as minority recruitment centers which focus on increased recruitment of these population subgroups. Current core support facilities of the DPT-1 include the Operations Coordinating Center (OCC), the Data Monitoring Unit (DMU), Core Laboratories, a Compounding Pharmacy, the Central Distribution Pharmacy, a consultant firm that provides the central telephone line and publicity/recruitment support, and the clinical cost reimbursement system. The OCC coordinates all interactions between the core support facilities, Clinical Centers and associated networks of Affiliates and Satellites, sponsoring agencies, study committees, and consultants. The OCC also develops and/or maintains financial management plans and all study protocols, manuals, agendas, and newsletters. The DMU is responsible for all study data management and statistical considerations. In addition, the DMU tracks clinical tests performed within the DPT-1 and provides this information to two fiscal cluster facilities that distribute payments to the appropriate Clinical Centers/Affiliates/Satellites. The core laboratories include the Islet Cell Antibody Laboratory, the Insulin Autoantibody Laboratory, the Class II Major Histocompatibility and DNA Extraction Laboratory, and the Beta Cell Function Laboratory. The Central Distribution Pharmacy dispenses all therapeutic agents and placebos in DPT-1 studies. It receives crystallized insulin and placebo in capsules from the separate compounding pharmacy. DPT-1 is presently funded through August 2001. The trial is jointly supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, the National Center for Research Resources through funding of General Clinical Research Centers, the American Diabetes Association, the Juvenile Diabetes Foundation International, and industry. 2.) Studies of New Immunologic Agents and Other Preventive and Treatment Strategies In recognition of the seriousness of diabetes in terms of both human toll and economic costs, Congress directed the establishment of the Diabetes Research Working Group (DRWG) and charged it with developing a comprehensive plan for diabetes research. During 1998, the DRWG and its subcommittees held a series of meetings, consulted with a wide range of experts in the field, and heard public commentary. A comprehensive strategic research plan was submitted to Congress in 1999 (http://www.niddk.nih.gov/federal/dwg/dwgsummary.htm). As part of the plan, the DRWG identified areas of extraordinary opportunity for making genuine and significant progress toward understanding, more effectively treating, and ultimately preventing and curing diabetes. Among these opportunities was the recommendation to define the immunological basis of type 1 diabetes and develop methods for prevention of the disease. Specific recommendations included: to intensify research to understand the immunological basis of type 1 diabetes, to complete mapping of T cell specificity of autoimmune responses to major pancreatic islet cell proteins and identify optimal strategies for immunotherapy, to expand the scope of efforts to identify immune response markers that reliably detect individuals predisposed to type 1 diabetes in the population at large, and to conduct additional clinical trials of immunoprevention of type 1 diabetes using antigen-specific, cytokine- or antibody-based immunotherapy. In response to these recommendations, the NIDDK and DPT-1 investigators have convened meetings to consider future natural history, pilot and intervention studies. A number of ideas were generated. Potential cohorts for study include: patients with type 1 diabetes who have evidence of residual pancreatic beta-cell function, individuals found to have biochemical antibodies in an ancillary study of the DPT-1 cohort, who do not meet eligibility criteria for the DPT-1, individuals found to be ICA positive in the DPT-1, who lack other beta-cell antibodies and have an intact first phase insulin response, individuals found during staging for the DPT-1 to be positive for protective HLA-haplotypes, individuals found to have diabetes during staging, and randomized DPT-1 subjects who develop diabetes on follow-up. Examples of potential agents to prevent or ameliorate type 1 diabetes include antigen-based therapies such as recombinant human GAD65 and the heat shock protein hsp60 p277 peptide, monoclonal antibodies such as anti-CD3 and anti-CD25, and certain cytokine-based therapies. Multiple pilot, feasibility, and efficacy studies could be done simultaneously to test promising agents in patients with type 1 diabetes who have evidence of residual beta cell function (including DPT-1 subjects who develop diabetes during follow- up), or in patients identified in the screening process for DPT-1 who are not eligible for the trial. Loss of C-peptide secretion would be a suitable design endpoint for such studies. On the basis of these pilot studies, expanded intervention studies might be launched in new-onset type 1 diabetic individuals to assess beta-cell function over time and ultimately in at-risk pre-diabetic individuals to prevent development of diabetes. 3.) Type 1 Diabetes TrialNet The Diabetes Research Working Group also noted that clinical research and clinical trials in diabetes have been hampered by the lack of infrastructure to organize and support them. The long-term natural history of the disease and its complications add to the complexity of clinical trials. Needed are efficient systems for clinical research to provide the necessary numbers of patients and the stability of operations for long-term studies, and opportunities to include sufficient numbers of appropriate minority groups. To that end it was recommended that there be established a national diabetes trial network of cooperative clinical research groups to create the stable, high-quality infrastructure necessary for the conduct of effective and efficient clinical trials in diabetes. The established network in the DPT-1 of Clinical Centers, Affiliates and Satellites is an excellent platform on which to build an enhanced network that could comprise the Type 1 Diabetes TrialNet. Currently there are nine parent Clinical Centers participating in screening, staging, randomization, and follow-up of volunteers in the DPT-1. Each Clinical Center provides administrative management and training for an extended network of institutions and physicians, including Affiliates that also screen, stage, randomize, and follow volunteers, as well as Satellites that screen potential participants. Expansion of the number of Clinical Centers and associated Affiliates and Satellites would enhance recruitment of subjects for the DPT-1 and future Type 1 Diabetes TrialNet studies. 4.) Potential Genetics Studies using Type 1 Diabetes TrialNet An additional extraordinary opportunity identified by the Diabetes Research Working Group was the study of the genetics of diabetes and its complications. While it was recognized that most of the basic tools for genetic studies were in place and that much progress had been made, it was noted that current approaches were inadequate to tackle vital genetics questions in a reasonable time frame. Impediments cited were inadequate resources, the lack of an appropriate mechanism to bring together groups of researchers and patient samples to conduct studies, and fragmented genetic repositories. The DPT-1 study population and populations identified by the Type 1 Diabetes TrialNet may be fruitful groups to study predisposing genes to type 1 diabetes and diabetic complications. While it has not been determined whether or how such studies might be implemented, samples and associated data from participants of the DPT-1 and TrialNet may be entered into genetic repositories for use by investigators inside or outside the TrialNet. Objectives and Scope The first objective of the Type 1 Diabetes TrialNet is to create an infrastructure that will enhance recruitment and follow-up of subjects in the DPT-1 and facilitate investigation of promising new approaches to prevent or ameliorate type 1 diabetes. To accomplish this, each Clinical Center will have a Principal Investigator, a Trial Coordinator, and a Recruitment Coordinator, at a level of effort to be determined by the number and scope of trials underway. Initially, each Clinical Center will be responsible for implementation of the protocols of the DPT-1, including screening and staging of potentially eligible individuals, and randomization and follow-up of participants. Screening of subjects involves identifying eligible subjects for screening (relatives of individuals with type 1 diabetes, either first-degree