Full Text DK-93-007 NON-INSULIN DEPENDENT DIABETES PRIMARY PREVENTION TRIAL NIH Guide, Volume 22, Number 18, May 7, 1993 RFA: DK-93-007 - (Reissued as RFA-DK-08-504) P.T. 34 Keywords: Diabetes Clinical Trial Disease Prevention+ National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Child Health and Human Development Office of Research on Minority Health Letter of Intent Receipt Date: September 17, 1993 Application Receipt Date: October 19, 1993 PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Child Health and Human Development (NICHD), and the Office of Research on Minority Health (ORMH) invite cooperative agreement applications for investigators to design and implement a full-scale, multicenter, randomized clinical trial to evaluate the efficacy of interventions designed to delay or prevent onset of non-insulin dependent diabetes mellitus (NIDDM) in individuals at increased risk for NIDDM. Within the broad range of this NIDDK and NICHD-sponsored initiative, ORMH is providing specific support for research focussing on the sub-population of obese minority women with a history of gestational diabetes. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, NIDDM Primary Prevention Trial, is related to the priority area of diabetes and chronic disabling conditions. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock Number 017-001-00474-0 or Summary Report: Stock Number 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325, telephone 202/783-3238. ELIGIBILITY REQUIREMENTS Applications may be submitted by for-profit and non-profit domestic organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Minority individuals and women are encouraged to submit as Principal Investigators. Applications from minority institutions are especially encouraged. Applications from foreign institutions will not be considered. The expertise appropriate for this research program includes a knowledge of the clinical and epidemiological aspects of diabetes. Institutions wishing to collaborate and function as a single Clinical Center are required to submit one application. In this regard, applicants are encouraged to form collaborative arrangements with investigators at minority institutions and/or minority investigators at other institutions. However, international collaborations are unacceptable. MECHANISM OF SUPPORT The administrative and funding mechanism to be used to undertake this program will be a cooperative agreement (U01), which is an assistance mechanism, rather than an acquisition mechanism. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by collaborating and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships and governance of this study funded under a cooperative agreement are discussed under the section "Terms and Conditions of Award." FUNDS AVAILABLE Support during the planning phase (Phase 1) of this trial for FY 1994 is expected to be approximately seven million dollars with total costs per center of approximately $350,000. It is anticipated that awards for 15 to 20 new Clinical Centers will be made. Additional centers will be recruited through a follow-up RFA if necessary to achieve adequate numbers of subjects. During Phase 2 (full scale trial period) it is expected that funding levels for each center will increase to approximately $500,000 reflecting the start of the full scale trial. During Phase 3 (close-out period) costs are expected to decrease to approximately $100,000 in keeping with the reduction in clinical personnel effort and the shift to close-out, analysis of data, and reporting. Cost for outcome measures should not be included individually for each center. These costs will be covered under the Data Coordinating Center funding. Although this program is provided for in the financial plans of the NIDDK and the NICHD, awards in response to this RFA are contingent on the availability of funds for this purpose. The total project period for applications submitted in response to the present RFA will be seven years due, in part, to the necessity to screen large numbers of potential participants to identify individuals with sufficient risk to answer the study question discussed below under "RESEARCH OBJECTIVES". The anticipated award date is July 1994. At this time, the NIDDK anticipates that there will not be a renewed competition after seven years. If the NIDDK does not continue the program, awardees may submit grant applications through the usual investigator-initiated grants program. RESEARCH OBJECTIVES Background A family history of diabetes, obesity, insulin resistance, hyperinsulinemia, a history of gestational diabetes, and impaired glucose tolerance (IGT) are risk factors for NIDDM (1). Based on the NHANES II survey data, IGT is present in 16 percent of adults aged 40 to 74 in the U.S. and in 23 percent of this age group who have a family history of diabetes and body weight greater than 120 percent of desirable weight (2). Minority populations have even higher rates of IGT (3). For high risk individuals the rate of progression to NIDDM is 5 to 10 per cent per year (4). Importantly, screening for IGT can identify individuals at increased risk for development of NIDDM (5,6,7). There is currently