relatives age 3-45 years or second-degree relatives age 3-20 years), obtaining informed consent, obtaining blood to determine the presence of islet cell antibodies (ICAs), and collecting demographic and contact information. Those individuals found to be ICA-positive are eligible for staging which involves obtaining informed consent, performing intravenous glucose tolerance (IVGTT) and oral glucose tolerance tests (OGTT), and drawing samples for insulin autoantibodies (IAA) and HLA-typing. Confirmatory tests are also required. For those individuals eligible for randomization, informed consent is again obtained and additional tests are performed, including the Wide Range Achievement Test (WRAT), an IVGTT and/or mixed meal tolerance test (MMTT), an OGTT, a 4-day insulin infusion (parenteral insulin arm), and blood draws for measuring blood glucose and HbA1c. A physical examination is performed and medical and family history data are obtained. Randomized subjects are followed every 6 months, at which time many of these same tests are performed and additional medical history is obtained. Clinical Centers and their associated Affiliates/Satellites will be reimbursed for medical tests performed during screening, staging, randomization, and follow-up at rates determined by the NIDDK. Each Clinical Center should have access to an NIH supported General Clinical Research Center (GCRC) or equivalent facility to support inpatient study costs occurring during staging and follow-up in the DPT-1 and in future studies conducted in the TrialNet. An equivalent GCRC facility is defined as dedicated inpatient beds staffed by personnel experienced in the conduct of research protocols and in performance of intravenous insulin infusions, with institutional commitment to provide such beds at no extra expense to the TrialNet. GCRCs also provide support for outpatient testing. For the DPT-1, Clinical Centers will collaborate with the Operations Coordinating Center, the Data Monitoring Unit, the Core Laboratories (Islet Cell Antibody Laboratory, Insulin Autoantibody Laboratory, Class II MHC and DNA Extraction Laboratory, and Beta-Cell Laboratory), the Central Distribution Pharmacy, as well as the Affiliates and Satellites. The Principal Investigator, Trial Coordinator, and Recruitment Coordinator will work with the Operations Coordinating Center, the Chair of the Steering Committee, other Steering Committee members, NIH staff, and Study Committees to conduct the study in accordance with the DPT-1 Protocol and Manual of Operations. (The Steering Committee and Chair of the Steering Committee are defined under SPECIAL REQUIREMENTS, Study Organization.) Clinical Centers and their network of Affiliates and Satellites are expected to meet patient recruitment goals as specified by the DPT-1 Study Group. To accomplish this, Clinical Centers and their network of Affiliates and Satellites are expected to develop and maintain successful outreach activities that identify eligible participants and that result in randomization and retention of participants. Clinical Centers will work with their Affiliates and Satellites, the Operations Coordinating Center, Data Monitoring Unit, and all Core Laboratories to achieve and maintain quality data that are obtained within expected timeframes. Clinical Centers will provide administrative support, supervision, and training for their Affiliates and Satellites, and will be responsible for completion of certification requirements of their Affiliates and Satellites for certain study tests. Affiliates of Clinical Centers should be medical centers with the capability to screen patients, perform tolerance tests (intravenous glucose, oral glucose and mixed meal) and conduct the two intervention protocols of the DPT-1. Affiliates must have available a GCRC or equivalent facility, and must obtain certification to perform intravenous insulin infusions from the parent Clinical Center. Affiliates must sign a Letter of Agreement that outlines the details of their participation in the study. Clinical Centers will provide oversight of Affiliates and the activities of the Affiliates will be intertwined with those of the parent Clinical Center. Affiliates will not receive core funding but will be reimbursed for patient tests performed during screening, staging, and randomization at rates set by the NIDDK. Each Affiliate must be directed by a Principal Investigator who is a physician. Affiliates are encouraged to participate on Study Committees. Affiliates may have the opportunity to convert to a Clinical Center based on the ability to screen, enroll, and retain substantial numbers of subjects, having access to a GCRC or equivalent facility, and other criteria, if approved by the TrialNet Steering Committee, and as funds permit. Satellites will be sites involved only in screening eligible volunteers. Clinical Centers will provide oversight of Satellites and the activities of the Satellites will be intertwined with those of the parent Clinical Center. Satellites will not receive core funding but will be reimbursed for screening tests at rates set by the NIDDK. Staging and randomization of subjects originally screened at a Satellite will take place at an Affiliate or Clinical Center closest to the subject geographically, or at the parent Clinical Center. Satellites are encouraged to participate on Study Committees. Clinical Centers, Affiliates, and Satellites must conform to the guidelines of the Office of Human Research Protections (OHRP) by obtaining an assurance, having an institutional review board (IRB) of record, and obtaining IRB approval annually. They must also comply with NIH policies on inclusion of minorities, both genders, and children in clinical research. A second objective of each parent Clinical Center and network of Affiliates and Satellites is to perform pilot and expanded intervention studies of new agents to prevent or ameliorate type 1 diabetes as well as natural history and genetics studies in populations identified by the DPT-1 and Type 1 Diabetes TrialNet. Applicants should submit proposals for a clinical protocol to be carried out by the TrialNet. Study procedures for future clinical trials will be determined as potential agents are selected and studies are designed. Study procedures for these studies may be similar to those used in the DPT-1, although the population for study will likely differ, for example, future populations for study may be individuals with recent onset type 1 diabetes (See Research Objectives, Background, under Studies of New Immunologic Agents and Other Preventive and Treatment Strategies). It is anticipated that multiple pilot studies would be performed simultaneously to test the feasibility of promising agents. On the basis of these pilot studies, expanded intervention studies might be launched in new-onset type 1 diabetic individuals to assess beta-cell function over time and in at- risk pre-diabetic individuals to prevent the development of diabetes. The Type 1 Diabetes TrialNet may draw on positive findings from studies of agents tested in the Immune Tolerance Network (http://www.immunetolerance.org). It is anticipated that many of the pilot and expanded intervention studies performed in the TrialNet will be proposed through this RFA. The TrialNet Steering Committee will refine the design and implement these studies. After awards are made in response to this RFA, research proposals for pilot and expanded intervention studies requiring TrialNet resources may be submitted by non-members of the TrialNet (see Eligibility Requirements above). The mechanism for receiving and evaluating future proposals, and prioritizing studies, will be determined by the TrialNet Steering Committee. The NIDDK expects that biologic samples and associated clinical data will be made available to the broader scientific community at an appropriate juncture to support further studies related to the prevention and etiology of type 1 diabetes, and in studies to identify genes predisposing to diabetes and its complications. SPECIAL REQUIREMENTS To promote the development of a collaborative program among the award recipients, Principal Investigators, trial coordinators, and recruitment coordinators are expected to attend DPT-1 and Diabetes TrialNet Steering Committee meetings where new studies will be designed, study progress will be monitored, issues related to study protocol and operations will be discussed, and ideas will be exchanged to enhance study progress. For established clinical trials, twice a year meetings are anticipated but more frequent meetings may be required for development of new