no accepted standard of care for patients with IGT. Screening for IGT, which is undiagnosed in most affected individuals, is not widely recommended or practiced, nor are there accepted interventions for patients with IGT. No large scale, randomized, prospective, controlled clinical trials have determined whether or not progression of IGT to NIDDM can be prevented. In addition, obesity and gestational diabetes (GDM), an apparently temporary condition of pregnancy, are important independent risk factors for the subsequent development of NIDDM. African, Hispanic, and Native American women have significantly increased prevalence of both of these conditions. It appears that excessive weight gain during pregnancy may play a role in the appearance of GDM and the documented lack of weight loss to pre-pregnancy levels following delivery may conspire to magnify the risk of future NIDDM in these groups of minority women. Insulin resistance is the earliest abnormality detected in individuals who will develop NIDDM and appears to be genetically determined (8). However, it is not known whether reversing insulin resistance will prevent or delay onset of NIDDM. Insulin resistance can be reduced through weight reduction and exercise (9). Corresponding to these findings, epidemiologic data indicate an association between exercise frequency and significant lowering of risk for NIDDM (10,11). Results of a study performed in Sweden suggest that moderate weight reduction of two to four percent of initial weight and increased maximal oxygen uptake of 10 to 14 percent can be maintained for a period of five years. This was found to be associated with improvement in glucose tolerance, blood pressure, lipids, hyperinsulinemia, and reduced mortality (12). Sustained intervention appears to be necessary to achieve these lifestyle changes (13), but importantly, such changes have the potential to slow the deterioration of glucose tolerance in IGT, thereby delaying the onset of diabetes. Pharmacologic agents also can potentially prevent or delay onset of NIDDM. Biguanides are suggested to reduce insulin resistance and improve glycemia and hyperinsulinemia, while sulfonylurea agents appear to improve glycemia by increasing insulin secretion and through extra-pancreatic effects. Data in the literature are inconclusive with respect to the ability of these agents to prevent or delay onset of NIDDM. One study using the biguanide metformin showed no effect on prevention or delay of onset (14). In contrast, studies with sulfonylureas have shown decreased rates of diabetes and of mortality in patients treated with modest doses for IGT (15,16) but are inconclusive. Nonetheless, these interventions could slow the deterioration of glucose tolerance in patients with IGT. In so doing, diabetic complications, including atherosclerosis, may also be delayed reducing morbidity and mortality due to diabetes. Methods are available for potentially reducing insulin resistance and improving glucose tolerance. Based on this and the high rates of IGT in the United States, the NIDDK has determined that a randomized controlled clinical trial is necessary. Such a trial would define the effectiveness of interventions for delaying or preventing NIDDM in high risk persons with impaired glucose tolerance. Since the estimated population prevalence of undiagnosed NIDDM is six percent screening for IGT will detect individuals with previously undiagnosed NIDDM, most of whom do not have fasting hyperglycemia (2). In addition, the NIDDK considers that those with newly diagnosed NIDDM should be treated in a randomized, prospective fashion to determine whether early detection and treatment of NIDDM can reverse the disease process or have favorable effects on the deterioration of glucose tolerance that is characteristic of NIDDM. The NIDDK also believes that obese minority women with a history of GDM constitute an excellent interventional target to establish whether the expected high rate of NIDDM in this population can be altered. Goal of the Activity The purpose of this RFA is to initiate a collaborative study of interventions to prevent NIDDM in people with IGT or a history of GDM and to prevent the worsening of glucose tolerance in people with newly diagnosed NIDDM. The study will determine whether onset of NIDDM can be delayed and whether interventions in newly diagnosed NIDDM can favorably influence glucose tolerance and progression to fasting hyperglycemia. The objectives of this RFA are to select centers to: o Participate in a full-scale trial. o Design the study protocol and write the manual of operations. o Develop operational plans for the trial in close collaboration with the communities they serve. These plans must include racially and ethnically sensitive strategies for recruitment, screening, enrollment and adherence to the study protocol. The collaborative protocol will be developed by a Steering Committee composed of the awardees, the Chairperson, the Principal Investigator of the Data Coordinating Center, and the NIDDK Project Coordinator. The protocol and manual of operations will be subject to review by an uninvolved expert group (Policy and Data Monitoring Committee), and