protocols. Trial coordinators and recruitment coordinators will meet on a regular basis by conference call, generally monthly, to discuss recruitment issues and study operations. Clinical Center Principal Investigators will also meet on a regular basis by conference call to discuss emerging issues. Clinical Center Principal Investigators, trial coordinators, and recruitment coordinators will be asked to serve as chairpersons or members of Study Committees as needed. Affiliate and Satellite staff may also be invited to participate in Study Committees. Site visits by members of the DPT-1 and Type 1 Diabetes TrialNet Study Group or the external Data Safety and Quality Monitoring Groups may be required to assess and improve methods used for recruitment/retention of participants and for data collection. Each Clinical Center applicant should have access to an NIH supported General Clinical Research Center (GCRC) or equivalent facility to support inpatient study costs occurring during staging and follow-up in the DPT-1 and in future studies conducted in the TrialNet. An equivalent GCRC facility is defined as dedicated inpatient beds staffed by personnel experienced in the conduct of research protocols and in performance of intravenous insulin infusions, with institutional commitment to provide such beds at no extra expense to the TrialNet. GCRCs also provide support for outpatient testing. The design and implementation of new intervention, natural history, and genetics studies under the Type 1 Diabetes TrialNet will be determined by the Steering Committee and will occur after Clinical Centers are selected and awards are made. Because the Principal Investigators will serve as voting members of the Steering Committee and will play a major role in the design of future studies, a significant aspect of review of applications will be the extent to which investigators can contribute to this process. Therefore applicants are required to propose one intervention study that could be carried out under the TrialNet. Natural history and genetics studies should not be proposed. These proposals should include the scientific rationale for the study proposed, the population to be studied, eligibility and exclusion criteria for the study, patient recruitment and data collection methods, primary and secondary endpoints to be determined, and a discussion of the sample size required given associated assumptions. The scientific rationale should include a discussion of what is the current state-of-the-art , future opportunities, and obstacles in the prevention of type 1 diabetes, and discuss how the field may best be moved forward. Study Organization The Type 1 Diabetes TrialNet, or TrialNet, will be a national network of cooperative clinical research groups, consisting of a consortia of clinical centers and core support facilities, whose aim is to recruit patients and to support studies that may eventually result in an improved understanding of type 1 diabetes and the prevention of the disease. Each Clinical Center will receive funding through a separate U01 award mechanism. Each Clinical Center will have responsibility for its associated network of Affiliates and Satellites as described above. Functions of the Clinical Centers have been described above under Objectives and Scope . In addition to the Clinical Centers and their networks, the Type 1 Diabetes TrialNet will include the Operations Coordinating Center, Data Management Unit, Compounding Pharmacy, Central Distribution Pharmacy, and Core Laboratories. A complementary RFA solicits proposals for these core support facilities (DK-01-004). Design, monitoring and analysis of the studies will be the responsibility of the Steering Committee (defined below) and will be accomplished through sub-committees. The Operations Coordinating Center has both scientific and administrative functions. Scientific functions include preparing and updating protocols and manuals of operations, developing meeting agendas, documenting minutes of meetings, overseeing the performance of quality control, and coordinating manuscript preparation and submission. Administrative functions include coordinating interactions among the Clinical Centers, and between the Data Management Unit, Core Laboratories, consultant firm providing the central telephone line and publicity/recruitment support, and NIH Staff, assisting in financial management of the study, overseeing subcontracts to other core facilities, such as the Core Laboratories, the Compounding Pharmacy, and consultant firm, and providing a mechanism for communication among investigators by developing newsletters, scheduling meetings and conference calls, and maintaining membership rosters and committee lists. The Data Management Unit (DMU) is responsible for all data management and statistical considerations for the DPT-1 and Type 1 Diabetes TrialNet. The DMU also has both administrative and scientific functions. The administrative functions include providing for central registration and random assignment of all individuals enrolled in trials, preparing data management aids, receiving and maintaining participant data, serving on all DPT-1 and TrialNet administrative committees, and coordinating with the Central Distribution Pharmacy and patient care cost reimbursement system. Scientific functions include the review of all proposed protocols and development of the statistical design for each study, analysis of study results, review of all manuscripts for statistical considerations, development and testing of predictive models for disease progression, providing statistical reports on progress of trials at all meetings, and conduct of statistical research concerning intervention trials in type 1 diabetes. The Central Distribution Pharmacy dispenses all therapeutic agents and placebos to Clinical Centers in a masked manner as directed by the DMU. Currently for DPT-1, it receives crystallized insulin and placebo from a separate compounding pharmacy. There are four Core Laboratories in the DPT-1. The Islet Cell Antibody Laboratory serves as the central laboratory for measuring various autoantibodies to islet cell markers, and for measurement of anti-islet cellular immunity. The Insulin Autoantibody Core Laboratory serves as the central laboratory for measurement of insulin autoantibodies. The Class II MHC Laboratory extracts and preserves DNA from all subjects staged for eligibility for enrollment in intervention protocols, and determines the presence of HLA-DQA1*0102, DQB1*0602 which is being used to exclude individuals who have this protective haplotype. The Class II MHC Laboratory may provide more complete class II HLA typing of all individuals entered into trials, as well as other genetic markers that influence susceptibility or progression of type 1 diabetes. The Beta Cell Function Laboratory serves as the central laboratory for assessing beta cell function by measurement of immunoreactive insulin and C- peptide, plasma glucose, and glycosylated hemoglobin HbA1c. New studies performed within the TrialNet may require additional core laboratory measurements. Core laboratory support may be consolidated under fewer laboratories if deemed possible and advantageous. Assay cores of the Immune Tolerance Network may also be used for assessments in the TrialNet. The Steering Committee has overall responsibility for the design, planning, execution, and publication of the research performed by the DPT-1 Study Group and Type 1 Diabetes TrialNet. The Steering Committee will approve all protocols, changes to protocols, and manuals of operations. It will define subcommittees, develop study policies, receive and act upon reports of subcommittees and review matters relevant to administrative, financial, medical, legal, and ethical considerations of studies. The Steering Committee will maintain surveillance of DPT-1 and Type 1 Diabetes TrialNet performance and, together with the NIDDK/NIAID/NICHD, is responsible for the addition or deletion of Clinical Centers. At the present time, voting members of the DPT-1 Steering Committee include each of the directors of the Clinical Centers, the director of the Operations Coordinating Center, the director of the Data Management Unit, each of the directors of the Core Laboratories, and the three representatives from the NIDDK, NIAID, and NICHD. The chair of the Planning Committee is also a voting member, the Planning Committee is responsible for coordinating other Working Committees and integrating the Working Committees input into the DPT-1 Steering Committee agenda. (Examples of current Working Committees are the Eligibility and Events Committee, Treatment Committee, Ancillary Studies Committee, Clinical Center Directors Committee, and Trial Coordinators Committee. Members of the Planning Committee consist of the Chair of the Steering Committee, Chairs of each Working Committee, and Operations Committee members. The Operations Committee consists of the Chair of the Steering Committee, and a representative from the Operations Coordinating Center, the Data Monitoring Unit, and the NIDDK. The Operations Committee selects the Chair of the Planning Committee.) The NIDDK will select a chairperson for the DPT-1 and Type 1 Diabetes TrialNet Steering Committee from among Study Group members or other experts in clinical trials in type 1 diabetes. The NIDDK may appoint a new Chairperson of the TrialNet once the DPT-1 is completed. The Chairperson of the Steering Committee is responsible for the overall administration and science of the DPT-1 and Type 1 Diabetes TrialNet activities by: reviewing all concepts for science and feasibility, reviewing all protocols prior to implementation, reviewing all manuscripts, posters, and abstracts prior to publication, monitoring committee activities, assuring compliance with protocol requirements, observing and enforcing all DPT-1 and TrialNet policies and guidelines, and facilitating performance of institutions and centers participating in the DPT-1 and TrialNet. It is anticipated that many of the pilot and expanded intervention studies performed in the TrialNet will be proposed through this RFA. The TrialNet Steering Committee will refine the design and implement these studies. After awards are made in response to this RFA, research proposals for pilot and expanded intervention studies requiring TrialNet resources may be submitted by non-members of the TrialNet (see Eligibility Requirements above). The mechanism for receiving and evaluating future proposals, and prioritizing studies, will be determined by the TrialNet Steering Committee. These competitions will be fair and open, and may involve external reviewers. The Data Safety and Quality Monitoring Group (DSQ) is an external oversight committee of the DPT-1 appointed by the NIDDK and is composed of members not directly involved in the study. The DSQ monitors the conduct and results of the DPT-1 study for safety and efficacy, with authority to recommend protocol or procedural changes or early termination of the study. The DSQ is advisory both to the NIDDK and to the DPT-1 Steering Committee. The NIDDK may also appoint members to an external oversight committee for natural history, genetics, and intervention studies conducted in the Type 1 Diabetes TrialNet. In addition to DSQ review, NIDDK may obtain review by external advisory groups to provide additional expertise pertaining to the design and implementation of natural history, genetics, and intervention studies to be conducted under TrialNet. The NIDDK expects that biologic samples and associated clinical data will be made available to the broader scientific community at an appropriate juncture to support further studies related to the prevention and etiology of type 1 diabetes, and in studies to identify genes predisposing to diabetes and its complications. The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator(s) as well as the institutional official at the time of award. TERMS AND CONDITIONS OF AWARD The Type 1 Diabetes TrialNet, or TrialNet, will be a national network of cooperative clinical research groups, consisting of a consortia of clinical centers and core support facilities, whose aim is to recruit patients and to support studies that may eventually result in an improved understanding of type 1 diabetes and the prevention of the disease. These special Terms of Award 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, PHS, and NIH Grant Administration policy statements. The administrative and funding instrument used for this program is a cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee(s) is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient"s activity by involvement in 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 dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NIDDK/NIAID/NICHD Program Officers. 1. Awardee Rights and Responsibilities Awardees will have primary and lead responsibilities for the DPT-1 and future studies performed in the Type 1 Diabetes TrialNet, including research design and protocol development and modification, participant recruitment and follow-up, data collection and adherence to protocol, quality control, interim data and safety monitoring, final data analysis and interpretation, and preparation of publications, with assistance from the NIDDK/NIAID/NICHD Program Officers. Awardees will collaborate with all individuals involved in conducting the DPT-1 and TrialNet studies, with investigators conducting ancillary studies, and with the NIDDK/NIAID/NICHD Program Officers. Modifications to the protocols will be approved by the Steering Committee. Clinical Centers and their networks of Affiliates and Satellites are expected to meet patient recruitment goals as specified by the DPT-1 and TrialNet Steering Committee. Performance measures, such as patient recruitment, data acquisition and transmission, use of budget, and timeliness of progress reports are expected to be assessed by the DPT-1 and Type 1 Diabetes TrialNet Steering Committee and subcommittees, and NIDDK/NIAID/NICHD, and may provide information needed to support future funding decisions. The inability to meet performance requirements and responsibilities may result in an adjustment of funding, withholding of support, restriction of funds already awarded, or suspension or termination of the award. The Operations Coordinating Center, Data Monitoring Unit, and Core Laboratories, together with the Clinical Centers and associated networks, must achieve and maintain quality data in accordance with the common protocols and manuals of operations specified by the DPT-1 and Type 1 Diabetes TrialNet Steering Committee. Clinical Centers will work with their Affiliates and Satellites, the Operations Coordinating Center, the Data Monitoring Unit, and Core Laboratories to achieve and maintain quality data in accordance with the common protocols and manuals of operations specified by the DPT-1 and Type 1 Diabetes TrialNet Steering Committee. The data must be obtained within expected timeframes as set by the DPT-1 and TrialNet Steering Committee. In addition, all study data must be transmitted continuously to the Data Monitoring Unit according to the timeframes specified by the Steering Committee. Clinical Centers will provide administrative support, supervision, and training for their Affiliates and Satellites. Affiliates must sign a Letter of Agreement that outlines the details of their participation in the study. All study investigators must agree to implement and adhere to an adverse event tracking system as designed by the DPT-1 Study Group and Type 1 Diabetes TrialNet Steering Committee. Awardees must provide periodic financial and administrative reports required by NIH for administration of cooperative agreements. The Operations Coordinating Center must provide an overall summary of study progress on an annual basis. As members of the DPT-1 and Type 1 Diabetes TrialNet Steering Committee, awardees will retain custody of and have primary rights to the data and biologic specimens developed and obtained under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. The NIDDK expects that biologic samples and associated clinical data will be made available to the broader scientific community at an appropriate juncture to support further studies related to the prevention and etiology of type 1 diabetes, and in studies to identify genes predisposing to diabetes and its complications. The Operations Coordinating Center and Data Monitoring Unit will be expected to put all study intervention materials and procedures manuals in the public domain and/or make them available to other investigators. Prompt and timely presentation and publication in the scientific literature of findings resulting from research undertaken by the DPT-1 and Type 1 Diabetes TrialNet is required. Awardees must agree to acknowledge NIH support in the publications and oral presentations resulting from research conducted under the cooperative agreements. Manuscripts and presentations will be written and reviewed according to the policies and procedures set forth by the DPT-1 and TrialNet Steering Committee. Awardees must conform to the guidelines pertaining to the accrual of women and minorities as subjects in clinical research, and