the NIDDK. The study will move into its operational phase only with the concurrence of the awardees, the Policy and Data Monitoring Committee, and the Institute. Scope of the Activity It is expected that the study will take place in fifteen to twenty Clinical Centers over a period of seven years. The clinical centers will randomize an approximate average of 200 study participants per center over a 12 month period of recruitment. The entire collaborative clinical trial will consist of the following three phases: Phase 1 (12 months): Planning phase, collaborative development of the protocol and manual of operations which includes procedures for data collection and pretesting of these procedures. There must also be included in the manual well-defined procedures for the training and certification of clinic personnel in study procedures. Phase 2 (60 months): Conduct of the full-scale collaborative clinical trial including patient recruitment and followup. Phase 3 (12 months): Close out, analysis of data, and reporting of results. Each applicant should propose the study design he or she believes best addresses the objectives of this project and is most appropriate for their patient population. The goal of the NIDDK and the NICHD is to have approximately 50 per cent of the subject population comprised of minorities. The study population mix at any one center may vary from this overall goal based on local demography. The overall study population may include, but is not limited to, Caucasians, Native Americans and Alaskan Natives, Blacks, Hispanics, and Asian/Pacific Islanders. In addition, applicants are encouraged, if a suitable population base exists, to include a cohort of obese women with a history of GDM. Applicants should provide a detailed justification for whatever strategy is proposed for subject selection as well as an estimate of the number of subjects in the source population and an estimate of the necessary time and effort needed for recruitment. Issues of racial and subgroup analysis will be dealt with by the Steering Committee. It is not the intent of this RFA to solicit elaborately detailed research plans for the conduct of the trial since the final protocols will be collaboratively developed by the investigators and the NIDDK during the planning phase (Phase 1) of the study described later under "Study Phases". SPECIAL REQUIREMENTS To promote the development of a collaborative program among the award recipients, the following minimum number of issues should be addressed: o The rationale and criteria for subject selection, as well as plans for and documentation of the ability to recruit sufficient numbers of study participants; o Documentation of specific competence and previous experience of the professional, technical, and administrative staff in the operation of a Clinical Center in the proposed study; o Documentation of experience in the treatment of persons with diabetes; o The willingness of the applicant to work cooperatively with the other Clinical and Data Coordinating Centers; and o The willingness to follow the common protocols that will be collaboratively developed in Phase 1. Personnel The participating members of the study team should include or have access to: o Diabetologists to enroll and maintain the patients in this study and coordinate the activities of the medical team. The diabetologists used in this study must have faculty appointments. o Nurse/Clinic Coordinator who can provide full-time attention to clinic administration and management, including logistical aspects of patient follow-up and data transmittal in addition to participating in management of patients; o Behavioral scientists to conduct standardized neuropsychological testing and psychological evaluations and to provide consultation to other clinic staff in the selection and management of the study subjects; o Exercise trainer\therapist to conduct the exercise related aspects of this trial o Nutritionists-dieticians and nurse educators to perform the educational aspects of the Protocol and provide diabetes care; and o clerical and technical support. Study Organization 1. Study Outline. The applicant's study design should include a detailed proposal of eligibility requirements including patient age, gender, and racial/ethnic background for study participation. In addition, exclusion criteria should be specified. Consideration should be given to screening individuals in the population at higher risk for NIDDM, such as those with obesity and a family history of diabetes. The procedure for screening for IGT should be provided in the application. The screening procedure should be designed to identify individuals at highest risk for progression to NIDDM and to minimize inclusion of individuals with transient IGT. It has been documented that women with a history of GDM are also at particularly high risk for the subsequent development of NIDDM. Thus, in addition to the NIDDK, the OMP is particularly interested in addressing this minority women's health issue. Applicants are therefore encouraged to include a GDM cohort in their study population where a suitable population base exists. Interventions may include diet, exercise, and pharmacologic agents in a randomized, placebo controlled, factorial design. Individuals with newly diagnosed NIDDM identified in the screening process should be included in the randomization scheme. Methods to monitor patient adherence to the trial protocol must be clearly defined. Proposed methods for management of cardiovascular risk factors, including hypertension, dyslipidemia, and smoking cessation in all subjects should be included. For IGT or for women with a history of GDM, outcome measures should be chosen to address the efficacy and adverse effects of interventions on deterioration of glucose tolerance and progression to NIDDM. For newly diagnosed diabetes, outcome measures should address the efficacy and adverse effects of interventions to prevent deterioration of glucose tolerance and progression of hyperglycemia. Outcome measures should include sequential evaluation of metabolic status. All centers must agree to implement the protocol and manual of operations that will be developed cooperatively by the Steering Committee during Phase 1 and agree to transmit all study data to a central Data Coordinating Center for combination and analysis. The recruitment of a Data Coordinating Center will be accomplished by means of a separate RFA (DK-93-008). 2. Study Components a. Clinical Centers. A Clinical Center is an institution that is actively involved in the recruitment, evaluation, treatment, and follow-up of study participants. It should consist of a core team of researchers, including Principal Investigator, full-time study coordinator, nutritionist, behaviorist, exercise therapist\trainer and clerical staff. Applications for Clinical Centers should provide evidence that the center will be capable of screening for IGT and NIDDM and, if applicable, have access to a patient base of women with a history of GDM. It will be the goal of each center to randomize approximately 200 participants into the study during the 12 month period of recruitment. Clinical Centers should describe their experience in recruiting and studying patients with diabetes including those with a history of GDM or other conditions, and in minimizing losses of patients to follow-up during long-term clinical studies. There should be evidence of strong institutional support for the Clinical Center, including documentation of adequate space in which to conduct clinic activities and office space for staff. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources are strongly encouraged to use this facility and to identify the GCRC as a resource for conducting the proposed study. If so, a letter of agreement from either the GCRC Program Director or Principal Investigator should be included with the application. An organizational structure for the Clinical Center should be provided in the application delineating lines of authority and responsibility for dealing with problems in all general areas. In addition, a statement of agreement to follow the common protocol agreed upon in Phase 1 should be included. The applicant should include a succinct discussion of previous relevant investigational efforts. The applicant also should discuss in detail the important design considerations for a clinical trial to investigate primary prevention of NIDDM, intervention in newly diagnosed NIDDM, and treatment of cardiovascular risk factors in study participants, and suggest solutions to likely problems. Clinical Centers will be required to submit protocol data expeditiously to a central Data Coordinating Center. The Principal Investigator and treatment team in each Clinical Center should be skilled in diabetes management and collaborative clinical investigation. b. Steering Committee. The primary governing body of the study will be the Steering Committee comprised of each of the Principal Investigators of the Clinical Centers and the Data Coordinating Center and The NIDDK Project Coordinator (described in detail under Terms and Conditions). c. Data Coordinating Center. A Data Coordinating Center recruited through a separate RFA (DK-93-008) will participate with the Clinical Centers and Institute staff during the entire clinical trial. The Data Coordinating Center will have primary responsibility for the biostatistical analyses and data management aspects of the trial. It will also manage through subcontracts the central laboratory and clinical support aspects of this trial. The Data Coordinating Center will perform interim analyses as needed to monitor the course of the trial as well as analyses needed for final reporting. Preparation of interim and final reports, however, will be collaborative undertakings by all participating Centers, the Data Coordinating Center, and the NIDDK. d. Policy and Data Monitoring Committee. An independent committee supported by the NIDDK and composed of experts in relevant medical, psychological, statistical, operational, and bioethical fields who are not otherwise involved in the study will be established to review periodically the progress of the study (described in detail under Terms and Conditions). e. Project Coordinator. The NIDDK will name the Director, Special Programs from within the Division of Diabetes, Endocrinology, and Metabolic