the reporting of results in these subgroups, as specified in the NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research. The NIDDK will select the Chairperson of the Steering Committee. This individual must not have responsibility for recruitment or follow-up of study participants. If a study investigator is selected as a Chairperson, he/she must designate a replacement investigator at his/her institution. The Chairperson must have proven evidence of leadership ability and adequate time commitment for DPT-1 and/or Type 1 Diabetes TrialNet activities. Core Laboratory Directors and the Director of the Data Monitoring Unit must not have responsibility for recruitment or follow-up of study participants. A Clinical Center and its institution may not be involved simultaneously in the DPT-1, other TrialNet protocols, and in studies not affiliated with TrialNet if enrollment criteria overlap between studies and if the studies are actively recruiting participants. Applicants should indicate their willingness to forego participating in studies that would compete for recruitment to the same study population. This restriction does not apply to Affiliates and Satellites. NIDDK may consider exemptions from this policy to allow institutions to participate in pilot studies of the ITN. 2. NIDDK and Other NIH Staff Responsibilities The NIDDK Program Officer and NIAID and NICHD Program Officers will provide scientific support to the awardees activities including protocol development and modification, quality control, interim data monitoring, final analysis, preparation of publications, and performance monitoring. Consistent with the cooperative agreement nature of this study, the Program Officers will be substantially involved as active partners in those aspects of the scientific and technical management of the trial as described in these Terms and Conditions. This level of involvement will be above and beyond the levels required for administration of traditional research grants. The NIDDK/NIAID/NICHD Program Officers each will have voting membership on the Steering Committee, and as appropriate, its subcommittees. The NIDDK will appoint the Chairperson of the DPT-1 and TrialNet Steering Committee from among investigators of the studies or other experts in clinical trials in type 1 diabetes. The NIDDK may appoint a new Chairperson of the TrialNet once the DPT-1 is completed. The NIDDK will maintain and appoint members of the Data Safety and Quality Monitoring Group and other external advisory groups as necessary for proper oversight of DPT-1 and TrialNet activities. The Data Safety and Quality Monitoring group, appointed by NIDDK, will provide overall monitoring of interim data and safety issues, and can advise the NIDDK/NIAID/NICHD on changes to protocol, elimination of Clinical Centers/Affiliates/Satellites, and study termination, if warranted. These meetings will be held twice per year. The NIDDK/NIAID/NICHD Program Officers, on behalf of their NIH Institutes, will have the same access, privileges and responsibilities regarding the collaborative data as the other members of the DPT-1 and Type 1 Diabetes TrialNet Steering Committee. The NIDDK, in consultation with the NIAID and NICHD, reserves the right to terminate or curtail the study (or an individual award) in the event of substantial shortfall in participant recruitment, follow-up, data reporting, quality control, or other major breach of the protocol. The NIDDK may terminate or curtail the study if a major study endpoint is reached substantially before schedule with persuasive statistical significance, if futility in reaching a significant difference between treatment groups is realized, if there is emergence of new information that diminishes the scientific importance of the study question, or if human subject safety or ethical issues dictate a premature termination. The NIDDK may also terminate the project in the event of a failure to develop or implement mutually agreeable collaborative protocols for the Type 1 Diabetes TrialNet or if there are substantial changes in the agreed-upon protocols with which the NIDDK cannot concur. 3. Collaborative Responsibilities The Steering Committee is composed of the Principal Investigator(s) of each Clinical Center, the director of the Operations Coordinating Center, the director of the Data Management Unit, each of the directors of the Core Laboratories, the Chair of the Planning Committee and the three representatives from the NIDDK, NIAID, and NICHD. (The Planning Committee is responsible for coordinating other Working Committees and integrating the Working Committees input into the Steering Committee agenda. Examples of current Working Committees are the Eligibility and Events Committee, Treatment Committee, Ancillary Studies Committee, Clinical Center Directors Committee, and Trial Coordinators Committee. Members of the Planning Committee consist of the Chair of the Steering Committee, chairs of each Working Committee, and Operations Committee members. The Operations Committee consists of the Chair of the Steering Committee, and a representative from the Operations Coordinating Center, the Data Monitoring Unit, and the NIDDK. The Chair of the Planning Committee is selected by the Operations Committee.) The Steering Committee has overall responsibility for the design, planning, execution, and publication of the research performed as part of the DPT-1 and Type 1 Diabetes TrialNet. External reviewers may be included in the review and planning of new trials in the Type 1 Diabetes TrialNet to gain the necessary expertise required for evaluating and implementing new proposals. The Steering Committee will approve all protocols, changes to protocols, and manuals of operations. Each member of the Steering Committee will have one vote. Subcommittees will be established by the Steering Committee, as it deems appropriate, the NIDDK/NIAID/NICHD Program Officers will serve on subcommittees as they deem appropriate. The Steering Committee will develop and maintain specific measures as outlined in the protocols and manuals of operations to assure the safety and protection of the rights of volunteers involved in the DPT-1 and Diabetes TrialNet. The Principal Investigator for each awardee and investigators at Affiliates and Satellites will assume and accept primary responsibility for ensuring that studies are conducted in compliance with all federal regulations. These include but are not limited to Title 21 CFR 50, 56, 312, and Title 45 CFR 46. All Clinical Centers, Affiliates and Satellites must be able to demonstrate that there is a current, approved Assurance on file with the HHS Office of Human Research Protections (OHRP), that each protocol and informed consent is approved and reviewed annually by the Institutional Review Board (IRB) of record, and that each subject has given written informed consent as set forth in the Study protocols and manuals of operations. The Principal Investigator agrees and assures that adequate records will be available, to enable outside monitors to assess compliance with applicable federal laws and regulations. To promote the development of a collaborative program among the award recipients, Principal Investigators, trial coordinators, and recruitment coordinators are expected to attend DPT-1 and TrialNet Steering Committee meetings. These are anticipated to meet twice a year for established trials but may meet more frequently for development of new protocols. Trial coordinators and recruitment coordinators will meet on a regular basis by conference call, perhaps monthly, to discuss recruitment issues and study operations. Clinical Center Principal Investigators will also meet on a regular basis by conference call to discuss emerging issues. Clinical Center Principal Investigators, trial coordinators, and recruitment coordinators will be asked to serve as Chairpersons or as members of Study Committees as needed. Members of Affiliates and Satellites are encouraged to participate in Committee meetings as well. As members of the DPT-1 and Type 1 Diabetes TrialNet Steering Committee, awardees will retain custody of and have primary rights to the data and biologic specimens developed and obtained under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. The NIDDK expects that biologic samples and associated clinical data will be made available to the broader scientific community at an appropriate juncture to support further studies related to the prevention and etiology of type 1 diabetes, and in studies to identify genes predisposing to diabetes and its complications. The Operations Coordinating Center and Data Monitoring Unit will be expected to put all study intervention materials and procedures manuals in the public domain and/or make them available to other investigators. 4. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NIDDK/NIAID/NICHD may be brought to arbitration. An arbitration panel will be composed of three members: one selected by the Steering Committee (with the NIDDK/NIAID/NICHD members not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NIDDK in consultation with NIAID and NICHD, and the third member selected by the two prior selected members. This 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 regulation 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. Under the statute, when an NIH defined Phase III clinical trial is proposed, evidence must be reviewed to show whether or not clinically important sex/gender and/or race/ethnicity differences in the intervention effect are to be expected. This evidence may include, but is not limited to, data derived from prior animal studies, clinical observations, metabolic studies, genetic studies, pharmacology studies, and observational, natural history, epidemiology and other relevant studies. Cost is not an acceptable reason for exclusion of women and minorities from clinical trials. When planning, conducting, and reporting an NIH defined Phase III clinical trial, it must be considered whether, based on prior studies, one of the following three situations apply: that prior studies support the existence of significant differences, that prior studies support no significant differences, and that prior studies neither support nor negate significant differences. The NIDDK believes that prior studies neither strongly support nor negate significant differences in expected intervention effects by sex/gender and/or race/ethnicity. In this case, the NIH Phase III clinical trial will be required to include sufficient and appropriate entry of sex/gender and/or racial/ethnic subgroups, so that valid analysis of the intervention effect in subgroups can be performed. However, the trial will not be required to provide high statistical power for each subgroup. The Research Plan in the application or proposal must include a description of plans to conduct the valid analyses of the intervention effect in subgroups. The final protocol(s) approved by the IRB(s) must include these plans for analysis. The award will require that the results of subset analyses must be reported to NIH in Progress Reports, Competitive Renewal Applications, and in the required Final Progress Report. Inclusion of the results of subset analyses is strongly encouraged in all publication submissions. If the analysis reveals no subset differences, a brief statement to that effect, indicating the subsets analyzed, will suffice. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research conducted or supported by the NIH unless there are scientific or ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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. URL FOR INFORMATION ABOUT RFA FOR PROSPECTIVE APPLICANTS Information about this RFA may be found at NIDDK’s website http://www.niddk.nih.gov/patient/trialnet.htm. The website links to answers to frequently asked questions (FAQs) that prospective applicants have submitted. Prospective applicants are encouraged to submit their questions to the email address: TrialNet@extra.niddk.nih.gov so that their questions and answers can be made available on the website. LETTER OF INTENT Prospective applicants are asked to submit, by February 28, 2001, a letter of intent that includes a descriptive title of the proposed research, name, address, and telephone number of the Principal Investigator, 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. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information allows NIDDK staff to estimate the potential review workload and plan the review. The Letter of Intent is to be sent to: 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 awards. These forms are available at most institutional offices of sponsored research, from the GrantsInfo, Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, Suite 6095, Bethesda, MD 20892-7910, telephone 301-710-0267, email: GrantsInfo@nih.gov. Additional Materials to Include in the Application Applicants must describe plans to achieve the stated Objectives and Scope , Special Requirements , and Terms and Conditions of Award stated in this RFA. In addition, applicants should address the following issues that are important to the successful development of a collaborative program to promote the DPT-1 and TrialNet. Qualifications and experience. Clinical Center applicants must include a description of investigators and staff with experience and expertise to collaborate in multicenter clinical trials and Phase II and Phase III studies to assess interventions for preventing or ameliorating type 1 diabetes. Applicants should describe their ability to lead clinical trials that could be performed using Type 1 Diabetes TrialNet resources. Applicants must give evidence of their ability to recruit and retain individuals in multicenter clinical trials, and describe their experience with prediabetic or diabetic subjects. Applicants who have participated in the DPT-1 must document the number of subjects screened, staged, randomized and currently under follow-up. Applications from DPT-1 Clinical Centers should provide this information for their network as a whole and also separately for the parent Clinical Center site and the individual Affiliate and Satellite sites. If applicants have particular expertise and accomplishments in recruiting individuals from minority groups, these should be described. Documentation of institutional support for participating in a multicenter clinical trial to prevent type 1 diabetes should be provided in the form of letters of support from the appropriate institution officials. It is important to establish the Principal Investigator’s ability to contribute to the scientific agenda and describe an adequate time commitment of the Principal Investigator (5-20%), Trial Coordinator (100%), and Recruitment Coordinator (50%). Clinical Center applicants that are currently DPT-1 Clinical Centers should list sites capable of performing the responsibilities required of Affiliates and Satellites, as well as associated Principal Investigators, and describe their qualifications and experience in clinical trials and clinical studies in diabetes. Affiliates and Satellites may include HMOs, clinics, or private practice physicians. A Letter of Collaboration Agreement from each Affiliate and Satellite should be included in the appendix. Clinical Center applicants must demonstrate the ability to train and maintain the proficiency of Affiliate and Satellite staff in performing Study operations. Current DPT-1 Affiliates/Satellites or other institutions not currently participating in the DPT-1 that are applying to be a Clinical Center should not recruit current DPT-1 Affiliates or Satellites as network sites for their Clinical Center. The DPT-1 and Type 1 Diabetes TrialNet are likely to redistribute Affiliates and Satellites once Clinical Centers are reviewed and selected. In addition, there will be an effort to recruit new Affiliates and Satellites and these will be distributed among Clinical Centers. For current DPT-1 Affiliates/Satellites applying to be a Clinical Center, a Letter of Collaboration Agreement should also be provided to their current parent Clinical Center, or another Clinical Center of choice, in case the applicant is unsuccessful in obtaining an award. Current DPT-1 Clinical Centers applying to be a Clinical Center should consider providing a Letter of Collaboration Agreement to be an Affiliate to another DPT-1 Clinical Center in case they are unsuccessful in obtaining a Clinical Center award. Affiliates and Satellites must not agree to be a network site to more than one Clinical Center applicant. Study populations. Clinical Center applications must discuss the number of type 1 diabetic patients to which the Center has access, so that they or their relatives may be approached about the DPT-1 and Type 1 Diabetes TrialNet. Applicants should also describe the study populations of their proposed Affiliates and Satellites (if applicable). A description of the pool of patients with type 1 diabetes, along with their demographic characteristics such as age range and ethnic/racial distribution should be provided. In addition to describing the pool of diabetic subjects from which to draw potential study participants, applicants should describe other methods that might be used to recruit eligible subjects. Applicants who have participated in the DPT-1 must document the number of subjects screened, staged, randomized and currently under follow-up. Applications from DPT-1 Clinical Centers should provide this information for their network as a whole and also separately for the parent Clinical Center site and the individual Affiliate and Satellite sites (if applicable). Current Affiliates/Satellites or other institutions not participating in DPT-1 who are applying to be a Clinical Center, and who are not proposing network sites, should describe the study population to which they have access at their own institution. In addition, the methods that will be used to maintain privacy and confidentiality of participant data should be provided. Willingness to participate in the DPT-1 and Type 1 Diabetes TrialNet. The Principal Investigator of the Clinical Center should state his/her general support of collaborative research and interaction with the NIDDK/NIAID/NICHD, their proposed Affiliates and Satellites (if applicable), the Operations Coordinating Center, the Data Monitoring Unit, the Central Distribution Pharmacy, and the Core Laboratories. Applicants should discuss the willingness of their proposed Affiliates and Satellites (if applicable), and the institutions involved, to pursue a per patient basis of operational costs. Clinical Centers must be able to interact with the Data Monitoring Unit to transmit and edit data if necessary, and should discuss their capability to participate in such a system. Willingness to forego participation in competing clinical trials and to collect biologic and genetic material as well as clinical data for the broader scientific community. Applicants must also state their willingness for their Clinical Center and its institution not to be involved simultaneously in the DPT-1, other TrialNet protocols, and in studies not affiliated with TrialNet studies if enrollment criteria overlap between studies and if the studies are actively recruiting participants. This restriction does not apply to Affiliates and Satellites. NIDDK may consider exemptions from this policy to allow institutions to participate in pilot studies of the ITN. Applicants should state in their application their willingness to collect biologic and genetic samples as well as clinical data that may be used for future studies related to the prevention, etiology, and genetics of type 1 diabetes by investigators both inside and outside the Type 1 Diabetes TrialNet. Institutional resources. Clinical Center applicants should state whether they and their Affiliates (if applicable) have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources, or an equivalent clinical research center funded by the institution, which can be a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC (or GCRC equivalent) Program Director or Principal Investigator should be included with the application. Resources for patient care and follow-up, including personnel, space, and facilities for insulin infusions, IVGTTs, OGTTs, and MMTTs should be described. Letters from institutional officials should describe any other institutional support that will be available for the TrialNet. Clinical Protocols. With one exception, applicants are required to propose one clinical trial protocol. The exception is if a current DPT-1 Clinical Center wishes only to complete DPT-1 and not to participate in future studies of the Type 1 Diabetes TrialNet. Applicants proposing clinical protocols should include a discussion of the current state-of- the-art , future opportunities, and obstacles in the prevention of type 1 diabetes, and discuss how the field may best be moved forward. For agents being proposed to prevent or ameliorate type 1 diabetes, scientific background must be provided about the agent, including results from animal and human studies, safety and any efficacy studies, and toxicity data. Techniques to monitor adverse events and adjust dosage should be described, as well as methods for assessing patient compliance to treatment. Any ethical concerns pertaining to use of the proposed agent must be addressed. A thorough description of the population to be studied must be provided, with justification, including a definition of the cohort by age, sex, and race. The ability to recruit this target population at the Clinical Center and network sites (if applicable) and the methods to be used should be described with an estimation of the current number of patients who fit the eligibility criteria and expected accrual rates. (Since the NIH envisions that agents might be tested first in new-onset type 1 diabetes patients and then in at-risk prediabetic individuals, a careful description of access to these patient pools should be included.) Applicants should provide a detailed description of the design of the study, including what eligibility, baseline, and follow-up tests are to be done, what surrogate markers and endpoints will be examined, and the duration of follow-up. Examples of data forms and questionnaires proposed should be given. The process for biologic sample collection, storage and handling needs must be included. A description of the laboratory tests that are needed with appropriate methods for performing them should be provided, as well as other core facilities and interactions with core facilities that are needed. Also included should be the methods that would be used to assure privacy and maintain confidentiality of data. Sample size needs and the criteria and calculations used to estimate sample sizes should be detailed. Analytical methods to be used must be included. Applicants must state their plans for reporting accrual by sex/gender and/or race/ethnicity and for the reporting of results that examine differences in treatment effects across these subgroups (see above under INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS ). Plans for follow-up studies should be provided if results from smaller pilot, feasibility, and efficacy studies of the intervention are found to be positive. A budget for the proposed clinical protocol should not be submitted because final design of these studies and allocation of costs will be determined by the TrialNet Steering Committee and NIDDK. Applicants should not exceed 20 pages in describing their proposed Clinical Center and associated network sites (if applicable) and not exceed 20 pages in describing their proposed clinical protocol. Budget Information Budget information should be provided only for the clinical center component of the application that would support completion of DPT-1 and not for future study components (see above under FUNDS AVAILABLE). For the Clinical Center component, applicants should request support for a Principal Investigator at 0.05-0.20 FTE, a trial coordinator at 1 FTE (preferably a nurse or certified diabetes educator), and a recruitment coordinator at 0.5 FTE. These levels of effort are the maximum levels allowed, levels of effort that are awarded will vary depending on recruitment history, potential for recruitment, and expected intellectual contributions to DPT-1 and the Type 1 Diabetes TrialNet. If additional FTE support is necessary, this will be determined by the NIDDK/NICHD/NIAID based on the requirements of the studies to be performed. Reimbursement schedules for study tests performed by Clinical Centers and network sites will be determined by the NIDDK, it is estimated that approximately $725,000 per year will be provided for patient care costs related to the screening, treatment, and follow-up of participants in the DPT-1. These reimbursement costs should not be included in budgets. The NIDDK estimates the annual cost for supplies and patient retention items at $4000 and for travel of Clinical Center personnel to two Steering Committee meetings per year at $9000. Additional funds will be added to support the Study Chairperson if the Chairperson is selected from among the principal investigators of Clinical Centers, FTE support for the principal investigator chosen as the Steering Committee Chairperson would increase to approximately 0.50. Affiliates and Satellites will also be reimbursed for clinical costs of tests performed for studies, but these costs also should not be included in submitted budgets. Affiliate or Satellite members participating to a significant degree on committees, who are not otherwise provided core funding, may be remunerated as funds permit. 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 Bethesda, MD 20827 (for express/courier service) At the time of submission, two additional copies of the application must also be sent to: 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 March 29, 2001. 