Diseases to be the Project Coordinator. The Project Coordinator's function will be to assist the Steering Committee and Policy and Data Monitoring Committee in carrying out the study (described in detail under Terms and Conditions). Study Phases After the protocol is completed by the study group during the planning phase (Phase 1), it will be reviewed by the Policy and Data Monitoring Committee and the NIDDK. Progression to Phase 2 is dependent on the favorable recommendation of the protocol by the Policy and Data Monitoring Committee and the concurrence of the NIDDK. The protocol for the study will be implemented in Phase 2. It is anticipated that the Clinical Centers will recruit and randomize participants, implement the protocol according to the manual of operations, collect the outcome data specified in the protocol, and provide all study data to the Data Coordinating Center. Twelve months will be allowed for subject recruitment and randomization. Clinical Centers will be responsible for collecting and shipping patient specimens and other study data to designated Central Resource Units. The final phase (Phase 3) of the study will be for close-out of Clinical Center activities, final data analysis, and reporting of results. Phase 3 will be for a period of 12 months. Budget Preparation by Study Phase Each applicant for a Clinical Center should submit adequately justified budgets for the entire anticipated project period of 84 months. The budgets for each phase of the study should be clearly delineated. Detailed budgets will vary according to policies of the applicant institution and specific needs identified in the response to this announcement. Applicants should prepare individual budgets for each of the three planned phases of the study. The Phase 1 budget period will be for development of the protocol and manual of operations, staff training and certification. The Phase 2 period will be for 60 months. Separate budgets for each 12-month budget period in Phase 2 should be submitted. Activities in this second phase will include subject recruitment, randomization, treatment, and clinical assessment of randomized study participants. The Phase 3 period will be for 12 months. This budget period will be concerned with study close-out, analysis of study data, and reporting of results. Phase 1 activities will require phasing-in of staff within six-months prior to initiating recruitment. Budgets should allow for approximately three persons, including the Principal Investigator, to attend Steering Committee and Subcommittee meetings. The detailed budget for this phase should be estimated on the basis of monthly meetings during Phase 1. Phase 2 budgets should include travel funds for three evenly spaced meetings per year during Phase 2. Phase 3 will involve two meetings over the twelve-month interval. Each meeting should be assumed to be for two days at a cost of $1000 per person. Detailed budget estimates for Phase 2 and 3 should be based on the applicant's proposed plan. Budgets for both Phases 2 and 3 will be modified based on the final protocol developed collaboratively during Phase 1. Terms and Conditions of Award 1. Cooperative Activities. The administrative and funding mechanism to be used to undertake this project will be cooperative agreements (U01), which is an assistance mechanism, rather than and acquisition mechanism. Under the cooperative agreement, the NIDDK and NICHD purpose is to support and/or stimulate the recipient's activity by collaborating and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the tasks and activities in carrying out the studies will be shared among the awardees and the NIDDK Project Coordinator. 2. Awardee Activities. Awardees will have substantial and lead responsibilities in all tasks and activities. These include protocol development, patient recruitment and follow-up, data collection, quality control, final data analysis and interpretation, preparation of publications. The awardee agrees to work cooperatively with the other Clinical and Data Coordinating Centers and agrees to follow the common protocol and manual of operations developed in Phase 1 of the study by the Steering Committee. The awardee also agrees to transmit all study data to a central Data Coordinating Center for combination and analysis. Awardees will retain custody of and have primary rights to their data developed under these awards, subject to Government, e.g., NIDDK, NIH, or PHS, rights or access consistent with current HHS, PHS, and NIH policies. 3. NIDDK Activities. It is the intention of the NIDDK that central resource units for the standardized assessment of key laboratory and clinical parameters will be established and utilized by all participating Clinical Centers. These central resources will function and be supported under the Data Coordinating Center award. The NIDDK will name a Project Coordinator from within the Division of Diabetes, Endocrinology, and Metabolic Diseases whose function will be to assist the Steering Committee and Policy and Data Monitoring Committee in carrying out the study. The Project Coordinator will be a voting member of all key study group committees. The Project Coordinator will serve as executive secretary of the independent Policy and Data Monitoring Committee. The NIDDK Project Coordinator will assist in quality control, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and coordination and performance monitoring. The NIDDK Project Coordinator will have voting membership on the Steering Committee, and as appropriate, its subcommittees. The NIDDK and NICHD reserves the right to terminate or curtail the study (or an individual award) in the event of (a) a major breach in the protocol or substantial changes in the agreed-upon protocol with which the Institute does not agree or (b) human subject ethical issues that may dictate a premature termination. 