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 announcement 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 a substantial revision of an application already reviewed, but such an application must follow the guidance in the PHS Form 398 application instructions for the preparation of revised applications, including an introduction addressing the previous critique. REVIEW CONSIDERATIONS General Considerations All applications will be judged on the basis of the scientific merit of the proposed project and the documented ability of the investigators to meet the RESEARCH OBJECTIVES of the RFA. Although the technical merit of the proposed protocol is important, it will not be the sole criterion for evaluation of a proposal. Other considerations, such as access to patients, ability to recruit minority participants, and experience of key personnel, will be a part of the evaluation criteria. It will be necessary to review the applications from current DPT-1 Clinical Centers differently than those from institutions applying for the first time. While current Clinical Centers and their networks of Affiliates and Satellites will have a performance record of enrollment in the DPT-1, new institutions will be evaluated based on demonstration of their ability to recruit participants to other clinical trials. Both current DPT-1 Clinical Centers and new centers will be evaluated on the basis experience of personnel, institutional commitment, and the scientific innovation and approach to their proposed clinical protocols. The different elements of the applications will be evaluated and scores will be summed to determine an overall score for the application, this overall score will be indicative of the potential of the Clinical Center to contribute to the completion of DPT-1 and attaining Type 1 Diabetes TrialNet goals. Review Method Applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK. Incomplete 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 in accordance with NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique. Those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the NDDK Advisory Council. Clinical Centers responding to this RFA will be reviewed based on the following considerations: o Recruitment Capability. Is there evidence of successful experience in recruitment and retention of research subjects in multicenter clinical trials? Is there evidence of the ability to recruit, enroll, and maintain minority and non-minority subjects in a randomized trial or other clinical studies at the proposed Clinical Center and Affiliates and Satellites? This includes documentation of access to an adequate patient population who may be approached in finding potentially eligible study participants. Since it is likely that future trials will focus on new- onset type 1 diabetes patients and prediabetic individuals, the ability to recruit these individuals will be evaluated carefully. o Investigators. Are the investigators appropriately trained and well- suited to carry out this work? Is the work proposed appropriate to the experience level of the investigators and staff? Is there an appropriate amount of time planned for the effective coordination of the Clinical Center with Affiliates and Satellites, Operations Coordinating Center, Data Monitoring Unit, and Core Laboratories? Is there evidence of prior experience in working collaboratively in carrying out a standard protocol in multicenter clinical trials or other clinical studies? Is there evidence of willingness to work cooperatively in the DPT-1 and Type 1 Diabetes TrialNet? This will be assessed both for the Clinical Center and for associated Affiliates and Satellites. o Environment. Does the scientific clinical environment in which the work will be done contribute to the probability of success? Is there evidence of institutional support and commitment for the proposed program? o Data and Sample Management. Are there adequate plans to ensure accurate collection and timely transmission of study data to the Data Monitoring Unit and patient samples to the Core Laboratories? Is there documented experience in meticulous and expeditious handling of laboratory specimens and study data? The clinical protocol which is required for all applications, except for those that propose only to complete DPT-1 and not to participate in subsequent activities of the Type 1 Diabetes TrialNet, will be reviewed based on the following criteria: o Significance. Is the proposed study relevant and will it contribute to the overall goals of the Type 1 Diabetes TrialNet? If the aims of the application 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? o Approach. Is the conceptual framework, design, proposed population, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the proposed study? Is the study feasible as proposed? Does the applicant acknowledge potential problem areas and consider alternative tactics? Does the applicant’s approach conform to NIH guidelines for inclusion of women and minorities as human subjects in clinical research? o Innovation. Does the proposed study employ novel concepts, approaches, or methods? Are the aims original and innovative? Does the study challenge existing paradigms or develop new methodologies or technologies? In addition to these criteria, in accordance with NIH policy, all applications will be reviewed with respect to the reasonableness of the proposed budget and the adequacy of the proposed protection for humans. AWARD CRITERIA Applications recommended by the NDDK Advisory Council will be considered for award based on the scientific merit of the proposed project and the documented ability of the investigators to meet the RESEARCH OBJECTIVES of the RFA. Award decisions will be made based on the applicants potential contribution to subject enrollment and study design and execution as assessed by peer review, as well as program balance in terms of geographic locations of sites and ability to recruit minority participants. Awards may be made to existing DPT-1 Clinical Centers only to complete DPT-1 and not to participate in other studies of the Type 1 Diabetes TrialNet. Letter of Intent Receipt Date: February 28, 2001 Application Receipt Date: March 29, 2001 Peer Review Date: June-August, 2001 NDDK Council Review Date: September, 2001 Earliest Anticipated Start Date: September, 2001 INQUIRIES Written and telephone inquiries concerning this RFA are strongly encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Catherine C. Cowie, PhD Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd, Rm 691, MSC 5460 Bethesda, MD 20892-5460 Telephone: (301) 594-8804 FAX: (301) 480-3503 Email: cowiec@extra.niddk.nih.gov Questions may also be submitted to the email address TrialNet@extra.niddk.nih.gov where they will be answered by email. In addition, these questions and answers will be posted at the NIDDK website http://www.niddk.nih.gov/patient/trialnet.htm which links to frequently asked questions that prospective applicants have submitted. Applicants are strongly encouraged to visit this website on a regular basis in the course of preparing their applications. For FEDEX, UPS, send to: Catherine C. Cowie, PhD Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd, Rm 691 Bethesda, MD 20817 Inquiries may also be made to representatives of NIAID and NICHD: Elaine Collier, MD Chief, Autoimmunity Section Division of Allergy, Immunology, and Transplantation National Institute of Allergy and Infectious Diseases 6700-B Rockledge Drive, Room 5135, MSC 7640 Bethesda, MD 20892-7640 Telephone: (301) 496-7104 FAX: (301) 402-2571 Email: ec5x@nih.gov Gilman D. Grave, MD Chief, Endocrinology, Nutrition, and Growth Branch National Institute of Child Health and Human Development 6100 Executive Blvd, Room 4B-11, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-5593 FAX: (301) 480-9791 Email: gg37v@nih.gov Direct inquiries regarding fiscal matters to: Cheryl Chick Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd, Rm 606, MSC 5456 Bethesda, MD 20892-5456 Telephone: (301) 594-8825 FAX: (301) 480-3504 Email: chickC@extra.niddk.nih.gov For FEDEX, UPS, send to : Cheryl Chick Grants Management Branch National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd, Rm 606 Bethesda, MD 20817 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847, No. 93.855, and No. 93.113. 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 NIH 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.

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