4. Governance. The primary governing body of the study will be the Steering Committee comprised of each of the Principal Investigators of the Clinical Centers and the Data Coordinating Center and the NIDDK Project Coordinator. The Steering Committee has primary responsibility for developing common clinical protocols, facilitating the conduct and monitoring of the studies, and reporting the study results. Topics for the protocols will be proposed and prioritized by the steering Committee. Each member of the Steering Committee will have one vote. A chairperson will be appointed by the voting members of the Steering Committee from among the Steering Committee members but not the Project Coordinator, or alternatively, from among experts in the field of diabetes and clinical trials who are not participating directly in the study. It is anticipated that the Steering Committee will meet on a monthly basis during protocol development (Phase 1), three times a year in Phase 2, and two times in Phase 3. Subcommittees of the Steering Committee may be established as necessary and will meet as necessary. The NIDDK Project Coordinator or designee and the Data Coordinating Center will be represented on each subcommittee. An independent Policy and Data Monitoring Committee supported by the NIDDK and composed of experts in relevant medical, psychological, statistical, operational, and bioethical fields who are not otherwise involved in the study will be established to review periodically the progress of the study. The committee will oversee participant safety, evaluate results, monitor data quality, and provide operational and policy advice to the Steering Committee and the NIDDK regarding the status of the study. The Principal Investigator of the Data Coordinating Center, the NIDDK Project Coordinator, and the Director of the Division of Diabetes, Endocrinology and Metabolism may participate as ex-officio, non-voting members of this Committee. Committee members will be appointed by the Director, NIDDK in consultation with members of the Steering Committee. The NIDDK named Project Coordinator will serve as executive secretary of the Policy and Data Monitoring Committee. 5. Arbitration. Any disagreement that may arise in scientific-programmatic matters between award recipients and NIDDK may be brought to arbitration. An arbitration panel will be composed of three members - one selected by the Steering Committee (with NIDDK member not voting) or by the individual awardees in the event of an individual disagreement, a second member selected by NIDDK and the third member selected by the preceding two members. This special arbitration procedure in no way affects the awardees' right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR part 50, subpart D and HHS regulations at 45 CFR part 16. The special terms of award (1-5) described above 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. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH policy is that applicants for NIH clinical research grants and cooperative agreements are required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis must be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale must be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues must be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information must be included in the form PHS 398 (rev. 9/91) in Item 4 (Research Design and Methods) of the Research Plan AND summarized in Item 5, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations; i.e., Native Americans [including American Indians or Alaskan Natives], Asian/Pacific Islanders, Blacks, Hispanics. The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research is defined as human biomedical and behavioral studies of etiology, epidemiology, prevention [and preventive strategies], diagnosis, or treatment of diseases, disorders or conditions, including, but not limited to, clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. If the required information is not contained within the application, the application will be returned without review. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. LETTER OF INTENT Prospective applicants are asked, but not required, to submit a letter of intent. This letter is to include the name, telephone number and mailing address of the Principal Investigator, the names of other key personnel, the name of the applicant institution, and the number and title of this RFA. Such a letter of intent is not binding and it will not enter into the review of any application subsequently submitted nor is it a requirement for application. Letters of intent are requested solely for planning purposes. The information contained in these letters is helpful in planning for the review of applications. It allows NIDDK staff to estimate the potential review workload and to avoid possible conflicts of interest in the review. The NIDDK staff will not provide responses to such letters. Letters of intent are to be received no later than September 17, 1993, and are to be addressed to: Robert D. Hammond, Ph.D. Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases Westwood Building, Room 605 Bethesda, MD 20892 Telephone: (301) 594-7515 FAX: (301) 594-7503 APPLICATION PROCEDURES Submit applications on form PHS 398 (rev. 9/91), the application form for NIH research project grants. This form is available in the applicant institution's office of sponsored research and may be obtained from the Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone (301) 594-7250. Use the conventional format for research project grant applications and ensure that the points identified in the SPECIAL REQUIREMENTS section above and in "Review Criteria" section below are fulfilled. To identify the application as a response to the RFA, Check "YES" on item 2a of page 1 of the application and enter the title "NIDDM Primary Prevention Trial" and enter the RFA number DK-93-007 in the space provided. The RFA label available in the form PHS 398 application kit must be affixed to the bottom of the face page of the original completed application form. 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. Send or deliver the completed, signed application and three complete photocopies to the following office, making sure that the original application with the RFA label attached is on top to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** Send two additional copies of the application to Dr. Hammond at the address listed under LETTER OF INTENT. It is important to send these two copies at the same time as the original and three copies are sent to the Division of Research Grants, otherwise the NIDDK cannot guarantee that the application will be reviewed in competition for the RFA. Applications must be received by October 19, 1993. An application not received by this date will be returned to the applicant. REVIEW CONSIDERATIONS Upon receipt, the Division of Research Grants (DRG) will review the application for completeness. Applications will be reviewed by NIDDK staff for responsiveness to the objectives of this RFA. If an application is judged incomplete or unresponsive, it will be returned to the applicant. If the number of applications is large compared to the number of awards to be made, the NIDDK will conduct a preliminary scientific peer review and will withdraw from further competition those applications that are not competitive for award. The NIDDK will notify the applicant and institutional official of this action. Those applications judged to be both competitive and responsive will be evaluated further according to the review criteria stated below for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities, NIDDK. Subsequently, they will be reviewed by the National Diabetes and Digestive and Kidney Diseases Advisory Council and the National Advisory Child Health and Human Development Council. Review Criteria Specific criteria for review of applications will be as follows: o The scientific merit of the proposed study design to address the objectives of the RFA. This includes criteria for subject selection, plans for recruitment of subjects, proposed follow-up assessments and schedule for data collection during follow-up (in tabular form), proposed diagnostic and therapeutic modalities, and techniques for monitoring and maintaining continued contact with subjects during the course of the study. o Documentation of the specific competence and previous experience of professional, technical, and administrative staff pertinent to the operation of a Clinical Center in the proposed study. Evaluation criteria will include the following: familiarity with and experience in recruiting research subjects, especially, the ability to access, enroll and maintain minority subjects in a randomized trial or other clinical studies; working in collaboration with other investigators under a common protocol; and experience with careful and expeditious handling of study data. o Documentation of experience in the treatment of persons with diabetes. This includes documentation of a sufficient patient population from which to recruit in order to meet the individual Clinical Center goal for number of randomized study participants (guidelines including examples of appropriate format for presenting this information should be requested from the NIDDK project coordinator indicated below). o Understanding and awareness of the scientific, ethical, and practical issues underlying the proposed study and appropriateness of plans to address them. o Appropriateness of the budget for the work proposed. o Adequacy of the proposed facility and space, including floor plans of proposed space. o Evidence of substantive institutional commitment and support for the proposed program. o A willingness to work cooperatively with other centers in a manner summarized in the RFA. Seminar for Prospective Applicants A special technical assistance workshop will be offered to assist potential applicants, especially those with limited experience with the NIH application process. The purpose of this seminar is to give background information and respond to any questions about the preparation of an application in response to this RFA. The workshop will be held in the Washington, DC metropolitan area approximately one month after the publication of this announcement. The NIH cannot support individuals who wish to attend the conference, but the conference will be open to any individual or organization who wishes to attend. Interested persons may contact Dr. Sanford A. Garfield, at the address listed under INQUIRIES, for further information. AWARD CRITERIA The anticipated date of award is July 1, 1994. Applications will compete for available funds with all other approved applications submitted in response to this RFA. The following will be considered in making funding decisions: o Quality of the proposed work as determined by peer review. o Availability of funds o Geographical balance among all applications considered for funding under this RFA. o Racial and ethnic balance among the populations to be accessed by the potential awardees. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues and address the letter of intent to: Sanford Garfield, Ph.D. Division of Diabetes, Endocrinology, and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Westwood Building, Room 626 Bethesda, MD 20892 Telephone: (301) 594-7535 FAX: (301) 594-9011 Dr. Gilman D. Grave Endocrinology, Nutrition and Growth Branch National Institute of Child Health and Human Development 6100 Building, Room 4B11 Bethesda, MD 20892 Telephone: (301) 496-5593 FAX: (301) 402-2085 Inquiries regarding fiscal matters should be directed to: Ms. Linda Stecklein Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases Westwood Building, Room 649B Bethesda, MD 20892 Telephone: (301) 594-7543 FAX: (301) 594-7594 Schedule Letter of Intent Receipt Date: September 17 ,1993 Application Receipt Date: October 19, 1993 Initial Review: February/March 1994 NIDDK/NICHD Council Review: May/June 1994 Anticipated Award Date: July 1994 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847. Awards are made under the authority of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99- 158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR Part 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. References 1. National Diabetes Data Group: Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28:1039-57, 1979 2. Harris MI, Hadden WC, Knowler WC, Bennett PH. Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in U.S. population aged 20-74 yr. Diabetes 36:523-534;1987 3. Harris MI Epidemiological correlates of NIDDM in Hispanics, Whites, and Blacks in the U.S. population. Diabetes Care 14:639-648:1991 4. Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennett PH. The natural history of impaired glucose tolerance in the Pima Indians. New Engl J Med 319:1500- 1506;1988 5. Yudkin JS, Alberti KGMM, Mclarty DG, Swai ABM Impaired glucose tolerance. Brit Med J 301:397-402;1990 6. Eriksson KF, Lindgarde F, Impaired glucose tolerance in a middle-aged male urban population: a new approach for identifying high risk cases. Diabetologia 33:526- 531;1990 7. Harris MI, Hadden WC, Knowler WC, Bennett PH: International criteria for the diagnosis of diabetes and impaired glucose tolerance. Diabetes Care 8:562-67, 1985 8. Lillioja S, Mott DM, Zawadzki JK, Young AA, Abbott WGH, Knowler WC, Bennett PH, Moll P, Bogardus C. In vivo insulin action is a familial characteristic in nondiabetic Pima Indians. Diabetes 36:1329;1987 9. Horton ES. Exercise and decreased risk of NIDDM. N Engl J Med 325:197;1991 (editorial) 10. Helmrich SP, Ragland DR, Leung RW, Paffenbarger RS. Physical activity and reduced occurrence of non-insulin- dependent diabetes mellitus. N Engl J Med 325:147;1991 11. Manson JE, Nathan DM, Krowlewski AS, Stampfer MJ, Willett WC, Hennekens CH. A prospective study of exercise and incidence of diabetes among US male physicians. JAMA 268:63;1992 12. Eriksson KF, Lindgarde F. Prevention of Type 2 (non-insulin-dependent) diabetes mellitus by diet and physical exercise: The 6-year Malmo feasibility study. Diabetologia 34:891-898;1991 13. Page RCL, Harnden KE, Cook JTE, Turner RC. Can life-styles of subjects with impaired glucose tolerance be changed? A feasibility study. Diabetic Medicine 9:562-566;1992 14. Jarrett RJ, Keen H, Fuller H, McCartney M. Worsening to diabetes in men with impaired glucose tolerance ("Borderline Diabetes"). Diabetologia 16:25- 30;1979 15. Sartor G, Schersten B, Carlstrom S, Melander A, Norden A, Persson G. Ten-year follow-up of subjects with impaired glucose tolerance. Diabetes 29:41;1980 16. Melander A, Bitzen P-O, Sartor G, Schersten B, Wahlin-Boll E. Will sulfonylurea treatment of impaired glucose tolerance delay development and complications of NIDDM? Diabetes Care 13:53-58;1990 .
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